[Construction of a Set of Secreting Expression Vectors for Saccharomyces Cerevisiea]

Wei Sheng Wu Xue Bao = Acta Microbiologica Sinica. Aug, 2002  |  Pubmed ID: 12557548

The DNA fragment ecoding the Signal peptide of inulinase of Kluyveromyces smarxianu was synthesized chemically. This fragment was cloned in-frame in the expression vector pYES2 of Saccharomyces cerevisiae, resulting in a set of new secreting expression vectors pYES2 I, pYES2 II, pYES2 III. The L-Asparaginase gene (ASN) of E. coli and alpha-acetylactate decarboxylase gene (ALDC) of B. brevis which were amplified by PCR and cloned into the new vectors respectively were transformed into Saccharomyces cerevisia, and most of enzyme activities were secreted into the medium. The new secreting expression vectors still have excellent segregational stability even after growth for 100 h in the absence of selective pressure.

RNA-dependent RNA Polymerase Gene Sequence from Foot-and-mouth Disease Virus in Hong Kong

Biochemical and Biophysical Research Communications. Sep, 2003  |  Pubmed ID: 12927804

A foot-and-mouth disease virus (FMDV, HKN/2002) was isolated in Hong Kong in 2002. The nucleotide sequence of the 3D(pol) gene encoding the viral RNA-dependent RNA polymerase was determined and compared with that of the same gene from other FMDVs. The 3D(pol) gene was 1410 nucleotides in length encoding a protein of 470 amino acid residues. Sequence comparisons indicated that HKN/2002 belonged to serotype O. An evolutionary tree based on the 3D(pol) sequences of 20 FMDV isolates revealed that the nucleotide sequence of the HKN/2002 3D(pol) gene was most similar to those of isolates found in Taiwan in 1997, suggesting that they share a common ancestor. The amino acid sequence of the HKN/2002 3D(pol) gene was determined and aligned with those of representative isolates from seven other Picornaviridae genera. Eight highly conserved regions were detected, indicating a conserved functional relevance for these motifs. Alignment of 20 FMDV 3D(pol) amino acid sequences revealed a hypermutation region near the N-terminus that may help the virus evade host immune systems.

Diabetes-associated Mutations in Insulin: Consecutive Residues in the B Chain Contact Distinct Domains of the Insulin Receptor

Biochemistry. Jul, 2004  |  Pubmed ID: 15222748

How insulin binds to and activates the insulin receptor has long been the subject of speculation. Of particular interest are invariant phenylalanine residues at consecutive positions in the B chain (residues B24 and B25). Sites of mutation causing diabetes mellitus, these residues occupy opposite structural environments: Phe(B25) projects from the surface of insulin, whereas Phe(B24) packs against the core. Despite these differences, site-specific cross-linking suggests that each contacts the insulin receptor. Photoactivatable derivatives of insulin containing respective p-azidophenylalanine substitutions at positions B24 and B25 were synthesized in an engineered monomer (DKP-insulin). On ultraviolet irradiation each derivative cross-links efficiently to the receptor. Packing of Phe(B24) at the receptor interface (rather than against the core of the hormone) may require a conformational change in the B chain. Sites of cross-linking in the receptor were mapped to domains by Western blot. Remarkably, whereas B25 cross-links to the C-terminal domain of the alpha subunit in accord with previous studies (Kurose, T., et al. (1994) J. Biol. Chem. 269, 29190-29197), the probe at B24 cross-links to its N-terminal domain (the L1 beta-helix). Our results demonstrate that consecutive residues in insulin contact widely separated sequences in the receptor and in turn suggest a revised interpretation of electron-microscopic images of the complex. By tethering the N- and C-terminal domains of the extracellular alpha subunit, insulin is proposed to stabilize an active conformation of the disulfide-linked transmembrane tyrosine kinase.

Cloning, Expression and Identification of a New Trehalose Synthase Gene from Thermobifida Fusca Genome

Acta Biochimica Et Biophysica Sinica. Jul, 2004  |  Pubmed ID: 15248022

A new open reading frame in Thermobifida fusca sequenced genome was identified to encode a new trehalose synthase, annotated as "glycosidase" in the GenBank database, by bioinformatics searching and experimental validation. The gene had a length of 1830 bp with about 65% GC content and encoded for a new trehalose synthase with 610 amino acids and deduced molecular weight of 66 kD. The high GC content seemed not to affect its good expression in E. coli BL21 in which the target protein could account for as high as 15% of the total cell proteins. The recombinant enzyme showed its optimal activities at 25 degrees and pH 6.5 when it converted substrate maltose into trehalose. However it would divert a high proportion of its substrate into glucose when the temperature was increased to 37 degrees, or when the enzyme concentration was high Its activity was not inhibited by 5 mM heavy metals such as Cu2+, Mn2+, and Zn2+ but affected by high concentration of glucose. Blasting against the database indicated that amino acid sequence of this protein had maximal 69% homology with the known trehalose synthases, and two highly conserved segments of the protein sequence were identified and their possible linkage with functions was discussed.

How Insulin Binds: the B-chain Alpha-helix Contacts the L1 Beta-helix of the Insulin Receptor

Journal of Molecular Biology. Aug, 2004  |  Pubmed ID: 15276842

Binding of insulin to the insulin receptor plays a central role in the hormonal control of metabolism. Here, we investigate possible contact sites between the receptor and the conserved non-polar surface of the B-chain. Evidence is presented that two contiguous sites in an alpha-helix, Val(B12) and Tyr(B16), contact the receptor. Chemical synthesis is exploited to obtain non-standard substitutions in an engineered monomer (DKP-insulin). Substitution of Tyr(B16) by an isosteric photo-activatable derivative (para-azido-phenylalanine) enables efficient cross-linking to the receptor. Such cross-linking is specific and maps to the L1 beta-helix of the alpha-subunit. Because substitution of Val(B12) by larger side-chains markedly impairs receptor binding, cross-linking studies at B12 were not undertaken. Structure-function relationships are instead probed by side-chains of similar or smaller volume: respective substitution of Val(B12) by alanine, threonine, and alpha-aminobutyric acid leads to activities of 1(+/-0.1)%, 13(+/-6)%, and 14(+/-5)% (relative to DKP-insulin) without disproportionate changes in negative cooperativity. NMR structures are essentially identical with native insulin. The absence of transmitted structural changes suggests that the low activities of B12 analogues reflect local perturbation of a "high-affinity" hormone-receptor contact. By contrast, because position B16 tolerates alanine substitution (relative activity 34(+/-10)%), the contribution of this neighboring interaction is smaller. Together, our results support a model in which the B-chain alpha-helix, functioning as an essential recognition element, docks against the L1 beta-helix of the insulin receptor.

Why Zinc Fingers Prefer Zinc: Ligand-field Symmetry and the Hidden Thermodynamics of Metal Ion Selectivity

Biochemistry. Nov, 2004  |  Pubmed ID: 15518539

The zinc finger, a motif of protein-nucleic acid recognition broadly conserved among eukaryotes, is a globular minidomain containing a tetrahedral metal-binding site. Preferential coordination of Zn(2+) (relative to Co(2+)) is proposed to reflect differences in ligand-field stabilization energies (LFSEs) due to complete or incomplete occupancy of d orbitals. LFSE predicts that the preference for Zn(2+) should be purely enthalpic in accord with calorