Influence of X-ray on the Autophagic-lysosomal System in Rat Pancreatic Acini

Micron (Oxford, England : 1993). 2002  |  Pubmed ID: 11567883

Lysosomes have an important role in radiation injury of cells and tissues. Activation of autophagy is frequently observed in different types of pathological tissue degeneration. In radiation response it increases in some cases, and lysosomes are responsible for regulated degradation of the autophagic vacuoles. Lysosomes are also involved in ionizing radiation induced cell death. In apoptosis lysosomes degrade content of the phagocytotic vacuoles derived from engulfed apoptotic blebs. On the other hand lysosomal enzymes discharged from disintegrated cells have a key role in induction of necrotic changes. In this work we investigate autophagy and lysosomal protein degradation in the relatively radiation insensitive exocrine pancreatic acini in vivo and in vitro. Type of cell death induced by X-ray was also examined in relation to the changes of the lysosomal processes. In 5h after 16 Gy in vivo whole body irradiation we observed significant increase in the cytoplasmic volume fraction of autophagic vacuoles and in the number of apoptotic cells in vivo. But in the acini isolated from irradiated rats we could not detect a change in the lysosomal degradation of intracellular proteins. Therefore irradiation probably influences the autophagy in an earlier step than lysosomal degradation. Extended necrotic lesions were not observed in vivo as long as 48 h. Isolated pancreatic acini usually contain more autophagic vacuoles than in vivo, but we could not observe additional increase in autophagy after 8 Gy, in vitro irradiation. Lysosomal degradation of intracellular proteins was also unaltered after 8 Gy, in vitro irradiation. Other biochemical functional parameters of the isolated pancreatic acini, like protein synthesis and amylase secretion were not changed either after 8 Gy, in vitro X-ray treatment. These results indicate that pancreatic acinar cells in vitro have a high tolerance to irradiation. The observed in vivo radiation induced changes of the exocrine pancreas are possibly indirectly induced by injuries of more sensitive mechanisms.

The Cardiac Phenotype Induced by PPARalpha Overexpression Mimics That Caused by Diabetes Mellitus

The Journal of Clinical Investigation. Jan, 2002  |  Pubmed ID: 11781357

Recent evidence has defined an important role for PPARalpha in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARalpha in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARalpha (MHC-PPAR) were produced and characterized. The expression of PPARalpha target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression-dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARalpha is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARalpha regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.

Cardiac Structure and Function in Young and Senescent Mice Heterozygous for a Connexin43 Null Mutation

Journal of Molecular and Cellular Cardiology. Feb, 2002  |  Pubmed ID: 11851357

Downregulation of connexin43 (Cx43) in the failing heart has been implicated not only in arrhythmogenesis but in contractile dysfunction as well. Cx43-deficient mice exhibit reduced baseline conduction velocity and increased arrhythmias in response to ischemia. However, it is not known whether Cx43-deficient mice have any abnormalities in contractile function or, furthermore, whether cardiac dysfunction may be manifested in Cx43-deficient mice with advancing age. Therefore, we analyzed echocardiographic images from young and senescent Cx43-deficient C57BL/6Jx129 mice compared to wild-type littermate controls. Only a few, modest genotype-related differences were observed. LV wall thickness during systole and % fractional shortening were diminished by 8-10% in Cx43-deficient v wild-type mice. Aging alone had a greater effect on cardiac structure and function. LV mass and relative wall thickness were significantly increased in senescent v young mice independent of genotype. Percent fractional shortening and LV internal chamber dimension were significantly reduced in senescent v young mice. Thus, aging in mice, as in humans, is associated with concentric remodeling, mild systolic dysfunction and fibrosis. Although diminished Cx43 expression could contribute to contractile dysfunction in patients with advanced heart failure, genetic deficiency in Cx43 does not appear significantly to alter cardiac structure or function even in aged mice.

Selective and AMPA Receptor-dependent Astrocyte Death Following Prolonged Blockade of Glutamate Reuptake in Rat Cerebellar Cultures

Experimental Neurology. Mar, 2002  |  Pubmed ID: 11869034

In this study we examined the effects of prolonged l-trans-pyrrolidine-2,4-dicarboxylate (PDC)-induced glutamate reuptake blockade on the viability of glial cells in cerebellar granule cell cultures. Immunofluorescence staining for the glial-specific intermediate filament protein, GFAP, revealed that the PDC- induced increase of extracellular glutamate concentration was accompanied by increased astrocyte death, while neurons and oligodendrocytes remained intact and viable. Astrocytic cell death was manifested as fragmentation of processes and cell bodies. The selective astrocyte death was completely prevented by the competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor antagonist, NBQX (10 microM), whereas MK-801 (10 microM), a noncompetitive blocker of N-methyl-D-aspartate receptors, gave only partial protection. Double staining for GFAP and the AMPA receptor subunits GluR2/3 showed that astrocytes had much higher immunoreactivity for GluR2/3 than neurons or oligodendrocytes, suggesting that the number of AMPA receptors is likely to be higher on astrocytes. Furthermore, we employed real-time RT-PCR to measure GluR1-4 subunit mRNA expression in control and PDC-exposed cultures. Following treatment with PDC, GluR1 and GluR4 mRNAs were reduced by 40% and GluR3 was reduced by 70% relative to control levels. In contrast, GluR2 expression was not affected by the PDC treatment, indicating that GluR3 was the dominant type of AMPA receptor subunit expressed on astrocytes. Our results show that astrocytes appear to be more vulnerable than neurons or oligodendrocytes to a gradual increase in the extracellular glutamate concentration, suggesting that astrocytes may be critically involved in the pathophysiology of slowly developing chronic neurodegenerative disorders.

Echocardiographic Evaluation of Ventricular Remodeling in a Mouse Model of Myocardial Infarction

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Jun, 2002  |  Pubmed ID: 12050601

Gene-targeting in mice is a powerful tool to define molecular mechanisms of ischemic heart disease that determine infarct size, postinfarct left ventricular (LV) remodeling, and arrhythmogenesis. Coronary ligation in mice is becoming a widely used model of myocardial infarction (MI), but the pathophysiologic consequences of MI in mice and its relevance to human MI have not been fully elucidated. To characterize structural and functional changes during evolving MI, we analyzed 2-dimensional-based reconstruction of the left ventricle by noninvasive echocardiography obtained 1 day and 1 week after surgical ligation of the left anterior descending coronary artery in mice. Sequential 2-dimensional short-axis cineloops of the left ventricle were used to measure LV mass, and LV volumes at end-diastole and end-systole. Echocardiographic infarct size was estimated by measuring the volume of akinetic LV segments. Histologic infarct size was measured by planimetry of 9 transverse sections of each heart. There was close correlation between the 2 methods (31% +/- 20% of LV mass and 34% +/- 17% of LV area, respectively; y =.83x + 7.9, r = 0.96, P <.01). LV volumes at end diastole increased significantly between 1 day and 1 week (51 +/- 17 microL vs 78 +/- 46 microL, respectively, P <.05). The relative change in LV volumes at end diastole varied as a function of infarct size (r = 0.93, P <.01). LV mass and the extent of hypertrophy of noninfarcted segments also varied with infarct size (r = 0.92, P <.01; r = 0.90, P <.01, respectively). Thus, echocardiography is an accurate noninvasive tool for determination of infarct size and quantitative characterization of postinfarct remodeling in the mouse model of MI. Alterations in cardiac structure and function after coronary ligation in mice closely resemble pathophysiologic changes in human ischemic heart disease.

Antioxidant Enzyme Activities Are Decreased in Preterm Infants and in Neonates Born Via Caesarean Section

European Journal of Obstetrics, Gynecology, and Reproductive Biology. Jul, 2002  |  Pubmed ID: 12069735

To investigate the antioxidant defense potential of human neonates according to gestational age and mode of delivery.

Membrane Transport in Caenorhabditis Elegans: an Essential Role for VPS34 at the Nuclear Membrane

The EMBO Journal. Apr, 2002  |  Pubmed ID: 11927551

Here we present a detailed genetic analysis of let-512/vps34 that encodes the Caenorhabditis elegans homologue of the yeast phosphatidylinositol 3-kinase Vps34p. LET-512/VPS34 has essential functions and is ubiquitously expressed in all tissues and developmental stages. It accumulates at a perinuclear region, and mutations in let-512/vps34 result in an expansion of the outer nuclear membrane as well as in a mislocalization and subsequent complete lack of expression of LRP-1, a C.elegans LDL receptor normally associated with the apical surface of hypodermal cells. Using a GFP::2xFYVE fusion protein we found that the phosphatidylinositol 3-phosphate (PtdIns 3-P) product of LET-512/VPS34 is associated with a multitude of intracellular membranes and vesicles located at the periphery, including endocytic vesicles. We propose that LET-512/VPS34 is required for membrane transport from the outer nuclear membrane towards the cell periphery. Thus, LET-512/VPS34 may regulate the secretory pathway in a much broader range of compartments than was previously suggested for the yeast orthologue.

Chemical Vapor Deposition of Gallium Nitride from the GaCl(3)+NH(3) System. Theoretical Study of the Structure and Thermodynamics of Potential Intermediates Formed in the Gaseous Phase

Inorganic Chemistry. Jun, 2002  |  Pubmed ID: 12054984

Quantum chemical calculations at the B3P86/6-311G(d,p) level have been performed on potential intermediate molecules in the chemical vapor deposition (CVD) of GaN from the GaCl(3) + NH(3) system. The investigated molecules included the monomer (Cl(x)GaNH(x), x = 1-3) and oligomer species (Cl(2)GaNH(2))(n) with n = 1-3 and (ClGaNH)(n) with n = 1-4 as well as the respective chain dimers and trimers. The calculations revealed the importance of intramolecular Cl...H hydrogen bonding and dipole-dipole interactions in determining the conformational properties of the larger species. Except for the ClGaNH monomer, the Ga[bond]N bonding has a single bond character with a strong ionic contribution. Our thermodynamic study of the composition of the gaseous phase supported the predominance of the Cl(3)GaNH(3) complex under equilibrium conditions. Additionally, the calculated Gibbs free energies of various GaCl(3) + NH(3) reactions imply the favored formation of "saturated" chain and cyclic oligomers below 1000 K.

Structural Characteristics of Intramolecular Hydrogen Bonding in Benzene Derivatives

Accounts of Chemical Research. Oct, 2002  |  Pubmed ID: 12379141

In this Account, the intramolecular hydrogen bonding (HB) properties of various proton acceptor groups (BX(n): C=N, NO(2), C=O, P=O, F, CF(3)) with OH and NH(2) (AH) in benzene derivatives are assessed on the basis of gas electron diffraction, spectroscopic, and quantum chemical results. The most important properties are the HB energy, the characteristic geometrical changes in the interacting groups (lengthening of the A-H and B-X, shortening of the C-A and C-B bonds) and in the benzene ring, and the vibrational properties of the AH groups. These properties are characteristic of the particular HB interaction (in particular of the AH and BX(n) pair in single and multiple hydrogen-bonded systems); however, they cannot be related directly to the computed HB energies.

[Psychiatric Sequelae of Interferon-alpha Therapy]

Orvosi Hetilap. Sep, 2002  |  Pubmed ID: 12395474

Psychopathologic conditions commonly complicate the treatment with the interferon-alpha. The most important among them is depression, which can induce suicidal attempt. The outcome of mental side effects of interferon-alpha necessitate the discontinuation of therapy and, in more severe cases, psychiatric treatment.

Delineation of Hypoxia in Canine Myocardium Using PET and Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone)

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Nov, 2002  |  Pubmed ID: 12411560

Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (copper-ATSM) is a hypoxia-avid tracer for the selective identification of hypoxic tissue. Using canine models of hypoxic myocardium, we report our findings on *Cu-ATSM PET (*Cu is defined as either (60)Cu, (61)Cu, or (64)Cu) for the delineation of ischemic and hypoxic myocardium.

A Critical Role for PPARalpha-mediated Lipotoxicity in the Pathogenesis of Diabetic Cardiomyopathy: Modulation by Dietary Fat Content

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2003  |  Pubmed ID: 12552126

To explore the role of peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPARalpha deficiency (PPARalpha(-/-)) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPARalpha(-/-) mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial long-chain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPARalpha gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy.

Theoretical Study of Mixed MLaX(4) (M = Na, K, Cs; X = F, Cl, Br, I) Rare Earth/alkali Metal Halide Complexes

Inorganic Chemistry. Feb, 2003  |  Pubmed ID: 12562199

The structure, bonding, and vibrational properties of the mixed MLaX(4) (M = Na, K, Cs; X = F, Cl, Br, I) rare earth/alkali metal halide complexes have been studied using the MP2 method in conjunction with polarized triple-zeta valence basis sets and quasi-relativistic effective core potentials for the heavy atoms. From the three characteristic structures, possessing 1- (C(3)(v)), 2- (C(2)(v)), or 3-fold coordination (C(3)(v)) between the alkali metal and the bridging halide atoms, the bi- and tridentate forms are stable isomers with close dissociation energies. In general, for the complexes existing of lighter alkali metals and halogens, the bidentate structure corresponds to the global minimum of the potential energy surface, while the heavier analogues favor the tridentate structure. At experimentally relevant temperatures (T > 800 K), however, the isomerization entropy leads to a domination of the bidentate structures over the tridentate forms for all complexes. An important effect of the size of the alkali metal is manifested in the larger stabilities of the K and Cs complexes. The natural atomic charges are in agreement with strong electrostatic interactions in the title complexes. The marginal covalent contributions show a slight increasing trend in the heavier analogues. The calculated vibrational data indicate that infrared spectroscopy may be an effective tool for experimental investigation and characterization of MLaX(4) molecules.

Connexin43 As a Determinant of Myocardial Infarct Size Following Coronary Occlusion in Mice

Journal of the American College of Cardiology. Feb, 2003  |  Pubmed ID: 12598083

The purpose of this study was to define the role of cell-cell coupling as an independent determinant of infarct size following coronary occlusion.

The Role of the Grb2-p38 MAPK Signaling Pathway in Cardiac Hypertrophy and Fibrosis

The Journal of Clinical Investigation. Mar, 2003  |  Pubmed ID: 12639989

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2(+/-) mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2(+/-) mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38alpha (DN-p38alpha) and p38beta (DN-p38beta) MAPK were examined. DN-p38alpha and DN-p38beta mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.

Pannonibacter Phragmitetus Gen. Nov., Sp. Nov., a Novel Alkalitolerant Bacterium Isolated from Decomposing Reed Rhizomes in a Hungarian Soda Lake

International Journal of Systematic and Evolutionary Microbiology. Mar, 2003  |  Pubmed ID: 12710626

Three alkalitolerant bacterial strains were isolated from the surface of decomposing rhizomes of reed [Phragmites australia (Cav.) Trin. et Steudel] in Lake Fertö (Hungary). Cells of the novel isolates were Gram-negative, motile rods and formed star-shaped aggregates. They were facultatively anaerobic and chemo-organotrophic. Bacteriochlorophyll a was not synthesized under aerobic conditions. The strains were catalase and oxidase positive, produced acid from D-glucose under aerobic and anaerobic conditions and reduced nitrate to nitrogen. They tolerated pH values from 7.0 to 11.0 and grew in the absence of NaCl as well as in up to 5% (w/v) NaCl. The G + C content of the DNA was 64.6 mol% and the major isoprenoid quinone was Q-10. The dominant cellular fatty acid was C18 : 1omega7c. The cell membrane contained phosphatidyl glycerol, diphosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl serine and one unknown phospholipid as polar lipids. Polyphasic taxonomic characterization revealed that strain C6/19T is most closely related to the Stappia-Roseibium cluster in the alpha-subclass of the Proteobacteria (showing 95.8-93.6% 16S rDNA sequence similarity). According to the phylogenetic and phenotypic evidence presented, a new genus and species is proposed, Pannonibacter phragmitetus gen. nov., sp. nov. The type strain is C6/19T (=DSM 14782T =NCAIM B02025T).

Loss of GABAergic Neuronal Phenotype in Primary Cerebellar Cultures Following Blockade of Glutamate Reuptake

Brain Research. Jul, 2003  |  Pubmed ID: 12834881

Prolonged inhibition of glutamate reuptake by L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a specific glutamate transporter blocker, reduced the number of GABA positive neurons in a primary cerebellar culture by 54%. The disappearance of immunostaining for GABA was gradual and was partially prevented by the N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, NBQX. Combined blockade of NMDA and AMPA receptors restored the original proportion of GABAergic neurons observed in control cultures. Following the PDC exposure, expression of other GABAergic markers, such as glutamic acid decarboxylase (GAD) and vesicular GABA transporter (VGAT) was also dramatically decreased in an AMPA receptor-dependent manner. Loss of GABA or GAD immunostaining is commonly regarded as a sign of degeneration of GABAergic neurons. However, none of the GABAergic neurons were positive for propidium iodide uptake or showed abnormal nuclear morphology. Based on the above data we conclude that prolonged activation of ionotropic glutamate receptors by endogenously released glutamate was not toxic to cerebellar GABAergic neurons, but lead to the loss of their characteristic neurotransmitter phenotype.

Energy Decomposition Analysis of the Chemical Bond in Main Group and Transition Metal Compounds

Faraday Discussions. 2003  |  Pubmed ID: 14527226

The nature of the chemical bond in the main group diborane(4) compounds X2B-BX2 (X = H,F,Cl,Br,I) and in the Fischer- and Schrock-type transition metal carbene and carbyne complexes and heavier homologues (CO)5W-CH2, (CO)5W-E(OH)2, Cl4W-EH2, Cl(CO)4W-EH and Cl3W-EH (E = C,Si,Ge,Sn,Pb) have been investigated with an energy decomposition analysis (EDA). The results give a deep insight into the nature of the chemical interactions. The EDA results can be used as a bridge between the heuristic models of experimental chemists which have been proven as useful ordering schemes for experimental observations and the physical mechanism which leads to a chemical bond. At the time the data give a well defined qantitative answer to the questions about the strength of the covalent and electrostatic interactions and about the contributions of sigma and pi electrons to the covalent bond.

Developmental Adaptation of the Mouse Cardiovascular System to Elastin Haploinsufficiency

The Journal of Clinical Investigation. Nov, 2003  |  Pubmed ID: 14597767

Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln+/-) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln+/- animals were found to be stably hypertensive from birth, with a mean arterial pressure 25-30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln+/- arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln+/- mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic fiber should be considered as causal genes for essential hypertension.

Genetics: Influence of TOR Kinase on Lifespan in C. Elegans

Nature. Dec, 2003  |  Pubmed ID: 14668850

Cardiac-specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-activated Receptor Gamma Coactivator-1alpha Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-dependent Manner

Circulation Research. Mar, 2004  |  Pubmed ID: 14726475

Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1alpha in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy.

Recent Advances in Imaging the Lungs of Intact Small Animals

American Journal of Respiratory Cell and Molecular Biology. Feb, 2004  |  Pubmed ID: 14729505

A new generation of imaging devices now make it possible to generate both structural and functional images for the study of lung biology in small animals, including common laboratory mouse and rat models. "Micro" X-ray computed tomography and positron emission tomography scanners, highly sensitive cooled charge coupled device cameras for bioluminescence and fluorescence imaging, high magnetic field magnetic resonance imaging scanners, and recent advances in ultrasound system technology can be used to study such diverse processes as ventilation, perfusion, pulmonary hypertension, lung inflammation, and gene transfer, among others. Images from more than one modality can also be fused, allowing structure-function and function-function relationships to be studied on a regional basis. These new instruments, part of an emerging suite of techniques collectively known as "molecular imaging," provide an enormous potential for elucidating lung biology in intact animal models and systems.

Targeted Activation of C-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects

The Journal of Biological Chemistry. Apr, 2004  |  Pubmed ID: 14742426

The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died approximately 7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor beta signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.

Mechanism of NF-kappaB Inactivation Induced by Survival Signal Withdrawal in Cerebellar Granule Neurons

The European Journal of Neuroscience. Jul, 2004  |  Pubmed ID: 15233744

Activity of the transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to be necessary for maintaining neuronal viability. In cultured rat cerebellar granule neurons, trophic factor withdrawal induces NF-kappaB inactivation, resulting in cell death. The exact mechanism of this inactivation, however, has not been revealed. Here we report that trophic factor deprivation in cultured cerebellar granule neurons leads to a rapid and sustained increase in the level of IkappaBalpha and IkappaBbeta, the inhibitory proteins of NF-kappaB, causing prolonged NF-kappaB inactivation. Transient NF-kappaB activation resulting in new IkappaBalpha mRNA and protein synthesis gives rise to the rapid increase of IkappaBalpha level. The importance of elevated IkappaB level in neuronal apoptosis was confirmed in transfection experiments. Ectopic expression of a stabilized form of IkappaBalpha protein promoted neuronal death. Our findings suggest a novel mode of initiation of neuronal apoptosis wherein survival signal withdrawal induces NF-kappaB to lethally turn itself off.

Ultrasonic Tissue Characterization of the Mouse Myocardium: Successful in Vivo Cyclic Variation Measurements

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Aug, 2004  |  Pubmed ID: 15282494

Measurements of the systematic variation of backscattered ultrasonic energy from myocardium during the heart cycle (cyclic variation) have been successfully used to characterize a wide spectrum of cardiac pathologies in large animal models and human subjects. The purpose of this study was to evaluate the feasibility of extending cyclic variation measurements to the study of genetically manipulated mouse models of cardiac diseases as a method for developing further insights into the disease-altered properties of the myocardium and its characterization with ultrasound.

Raf-1 Kinase is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

Circulation. Aug, 2004  |  Pubmed ID: 15289381

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart results in the activation of the small GTPase ras and the Raf-1/MEK/ERK signaling cascade in addition to other signaling pathways.

Cardiovascular Autonomic Dysfunction in Primary Sjögren's Syndrome

Rheumatology (Oxford, England). Jan, 2004  |  Pubmed ID: 12949253

To assess the occurrence and clinical significance of a cardiovascular autonomic nervous system dysfunction in primary Sjögren's syndrome (pSS).

Liver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease in Mucopolysaccharidosis I Mice

Molecular Therapy : the Journal of the American Society of Gene Therapy. Jan, 2005  |  Pubmed ID: 15585404

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.

Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy

Circulation Research. Feb, 2005  |  Pubmed ID: 15618539

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.

The Nature of the Chemical Bond Revisited: an Energy-partitioning Analysis of Nonpolar Bonds

Chemistry (Weinheim an Der Bergstrasse, Germany). Mar, 2005  |  Pubmed ID: 15672434

The nature of the chemical bond in nonpolar molecules has been investigated by energy-partitioning analysis (EPA) of the ADF program using DFT calculations. The EPA divides the bonding interactions into three major components, that is, the repulsive Pauli term, quasiclassical electrostatic interactions, and orbital interactions. The electrostatic and orbital terms are used to define the nature of the chemical bond. It is shown that nonpolar bonds between main-group elements of the first and higher octal rows of the periodic system, which are prototypical covalent bonds, have large attractive contributions from classical electrostatic interactions, which may even be stronger than the attractive orbital interactions. Fragments of molecules with totally symmetrical electron-density distributions, like the nitrogen atoms in N(2), may strongly attract each other through classical electrostatic forces, which constitute 30.0 % of the total attractive interactions. The electrostatic attraction can be enhanced by anisotropic charge distribution of the valence electrons of the atoms that have local areas of (negative) charge concentration. It is shown that the use of atomic partial charges in the analysis of the nature of the interatomic interactions may be misleading because they do not reveal the topography of the electronic charge distribution. Besides dinitrogen, four groups of molecules have been studied. The attractive binding interactions in H(n)E-EH(n) (E=Li to F; n=0-3) have between 20.7 (E=F) and 58.4 % (E=Be) electrostatic character. The substitution of hydrogen by fluorine does not lead to significant changes in the nature of the binding interactions in F(n)E-EF(n) (E=Be to O). The electrostatic contributions to the attractive interactions in F(n)E-EF(n) are between 29.8 (E=O) and 55.3 % (E=Be). The fluorine substituents have a significant effect on the Pauli repulsion in the nitrogen and oxygen compounds. This explains why F(2)N-NF(2) has a much weaker bond than H(2)N-NH(2), whereas the interaction energy in FO-OF is much stronger than in HO-OH. The orbital interactions make larger contributions to the double bonds in HB=BH, H(2)C=CH(2), and HN=NH (between 59.9 % in B(2)H(2) and 65.4 % in N(2)H(2)) than to the corresponding single bonds in H(n)E-EH(n). The orbital term Delta E(orb) (72.4 %) makes an even greater contribution to the HC triple bond CH triple bond. The contribution of Delta E(orb) to the H(n)E=EH(n) bond increases and the relative contribution of the pi bonding decreases as E becomes more electronegative. The pi-bonding interactions in HC triple bond CH amount to 44.4 % of the total orbital interactions. The interaction energy in H(3)E-EH(3) (E=C to Pb) decreases monotonically as the element E becomes heavier. The electrostatic contributions to the E-E bond increases from E=C (41.4 %) to E=Sn (55.1 %) but then decreases when E=Pb (51.7 %). A true understanding of the strength and trends of the chemical bonds can only be achieved when the Pauli repulsion is considered. In an absolute sense the repulsive Delta E(Pauli) term is in most cases the largest term in the EPA.

Opposite Effects of Lithium and Valproic Acid on Trophic Factor Deprivation-induced Glycogen Synthase Kinase-3 Activation, C-Jun Expression and Neuronal Cell Death

Neuropharmacology. Mar, 2005  |  Pubmed ID: 15755485

Recent studies demonstrate that lithium and valproic acid (VPA), two commonly used mood-stabilizing drugs, have neuroprotective effects against a variety of insults. Inhibition of the proapoptotic enzyme, glycogen synthase kinase-3 (GSK-3), has been suggested to be the mechanism of action of neuroprotection for both drugs. In this study, we tested if lithium and VPA could protect cultured cerebellar granule neurons (CGNs) from GSK-3-mediated apoptosis induced by trophic factor withdrawal (serum/potassium deprivation). Both lithium and indirubin, a specific GSK-3 inhibitor, protected CGNs in a dose-dependent manner. In contrast, VPA did not provide any neuroprotection and even potentiated cell death. Immunoblot analysis revealed that lithium inhibited the trophic factor deprivation-induced activation of GSK-3 as well as the in vivo phosphorylation of the microtubule-associated protein Tau on Ser199, a specific target site for GSK-3. Under these same experimental conditions, however, VPA neither inhibited GSK-3 activation nor hindered GSK-3 mediated Tau phosphorylation. Furthermore, in accordance with their effects on neuronal survival, lithium prevented the induction of c-Jun expression in trophic factor-deprived CGNs, whereas VPA potentiated it. Collectively, these results show that VPA is not a universal inhibitor of neuronal GSK-3, and that instead of being neuroprotective, VPA can even exacerbate neuronal death under some conditions.

Role of P38alpha MAPK in Cardiac Apoptosis and Remodeling After Myocardial Infarction

Journal of Molecular and Cellular Cardiology. Apr, 2005  |  Pubmed ID: 15808838

Acute coronary occlusion results in ischemia-mediated death of cardiomyocytes. In the days and weeks following myocardial infarction (MI), left ventricular remodeling occurs that is characterized by persistent cardiomyocyte apoptosis, thinning and fibrosis at the site of infarction, ventricular chamber dilatation, and growth of remaining viable cardiomyocytes. The p38 mitogen-activated protein kinase (MAPK) signaling cascade has been implicated in the remodeling process. In this work, mice with cardiac-specific expression of a dominant negative mutant form of p38 MAPK (DN-p38alpha) were subjected to MI by occlusion of the left coronary artery. Acute ischemia area was determined by transthoracic echocardiography 2 h after MI surgery, and was found to be nearly identical in DN-p38 mice and their wild-type littermates. Seven days after MI, mice were subjected to repeat echocardiography and histological examination of infarct size. DN-p38 mice had markedly reduced infarct size and increased ventricular systolic function 7 days after MI when compared to wild-type littermates. In addition, DN-p38 mice had less cardiomyocyte apoptosis than wild-type mice in the infarct border zone. Recently, it was discovered that Bcl-X(L) deamidation occurs in vivo, and this results in Bcl-X(L) degradation that sensitizes cells to apoptosis by enhancing BAX activity. Bcl-X(L) deamidation was found to occur in the cardiac tissue of wild-type mice after MI, but was reduced in DN-p38 mice. These results establish that p38 MAPK activity is required for pathological remodeling after MI and suggest that p38 MAPK may promote cardiomyocyte apoptosis through Bcl-X(L) deamidation.

[The Role of Pneumoperitoneum and the "chimney Effect" on the Development of Port Site Metastasis. A New Experimental Animal Model Using Furka's Spleen Tissue Suspension]

Magyar Sebészet. Apr, 2005  |  Pubmed ID: 16018274

Following the introduction of laparoscopic cholecystectomy, laparoscopic technology has been applied in many other fields of surgery, including surgery for malignancies, even before prospective, randomised trials were available. Many authors observed development of port site metastases following laparoscopic surgery in malignancies (1-2%). The studies report about the pathomechanism of the development of port site metastasis, some describe the role of pneumoperitoneum. We developed a new model to show the role of pneumoperitoneum and the "chimney effect" on the development of port site metastasis, using a large experimental animal with a suspension of its own spleen tissue. On follow up histology viable spleen tissue was found between the layers of the trocar incisions.

Inactivation of the Autophagy Gene Bec-1 Triggers Apoptotic Cell Death in C. Elegans

Current Biology : CB. Aug, 2005  |  Pubmed ID: 16111945

Programmed cell death (PCD) is an essential and highly orchestrated process that plays a major role in morphogenesis and tissue homeostasis during development. In humans, defects in regulation or execution of cell death lead to diabetes, neurodegenerative disorders, and cancer. Two major types of PCD have been distinguished: the caspase-mediated process of apoptosis and the caspase-independent process involving autophagy. Although apoptosis and autophagy are often activated together in response to stress, the molecular mechanisms underlying their interplay remain unclear. Here we show that BEC-1, the C. elegans ortholog of the yeast and mammalian autophagy proteins Atg6/Vps30 and Beclin 1, is essential for development. We demonstrate that BEC-1 is necessary for the function of the class III PI3 kinase LET-512/Vps34, an essential protein required for autophagy, membrane trafficking, and endocytosis. Furthermore, BEC-1 forms a complex with the antiapoptotic protein CED-9/Bcl-2, and its depletion triggers CED-3/Caspase-dependent PCD. Based on our results, we propose that bec-1 represents a link between autophagy and apoptosis, thus supporting the view that the two processes act in concerted manner in the cell death machinery.

Suicide Attempt and Melancholic Depression in a Male with Erotomania: Case Report

Archives of Suicide Research : Official Journal of the International Academy for Suicide Research. 2005  |  Pubmed ID: 16179333

Erotomania is a delusional disorder, which is more common among women. A case of erotomania in a 34-year-old male associated with depression and suicidal behavior is presented. At the time he attempted suicide his erotomania fulfilled the diagnostic criteria of "pure" erotomania, described by de Clérambault. A depressive picture with melancholic features emerged four months later. Antidepressant medication was given and two months later he became euthymic. The erotomanic delusion disappeared in the third month of the euthymic state. In this case primary erotomania was associated with a depressive illness, presumably unipolar depression. The patient developed delusional guilt and suicidal ideation before the unequivocal change in his mood. To the authors' knowledge this is the first reported case where the erotomanic symptomatology led to suicidal attempt.

Patients with Malignancy Requiring Urgent Therapy: CASE 1. Central Airway Obstruction As First Presentation of Ovarian Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Sep, 2005  |  Pubmed ID: 16170186

[The Attendance of the First Screening Round (2002-2003) of the Hungarian Organized Breast Cancer Screening Program and Its Effect on the Number of Diagnostic and Screening Mammography]

Orvosi Hetilap. Sep, 2005  |  Pubmed ID: 16238249

Organised, nationwide screening for breast cancer with mammography in the age group 45-65 years with 2 years screening interval started in Hungary in January 2002. The aim of this study is to analyze the attendance rate of breast screening programme, including the analysis of the ratio of screening and diagnostic mammography examinations.

Endotoxin Can Decrease Isolated Rat Parotid Acinar Cell Amylase Secretion in a Nitric Oxide-independent Manner

European Journal of Pharmacology. Nov, 2005  |  Pubmed ID: 16253235

Salivary mucus and amylase have an anti-bacterial nature. Bacterial endotoxin is considered to decrease mucus secreting cell activity by nitric oxide-dependent mechanisms. In this study, the actions of endotoxin on amylase secreting cell activity have been studied. Endotoxin (Escherichia coli lipopolysaccharide; 3 mg/kg, i.v., 5 h) evoked nitric oxide synthase 2 (NOS2) induction in the rat whole parotid tissue (assessed by Western blot and the citrulline assay) and in rat isolated parotid acinar cells (assessed by Western blot and immunohistochemistry), and reduced basal and acetylcholine-stimulated amylase secretion from these isolated cells. However, N(G)-nitro-L-arginine methyl ester (0.1 mg/ml, 4 days in drinking water, yielding a dose of 25 mg/kg/day) did not affect amylase release under basal or acetylcholine-stimulated conditions, either in control acinar cells or those from endotoxin challenged rats. Thus, basal, acetylcholine-evoked or endotoxin-decreased cellular amylase secretion from rat isolated parotid acinar cells does not appear to be modulated by endogenous nitric oxide.

Anisotropy of Apparent Backscatter in the Short-axis View of Mouse Hearts

Ultrasound in Medicine & Biology. Dec, 2005  |  Pubmed ID: 16344125

The goals of this investigation were to measure the anisotropy of backscattered ultrasound observed in the short-axis view of mouse hearts in systole and diastole and to compare these measurements with predictions from a computer simulation. Measurements of midmyocardial apparent backscatter were obtained from analyses of the hearts of seven wild-type mice using a clinical imaging system utilizing a linear array with a nominal center frequency of 13 MHz. A computer model simulating the short-axis view was implemented based on previous measurements of the angle of insonification dependence of myocardial backscatter and attenuation. Results demonstrate that the measured backscatter was largest for those myocardial regions corresponding to approximately perpendicular insonification relative to the myofibers and the smallest for regions of approximately parallel insonification, with the minimum to maximum values of apparent backscatter differing by approximately 10 dB. The measured anisotropy of backscatter was similar for end-systole and end-diastole and was in good agreement with the predicted anisotropy obtained from the computer simulations.

Density Functional Study of the Conformational Space of 4C1 D-glucuronic Acid

The Journal of Physical Chemistry. A. Feb, 2005  |  Pubmed ID: 16838961

The conformational space of (4)C(1) alpha- and beta-d-glucuronic acid was scanned by HF/3-21G(p) calculations followed by optimization of the 15 most stable structures for each, using the B3LYP density functional theory method in conjunction with a diffuse polarized valence triple-zeta basis set. We found a general preference of the alpha anomers in the isolated molecules in agreement with the large endo-anomeric hyperconjugation effects in these structures. From the other intramolecular interactions (exo-anomeric hyperconjugation, hydrogen-bonding, dipole-dipole, and steric interactions), the effect of the hydrogen bonding is the most pronounced and plays a major role in determining the stability order within the alpha and beta series. The most stable conformer of both alpha and beta (4)C(1) d-glucuronic acid is the structure with the maximum number (5) of intramolecular hydrogen bonds. Introduction of solvent (water) effects by the SCI-PCM model resulted in two characteristic changes of the energetic properties: the gas-phase stability order changed considerably, and the energy range of the 15 most stable conformers decreased from 30 to 15 kJ/mol. The geometrical parameters reflect well the superimposed effects of hyperconjugation and hydrogen-bonding interactions. Most characteristics are the variations of the C-O bond distances (within a range of 0.04 A) upon the combined intramolecular effects.

Effects of Sex and Insulin/insulin-like Growth Factor-1 Signaling on Performance in an Associative Learning Paradigm in Caenorhabditis Elegans

Genetics. Sep, 2006  |  Pubmed ID: 16849598

Learning is an adaptive change in behavior in response to environmental stimuli. In mammals, there is a distinct female bias to learn skills that is still unprecedented in other animal taxa. Here we have investigated the biological determinants of performance in an associative learning paradigm in the nematode Caenorhabditis elegans. Using an assay of chemotactic reactions associated with food deprivation, wild-type male worms show inferior learning ability relative to hermaphrodites. Sex-based learning difference is therefore an ancient evolutionary feature appearing even in relatively simple animals. C. elegans mutants with reduced insulin/IGF-1 signaling also exhibit a greatly reduced learning ability in this assay. In addition, hyperactivation of insulin/IGF-1 signaling through loss-of-function mutations in the PTEN phosphatase daf-18, a negative regulator of insulin/IGF-1 signaling, enhances learning ability beyond that of wild type. According to our epistasis analysis, the effect of DAF-2 on learning acts via phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) production, but not the DAF-16 FOXO transcription factor. This implies that the signaling pathway from DAF-2 affecting this learning paradigm branches between PIP(3) production and DAF-16. However, learning capacity of nematodes is lowered by loss-of-function mutations in daf-16, suggesting involvement of noninsulin/IGF-1 signaling-dependent DAF-16 activation in learning. Potentially, sex and insulin/IGF-1 signaling affect performance in this learning assay via effects on the neurobiology of learning.

A Theoretical Study of the Structure and Bonding of UOX4 (X = F, Cl, Br, I) Molecules: the Importance of Inverse Trans Influence

Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry. Feb, 2006  |  Pubmed ID: 16463335

During nitroxide-mediated polymerization (NMP) in the presence of a nitroxide R2(R1)NO*, the reversible formation of N-alkoxyamines [P-ON(R1)R2] reduces significantly the concentration of polymer radicals (P*) and their involvement in termination reactions. The control of the livingness and polydispersity of the resulting polymer depends strongly on the magnitude of the bond dissociation energy (BDE) of the C-ON(R1)R2 bond. In this study, theoretical BDEs of a large series of model N-alkoxyamines are calculated with the PM3 method. In order to provide a predictive tool, correlations between the calculated BDEs and the cleavage temperature (T(c)), and the dissociation rate constant (k(d)), of the N-alkoxyamines are established. The homolytic cleavage of the N-OC bond is also investigated at the B3P86/6-311++G(d,p)//B3LYP/6-31G(d), level. Furthermore, a natural bond orbital analysis is carried out for some N-alkoxyamines with a O-C-ON(R1)R2 fragment, and the strengthening of their C-ON(R1)R2 bond is interpreted in terms of stabilizing anomeric interactions.

Selectively Increased Sensitivity of Cerebellar Granule Cells to AMPA Receptor-mediated Excitotoxicity in a Mouse Model of Batten Disease

Neurobiology of Disease. Jun, 2006  |  Pubmed ID: 16483786

Batten disease, a lysosomal storage disorder, is caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3-/-) mouse model of the disease exhibits many characteristic pathological features of the human disorder. Here, we show that Cln3-/- mice, similarly to Batten disease patients, have a deficit in cerebellar motor coordination. To explore the possible cellular cause of this functional impairment, we compared the vulnerability of wild type (WT) and Cln3-/- cerebellar granule cell cultures to different toxic insults. We have found that cultured Cln3-/- cerebellar granule cells are selectively more vulnerable to AMPA-type glutamate receptor-mediated toxicity than their WT counterparts. This selective sensitivity was also observed in organotypic cerebellar slice cultures. Our results suggest that lack of the CLN3 protein has a significant influence on the function of AMPA receptors in cerebellar granule neurons, and that AMPA receptor dysregulation may be a major contributor to the cerebellar dysfunction in Batten disease.

[Assessment of Suicidal Behaviour in General Practice]

Orvosi Hetilap. Feb, 2006  |  Pubmed ID: 16610617

To assess the prevalence of suicidal behavior (wish to die, suicidal thoughts, suicide attempts) and to determine the characteristics of suicide attempters in primary care, including screening for major mental disorders.

Akt1 is Required for Physiological Cardiac Growth

Circulation. May, 2006  |  Pubmed ID: 16636172

Postnatal growth of the heart chiefly involves nonproliferative cardiomyocyte enlargement. Cardiac hypertrophy exists in a "physiological" form that is an adaptive response to long-term exercise training and as a "pathological" form that often is a maladaptive response to provocative stimuli such as hypertension and aortic valvular stenosis. A signaling cascade that includes the protein kinase Akt regulates the growth and survival of many cell types, but the precise role of Akt1 in either form of cardiac hypertrophy is unknown.

Possible Paradoxical Embolism As a Rare Cause for an Acute Myocardial Infarction

Echocardiography (Mount Kisco, N.Y.). May, 2006  |  Pubmed ID: 16686626

Paradoxical embolus is a rare entity and it has been incriminated as a cause of both cryptogenic strokes and myocardial infarctions (MI). Herein, we present a case of a patient diagnosed with a pulmonary embolism 1 week prior who now presented with an acute MI. Subsequent evaluation revealed a patent foramen ovale and a large thrombus in the right pulmonary artery. It was presumed that the etiology of her infarct was due to paradoxical embolus. The management of the patient is discussed and the literature is reviewed.

Recruitment of Active Glycogen Synthase Kinase-3 into Neuronal Lipid Rafts

Biochemical and Biophysical Research Communications. Jul, 2006  |  Pubmed ID: 16735023

Glycogen synthase kinase (GSK)-3beta has emerged as a key molecule that regulates neuronal apoptosis. To examine the molecular mechanism(s) through which GSK-3beta regulates this process, we studied the subcellular localization of GSK-3beta following exposure of the cells to well-characterized apoptotic stimuli. Here, we report that the induction of apoptosis by withdrawal of serum and potassium triggers dephosphorylation of GSK-3beta at serine 9 and subsequent translocation of these molecules into neuronal lipid raft microdomains. Inhibition of GSK-3beta by small molecule inhibitors blocks specific phosphorylation of lipid raft associated protein Tau. Consistent with the notion that the lipid raft domains may serve as a platform for the cellular signaling complexes, disruption of lipid rafts protected neurons from apoptosis induced by withdrawal of serum and potassium as well as by HIV-1 Tat. Our observations reveal novel interaction of GSK-3beta and raft domains, and suggest that such interaction could contribute to neuronal apoptosis.

Oxidative Addition of Hydrogen Halides and Dihalogens to Pd. Trends in Reactivity and Relativistic Effects

The Journal of Physical Chemistry. A. Jun, 2006  |  Pubmed ID: 16789784

We have theoretically studied the oxidative addition of HX and X(2) to palladium for X = F, Cl, Br, I and At, using both nonrelativistic and ZORA-relativistic density functional theory at BLYP/QZ4P. The purpose is 3-fold: (i) to obtain a set of consistent potential energy surfaces (PESs) to infer accurate trends in reactivity for simple, archetypal oxidative addition reactions; (ii) to assess how relativistic effects modify these trends along X = F, Cl, Br, I and At; and (iii) to rationalize the trends in reactivity in terms of the reactants' molecular-orbital (MO) electronic structure and the H-X and X-X bond strengths. For the latter, we provide full Dirac-Coulomb CCSD(T) benchmarks. All oxidative additions to Pd are exothermic and have a negative overall barrier, except that of HF which is approximately thermoneutral and has a positive overall barrier. The activation barriers of the HX oxidative additions decrease systematically as X descends in group 17 of the periodic table; those of X(2) first increase, from F to Cl, but then also decrease further down group 17. On the other hand, HX and X(2) show clearly opposite trends regarding the heat of reaction: that of HX becomes more exothermic and that of X(2) less exothermic as X descends in group 17. Relativistic effects can be as large as 15-20 kcal/mol but they do not change the qualitative trends. Interestingly, the influence of relativistic effects on activation barriers and heats of reaction decreases for the heavier halogens due to counteracting relativistic effects in palladium and the halogens.

Human Immunodeficiency Virus-encoded Tat Activates Glycogen Synthase Kinase-3beta to Antagonize Nuclear Factor-kappaB Survival Pathway in Neurons

The European Journal of Neuroscience. May, 2006  |  Pubmed ID: 16817865

The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia.

The 14-3-3tau Phosphoserine-binding Protein is Required for Cardiomyocyte Survival

Molecular and Cellular Biology. Feb, 2007  |  Pubmed ID: 17145769

14-3-3 family members are intracellular dimeric phosphoserine-binding proteins that regulate signal transduction, cell cycle, apoptotic, and metabolic cascades. Previous work with global 14-3-3 protein inhibitors suggested that these proteins play a critical role in antagonizing apoptotic cell death in response to provocative stimuli. To determine the specific role of one family member in apoptosis, mice were generated with targeted disruption of the 14-3-3tau gene. 14-3-3tau(-/-) mice did not survive embryonic development, but haploinsufficient mice appeared normal at birth and were fertile. Cultured adult cardiomyocytes derived from 14-3-3tau(+/-) mice were sensitized to apoptosis in response to hydrogen peroxide or UV irradiation. 14-3-3tau(+/-) mice were intolerant of experimental myocardial infarction and developed pathological ventricular remodeling with increased cardiomyocyte apoptosis. ASK1, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase (MAPK) activation was increased, but extracellular signal-regulated kinase MAPK activation was reduced, in 14-3-3tau(+/-) cardiac tissue. Inhibition of p38 MAPK increased survival in 14-3-3tau(+/-) mice subjected to myocardial infarction. These results demonstrate that 14-3-3tau plays a critical antiapoptotic function in cardiomyocytes and that therapeutic agents that increase 14-3-3tau activity may be beneficial to patients with myocardial infarction.

The New 2,3-benzodiazepine Derivative EGIS-8332 Inhibits AMPA/kainate Ion Channels and Cell Death

Neurochemistry International. Feb, 2007  |  Pubmed ID: 17147974

We observed in vitro neuroprotective and AMPA/kainate receptor antagonist effects of the new 2,3-benzodiazepine derivative EGIS-8332 (R,S-1-(4-aminophenyl)-7,8-methylenedioxy-4-cyano-4-methyl-3-N-acetyl-5H-3,4-dihydro-2,3-benzodiazepine) using the lactate dehydrogenase (LDH) release assay and patch clamp recordings on primary cultures of rat embryonic telencephalon neurons exposed to AMPA/kainate receptor agonists. EGIS-8332 potently decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and quisqualate induced LDH release (IC(50)=5.2+/-0.4 and 7.4+/-1.3 microM, respectively) from the cells. Whole-cell patch clamp studies carried out on the ionotropic glutamate receptors N-methyl D-aspartate (NMDA), as well as AMPA (and kainate) in cultured telencephalon neurons verified that EGIS-8332 blocked steady state responses to AMPA and kainate (IC(50)=1.7+/-0.4 and 6.2+/-1.6 microM, respectively), but hardly influenced currents evoked by NMDA. EGIS-8332 also inhibited kainate-evoked response in CHO cells expressing the flop variant of GluR1 receptor and, in cerebellar Purkinje cells at similar efficiency. The stereoselectivity of the inhibitory site is established by the clearly dissimilar inhibitory potency of the enantiomer components of EGIS-8332 differing in the configuration of methyl and cyano substituents on carbon C(4): the R(-) enantiomer was found to be the efficient species. This finding suggests that the inhibitory interaction between the channel protein and drug is promoted by presence of the C(4) methyl group. The inhibition of the AMPA/kainate ion channels by EGIS-8332 is non-competitive, not use dependent, and depends neither on the closed/open state of the channel, nor the membrane potential. These findings suggest an allosteric mechanism for the inhibition. These in vitro observations suggest that the compound might be useful in the treatments of certain acute and chronic neurological syndromes initiated by derangements of ionotropic glutamate receptor function.

Rickettsia Rickettsii Infection Causes Apoptotic Death of Cultured Cerebellar Granule Neurons

Journal of Medical Microbiology. Jan, 2007  |  Pubmed ID: 17172530

Improvements in Mucopolysaccharidosis I Mice After Adult Retroviral Vector-mediated Gene Therapy with Immunomodulation

Molecular Therapy : the Journal of the American Society of Gene Therapy. May, 2007  |  Pubmed ID: 17311010

Mucopolysaccharidosis I (MPS I) is caused by deficient alpha-L-iduronidase (IDUA) activity and results in the accumulation of glycosaminoglycans and multisystemic disease. Gene therapy could program cells to secrete mannose 6-phosphate-modified IDUA, and enzyme in blood could be taken up by other cells. Neonatal retroviral vector (RV)-mediated gene therapy has been shown to reduce the manifestations of murine MPS I; however, intravenous injection of RV into adults was ineffective owing to a cytotoxic T lymphocyte (CTL) response against transduced cells. In this study, prolonged inhibition of CD28 signaling with CTLA4-Ig, or transient administration of CTLA4-Ig with an anti-CD40 ligand antibody or with an anti-CD4 antibody, resulted in stable expression in most mice that received RV as adults. Mice with stable expression had 81 +/- 41U/ml IDUA activity in serum. This resulted in reductions in bone disease, improvements in hearing and vision, and reductions in biochemical and pathological evidence of lysosomal storage in most organs. Improvements in brain were likely due to diffusion of enzyme from blood. However, aortic disease was refractory to treatment. This demonstrates that most manifestations of MPS I can be prevented using adult gene therapy if an immune response is blocked.

Influence of Autophagy Genes on Ion-channel-dependent Neuronal Degeneration in Caenorhabditis Elegans

Journal of Cell Science. Mar, 2007  |  Pubmed ID: 17327275

Necrotic cell death is a common feature in numerous human neurodegenerative disorders. In the nematode Caenorhabditis elegans, gain-of-function mutations in genes that encode specific ion channel subunits such as the degenerins DEG-1 and MEC-4, and the acetylcholine receptor subunit DEG-3 lead to necrotic-like degeneration of a subset of neurons. Neuronal demise caused by ion channel hyperactivity is accompanied by intense degradation of cytoplasmic contents, dramatic membrane infolding and vacuole formation; however, the cellular pathways underlying such processes remain largely unknown. Here we show that the function of three autophagy genes, whose yeast and mammalian orthologs are implicated in cytoplasmic self-degradation, membrane trafficking and the cellular response to starvation, contributes to ion-channel-dependent neurotoxicity in C. elegans. Inactivation of unc-51, bec-1 and lgg-1, the worm counterparts of the yeast autophagy genes Atg1, Atg6 and Atg8 respectively, partially suppresses degeneration of neurons with toxic ion channel variants. We also demonstrate that the TOR-kinase-mediated signaling pathway, a nutrient sensing system that downregulates the autophagy gene cascade, protects neurons from undergoing necrotic cell death, whereas nutrient deprivation promotes necrosis. Our findings reveal a role for autophagy genes in neuronal cell loss in C. elegans.

[The State of the Organized Screening in Hungary in 2006]

Orvosi Hetilap. Mar, 2007  |  Pubmed ID: 17350908

Hungary carries a heavy burden of cancer. At present, the organized screening of symptomless people seems to be the most promising strategy. According to the state-of-the art, those are the mammography-based breast screening, the cytology screening of cervix uteri, and the colorectal screening using immunochemical detection of the fecal occult blood satisfy the criteria of organized screening. The screening for cancers of the oral cavity, and the methods suitable for early detection of prostate cancer are not based on epidemiological evidence, therefore can only be applied opportunistically, as part of the medical practice. For the time belong, there are no suitable methods for detection of early lung cancer. The organized screening which applies personal call-and-recall has been incorporated in the National Public Health Programme. The concepts underlying the organized screening are fully in accordance with the recommendations by the European Union. The Chief Medical Officers' Office (OTH) is being charged with the organization, coordination and evaluation of organized screening programmes for the above screening modalities. In the past few years, an appropriate system for administration and information (including a country-wide screening registry) has been established, in addition to a regional coordination system based on the institutes of National Public Health and Medical Officers' Service (ANTSZ) and a nation-wide network of mammography and cytological laboratories, capable of meeting the requirements. This publication is to summarize the problems yet to be solved and the results expected from the organized screening programmes.

CD36 Deficiency Rescues Lipotoxic Cardiomyopathy

Circulation Research. Apr, 2007  |  Pubmed ID: 17363697

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARalpha (myosin heavy chain [MHC]-PPARalpha) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARalpha mice were crossed with CD36-deficient mice (MHC-PPARalpha/CD36-/- mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARalpha phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARalpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARalpha mice was unchanged in the CD36-deficient background. However, PPARalpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARalpha/ CD36-/- mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARalpha mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.

[The State of Organized Cervical Screening Program in Hungary in 2006]

Orvosi Hetilap. Mar, 2007  |  Pubmed ID: 17444018

Theoretically, there is a real prospect for full eradication of cervical cancer by cytology screening. In several countries the burden of cervical cancer significantly decreased due to regular screening of the population. In Hungary, the complex "gynecological screening", including colposcopic examination, has a long tradition, however, the efforts of several decades are not reflected in the mortality: about 500 women are killed by cervical cancer each year. The screening protocol represents a compromise between the traditional "gynecological screening" and the internationally recommended organized screening: taking sample for cytology is an essential element of the gynecological examination. The National Public Health Programme has established the technical and organizational preconditions of an organized screening programme. The early experiences with the "call-and-recall" organized screening -- started at the end of 2003 -- are unfavourable, because the compliance rates are unacceptably low. The majority of the women receive screening in a traditional way, i.e. outside the programme; another proportion of them simply ignores the invitation, and does not accept the offered screening. To improve the current situation, following the recommendation of "the-state-of-the-art", an attempt is made to intensify the involvement of the primary care personnel. There is a need to revise the current financing system by the political decision-makers in the health field. The access to the screening facilities needs to be improved, the attitude of the medical community changed, and the efficiency of the communication with the public significantly improved.

Association of Apolipoprotein E Polymorphism with Age-related Macular Degeneration and Alzheimer's Disease in South-western Hungary

Ideggyógyászati Szemle. Mar, 2007  |  Pubmed ID: 17451062

Age-related macular degeneration (AMD) and Alzheimer dementia (AD) show similarities (advanced age, formation of deposits of similar content). Recently apolipoprotein E 2 (apoE 2) has been associated with AMD, while apoE4 with AD. The question of coexistence, especially with respect to the genetic background has not been studied earlier. We investigated, therefore, the occurrence of AMD in AD patients and compared their lipid profile and apoE polymorphism.

Janus-faced Autophagy: a Dual Role of Cellular Self-eating in Neurodegeneration?

Autophagy. Sep-Oct, 2007  |  Pubmed ID: 17471017

Autophagy is a highly regulated cellular pathway used by eukaryotic cells to consume parts of their constituents during development or starvation. It is associated with extensive rearrangements of intracellular membranes, and involves the cooperation of many gene products in the regulation and execution phase by largely unknown mechanisms. Recent results strongly indicate the role of autophagy in the degradation of damaged macromolecules, in particular misfolded, aberrant proteins, and in organelle turnover; in mutant mice with reduced autophagy, accumulation of abnormal cytosolic proteins as inclusion bodies and massive cell loss occur similarly to human neurodegenerative disorders. Thus, autophagy seems to prevent neurons from undergoing protein aggregation-induced degeneration. In contrast, we have shown that inactivation of genes involved in autophagosome formation suppresses neuronal demise induced by various hyperactivating ion channel mutations or by neurotoxins in the nematode Caenorhabditis elegans. These results raise the possibility that autophagy may also contribute to excitotoxic necrotic-like cell death. This way, autophagic degradation of cytoplasmic materials might have a dual role in the survival of neurons. Depending on the actual cellular milieu and insulting factor, it can act both as a protector and contributor to neuronal damage.

[The State of the Organised Mammography Screening in Hungary in 2006]

Orvosi Hetilap. May, 2007  |  Pubmed ID: 17478403

Breast cancer represents a serious public health concern in Hungary. The most promising way of mortality reduction is organised screening which applies personal invitation, recall and follow-up. Screening women between 50-65 years of age by mammography combined with clinical breast examination is a method of proved effectiveness. The effectiveness has not yet been proved in premenopausal women, however, as a result of the public and professional pressure on decision-makers, perimenopausal women (above 45 years of age) are not excluded. In Hungary, the National Public Health Programme has established the managerial, administrative, legal and financial frame for an organised screening, therefore, since 2002, the programme has been in operation. Screening is provided in every other year. In the first two screening cycles, approximately 40% of invitees attended the screening test. According to the National Health Insurance Fund (OEP), under the influence of personal call-and-recall programme, the annual numbers of diagnostic mammography examinations have substantially increased, indicating that many invited women are looking for screening facility outside the programme. The detection rate and the small cancer detection rate are in line with the international standard values. To establish the number of "interval cancers", establishment of a pathological database ("patho-bank") is in progress, in close cooperation with the screening registry. According to the health economical analysis, the organised breast screening program is "affordable" for the financing agency.

[Is the Mass Screening for Prostate Cancer Justifiable?]

Orvosi Hetilap. Jul, 2007  |  Pubmed ID: 17588854

In Hungary, prostate cancer is a major public health problem, therefore screening should be considered to reduce the number of deaths. Screening tests are available, i.e. prostate-specific antigen (PSA) and digital-rectal examination, nevertheless their sensitivity, specificity and positive predictive value are far from being perfect. Evidences from non-randomized screening trials suggest possible benefit but randomized controlled trials are still needed for conclusive evidence. The screening might cause more harm than good due to overdiagnosis and overtreatment as a result of limited specificity of the test. According to authors' point of view, opportunistic screening as part of diagnostics of patients having symptoms indicative of prostatic disorder is fully justified but mass screening of population of average risk should not be introduced until supportive evidence is available from the ongoing randomized-controlled screening trials.

Sequestration Revisited: Integrating Traditional Electron Microscopy, De Novo Assembly and New Results

Autophagy. Nov-Dec, 2007  |  Pubmed ID: 17603297

Electron microscopy analysis of the autophagic sequestration membrane (SM) in various metazoan cell types after different fixation methods shows that: (1) the growing SM cannot derive from preformed rough surfaced endoplasmic reticulum (RER) membranes by transformation; (2) the empty cleft between the two layers of the SM after aldehyde fixation is an artifact of sample preparation; (3) the SM emerges from and grows de novo in cytoplasmic areas where membranous precursors cannot be identified by traditional electron microscopy; (4) the growing SM consists of two tightly packed membrane layers with a sharp bend at the edge; (5) changes in the environment of the growing SM participate in the determination of the size and shape of the autophagosome. We suggest that expansion as well as regression takes place at the edge of the growing SM. Stabilization and irreversibility of formation of the SM is achieved by closure. The immediate source of lipids for the SM must be in the cytoplasmic matrix, supposedly in the form of special phospholipid carrying vesicles that might involve the transmembrane Atg9 protein. To explain the apparent lack of such vesicles by electron microscopy we suggest that they are too small, have a similar density to other frequently occurring structures, or are destroyed during sample preparation.

[Oral Cancer Screening: How to Develop a Country-wide Opportunistic System in Hungary]

Orvosi Hetilap. Jul, 2007  |  Pubmed ID: 17604263

In Hungary, oral cancer represents a very heavy public health problem. Even epidemiological evidence in support of the effectiveness of organized screening for early detection does not exist, the efforts to detect the precancerous lesions and early cancers of oral cavity must be continued. The mass screening component of the National Public Health program provides a good opportunity for that. Following the Government decision, a multidisciplinary Working Group has been brought together, and a proposal made to develop a country-wide opportunistic system to regularly examine those at high risk for oral cancer. In addition to dentists, primary care personnel as well as the occupational health service have a lot to offer to the desired effect: reduction of mortality from oral cancer.

[Screening for Early Detection of Lung Cancer: Conflict Between Clinical and Public Health Viewpoints]

Orvosi Hetilap. Aug, 2007  |  Pubmed ID: 17702686

In Hungary, lung cancer, gradually increasing among women, is the leading cause of cancer mortality. The screening, using chest x-ray and sputum cytology as screening tool, does not reduce the mortality from lung cancer, therefore, screening for lung cancer is not recommended. The low-dose spiral CT is a sensitive and promising method, however, its specificity is far from being ideal. The results of the on-going RCTs are expected in a few years time, and so far it is not applicable for routine screening. In this country, the one-third of lung cancer cases are detected by the routine chest x-ray for tuberculosis, obligatory by law, and most of the detected cases are still resectable, but this does not have any influence on the mortality. According to our view, the detection of the lung cancer, particularly in those at high risk, is a by-product of periodic chest x-ray aiming at early detection of tuberculosis, however, mass screening for lung cancer as public health measure is not recommended. For the time being, the implementation of tobacco control measures is the only way to reduce the risk of lung cancer in the long run.

Autophagy Genes Unc-51 and Bec-1 Are Required for Normal Cell Size in Caenorhabditis Elegans

Genetics. Sep, 2007  |  Pubmed ID: 17890369

Here we show that in the nematode Caenorhabditis elegans mutational inactivation of two autophagy genes unc-51/atg1 and bec-1/atg6/beclin1 results in small body size without affecting cell number. Furthermore, loss-of-function mutations in unc-51 and bec-1 suppress the giant phenotype of mutant animals with aberrant insulin-like growth factor-1 (insulin/IGF-1) or transforming growth factor-beta (TGF-beta) signaling. This function for unc-51 and bec-1 in cell size control and their interaction with these two growth modulatory pathways may represent a link between the hormonal and nutritional regulation of cell growth.

[The Undesirable, Psychologically Adverse Effects of Screening]

Orvosi Hetilap. Sep, 2007  |  Pubmed ID: 17766222

The psychological adverse effects might play an important role in the non-compliance with the offered screening examination. The possible sources of them are three-fold: 1. The general human attitude, such as the rejection of health interventions, particularly those aiming at the prevention of eventual future health problems instead of handling existing complaints and symptoms at present; the screening can be seen as a "future-oriented" intervention. 2. The cultural image of cancer and the disbelief of its curability. 3. The subjective experiences in relation to the screening process. The providers have to do their best to eliminate these causes: by means of a) health education addressing people of various ages, social classes and cultural levels, promoting the understanding of the importance of disease prevention, and, changing their negative, defeatist attitude towards cancer; b) minimizing the psychological adverse effects of all kinds. This can be done by proper organisation of the screening process; optimizing the quality of work, and, provision of good quality of information and advice to the screenees before, during and after the screening.

[The State of the Colorectal Screening in Hungary: Lessons of the Pilot Programs]

Orvosi Hetilap. Sep, 2007  |  Pubmed ID: 17872333

In Hungary, colorectal cancer is the second most common malignant disease. Due to its natural history, colorectal cancer is particularly suitable for screening. At present, epidemiological evidences of the effectiveness of detection of the symptomless colorectal cancer and its precursors are only available for the demonstration of fecal occult blood, endoscopic methods are also in use. For mass screening, fecal occult blood tests are recommended. Guaiac-type chemical methods are widely criticized because of the lack of specificity. Out of the emerging technologies, immunochemical methods based on the antigenicity of blood proteins (hemoglobin) seem to be the most suitable. In the model programmes organized in the frame of the National Public Health Programme, an immunochemical method using two blood proteins (hemoglobin and albumin) have been used. The compliance was not more than 30-45%. About one-third of those with positive blood test refused colonoscopy. The programmes revealed a great number of adenomatous polyps and early cancers, and in the way, the effectiveness of the method has been proved. The model programmes are still continued. Before the continuous and gradual extension of colorectal screening, the validity of the specific method needs to be tested and proved in order to be recognized as a routine procedure for screening. There is a need to test the feasibility of total colonoscopy, however, to this effect the colonoscopic capacity in the country has to be further developed.

[The Coverage of Cervical Screening in Hungary]

Orvosi Hetilap. Nov, 2007  |  Pubmed ID: 17988975

The purpose of this study is to calculate the proportion of women having cytological examination (Pap smear) of cervix either within or outside of the Hungarian organized cervical cancer screening programme.

Contact Angle Determination of Nanoparticles: Film Balance and Scanning Angle Reflectometry Studies

Physical Chemistry Chemical Physics : PCCP. Dec, 2007  |  Pubmed ID: 18060166

Stöber silica nanoparticles of diameter about 45, 60 and 100 nm and different hydrophobicity are used to produce monolayers at a water-air interface. Both the surface pressure-area isotherms and the reflectivity angle of incidence curves of the layers have been measured in a Wilhelmy film balance. The contact angle of the as-prepared particles have been determined from the isotherms by two different evaluation methods, and compared to those obtained from in situ scanning angle reflectometry (SAR) measurements. SAR is proved to be an effective tool for the estimation of contact angles on nanoparticles of different wettability, using a modified version of the previously published gradient layer model (E. Hild, T. Seszták, D. Völgyes and Z. Hórvölgyi, Prog. Colloid Polym. Sci., 2004, 125, 61, ref. 1) for evaluation. The results are in fairly good agreement with those determined from the non-dissipative part of the isotherms of the as prepared particles, assuming a weakly cohesive film model (S. Bordács, A. Agod and Z. Hórvölgyi, Langmuir, 2006, 22, 6944, ref. 2). It seems that the traditional way to calculate the contact angle from the film balance experiments (J.H. Clint and N. Quirke, Colloids Surf., A, 1993, 78, 277, ref. 3) results in unreasonably high contact angles for the investigated systems and the homogeneous layer optical model gives unrealistic film thickness values in the case of hydrophobic particles.

Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy in Higher Eukaryotes

Autophagy. Feb, 2008  |  Pubmed ID: 18188003

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

Longevity Pathways Converge on Autophagy Genes to Regulate Life Span in Caenorhabditis Elegans

Autophagy. Apr, 2008  |  Pubmed ID: 18219227

Aging is a multifactorial process with many mechanisms contributing to the decline. Mutations decreasing insulin/IGF-1 (insulin-like growth factor-1) or TOR (target of rapamycin) kinase-mediated signaling, mitochondrial activity and food intake each extend life span in divergent animal phyla. Understanding how these genetically distinct mechanisms interact to control longevity is a fundamental and fascinating problem in biology. Here we show that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans. According to our results Drosophila flies deficient in autophagy are also short-lived. We further demonstrate that reduced activity of autophagy genes suppresses life span extension in mutant nematodes with inherent dietary restriction, aberrant insulin/IGF-1 or TOR signaling, and lowered mitochondrial respiration. These findings suggest that the autophagy gene cascade functions downstream of and is inhibited by different longevity pathways in C. elegans, therefore, their effects converge on autophagy genes to slow down aging and lengthen life span. Thus, autophagy may act as a central regulatory mechanism of animal aging.

Regulation of Cell Growth by Autophagy

Autophagy. May, 2008  |  Pubmed ID: 18259117

Cell growth-the primary determinant of cell size-has an intimate relationship with proliferation; cells divide only after they reach a critical size. Despite its developmental and medical significance, little is known about cellular pathways that mediate the growth of cells. Accumulating evidence demonstrates a role for autophagy-a mechanism of eukaryotic cells to digest their own constituents during development or starvation-in cell size control. Increasing autophagic activity by prolonged starvation, rapamycin treatment inhibiting TOR (target of rapamycin) signaling, or genetic intervention, causes cellular atrophy in worms, flies and mammalian cell cultures. In contrast, we have shown that in the nematode Caenorhabditis elegans mutational inactivation of two autophagy genes, unc-51/Atg1 and bec-1/Atg6, confers reduced cell size. We argue that physiological levels of autophagy are required for normal cell size, whereas both insufficient and excessive levels of autophagy lead to retarded cell growth. Furthermore, we discuss data suggesting that the insulin/IGF-1 (insulin-like growth factor receptor-1) and TGF-beta (transforming growth factor-beta) signaling systems acting as major growth regulatory pathways converge on autophagy genes to control cell size. Thus, autophagy may act as a central regulatory mechanism of cell growth.

A Theoretical Study of AmOn and CmOn (n = 1, 2)

Physical Chemistry Chemical Physics : PCCP. Feb, 2008  |  Pubmed ID: 18270612

Americium and curium oxides AmOn and CmOn (n = 1, 2) were studied using state-of-the-art multiconfigurational, relativistic, quantum chemical methods. Spectroscopic properties for the ground state and several excited states of the four target compounds were determined. The computed dissociation energy of AmO (4.6 eV) agrees fairly well with estimates derived from experimental studies (5.73 +/- 0.37 eV) while the computed dissociation energy of CmO (7.1 eV) agrees well with the experimental value (7.5 eV). The computed ionization energy of AmO (6.3 eV) is in good agreement with the current experimental value (5.9 +/- 0.2 eV).

Bacillus Aurantiacus Sp. Nov., an Alkaliphilic and Moderately Halophilic Bacterium Isolated from Hungarian Soda Lakes

International Journal of Systematic and Evolutionary Microbiology. Apr, 2008  |  Pubmed ID: 18398180

Three alkaliphilic and moderately halophilic strains designated K1-5T, K1-10 and B1-1, characterized by optimal growth at pH 9.0-10.0 and at 3-7 % (w/v) NaCl, were isolated from extremely shallow, alkaline soda lakes located in Hungary. Cells of the strains are Gram-positive, straight rods and form a central to subterminal, ellipsoidal endospore. The isolates are strictly aerobic, catalase-positive, oxidase-negative and contain a peptidoglycan of type A1 gamma based on meso-diaminopimelic acid. In strain K1-5T, menaquinone-7 (MK-7) is the predominant isoprenoid quinone and anteiso-C15 : 0 is the major cellular fatty acid. The DNA G+C content of strain K1-5T is 42.9 mol%. 16S rRNA gene-based phylogenetic analysis revealed that the strains exhibit levels of sequence similarity of less than 95.8 % to known Bacillus species. According to the polyphasic characterization, the strains represent a novel species, for which the name Bacillus aurantiacus sp. nov. is proposed. The type strain is K1-5T (=DSM 18675T =CCM 7447T =NCAIM B002265T).

Wohlfahrtiimonas Chitiniclastica Gen. Nov., Sp. Nov., a New Gammaproteobacterium Isolated from Wohlfahrtia Magnifica (Diptera: Sarcophagidae)

International Journal of Systematic and Evolutionary Microbiology. Apr, 2008  |  Pubmed ID: 18398205

New Gammaproteobacteria were isolated from 3rd stage fly larvae of the parasitic fly Wohlfahrtia magnifica. Phylogenetic analysis of the new isolates showed that these bacteria belong to a distinct lineage close to Ignatzschineria larvae, which was originally isolated from the same species of fly. The low similarity values in 16S rRNA gene sequences (93.8-94.8 %), and differences in fatty acid profiles, RiboPrint patterns, MALDI-TOF mass spectra of cell extracts, and physiological and biochemical characteristics differentiate the isolates from the type strain of Ignatzschineria larvae (DSM 13226T), and indicate that our isolates represent a new genus within the Gammaproteobacteria. The major isoprenoid quinone of the strains is Q8, the major fatty acids are C18 : 1 and C14 : 0, and the predominant polar lipids are phosphatidylglycerol, phosphatidylethanolamine and phosphatidylserine. The G+C content of the DNA of the type strain is 44.3 mol%. The name Wohlfahrtiimonas chitiniclastica gen. nov., sp. nov., is proposed for this novel genus and species. The type strain is S5T (=DSM 18708T=CCM 7401T).

Vibrational Analysis of N-acetyl-alpha-D-glucosamine and Beta-D-glucuronic Acid

The Journal of Physical Chemistry. B. May, 2008  |  Pubmed ID: 18412409

Infrared spectra of solid and aqueous solutions of N-acetyl-alpha-D-glucosamine and beta-D-glucuronic acid have been investigated by means of Fourier transform infrared (FT-IR) spectroscopy and quantum chemical density functional theory (DFT) calculations. The errors of the computed harmonic force field were corrected according to the scaled quantum mechanical (SQM) method of Pulay, with scale factors partly from the literature and partly developed here. Scale factors for the hydrogen-bonded OH groups were determined by SQM treatment of ethylene glycol. The IR spectra and test computations revealed that beta-D-glucuronic acid is present as a dimer, formed by hydrogen-bonding between the COOH groups, in the solid phase. On the basis of the calculated results, 64 and 56 bands in the 4000-50 cm(-1) range of the FT-IR spectra have been assigned for N-acetyl-alpha-D-glucosamine and beta-D-glucuronic acid, respectively.

Upregulation of Elastase Proteins Results in Aortic Dilatation in Mucopolysaccharidosis I Mice

Molecular Genetics and Metabolism. Jul, 2008  |  Pubmed ID: 18479957

Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to alpha-L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

Intimal Flap Movement in Aortic Stanford Type-A Dissection Visualized by 64-slice Computed Tomography

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Aug, 2008  |  Pubmed ID: 18524613

FT-IR and Theoretical Study of 3,5-dimethyl-1H-pyrazole-1-carboxamidine (L) and the Complexes CoL2(H2O)2(NO3)2, NiL2(H2O)2(NO3)2

Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. Dec, 2008  |  Pubmed ID: 18562246

In the paper a joint experimental and theoretical study of 3,5-dimethyl-1H-pyrazole-1-carboxamidine (L) as well as its complexes CoL2(H2O)2(NO3)2 and NiL2(H2O)2(NO3)2 is reported. On the basis of FT-IR experiments and a DFT-derived scaled quantum mechanical force field the normal coordinate analysis of L was carried out. The FT-IR spectra of the two complexes were interpreted using the present assignment of L and computed vibrational data of the complexes. The ionic and charge transfer interactions in the complexes were assessed by means of natural bond orbital (NBO) analysis.

Hedgehog Signaling is Critical for Maintenance of the Adult Coronary Vasculature in Mice

The Journal of Clinical Investigation. Jul, 2008  |  Pubmed ID: 18568073

Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of HH signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure, and subsequent lethality. We further showed that HH signaling specifically controlled the survival of small coronary arteries and capillaries. Together, these data demonstrate that HH signaling is essential for cardiac function at the level of the coronary vasculature and caution against the use of HH antagonists in patients with prior or ongoing heart disease.

Improved Retroviral Vector Design Results in Sustained Expression After Adult Gene Therapy in Mucopolysaccharidosis I Mice

The Journal of Gene Medicine. Sep, 2008  |  Pubmed ID: 18613275

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to alpha-L-iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Gene therapy can reduce most clinical manifestations, but mice that receive transfer as adults lose expression unless they receive immunosuppression. Increasing liver specificity of transgene expression has reduced immune responses to other genes.

Transcriptional Coactivators PGC-1alpha and PGC-lbeta Control Overlapping Programs Required for Perinatal Maturation of the Heart

Genes & Development. Jul, 2008  |  Pubmed ID: 18628400

Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPARgamma coactivator-1 (PGC-1) alpha and beta have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1alpha and PGC-1beta (PGC-1alphabeta(-/-) mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1beta(-/-) mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1alpha(-/-) mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1alphabeta(-/-) mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1beta gene on a PGC-1alpha-deficient background phenocopied the generalized PGC-1alphabeta(-/-) mice. The hearts of the PGC-1alphabeta(-/-) mice exhibited signatures of a maturational defect including reduced growth, a late fetal arrest in mitochondrial biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue (BAT) of PGC-1alphabeta(-/-) mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1alpha and PGC-1beta share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.

Time Course of Alterations in Myocardial Glucose Utilization in the Zucker Diabetic Fatty Rat with Correlation to Gene Expression of Glucose Transporters: a Small-animal PET Investigation

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Aug, 2008  |  Pubmed ID: 18632819

Diabetic cardiomyopathy is associated with abnormalities in glucose metabolism. We evaluated myocardial glucose metabolism in a rodent model of type 2 diabetes, namely the Zucker diabetic fatty (ZDF) rat, and validated PET measurements of glucose uptake against gene and protein expression of glucose transporters (GLUTs).

Embolization of Varicocles: Pretreatment Sperm Motility Predicts Later Pregnancy in Partners of Infertile Men

Radiology. Aug, 2008  |  Pubmed ID: 18641252

To identify predictors of future pregnancy in partners of infertile men undergoing embolization of varicoceles.

[Attendance in the Second Phase (2004-2005) of the Hungarian Organized Breast Cancer Screening Program]

Orvosi Hetilap. Aug, 2008  |  Pubmed ID: 18672438

Organised, nationwide screening for breast cancer with mammography in the age group of 45-65 years with a 2-year screening interval started in Hungary in January 2002. The aim of this study is to analyze the attendance rate of breast screening programme, including the analysis of the ratio of screening and diagnostic mammography examinations.

A Murine Model of Infantile Neuronal Ceroid Lipofuscinosis-ultrastructural Evaluation of Storage in the Central Nervous System and Viscera

Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. May-Jun, 2008  |  Pubmed ID: 17990914

Infantile neuronal ceroid lipofuscinosis (INCL), also known as Santavuori-Haltia disease, is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the lysosomal enzyme palmitoyl-protein-thioesterase-1 (PPT1). Fatty acid-modified proteins are not degraded and accumulate as granular osmiophilic deposits in cells in the central nervous system; patients have blindness, seizures, progressive psychomotor deterioration, and die in early childhood. Although the disease manifests clinically primarily with neurological symptoms, visceral storage also accumulates. A murine model of INCL due to PPT1 deficiency exhibits clinical findings and pathology similar to those seen in patients with INCL. Homozygous PPT1-deficient mice have a shortened life span and neurological abnormalities including seizures, blindness, and mental and motor deficits. Widespread granular osmiophilic deposits (GRODs) accumulate in lysosomes in neurons and glia in the brain, retinal cells, kidney glomerular cells, aortic smooth muscle cells, and, in lesser amounts, in the fixed-tissue macrophage system. Accumulation of GRODs in aortic smooth muscle cells is accompanied by abnormalities in cardiac function and aortic root dilatation. This PPT1-deficient murine model is a well-defined genetic system that can be used to test potential therapies for lysosomal storage disease and to study the pathophysiology of INCL.

Attenuation of AMPA Receptor Activity Improves Motor Skills in a Mouse Model of Juvenile Batten Disease

Experimental Neurology. Jan, 2008  |  Pubmed ID: 17963751

Juvenile Batten disease, caused by mutations in the CLN3 gene, is a fatal, incurable neurodegenerative disorder in children. The Cln3-loss-of-function (Cln3(Deltaex1-6)) mouse model of the disease exhibits many characteristic pathological features of the human disorder including a deficit in motor skills. Our recent findings [Kovács, A.D., Weimer, J.M., Pearce, D.A., 2006. Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease. Neurobiol. Dis. 22, 575-585] suggested that the neurological deficit in the Cln3(Deltaex1-6) mouse model of the disease might result from an abnormally increased AMPA receptor activity in the cerebellum. Therefore, we tested if administration of low doses of an AMPA receptor antagonist, that attenuate AMPA receptor function but avoid a toxic, complete blockade of the receptor, have beneficial effects in Cln3(Deltaex1-6) mice. Here we show that attenuation of AMPA receptor activity by a single intraperitoneal injection of the non-competitive AMPA antagonist, EGIS-8332 (1 mg/kg), significantly improves the motor skills of Cln3(Deltaex1-6) mice. Our results provide a new, promising therapeutic approach for juvenile Batten disease.

Transfer of Movement Sequences: Bigger is Better

Acta Psychologica. Feb, 2008  |  Pubmed ID: 17723220

Experiment 1 was conducted to determine if proportional transfer from "small to large" scale movements is as effective as transferring from "large to small." We hypothesize that the learning of larger scale movement will require the participant to learn to manage the generation, storage, and dissipation of forces better than when practicing smaller scale movements. Thus, we predict an advantage for transfer of larger scale movements to smaller scale movements relative to transfer from smaller to larger scale movements. Experiment 2 was conducted to determine if adding a load to a smaller scale movement would enhance later transfer to a larger scale movement sequence. It was hypothesized that the added load would require the participants to consider the dynamics of the movement to a greater extent than without the load. The results replicated earlier findings of effective transfer from large to small movements, but consistent with our hypothesis, transfer was less effective from small to large (Experiment 1). However, when a load was added during acquisition transfer from small to large was enhanced even though the load was removed during the transfer test. These results are consistent with the notion that the transfer asymmetry noted in Experiment 1 was due to factors related to movement dynamics that were enhanced during practice of the larger scale movement sequence, but not during the practice of the smaller scale movement sequence. The findings that the movement structure is unaffected by transfer direction but the movement dynamics are influenced by transfer direction is consistent with hierarchal models of sequence production.

Qualitative and Quantitative Characterization of Autophagy in Caenorhabditis Elegans by Electron Microscopy

Methods in Enzymology. 2008  |  Pubmed ID: 19185736

Caenorhabditis elegans has been introduced relatively late into the field of autophagy with no previous results by classical methods. Therefore, it has to be studied in parallel with both traditional electron microscopy and modern molecular approaches. In general, correct identification of autophagic elements by electron microscopy is indispensable to establish a firm basis for our understanding of the process. The principles and the method for identification, applied also for C. elegans, are summarized first in this article, to facilitate their utilization both for further studies and the analysis of new cell types and to support researchers new to electron microscopy techniques. Studying autophagy in the worm by electron microscopy has required the development of special handling and sampling techniques in addition to overcoming the general technical difficulties due to the nature of C. elegans samples. These are described in detail, together with some initial qualitative and quantitative results obtained by them. The feasibility of the presented method is supported by data which show that in continuously fed worms the autophagic compartment is in the lower range of the 10(-2)% order of magnitude of the cytoplasmic volume, while immediately after molting or upon starvation in the second larval period, usually more than a 10-fold increase can be measured. In dauer larvae, individual variation of the autophagic compartment is very high. The predauer stage in daf-2 mutants does not seem to show significant constitutive autophagic activity. Some autophagy-related gene mutants show characteristic ultrastuctural features, such as autophagosomes with membrane abnormalities (unc-51/Atg1) or the hypertrophy of multivesicular bodies (let-512/Vps34, bec-1/Atg6).

Autophagy in Caenorhabditis Elegans

Methods in Enzymology. 2008  |  Pubmed ID: 19185738

Autophagy (cellular self-eating) is a highly regulated, lysosome-mediated catabolic process of eukaryotic cells to segregate by a special membrane and subsequently degrade their own constituents during development or starvation. Electron microscopy analysis reveals autophagic elements in various cell types of the nematode Caenorhabditis elegans, whose genome contains counterparts of several yeast genes involved in autophagy. Genetic manipulation inactivating autophagy-related genes in C. elegans causes defects in development, affects dauer larval morphogenesis, accelerates aging thereby shortening life span, reduces cell size, decreases survival during starvation, promotes apoptotic cell death, and protects neurons from undergoing hyperactive ion channel- or neurotoxin-induced degeneration. These results implicate autophagy in various developmental and cellular functions such as reproductive growth, aging, and cell growth, as well as cell survival and loss. This chapter discusses methods of inactivating C. elegans autophagy genes by RNA interference, testing the resistance of autophagy-deficient nematodes to starvation-induced stress, handling mutants carrying a deletion in the autophagy pathway, and monitoring autophagic activity by using LysoTracker Red dye or reporters labeled with green fluorescent protein. Such methods may be adaptable to identify additional roles of autophagy in development and cellular function, and may also help to detect the intracellular accumulation of autophagy proteins and monitor autophagosome formation.

The Coding and Effector Transfer of Movement Sequences

Journal of Experimental Psychology. Human Perception and Performance. Apr, 2009  |  Pubmed ID: 19331496

Three experiments utilizing a 14-element arm movement sequence were designed to determine if reinstating the visual-spatial coordinates, which require movements to the same spatial locations utilized during acquisition, results in better effector transfer than reinstating the motor coordinates, which require the same pattern of homologous muscle activation. Results demonstrated better transfer when visual-spatial coordinates were reinstated than when motor coordinates where reinstated regardless of the amount of practice (1, 4, or 12 days; Experiments 1-3, respectively). Transfer (left to right and right to left) was symmetric when visual-spatial coordinates were reinstated but not when motor coordinates were reinstated. When motor coordinates were reinstated after 12 days of practice and vision occluded, transfer was better from right limb to left than vice versa. The data are also consistent with the notion that multiple codes (visual, spatial, and motor) are developed over practice, with each contributing to transfer performance when the respective coordinates are reinstated. Further, the results indicate a disruption of the linkage (concatenation) between subsequences when one or more coordinates are changed on the transfer test.

Reduced Vessel Elasticity Alters Cardiovascular Structure and Function in Newborn Mice

Circulation Research. May, 2009  |  Pubmed ID: 19372465

Elastic blood vessels provide capacitance and pulse-wave dampening, which are critically important in a pulsatile circulatory system. By studying newborn mice with reduced (Eln(+/)(-)) or no (Eln(-)(/)(-)) elastin, we determined the effects of altered vessel elasticity on cardiovascular development and function. Eln(-)(/)(-) mice die within 72 hours of birth but are viable throughout fetal development when dramatic cardiovascular structural and hemodynamic changes occur. Thus, newborn Eln(-)(/)(-) mice provide unique insight into how a closed circulatory system develops when the arteries cannot provide the elastic recoil required for normal heart function. Compared with wild type, the Eln(-)(/)(-) aorta has a smaller unloaded diameter and thicker wall because of smooth muscle cell overproliferation and has greatly reduced compliance. Arteries in Eln(-)(/)(-) mice are also tortuous with stenoses and dilations. Left ventricular pressure is 2-fold higher than wild type, and heart function is impaired. Newborn Eln(+/)(-) mice, in contrast, have normal heart function despite left ventricular pressures 25% higher than wild type. The major vessels have smaller unloaded diameters and longer lengths. The Eln(+/)(-) aorta has additional smooth muscle cell layers that appear in the adventitia at or just before birth. These results show that the major adaptive changes in cardiovascular hemodynamics and in vessel wall structure seen in the adult Eln(+/)(-) mouse are defined in late fetal development. Together, these results show that reduced elastin in mice leads to adaptive remodeling, whereas the complete lack of elastin leads to pathological remodeling and death.

Inter-manual Transfer and Practice: Coding of Simple Motor Sequences

Acta Psychologica. Jun, 2009  |  Pubmed ID: 19389659

Previous research suggests that movements are represented early in practice in visual-spatial coordinates/codes, which are effector independent, and later in practice in motor coordinates/codes (e.g., joint angles, activation patterns), which are effector dependent. In the present experiments, the task was to reproduce 1.3 s patterns of elbow flexions and extensions. An inter-manual transfer paradigm was used in Experiment 1 and an inter-manual practice paradigm was used in Experiment 2. The present results clearly indicated a strong advantage of effector transfer when the motor coordinates available during acquisition were reinstated (Experiment 1) and demonstrate that inter-manual practice with the same motor coordinates results in enhanced retention performance relative to transfer and practice where the same visual-spatial coordinates are used. These results demonstrate that the more effective movement code (motor or visual-spatial) is dependent on the movement sequence characteristics (e.g., difficulty, number of elements, and mode of control [preplanned or on-line]). These results are also interesting because they indicate, contrary to previous findings with more complex movement sequences, that an effective motor code can be developed relatively early in practice for rapid movement sequences.

Vibrational Analysis of Alpha-D-glucose Trapped in Ar Matrix

The Journal of Physical Chemistry. B. Feb, 2009  |  Pubmed ID: 19408405

The FT-IR spectra of alpha-D-glucose have been investigated by means of matrix-isolation FT-IR spectroscopy in the 3700-200 cm-1 range and by B3LYP/6-311++G** density functional calculations. The joint analysis of the experimental and computed IR spectra supported the expected predominance of the most stable gg and gt conformers in the vapor phase and the minor contribution of the less stable tg conformer. Weak absorption bands at the edge of the OH stretching region are in agreement with small amounts of analogous conformers with clockwise arrangement of the hydrogen bonds (c-gg, c-gt, c-tg). The assignment of the IR spectra was carried out on the basis of the computed harmonic force field using the scaled quantum mechanical method of Pulay. Scale factors developed previously for the B3LYP/6-311++G** level proved to be well transferable except that for the OH torsion. The latter scale factor was adjusted on the basis of the present experimental data. On the basis of the calculated results, 99 bands have been assigned to the gg, gt, and tg conformers of alpha-D-glucose with average deviations of 5.0, 5.9, and 6.1 cm-1, respectively.

Using Scanning Trials to Assess Intrinsic Coordination Dynamics

Neuroscience Letters. May, 2009  |  Pubmed ID: 19429113

Bimanual 1:1 coordination patterns other than in-phase (0 degrees ) and anti-phase (180 degrees ) have proven difficult to perform even with extended practice. The difficulty has been attributed to phase attraction that draws the coordination between the limbs towards the bimanual patterns of in-phase and anti-phase and variability associated with the activation of non-homologous muscles via crossed and uncrossed cortical pathways. We found participants could very effectively produce a large range of supposedly unstable coordination patterns (between 0 degrees and 180 degrees in 30 degrees increments) after only 3 min of practice when integrated feedback (Lissajous plots) was provided and other perceptual and attentional distractions were minimized. These findings clearly indicate that the perception-action system is fully capable of producing a wide range of bimanual coordination patterns and that the reason for the failure to produce these patterns in previous experiments reside in the perceptual information and attentional requirements typically found in experimental testing environments.

[Efficacy and Safety of Ezetimibe/simvastatin Combination Therapy in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease]

Orvosi Hetilap. May, 2009  |  Pubmed ID: 19443308

Nonalcoholic fatty liver disease is commonly associated with type 2 diabetes, dyslipidemia and obesity all of which are components of the metabolic syndrome.

Conformational Properties of the Disaccharide Building Units of Hyaluronan

Carbohydrate Research. Sep, 2009  |  Pubmed ID: 19559407

The conformational space of the disaccharide building units of hyaluronan, beta-(1-->4) and beta-(1-->3)-linked N-acetyl-beta-d-glucosamine (GN) and beta-D-glucuronic acid (GA), has been investigated by density functional theory calculations at the B3LYP/6-31G(**) level. The study covered the anionic disaccharides, the neutral acids as well as the sodium salts in the isolated state and in aqueous solution using the PCM model approach. We elucidated the intramolecular hydrogen bonding interactions characterizing the most favoured conformers. The protonation and salt formation change these secondary interactions in the vicinity of the carboxyl group, resulting often in a considerable alteration of the conformational preferences. The Na(+) ion in the salt is involved in multiple bonding in the most stable structures: beyond the primary ionic bond with the carboxylate group it forms slightly weaker interactions with neighbouring oxygens. The main effect of protonation and salt formation on the electron density distribution is restricted to the surroundings of the broken/formed interactions near the carboxylate group.

Differences in the Expression of Histamine-related Genes and Proteins in Normal Human Adrenal Cortex and Adrenocortical Tumors

Virchows Archiv : an International Journal of Pathology. Aug, 2009  |  Pubmed ID: 19568768

Histamine is involved in the pathogenesis of several tumors; however, there are no data on its possible involvement in human adrenocortical tumorigenesis. The expression of genes and proteins involved in the biosynthesis (histidine decarboxylase, HDC), action (histamine receptors: HRH1-HRH4), and metabolism of histamine is largely unknown both in the normal human adrenal cortex and in adrenocortical tumors. In this study, we examined the expression of histamine-related genes and proteins and histamine content in normal adrenal cortex, benign adrenocortical adenomas, and malignant adrenocortical cancer (ACC). Fifteen normal adrenals and 43 tumors were studied. mRNA expression was examined by real time RT-PCR. Western-blotting and immunohistochemistry were used for the study of proteins. Tissue histamine content was determined by enzyme-linked immunosorbent assay. We found that all proteins involved in histamine biosynthesis and action are present both in the normal adrenal cortex and in the tumors studied. HDC expression and histamine content was highest in the normal tissues and lower in benign tumors, whereas it was significantly less in ACCs. HRH3 expression was significantly higher in ACC samples than in the other groups. Adrenocortical tumorigenesis might, thus, be characterized by reduced histamine biosynthesis; furthermore, different adrenocortical tumor subtypes may show unique histamine receptor expression profiles.

Representation of Movement Sequences is Related to Task Characteristics

Acta Psychologica. Sep, 2009  |  Pubmed ID: 19631919

Recent experiments have produced mixed results in terms of performance when, after learning a sequential task, the same visual-spatial coordinates or the same motor coordinates were reinstated on a subsequent effector transfer test. Given the diversity of tasks and especially sequence characteristics used in previous experiments, the cross-experimental comparison makes inferences and unambiguous interpretations difficult. The purpose of the present experiment was to determine in a principled manner how the spatio-temporal structure of a sequence influences the way the sequence is represented. The results indicated that after limited amount of practice relatively more simple sequences (S1) are coded more efficiently in a mirror (motor) representation which requires the same pattern of homologous muscle activation. Conversely, relatively more complex sequences (S2) are more efficiently coded in a visual-spatial coordinate system which requires movements to the same spatial locations as during acquisition. The data are also consistent with the notion that sequences with different spatio-temporal structures rely to a different degree on distinct control mechanisms (pre-planned vs. on-line, respectively).

Impaired Contractile Function and Calcium Handling in Hearts of Cardiac-specific Calcineurin B1-deficient Mice

American Journal of Physiology. Heart and Circulatory Physiology. Oct, 2009  |  Pubmed ID: 19700627

To define the necessity of calcineurin (Cn) signaling for cardiac maturation and function, the postnatal phenotype of mice with cardiac-specific targeted ablation of the Cn B1 regulatory subunit (Ppp3r1) gene (csCnb1(-/-) mice) was characterized. csCnb1(-/-) mice develop a lethal cardiomyopathy, characterized by impaired postnatal growth of the heart and combined systolic and diastolic relaxation abnormalities, despite a lack of structural derangements. Notably, the csCnb1(-/-) hearts did not exhibit diastolic dilatation, despite the severe functional phenotype. Myocytes isolated from the mutant mice exhibited reduced rates of contraction/relaxation and abnormalities in calcium transients, consistent with altered sarcoplasmic reticulum loading. Levels of sarco(endo) plasmic reticulum Ca-ATPase 2a (Atp2a2) and phospholamban were normal, but phospholamban phosphorylation was markedly reduced at Ser(16) and Thr(17). In addition, levels of the Na/Ca exchanger (Slc8a1) were modestly reduced. These results define a novel mouse model of cardiac-specific Cn deficiency and demonstrate novel links between Cn signaling, postnatal growth of the heart, pathological ventricular remodeling, and excitation-contraction coupling.

The Enterprise Stent for the Treatment of Intracranial Aneurysms: Stenting Strategies

Klinische Neuroradiologie. Aug, 2009  |  Pubmed ID: 19705074

Self-expanding microstents are typically placed before a wide-necked aneurysm is filled with coils. Alternatively, the stent may be placed at the end of the procedure, when the coil mass blocks or slows down the flow in the parent artery or a branching vessel.

Safety and Efficacy of Combined Ezetimibe/simvastatin Treatment and Simvastatin Monotherapy in Patients with Non-alcoholic Fatty Liver Disease

Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. Dec, 2009  |  Pubmed ID: 19946244

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases all over the world. In patients with a high cardiovascular risk the decrease of cholesterol level is especially important. The primary goal of this study is to observe the safety and efficacy of combined ezetimibe / simvastatin treatment and simvastatin monotherapy in patients with NAFLD and high cardiovascular risk disease. The secondary goal of this investigation was to compare the safety and efficacy of combined ezetimibe / simvastatin treatment with simvastatin monotherapy.

Ca2+-independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy

Circulation Research. Jan, 2009  |  Pubmed ID: 19023131

Previous studies demonstrated increased fatty acid uptake and metabolism in MHC-FATP transgenic mice that overexpress fatty acid transport protein (FATP)1 in the heart under the control of the alpha-myosin heavy chain (alpha-MHC) promoter. Doppler tissue imaging and hemodynamic measurements revealed diastolic dysfunction, in the absence of changes in systolic function. The experiments here directly test the hypothesis that the diastolic dysfunction in MHC-FATP mice reflects impaired ventricular myocyte contractile function. In vitro imaging of isolated adult MHC-FATP ventricular myocytes revealed that mean diastolic sarcomere length is significantly (P<0.01) shorter than in wild-type (WT) cells (1.79+/-0.01 versus 1.84+/-0.01 microm). In addition, the relaxation rate (dL/dt) is significantly (P<0.05) slower in MHC-FATP than WT myocytes (1.58+/-0.09 versus 1.92+/-0.13 microm/s), whereas both fractional shortening and contraction rates are not different. Application of 40 mmol/L 2,3-butadionemonoxime (a nonspecific ATPase inhibitor that relaxes actin-myosin interactions) increased diastolic sarcomere length in both WT and MHC-FATP myocytes to the same length, suggesting that MHC-FATP myocytes are partially activated at rest. Direct measurements of intracellular Ca(2+) revealed that diastolic [Ca(2+)](i) is unchanged in MHC-FATP myocytes and the rate of calcium removal is unexpectedly faster in MHC-FATP than WT myocytes. Moreover, diastolic sarcomere length in MHC-FATP and WT myocytes was unaffected by removal of extracellular Ca(2+) or by buffering of intracellular Ca(2+) with the Ca(2+) chelator BAPTA (100 micromol/L), indicating that elevated intracellular Ca(2+) does not underlie impaired diastolic function in MHC-FATP ventricular myocytes. Functional assessment of skinned myocytes, however, revealed that myofilament Ca(2+) sensitivity is markedly increased in MHC-FATP, compared with WT, ventricular cells. In addition, biochemical experiments demonstrated increased expression of the beta-MHC isoform in MHC-FATP, compared with WT ventricles, which likely contributes to the slower relaxation rate observed in MHC-FATP myocytes. Collectively, these data demonstrate that derangements in lipid metabolism in MHC-FATP ventricles, which are similar to those observed in the diabetic heart, result in impaired diastolic function that primarily reflects changes in myofilament function, rather than altered Ca(2+) cycling.

Bimanual 1:1 with 90 Degrees Continuous Relative Phase: Difficult or Easy!

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Feb, 2009  |  Pubmed ID: 19093104

The purpose of the present experiment was to observe the performance of participants attempting to produce a 1:1 bimanual coordination pattern with 90 degrees relative phase between the arms when feedback concerning the movement of the two limbs was integrated within a Lissajous plot and when this information was withdrawn. One group was paced with an auditory metronome and the other was encouraged to increase frequency when they fell below the goal frequency. We predicted that providing a salient integrated feedback display without a metronome would allow participants to effectively tune-in the goal relative phase pattern within several minutes; instead of several days as typically found in the literature when the metronome was used. The data indicated remarkably effective performances after 5 min of practice when the metronome was not used, with motion of both limbs harmonic in nature, and continuous relative phase errors (approximately 10 degrees) and standard deviation of continuous relative phase (approximately 10 degrees) relatively small. This seems remarkable given that this coordination pattern has proven relatively difficult to perform under normal and Lissajous feedback conditions even after several days of practice. As predicted relative phase errors and variability increased substantially when the metronome was used. When the extrinsic feedback was withdrawn all participants tended to drift from the required 90 degrees relative phase, but the cycle duration variability in the two limbs remained stable and limb motion remained harmonic in nature. The current findings suggest that some of the difficulty typically associated with producing various relative phase patterns is due to the less than optimal perceptual information available in the various testing situations and the use of pacing metronomes.

Reduced Expression of Cx43 Attenuates Ventricular Remodeling After Myocardial Infarction Via Impaired TGF-beta Signaling

American Journal of Physiology. Heart and Circulatory Physiology. Feb, 2010  |  Pubmed ID: 19966054

In addition to mediating cell-to-cell electrical coupling, gap junctions are important in tissue repair, wound healing, and scar formation. The expression and distribution of connexin43 (Cx43), the major gap junction protein expressed in the heart, are altered substantially after myocardial infarction (MI); however, the effects of Cx43 remodeling on wound healing and the attendant ventricular dysfunction are incompletely understood. Cx43-deficient and wild-type mice were subjected to proximal ligation of the anterior descending coronary artery and followed for 6 days or 4 wk to test the hypothesis that reduced expression of Cx43 influences wound healing, fibrosis, and ventricular remodeling after MI. We quantified the progression of infarct healing by measuring neutrophil expression, collagen content, and myofibroblast expression. We found significantly reduced transformation of fibroblasts to myofibroblasts at 6 days and significantly reduced collagen deposition both in the infarct at 6 days and at 4 wk in the noninfarcted region of Cx43-deficient mice. As expected, transforming growth factor (TGF)-beta, a profibrotic cytokine, was dramatically upregulated in MI hearts, but its phosphorylated comediator (pSmad) was significantly downregulated in the nuclei of Cx43-deficient hearts post-MI, suggesting that downstream signaling of TGF-beta is diminished substantially in Cx43-deficient hearts. This diminution in profibrotic TGF-beta signaling resulted in the attenuation of adverse structural remodeling as assessed by echocardiography. These findings suggest that efforts to enhance the expression of Cx43 to maintain intercellular coupling or reduce susceptibility to arrhythmias should be met with caution until the role of Cx43 in infarct healing is fully understood.

Amplitude Differences, Spatial Assimilation, and Integrated Feedback in Bimanual Coordination

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Apr, 2010  |  Pubmed ID: 20069285

The purpose of the experiment was to determine the influence of Lissajous feedback on 1:1 bimanual coordination patterns (0 degrees , 90 degrees , and 180 degrees phase lags) when the movement amplitudes of the two limbs were different (30 degrees , 60 degrees ). The present data supports the notion that the lead-lag relationship as well as amplitude assimilation observed in the literature can be partially attributed to the visual-perceptual factors present in the testing environment. When participants are provided integrated feedback in the form of Lissajous plots much of the lead-lag and amplitude assimilation effects were eliminated, and relative phase error and variability were also greatly reduced after only 3 min of practice under each condition.

Role of Autophagy in Caenorhabditis Elegans

FEBS Letters. Apr, 2010  |  Pubmed ID: 20138173

Autophagy is an evolutionarily conserved intracellular catabolic system. During Caenorhabditis elegans development, autophagy plays an important role in many physiological processes, including survival under starvation conditions, modulation of life span, and regulation of necrotic cell death caused by toxic ion-channel variants. Recently, it has been demonstrated that during embryogenesis, basal levels of autophagy selectively remove a group of proteins in somatic cells, including the aggregate-prone components of germline P granules. Degradation of these protein aggregates provides a genetic model to identify essential autophagy components and also to elucidate how the autophagic machinery selectively recognizes and degrades specific targets during animal development.

Langmuir and Langmuir-Blodgett Films of Bidisperse Silica Nanoparticles

Langmuir : the ACS Journal of Surfaces and Colloids. Feb, 2010  |  Pubmed ID: 20141210

We present the studies on the structure and optical properties of bidisperse Stöber silica nanoparticulate Langmuir films prepared at the air/water interface in a Wilhelmy film balance and transferred onto glass slides using the Langmuir-Blodgett technique. Three different compositions (covered area ratios: 4:1; 1:1, and 1:4) of two bidisperse systems were used in the experiments. Bidisperse samples (B1 and B2) were prepared by mixing the appropriate amount of monodisperse sols of particles with 61 and 100 nm diameters (B1) and those with 37 and 100 nm diameters (B2). By surface pressure-area isotherms and (transmission and scanning) electron microscopy images we provide information about the structure of the films. Optical properties of the supported films were measured with UV-vis spectroscopy and the transmittance spectra were evaluated in terms of an optical model which allows monotonous in-depth variation of the refractive index across the film. (1) We have found that the refractive index decreased from the substrate-layer interface toward the air-layer interface when the smaller particles were in majority, and increased otherwise. That would suggest that the smaller particles of each bidisperse system can be positioned at the air side of the film if they are in minority in the sample and they can be situated on the substrate if they are in majority. The scanning electron microscope images of bidisperse films supported the in-depth film structure suggested by optical studies.

Human Cord Blood Progenitors with High Aldehyde Dehydrogenase Activity Improve Vascular Density in a Model of Acute Myocardial Infarction

Journal of Translational Medicine. 2010  |  Pubmed ID: 20214792

Human stem cells from adult sources have been shown to contribute to the regeneration of muscle, liver, heart, and vasculature. The mechanisms by which this is accomplished are, however, still not well understood. We tested the engraftment and regenerative potential of human umbilical cord blood-derived ALDH(hi)Lin(-), and ALDH(lo)Lin(-) cells following transplantation to NOD/SCID or NOD/SCID beta2m null mice with experimentally induced acute myocardial infarction. We used combined nanoparticle labeling and whole organ fluorescent imaging to detect human cells in multiple organs 48 hours post transplantation. Engraftment and regenerative effects of cell treatment were assessed four weeks post transplantation. We found that ALDH(hi)Lin(-) stem cells specifically located to the site of injury 48 hours post transplantation and engrafted the infarcted heart at higher frequencies than ALDH(lo)Lin(-) committed progenitor cells four weeks post transplantation. We found no donor derived cardiomyocytes and few endothelial cells of donor origin. Cell treatment was not associated with any detectable functional improvement at the four week endpoint. There was, however, a significant increase in vascular density in the central infarct zone of ALDH(hi)Lin(-) cell-treated mice, as compared to PBS and ALDH(lo)Lin(-) cell-treated mice. CONCLUSIONS: Our data indicate that adult human stem cells do not become a significant part of the regenerating tissue, but rapidly home to and persist only temporarily at the site of hypoxic injury to exert trophic effects on tissue repair thereby enhancing vascular recovery.

Ionization Energies for the Actinide Mono- and Dioxides Series, from Th to Cm: Theory Versus Experiment

The Journal of Physical Chemistry. A. May, 2010  |  Pubmed ID: 20329784

The results of a computational study with multiconfigurational quantum chemical methods on actinide monoxides (AnO) and dioxides (AnO(2)) for An = Th, Pa, U, Np, Pu, Am, and Cm, are presented. First and second ionization energies were determined and compared with experimental values, when available. The trend along the series is analyzed in terms of the electronic configurations of the various species. The agreement with experiment is excellent in most cases. Of particular interest is the first ionization of PuO(2). We applied cutting-edge theoretical methods to refine the ionization energy, but our computed data fall in the range of approximately 6 eV and not in the approximately 7 eV region as the experiment dictates. Such a system requires further computational and experimental attention.

Reversible Multifocal Leukoencephalopathy Associated with a Nocturnal Blood Pressure Non-dipper Pattern

Blood Pressure. Aug, 2010  |  Pubmed ID: 20353314

The majority of cases of leukoencephalopathy related to hypertensive crisis show brain lesions predominantly in the posterior lobe. Such cases are usually classified as reversible posterior leukoencephalopathy syndrome (RPLS). A multifocal distribution pattern is also possible, but occurs seldom. Here we report two patients with extensive white matter lesions that affect the entire brain, related to hypertensive crisis associated with a non-dipper pattern of blood pressure during the night as well as renal dysfunction. This nocturnal blood pressure abnormality may be relevant for the distribution pattern of cerebral white matter lesions and underlines the concept that in these cases a 24-h ambulatory blood pressure monitoring is needed.

The Importance of Elastin to Aortic Development in Mice

American Journal of Physiology. Heart and Circulatory Physiology. Aug, 2010  |  Pubmed ID: 20495146

Elastin is an essential component of vertebrate arteries that provides elasticity and stores energy during the cardiac cycle. Elastin production in the arterial wall begins midgestation but increases rapidly during the last third of human and mouse development, just as blood pressure and cardiac output increase sharply. The aim of this study is to characterize the structure, hemodynamics, and mechanics of developing arteries with reduced elastin levels and determine the critical time period where elastin is required in the vertebrate cardiovascular system. Mice that lack elastin (Eln(-/-)) or have approximately one-half the normal level (Eln(+/-)) show relatively normal cardiovascular development up to embryonic day (E) 18 as assessed by arterial morphology, left ventricular blood pressure, and cardiac function. Previous work showed that just a few days later, at birth, Eln(-/-) mice die with high blood pressure and tortuous, stenotic arteries. During this period from E18 to birth, Eln(+/-) mice add extra layers of smooth muscle cells to the vessel wall and have a mean blood pressure 25% higher than wild-type animals. These findings demonstrate that elastin is only necessary for normal cardiovascular structure and function in mice starting in the last few days of fetal development. The large increases in blood pressure during this period may push hemodynamic forces over a critical threshold where elastin becomes required for cardiovascular function. Understanding the interplay between elastin amounts and hemodynamic forces in developing vessels will help design treatments for human elastinopathies and optimize protocols for tissue engineering.

Perceptual and Attentional Influences on Continuous 2:1 and 3:2 Multi-frequency Bimanual Coordination

Journal of Experimental Psychology. Human Perception and Performance. Aug, 2010  |  Pubmed ID: 20695710

Two experiments were conducted to determine if multi-frequency (2:1 and 3:2) coordination between the limbs is enhanced when integrated feedback is provided in the form of Lissajous plots, attention demands are reduced, and attempts to consciously coordinate the limbs are not encouraged. To determine the influence of vision of the limbs, covered and uncovered limb groups were provided online Lissajous feedback. To determine the impact of the Lissajous feedback, a control group that was not provided Lissajous feedback was also tested. The data indicated remarkably effective performances after 5 min of practice when limbs were covered and Lissajous feedback was provided. When Lissajous feedback was provided and vision of the limbs was permitted, performance deteriorated. Performance by the group not provided Lissajous feedback was quite poor. The findings suggest that some of the difficulty associated with producing difficult bimanual coordination patterns are due to the less than optimal perceptual information available in various testing situations and the attentional focus imposed by the participant.

MicroRNA Expression Profiling in Benign (sporadic and Hereditary) and Recurring Adrenal Pheochromocytomas

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Dec, 2010  |  Pubmed ID: 20818339

MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n=33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffin-embedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch- and G-protein-coupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffin-embedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

Central Nervous System Involvement in CD4+/CD56+ Hematodermic Neoplasm: a Report of Two Cases

Journal of Neuro-oncology. Apr, 2010  |  Pubmed ID: 19798469

CD4+/CD56+ hematodermic neoplasm, formerly known as blastic NK-cell lymphoma, is an uncommon, aggressive non-Hodgkin's lymphoma with cutaneous, lymph node, and bone marrow involvement at presentation. The disease is characterized by early leukemic phase; however, central nervous system involvement is rarely reported. Herein we describe two cases of CD4+/CD56+ hematodermic neoplasm with meningeal manifestation. Microscopic analysis and flow cytometry of cerebrospinal fluid proved to be diagnostic; however, imaging studies were not informative. These observations call attention to the possibility of central nervous system involvement, which could be more common than expected previously. Authors recommend routine cerebrospinal fluid analysis and prophylactic intrathecal chemotherapy in patients with this highly aggressive disease.

Impossible is Nothing: 5:3 and 4:3 Multi-frequency Bimanual Coordination

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Mar, 2010  |  Pubmed ID: 19798488

The present findings demonstrate that when participants are provided a Lissajous display with cursor indicating the position of the limbs and a template illustrating the desired movement pattern they can rapidly (10 min) and effectively (continuous relative phase errors and variability ~10 degrees ) tune in a difficult 5:3 bimanual coordination pattern and without additional practice re-tune their responding to an equally difficult 4:3 coordination pattern. The findings indicate the extreme difficulty associated with producing complex polyrhythms in previous experiments has been due to split attention when Lissajous feedback has been provided and inability of the participant to detect and correct coordination errors when only provided vision of the limbs. Effective transfer to the 4:3 polyrhythm without previous practice suggests that the perception-action system's capabilities are extensive. The present findings when viewed in the context of recent experiments using similar protocols suggest that much, but not all, of the difficulty associated with producing a variety of bimanual coordination tasks should be viewed in terms of perceptual constraints imposed by the testing environment.

A Self-inactivating Gamma-retroviral Vector Reduces Manifestations of Mucopolysaccharidosis I in Mice

Molecular Therapy : the Journal of the American Society of Gene Therapy. Feb, 2010  |  Pubmed ID: 19844196

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficiency in alpha-L-iduronidase (IDUA) that results in accumulation of glycosaminoglycans (GAGs) throughout the body, causing numerous clinical defects. Intravenous administration of a gamma-retroviral vector (gamma-RV) with an intact long terminal repeat (LTR) reduced the clinical manifestations of MPS I, but could cause insertional mutagenesis. Although self-inactivating (SIN) gamma-RVs in which the enhancer and promoter elements in the viral LTR are absent after transduction reduces this risk, such vectors could be less effective. This report demonstrates that intravenous (i.v.) injection of a SIN gamma-RV expressing canine IDUA from the liver-specific human alpha(1)-antitrypsin promoter into adult or newborn MPS I mice completely prevents biochemical abnormalities in several organs, and improved bone disease, vision, hearing, and aorta to a similar extent as was seen with administration of the LTR-intact vector to adults. Improvements were less profound than when using an LTR-intact gamma-RV in newborns, which likely reflects a lower level of transduction and expression for the SIN vector-transduced mice, and might be overcome by using a higher dose of SIN vector. A SIN gamma-RV vector ameliorates clinical manifestations of MPS I in mice and should be safer than an LTR-intact gamma-RV.

Coding of On-line and Pre-planned Movement Sequences

Acta Psychologica. Feb, 2010  |  Pubmed ID: 19939342

Recent experiments have demonstrated that complex multi-element movement sequences were coded in visual-spatial coordinates even after extensive practice, while relatively simple spatial-temporal movement sequences are coded in motor coordinates after a single practice session. The purpose of the present experiment was to determine if the control process rather than the difficulty of the sequence played a role in determining the pattern of effector transfer. To accomplish this, different concurrent feedback conditions were provided to two groups of participants during practice of the same movement sequence. The results indicated that when concurrent visual feedback was provided during the production of the movement, which was thought to encourage on-line control, the participants performed transfer tests with the contra-lateral limb better when the visual-spatial coordinates were reinstated than when the motor coordinates were reinstated. When concurrent visual feedback was not provided, which was thought to encourage pre-planned control, the opposite was observed. The data are consistent with the hypothesis that the mode of control dictates the coordinate system used to code the movement sequence rather than sequence difficulty or stage of practice as has been proposed.

TRB3 Function in Cardiac Endoplasmic Reticulum Stress

Circulation Research. May, 2010  |  Pubmed ID: 20360254

Tribbles (TRB)3 is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 has been reported to inhibit the activity of Akt protein kinases. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation, hypoxia, or endoplasmic reticulum (ER) stress promotes TRB3 expression in noncardiac cells.

Quantification of the Magnetic Resonance Signal Response to Dynamic (C)O(2)-enhanced Imaging in the Brain at 3 T: R*(2) BOLD Vs. Balanced SSFP

Journal of Magnetic Resonance Imaging : JMRI. Jun, 2010  |  Pubmed ID: 20512881

To compare two magnetic resonance (MR) contrast mechanisms, R*(2) BOLD and balanced SSFP, for the dynamic monitoring of the cerebral response to (C)O(2) respiratory challenges.

Altered Sensitivity to Excitotoxic Cell Death and Glutamate Receptor Expression Between Two Commonly Studied Mouse Strains

Journal of Neuroscience Research. Sep, 2010  |  Pubmed ID: 20544821

Alterations in glutamatergic synapse function have been implicated in the pathogenesis of many different neurological disorders, including ischemia, epilepsy, Parkinson's disease, Alzheimer's disease, and Huntington's disease. While studying glutamate receptor function in juvenile Batten disease on the C57BL/6J and 129S6/S(v)E(v) mouse backgrounds, we noticed differences unlikely to be due to mutation difference alone. We report here that primary cerebellar granule cell cultures from C57BL/6J mice are more sensitive to N-methyl-D-aspartate (NMDA)-mediated cell death. Moreover, sensitivity to AMPA-mediated excitotoxicity is more variable and is dependent on the treatment conditions and age of the cultures. Glutamate receptor surface expression levels examined in vitro by in situ ELISA and in vivo by Western blot in surface cross-linked cerebellar samples indicated that these differences in sensitivity likely are due to strain-dependent differences in cell surface receptor expression levels. We propose that differences in glutamate receptor expression and in excitotoxic vulnerability should be taken into consideration in the context of characterizing disease models on the C57BL/6J and 129S6/S(v)E(v) mouse backgrounds.

C. Elegans Screen Identifies Autophagy Genes Specific to Multicellular Organisms

Cell. Jun, 2010  |  Pubmed ID: 20550938

The molecular understanding of autophagy has originated almost exclusively from yeast genetic studies. Little is known about essential autophagy components specific to higher eukaryotes. Here we perform genetic screens in C. elegans and identify four metazoan-specific autophagy genes, named epg-2, -3, -4, and -5. Genetic analysis reveals that epg-2, -3, -4, and -5 define discrete genetic steps of the autophagy pathway. epg-2 encodes a coiled-coil protein that functions in specific autophagic cargo recognition. Mammalian homologs of EPG-3/VMP1, EPG-4/EI24, and EPG-5/mEPG5 are essential for starvation-induced autophagy. VMP1 regulates autophagosome formation by controlling the duration of omegasomes. EI24 and mEPG5 are required for formation of degradative autolysosomes. This study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway and provides mechanistic insights into the metazoan-specific autophagic process.

Factors of Influence Upon Overall Survival in the Treatment of Intracranial MPNSTs. Review of the Literature and Report of a Case

Radiation Oncology (London, England). 2010  |  Pubmed ID: 21106096

Intracranial malignant peripheral nerve sheath tumors are rare entities that carry a poor prognosis. To date, there are no established therapeutic strategies for these tumors.

Changes in the MR Relaxation Rate R(2)* Induced by Respiratory Challenges at 3.0 T: a Comparison of Two Quantification Methods

NMR in Biomedicine. Nov, 2010  |  Pubmed ID: 20963801

The consistent determination of changes in the transverse relaxation rate R(2)* (ΔR(2)*) is essential for the mapping of the effect of hyperoxic and hypercapnic respiratory challenges, which enables the noninvasive assessment of blood oxygenation changes and vasoreactivity by MRI. The purpose of this study was to compare the performance of two different methods of ΔR(2)* quantification from dynamic multigradient-echo data: (A) subtraction of R(2)* values calculated from monoexponential decay functions; and (B) computation of ΔR(2)* echo-wise from signal intensity ratios. A group of healthy volunteers (n = 12) was investigated at 3.0 T, and the brain tissue response to carbogen and CO(2)-air inhalation was registered using a dynamic multigradient-echo sequence with high temporal and spatial resolution. Results of the ΔR(2)* quantification obtained by the two methods were compared with respect to the quality of the voxel-wise ΔR(2)* response, the number of responding voxels and the behaviour of the 'global' response of all voxels with significant R(2)* changes. For the two ΔR(2)* quantification methods, we found no differences in the temporal variation of the voxel-wise ΔR(2)* responses or in the detection sensitivity. The maximum change in the 'global' response was slightly smaller when ΔR(2)* was derived from signal intensity ratios. In conclusion, this first methodological comparison shows that both ΔR(2)* quantifications, from monoexponential approximation as well as from signal intensity ratios, are applicable for the monitoring of R(2)* changes during respiratory challenges.

Temporary Inhibition of AMPA Receptors Induces a Prolonged Improvement of Motor Performance in a Mouse Model of Juvenile Batten Disease

Neuropharmacology. Feb-Mar, 2011  |  Pubmed ID: 20971125

Mutations in the CLN3 gene cause juvenile Batten disease, a fatal pediatric neurodegenerative disorder. The Cln3-knockout (Cln3(Δex1-6)) mouse model of the disease displays many pathological characteristics of the human disorder including a deficit in motor coordination. We have previously found that attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity in one-month-old Cln3(Δex1-6) mice resulted in an immediate improvement of their motor skills. Here we show that at a later stage of the disease, in 6-7-month-old Cln3(Δex1-6) mice, acute inhibition of AMPA receptors by a single intraperitoneal injection (1mg/kg) of the non-competitive AMPA antagonist, EGIS-8332, does not have an immediate effect. Instead, it induces a delayed but prolonged improvement of motor skills. Four days after the injection of the AMPA antagonist, Cln3(Δex1-6) mice reached the same motor skill level as their wild type (WT) counterparts, an improvement that persisted for an additional four days. EGIS-8332 was rapidly eliminated from the brain as measured by HPLC-MS/MS. Histological analysis performed 8 days after the drug administration revealed that EGIS-8332 did not have any impact upon glial activation or the survival of vulnerable neuron populations in 7-month-old Cln3(Δex1-6) mice. We propose that temporary inhibition of AMPA receptors can induce a prolonged correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease.

Pseudohypoxic Brain Swelling (postoperative Intracranial Hypotension-associated Venous Congestion) After Spinal Surgery: Report of 2 Cases

Neurosurgery. Jan, 2011  |  Pubmed ID: 21150743

Pseudohypoxic brain swelling is a rare event that may occur after uneventful brain surgery when subgaleal vacuum drainage is used. To date, such cases of unexpected postoperative disturbances of consciousness associated with radiological signs of basal ganglia, thalamic, brainstem, and cerebellum damage without any signs of vessel occlusion have not been known to occur after spinal surgery.

The Transcriptional Coactivators, PGC-1α and β, Cooperate to Maintain Cardiac Mitochondrial Function During the Early Stages of Insulin Resistance

Journal of Molecular and Cellular Cardiology. Oct, 2011  |  Pubmed ID: 22080103

We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPARα. We hypothesized that the PPARα coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is necessary for mitochondrial biogenesis in insulin resistant hearts and that this response was adaptive. Mitochondrial phenotype was assessed in insulin resistant mouse models in wild-type (WT) versus PGC-1α deficient (PGC-1α(-/-)) backgrounds. Both high fat-fed (HFD) WT and 6week-old Ob/Ob animals exhibited a significant increase in myocardial mitochondrial volume density compared to standard chow fed or WT controls. In contrast, HFD PGC-1α(-/-) and Ob/Ob-PGC-1α(-/-) hearts lacked a mitochondrial biogenic response. PGC-1α gene expression was increased in 6week-old Ob/Ob animals, followed by a decline in 8week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6week-old Ob/Ob animals, but not in Ob/Ob-PGC-1α(-/-) mice and not in 8week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1α upregulation. Animals that were deficient for PGC-1α and heterozygous for the related coactivator PGC-1β (PGC-1α(-/-)β(+/-)) were bred to the Ob/Ob mice. Ob/Ob-PGC-1α(-/-)β(+/-) hearts exhibited dramatically reduced mitochondrial respiratory capacity. Finally, the mitochondrial biogenic response was triggered in H9C2 myotubes by exposure to oleate, an effect that was blunted with shRNA-mediated PGC-1 "knockdown". We conclude that PGC-1 signaling is important for the adaptive cardiac mitochondrial biogenic response that occurs during the early stages of insulin resistance. This response occurs in a cell autonomous manner and likely involves exposure to high levels of free fatty acids.

Association of Systemic Lupus Erythematosus Clinical Features with European Population Genetic Substructure

PloS One. 2011  |  Pubmed ID: 22194982

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.

A Plasmid DNA Immunogen Expressing Fifteen Protein Antigens and Complex Virus-like Particles (VLP+) Mimicking Naturally Occurring HIV

Vaccine. Jan, 2011  |  Pubmed ID: 21109034

We describe here a single plasmid DNA immunogen representing the broadest antigen repertoire among HIV vaccine candidates. This pDNA was "ANTIGENeered" for the regulated expression of thirteen complete and two non-functional HIV protein antigens. These proteins self assemble into complex virus-like particles (VLP(+)). Multiple irreversible safety features were introduced by genetic modifications including the complete impairment of integration, reverse transcription, the function of Nef and the 3'LTR. Epitope analysis predicted that the pDNA-derived protein repertoire can potentially present over 3000 T cell epitopes. However, the expressed antigens have different potential to induce HIV-specific CD4(+) and CD8(+) T cells supporting our hypothesis that HIV vaccines should contain all possible regulatory and structural proteins. This immunogen is the active pharmaceutical ingredient of DermaVir, a therapeutic vaccine product candidate that recently successfully completed Phase II clinical trials and meets the safety, immunogenicity and cost requirements of an HIV vaccine.

The Learning of 90° Continuous Relative Phase with and Without Lissajous Feedback: External and Internally Generated Bimanual Coordination

Acta Psychologica. Mar, 2011  |  Pubmed ID: 21216384

Results from recent experiments (e.g., Kovacs, Buchanan, & Shea, 2009a-b, 2010a,b) suggest that when salient visual information is presented using Lissajous plots bimanual coordination patterns typically thought to be very difficult to perform without extensive practice can be performed with remarkably low relative phase error and variability with 5min or less of practice. However, when this feedback is removed, performance deteriorates. The purpose of the present experiment was to determine if reducing the frequency of feedback presentation will decrease the participant's reliance on the feedback and will facilitate the development of an internal representation capable of sustaining performance when the Lissajous feedback is withdrawn. The results demonstrated that reduced frequency Lissajous feedback results in very effective bimanual coordination performance on tests with Lissajous feedback available and when feedback is withdrawn. Taken together the present experiments add to the growing literature that supports the notion that salient perceptual information can override some aspects of the system's intrinsic dynamics typically linked to motor output control. Additionally, the present results suggest that the learning of both externally and internally driven bimanual coordination is facilitated by providing reduced frequency Lissajous feedback.

Altered Sensitivity of Cerebellar Granule Cells to Glutamate Receptor Overactivation in the Cln3(Δex7/8)-knock-in Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Neurochemistry International. May, 2011  |  Pubmed ID: 21315126

The juvenile onset form of neuronal ceroid lipofuscinoses (JNCL) is a recessively inherited lysosomal storage disorder characterized by progressive neurodegeneration. JNCL results from mutations in the CLN3 gene that encodes a lysosomal membrane protein with unknown function. Utilizing a Cln3-knock-out mouse model of JNCL that was created on the 129S6/SvEv genetic background, we have previously demonstrated that CLN3-deficient cerebellar granule cells (CGCs) have a selectively increased sensitivity to AMPA-type glutamate receptor-mediated toxicity. Our recent findings that CGCs from 129S6/SvEv and C57BL/6J wild type (WT) mice have significant differences in glutamate receptor expression and in excitotoxic vulnerability indicated that the genetic background possibly have a strong influence on how glutamate receptor function is dysregulated in CLN3-deficient neurons. Indeed, here we show that in the Cln3(Δex7/8)-knock-in mouse model, that is on the C57BL/6J genetic background, mimics the most frequent mutation observed in JNCL patients and considered a null mutant, the sensitivity of CGCs to both AMPA- and NMDA-type glutamate receptor overactivations is altered. Cultured wild type and Cln3(Δex7/8) CGCs were equally sensitive to AMPA toxicity after 2 or 3 weeks in vitro, whereas the subunit-selective AMPA receptor agonist, CPW-399, induced significantly more cell death in mature, 3-week-old Cln3(Δex7/8) cultures. NMDA receptor-mediated toxicity changed during in vitro development: Cln3(Δex7/8) CGCs were less sensitive to high concentration of NMDA after 2 weeks in culture but became more vulnerable than their WT counterparts after 3 weeks in vitro. Abnormally altered glutamate receptor function in the cerebellum may result in motor deficits, and we confirmed that 7-week-old Cln3(Δex7/8) mice, similarly to Cln3-knock-out mice, have a motor coordination deficit as measured by an accelerating rotarod. Our results demonstrate altered glutamate receptor function in Cln3(Δex7/8) neurons and suggest that both AMPA and NMDA receptors are potential therapeutic targets in JNCL.

Chronic Inhibition of Pyruvate Dehydrogenase in Heart Triggers an Adaptive Metabolic Response

The Journal of Biological Chemistry. Apr, 2011  |  Pubmed ID: 21321124

Diabetic cardiac dysfunction is associated with decreased rates of myocardial glucose oxidation (GO) and increased fatty acid oxidation (FAO), a fuel shift that has been shown to sensitize the heart to ischemic insult and ventricular dysfunction. We sought to evaluate the metabolic and functional consequences of chronic suppression of GO in heart as modeled by transgenic mice with cardiac-specific overexpression of pyruvate dehydrogenase kinase 4 (myosin heavy chain (MHC)-PDK4 mice), an inhibitor of pyruvate dehydrogenase. Hearts of MHC-PDK4 mice were shown to exhibit an insulin-resistant substrate utilization profile, characterized by low GO rates and high FAO flux. Surprisingly, MHC-PDK4 mice were not sensitized to cardiac ischemia-reperfusion injury despite a fuel utilization pattern that phenocopied the diabetic heart. In addition, MHC-PDK4 mice were protected against high fat diet-induced myocyte lipid accumulation, likely related to increased capacity for FAO. The high rates of mitochondrial FAO in the MHC-PDK4 heart were related to heightened activity of the AMP-activated protein kinase, reduced levels of malonyl-CoA, and increased capacity for mitochondrial uncoupled respiration. The expression of the known AMP-activated protein kinase target, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial function and biogenesis, was also activated in the MHC-PDK4 heart. These results demonstrate that chronic activation of PDK4 triggers transcriptional and post-transcriptional mechanisms that re-program the heart for chronic high rates of FAO without the expected deleterious functional or metabolic consequences.

Screening the Toxic Potential of Cylindrospermopsis Raciborskii Strains Isolated from Lake Balaton, Hungary

Toxicon : Official Journal of the International Society on Toxinology. May, 2011  |  Pubmed ID: 21333666

Cylindrospermopsis raciborskii is becoming a major concern among cyanobacteria, due to its potential ability to produce toxic metabolites. We assessed the cytotoxic potential of four C. raciborskii strains (ACT 9502, ACT 9503, ACT 9504 and ACT 9505) isolated from Lake Balaton (Hungary), by lactate dehydrogenase (LDH) leakage measurements and by detecting morphological alterations in CHO-K1 (Chinese Hamster Ovary) cells. The Australian AQS (cylindrospermopsin producer) strain of C. raciborskii and purified cylindrospermopsin (CYN) were used as positive references in both the biochemical and morphological studies. Chemical analysis for known cyanotoxins was performed on aqueous extracts of ACT and AQS strains by the HPLC-MS technique. Comparing threshold values of LDH leakage data, different toxic potentials of cyanobacterial extracts are suggested in short term (3 h) and long (24 h) exposure regimes. In the acute (3 h) experiments the aqueous extract of the ACT 9505 strain proved to be most toxic (EC(50) = 7.4 mg mL(-1)), while after 24 h the ACT 9504 extract was the most effective (EC(50) = 0.65 mg mL(-1)). The extract of the AQS strain and the purified CYN exerted most of their toxic effects after 3 h exposure (EC(50) = 0.74 mg mL(-1), and 0.9 μg mL(-1) respectively). The morphological changes of CHO-K1 cells induced by the crude extracts of the ACT strains included fragmentation of the actin filaments then relocation of the depolymerized actin to the perinuclear region, resulting cell rounding and loss of adhesion. Exposure of CHO-K1 cells to the crude extract of the AQS strain, moreover, resulted cell shrinking and formation of filopodia, i.e. distinctly different cytological alterations from that induced by the ACT extracts and the purified CYN. Chemical analysis of the cyanobacterial crude extracts confirmed the presence of cylindrospermopsin in the extract of the AQS strain (8.5 mg CYN g(-1) dry weight), and none of the presently known cyanotoxins have been analytically confirmed in the extracts of the ACT strains isolated from the Lake Balaton. Although a significant toxicity of all four ACT C. raciborskii strains is confirmed by both biochemical and morphological studies, our results also pointed out the necessity of further studies to identify the toxic, but still unknown metabolic components produced by these cyanobacterial members of the phytoplankton communities.

Exenatide Improves Glucose Homeostasis and Prolongs Survival in a Murine Model of Dilated Cardiomyopathy

PloS One. 2011  |  Pubmed ID: 21359201

There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.

Shared Developmental Roles and Transcriptional Control of Autophagy and Apoptosis in Caenorhabditis Elegans

Journal of Cell Science. May, 2011  |  Pubmed ID: 21502138

Autophagy is a lysosome-mediated self-degradation process of eukaryotic cells that, depending on the cellular milieu, can either promote survival or act as an alternative mechanism of programmed cell death (PCD) in terminally differentiated cells. Despite the important developmental and medical implications of autophagy and the main form of PCD, apoptosis, orchestration of their regulation remains poorly understood. Here, we show in the nematode Caenorhabditis elegans, that various genetic and pharmacological interventions causing embryonic lethality trigger a massive cell death response that has both autophagic and apoptotic features. The two degradation processes are also redundantly required for normal development and viability in this organism. Furthermore, the CES-2-like basic region leucine-zipper (bZip) transcription factor ATF-2, an upstream modulator of the core apoptotic cell death pathway, is able to directly regulate the expression of at least two key autophagy-related genes, bec-1/ATG6 and lgg-1/ATG8. Thus, the two cell death mechanisms share a common method of transcriptional regulation. Together, these results imply that under certain physiological and pathological conditions, autophagy and apoptosis are co-regulated to ensure the proper morphogenesis and survival of the developing organism. The identification of apoptosis and autophagy as compensatory cellular pathways in C. elegans might help us to understand how dysregulated PCD in humans can lead to diverse pathologies, including cancer, neurodegeneration and diabetes.

Coexistence of Ankylosing Spondylitis and Rheumatoid Arthritis in a Female Patient

Clinical Rheumatology. Aug, 2011  |  Pubmed ID: 21505766

Ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are two distinguished representatives of inflammatory rheumatic diseases. The two diseases differ significantly in their etiology, pathology, clinical signs, and in the nature of articular manifestations. Their association has been a rarity in the literature. Here, authors describe a case of a 55-year-old female patient with AS associated with RA. Her spinal symptoms started in 1979, and the diagnosis of AS was established based on the typical clinical picture and X-ray. She developed severe spinal deformity during the next decades. In 2005, peripheral polyarthritis developed, although neither the diagnosis nor the treatment was modified. In 2007, authors diagnosed seropositive RA. Therapy included anti-inflammatory therapy and traditional disease-modifying agents, eventually followed by biological therapy.

Seeing is Believing: the Impact of Electron Microscopy on Autophagy Research

Autophagy. Sep, 2011  |  Pubmed ID: 21566462

Autophagy was first discovered by transmission electron microscopy more than 50 years ago. For decades, electron microscopy was the only way to reliably detect autophagic compartments in cells because no specific protein markers were known. In the 1970s, however, the introduction of biochemical methods enabled quantitative studies of autophagic-lysosomal degradation, and in the 1980s specific biochemical assays for autophagic sequestration became available. Since the identification of autophagy-related genes in the 1990s, combined fluorescence microscopy, biochemical and genetic methods have taken the leading role in autophagy research. However, electron microscopy is still needed to confirm and verify results obtained by other methods, and also to produce novel knowledge that would not be achievable by any other experimental approach. Confocal microscopy, with its ever-improving resolution, is probably the best-suited morphological approach to investigate the dynamic aspects of autophagy. However, for analyzing the ultrastructural details of the many novel organelles and mechanisms involved in specific subtypes of autophagy, the electron microscope is still indispensable. This review will summarize the impact that electron microscopy has had on autophagy research since the discovery of this self-degradation process in the mid-1950s. Astonishingly, some of the "novel" concepts and principles of autophagy, presented in the recent studies, were already proposed several decades ago by the pioneering, accurate and passionate work of virtuoso electron microscopists.

Vascular Calcification and Aortic Fibrosis: a Bifunctional Role for Osteopontin in Diabetic Arteriosclerosis

Arteriosclerosis, Thrombosis, and Vascular Biology. Aug, 2011  |  Pubmed ID: 21597007

Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet.

Computed Vibrational Frequencies of Actinide Oxides AnO(0/+/2+) and AnO2(0/+/2+) (An = Th, Pa, U, Np, Pu, Am, Cm)

The Journal of Physical Chemistry. A. Jun, 2011  |  Pubmed ID: 21604729

The vibrational frequencies of the actinide oxides AnO and AnO(2) (An = Th, Pa, U, Np, Pu, Am, Cm) and of their mono- and dications have been calculated using advanced quantum chemical techniques. The stretching fundamental frequencies of the monoxides have been determined by fitting the potential function to single-point energies obtained by relativistic CASPT2 calculations along the stretching coordinate and on this basis solving numerically the ro-vibrational Schrödinger equation. To obtain reliable fundamental frequencies of the dioxides, we developed an empirical approach. In this approach the harmonic vibrational frequencies of the AnO(2)(0/+/2+) species were calculated using eight different exchange-correlation DFT functionals. On the basis of the good correlation found between the vibrational frequencies and computed bond distances, the final frequency values were derived for the CASPT2 reference bond distances from linear regression equations fitted to the DFT data of each species. As a test, the approach provided excellent agreement with accurate experimental data of ThO, ThO(+), UO, and UO(+). The joint analysis of literature experimental and our computed data facilitated the prediction of reliable gas-phase molecular properties for some oxides. They include the stretching frequencies of PuO, ThO(2), UO(2), and UO(2)(+) and the bond distance of PuO (1.818 Å, being likely within 0.002 Å of the real value). Also the derived equilibrium bond distances of ThO(2), UO(2), and UO(2)(+) (1.896, 1.790, and 1.758 Å, respectively) should approximate closely the (yet unknown) experimental values. On the basis of the present results, we suggest that the ground electronic state of PuO(2) in Ar and Kr matrices is probably different from that in the gaseous phase, similarly to UO(2) observed previously.

Double Membranes Vs. Lipid Bilayers, and Their Significance for Correct Identification of Macroautophagic Structures

Autophagy. Sep, 2011  |  Pubmed ID: 21642767

The Coding and Inter-manual Transfer of Movement Sequences

Frontiers in Psychology. 2011  |  Pubmed ID: 21716583

The manuscript reviews recent experiments that use inter-manual transfer and inter-manual practice paradigms to determine the coordinate system (visual-spatial or motor) used in the coding of movement sequences during physical and observational practice. The results indicated that multi-element movement sequences are more effectively coded in visual-spatial coordinates even following extended practice, while very early in practice movement sequences with only a few movement elements and relatively short durations are coded in motor coordinates. Likewise, inter-manual practice of relatively simple movement sequences show benefits of right and left limb practice that involves the same motor coordinates while the opposite is true for more complex sequences. The results suggest that the coordinate system used to code the sequence information is linked to both the task characteristics and the control processes used to produce the sequence. These findings have the potential to greatly enhance our understanding of why in some conditions participants following practice with one limb or observation of one limb practice can effectively perform the task with the contralateral limb while in other (often similar) conditions cannot.

Vertebral Artery Injuries Following Cervical Spine Trauma: a Prospective Observational Study

European Spine Journal : Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. Dec, 2011  |  Pubmed ID: 21717238

The purpose of this study was to report on the incidence, diagnosis and clinical manifestation of VAI following cervical spine injuries observed in a prospective observational study with a standardized clinical and radiographical protocol.

FGF10/FGFR2b Signaling is Essential for Cardiac Fibroblast Development and Growth of the Myocardium

Development (Cambridge, England). Aug, 2011  |  Pubmed ID: 21750042

The epicardium serves as a source of growth factors that regulate myocardial proliferation and as a source of epicardial-derived cells (EPDC), which give rise to interstitial cardiac fibroblasts and perivascular cells. These progenitors populate the compact myocardium to become part of the mature coronary vasculature and fibrous skeleton of the heart. Little is known about the mechanisms that regulate EPDC migration into the myocardium or the functions carried out by these cells once they enter the myocardium. However, it has been proposed that cardiac fibroblasts are important for growth of the heart during late gestation and are a source of homeostatic factors in the adult. Here, we identify a myocardial to epicardial fibroblast growth factor (FGF) signal, mediated by FGF10 and FGFR2b, that is essential for movement of cardiac fibroblasts into the compact myocardium. Inactivation of this signaling pathway results in fewer epicardial derived cells within the compact myocardium, decreased myocardial proliferation and a resulting smaller thin-walled heart.

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

The Journal of Biological Chemistry. Sep, 2011  |  Pubmed ID: 21757749

Fatty acid synthase (FAS) promotes energy storage through de novo lipogenesis and participates in signaling by the nuclear receptor PPARα in noncardiac tissues. To determine if de novo lipogenesis is relevant to cardiac physiology, we generated and characterized FAS knockout in the myocardium (FASKard) mice. FASKard mice develop normally, manifest normal resting heart function, and have normal cardiac PPARα signaling as well as fatty acid oxidation. However, they decompensate with stress. Most die within 1 h of transverse aortic constriction, probably due to arrhythmia. Voltage clamp measurements of FASKard cardiomyocytes show hyperactivation of L-type calcium channel current that could not be reversed with palmitate supplementation. Of the classic regulators of this current, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but not protein kinase A signaling is activated in FASKard hearts, and knockdown of FAS in cultured cells activates CaMKII. In addition to being intolerant of the stress of acute pressure, FASKard hearts were also intolerant of the stress of aging, reflected as persistent CaMKII hyperactivation, progression to dilatation, and premature death by ∼1 year of age. CaMKII signaling appears to be pathogenic in FASKard hearts because inhibition of its signaling in vivo rescues mice from early mortality after transverse aortic constriction. FAS was also increased in two mechanistically distinct mouse models of heart failure and in the hearts of humans with end stage cardiomyopathy. These data implicate a novel relationship between FAS and calcium signaling in the heart and suggest that FAS induction in stressed myocardium represents a compensatory response to protect cardiomyocytes from pathological calcium flux.

[Controversial Issues in Colorectal Screening in Hungary: Conflict of Clinical and Public Health Viewpoints]

Orvosi Hetilap. Jul, 2011  |  Pubmed ID: 21788205

In Hungary, mortality rates from colorectal cancer are dramatically high, therefore the reduction by population screening as a public health measure is considered as one of the priorities of National Public Health Program. In the beginning, a human-specific immunological test was applied in the "model programs", as a screening tool, to detect the occult blood in the stool; compliance was 32% in average. However, the objectives of the model programs have not been achieved, because, among other reasons, a debate on the method of choice and the strategy to follow have divided the professional public opinion. In this study the debated issues are critically discussed, being convinced that, at present, population screening seems to be the most promising way to alleviate the burden of colorectal cancer.

The WD40 Repeat PtdIns(3)P-binding Protein EPG-6 Regulates Progression of Omegasomes to Autophagosomes

Developmental Cell. Aug, 2011  |  Pubmed ID: 21802374

PtdIns(3)P plays critical roles in the autophagy pathway. However, little is known about how PtdIns(3)P effectors act with autophagy proteins in autophagosome formation. Here we identified an essential autophagy gene in C. elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity. EPG-6 directly interacts with ATG-2. epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures. Another WD40 repeat PtdIns(3)P effector, ATG-18, plays a distinct role in autophagosome formation. We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates and revealed that the UNC-51/Atg1 complex, EPG-8/Atg14, and binding of lipidated LGG-1 to protein aggregates are required for omegasome formation. Our study demonstrates that autophagic PtdIns(3)P effectors play distinct roles in autophagosome formation and also provides a framework for understanding the concerted action of autophagy genes in protein aggregate degradation.

Noninvasive Imaging After Stent-assisted Coiling of Intracranial Aneurysms: Comparison of 3-T Magnetic Resonance Imaging and 64-row Multidetector Computed Tomography--a Pilot Study

Journal of Computer Assisted Tomography. Sep-Oct, 2011  |  Pubmed ID: 21926852

Follow-up imaging after stent-assisted coiling of intracranial aneurysms is limited by signal loss in the stented vessel segment using magnetic resonance imaging or by streak artifacts caused by aneurysm coils using multidetector computed tomography. In the search for a noninvasive surveillance in this condition, we propose a technique to minimize streak artifacts in multidetector computed tomography by gated data reconstruction and shifting the reconstruction window.

Bacillus Alkalisediminis Sp. Nov., an Alkaliphilic and Moderately Halophilic Bacterium Isolated from Sediment of Extremely Shallow Soda Ponds

International Journal of Systematic and Evolutionary Microbiology. Aug, 2011  |  Pubmed ID: 20833886

Alkaliphilic strains characterized by optimal growth at pH 9.0 and 5 % (w/v) NaCl designated K1-25(T) and H3-93 were isolated from extremely shallow soda ponds located in Hungary. Cells of both strains were Gram-stain-positive, non-motile, straight rods and formed central, ellipsoidal endospores with swollen sporangia. The isolates were aerobic, catalase-positive, oxidase-negative and contained a peptidoglycan of type A1γ based on meso-diaminopimelic acid. In both strains, menaquinone-7 (MK-7) was the predominant isoprenoid quinone and the major cellular fatty acids were anteiso-C(15 : 0) and iso-C(15 : 0). The DNA G+C contents of strains K1-25(T) and H3-93 were 39.0 and 36.3 mol%, respectively. 16S rRNA gene sequence-based phylogenetic analysis revealed 99.2 % similarity between strains K1-25(T) and H3-93 and the novel isolates had the highest similarities to Bacillus akibai 1139(T) (97.8 and 98.3 %, respectively), Bacillus wakoensis N-1(T) (97.0 and 97.4 %), Bacillus okhensis Kh10-101(T) (97.1 and 97.4 %) and Bacillus krulwichiae AM31D(T) (96.9 and 97.1 %). DNA-DNA hybridization between our strains and the type strains of closely related Bacillus species was lower than 70 %. Although DNA-DNA hybridization between strains K1-25(T) and H3-93 was 27 %, the phenotypic and chemotaxonomic data did not support the differentiation of these two strains into separate species. Therefore, they represent genomovars of a novel species, for which the name Bacillus alkalisediminis sp. nov. is proposed. The type strain is K1-25(T) ( = DSM 21670(T)  = NCAIM B02301(T)).

Altered Glutamate Receptor Function in the Cerebellum of the Ppt1(-/-) Mouse, a Murine Model of Infantile Neuronal Ceroid Lipofuscinosis

Journal of Neuroscience Research. Feb, 2012  |  Pubmed ID: 21971706

The neuronal ceroid lipofuscinoses (NCLs) are a family of devastating pediatric neurodegenerative disorders and currently represent the most common form of pediatric-onset neurodegeneration. Infantile NCL (INCL), the most aggressive of these disorders, is caused by mutations in the CLN1 gene that encodes the enzyme palmitoyl protein thioesterase 1 (PPT1). Previous studies have suggested that glutamatergic neurotransmission may be disrupted in INCL, so the present study investigates glutamate receptor function in the Ppt1(-/-) mouse model of INCL by comparing the sensitivity of cultured wild-type (WT) and Ppt1(-/-) cerebellar granule cells to glutamate receptor-mediated toxicity. Ppt1(-/-) neurons were significantly less sensitive to AMPA receptor-mediated toxicity but markedly more vulnerable to NMDA receptor-mediated cell death. Because glutamate receptor function is regulated primarily by the surface expression level of the receptor, the surface level of AMPA and NMDA receptor subunits in the cerebella of WT and Ppt1(-/-) mice was also examined. Western blotting of surface cross-linked cerebellar samples showed a significantly lower surface level of the GluR4 AMPA receptor subunit in Ppt1(-/-) mice, providing a plausible explanation for the decreased vulnerability of Ppt1(-/-) cerebellar neurons to AMPA receptor-mediated cell death. The surface expression of the NR1, NR2A, and NR2B NMDA receptor subunits was similar in the cerebella of WT and Ppt1(-/-) mice, indicating that there is another mechanism behind the increased sensitivity of Ppt1(-/-) cerebellar granule cells to NMDA toxicity. Our results indicate an AMPA receptor hypofunction and NMDA receptor hyperfunction phenotype in Ppt1(-/-) neurons and provide new therapeutic targets for INCL.

Bimanual Fitts' Tasks: Kelso, Southard, and Goodman, 1979 Revisited

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Jan, 2012  |  Pubmed ID: 22045299

The experiment was designed to replicate and extend to an integrated feedback condition the pattern of movement time results found by Kelso et al. (J Exp Psychol Hum Percept Perform 5:229-238, 1979a, Science 204:1029-1031, 1979b) where the simultaneous movement of one hand to a low ID target and the other to a higher ID target indicated "a tight coordinate coupling between the hands" (p. 229). In the present experiment, a control group was provided feedback that depicted the independent movement of the two limbs under low and higher indexes of difficulty (ID). A Lissajous group was provided integrated feedback in the form of a Lissajous plot. The results indicated a pattern of results for the control and Lissajous groups similar to that found by Kelso et al. for one and two-limb movements to the same difficulty targets. The control group also replicated the finding for two-limb movements to mixed ID tasks. However, the Lissajous group simultaneously produced disparate movement in the mixed target conditions. The results are consistent with recent findings indicating that when provided salient integrated feedback participants can effectively produce disparate movements of the two limbs.

A Novel Actin Binding Site of Myosin Required for Effective Muscle Contraction

Nature Structural & Molecular Biology. Feb, 2012  |  Pubmed ID: 22343723

F-actin serves as a track for myosin's motor functions and activates its ATPase activity by several orders of magnitude, enabling actomyosin to produce effective force against load. Although actin activation is a ubiquitous property of all myosin isoforms, the molecular mechanism and physiological role of this activation are unclear. Here we describe a conserved actin-binding region of myosin named the 'activation loop', which interacts with the N-terminal segment of actin. We demonstrate by biochemical, biophysical and in vivo approaches using transgenic Caenorhabditis elegans strains that the interaction between the activation loop and actin accelerates the movement of the relay, stimulating myosin's ATPase activity. This interaction results in efficient force generation, but it is not essential for the unloaded motility. We conclude that the binding of actin to myosin's activation loop specifically increases the ratio of mechanically productive to futile myosin heads, leading to efficient muscle contraction.

Molecular Structure and Vibrational Spectra of Mixed MDyX4 (M = Li, Na, K, Rb, Cs; X = F, Cl, Br, I) Vapor Complexes: a Computational and Matrix-isolation Infrared Spectroscopic Study

Inorganic Chemistry. Jan, 2012  |  Pubmed ID: 22136352

The structures, energetic, and vibrational properties of MDyX(4) (M = Li, Na, K, Rb, Cs; X = F, Cl, Br, I) mixed alkali halide/dysprosium halide complexes have been investigated by a joint computational and experimental, matrix-isolation Fourier-transform infrared spectroscopic (MI-IR), study. According to our DFT computations for the complexes with heavier halides and alkali metals the ground-state structure is the tridentate isomer; while at high temperatures the bidentate structural isomer dominates. The survey of various dissociation processes revealed the preference of the dissociation to neutral MX and DyX(3) fragments over ionic and radical dissociation products. Cationic complexes are considerably less stable at 1000 K than the neutral complexes, and they prefer to dissociate to M(+) + DyX(4)(•) fragments. The vapor species of selected mixtures of NaBr and CsBr with DyBr(3) and of CsI with DyI(3) in the temperature range 900-1000 K have been isolated in krypton and xenon matrices and investigated by infrared spectroscopy. Besides the characteristic vibrational frequencies of the monomeric and dimeric alkali halide species and of the dysprosium trihalide molecules, certain signals indicated the formation of MDyX(4) (M = Na, Cs; X = Br, I) mixed complexes. Comparison with the computed vibrational and thermodynamic characteristics of the relevant species lead to the conclusion that these complexes appear in the vapor predominantly as the C(2v)-symmetry bidentate isomer. This is the first time that this structure was identified in an experimental vibrational spectroscopic study. The signals appearing upon performing a thermal anneal cycle were tentatively assigned to the double complex M(2)DyX(5) (M = Na, Cs; X = Br, I). A structure in which one alkali atom is bound to dysprosium by three and the other by two bridges is proposed for these double complexes.

Theoretical Study of the Structure and Bonding in ThC2 and UC2

The Journal of Physical Chemistry. A. Jan, 2012  |  Pubmed ID: 22191481

The electronic structure and various molecular properties of the actinide (An) dicarbides ThC(2) and UC(2) were investigated by relativistic quantum chemical calculations. We probe five possible geometrical arrangements: two triangular structures including an acetylide (C(2)) moiety, as well as the linear AnCC, CAnC, and bent CAnC geometries. Our calculations at various levels of theory indicate that the triangular species are energetically more favorable, while the latter three arrangements proved to be higher-energy structures. Our SO-CASPT2 calculations give the ground-state molecular geometry for both ThC(2) and UC(2) as the symmetric (C(2v)) triangular structure. The similar and, also very close in energy, asymmetric (C(s)) triangular geometry belongs to a different electronic state. DFT and single-determinant ab initio methods failed to distinguish between these two similar electronic states demonstrating the power of multiconfiguration ab initio methods to deal with such subtle and delicate problems. We report detailed data on the electronic structure and bonding properties of the most relevant structures.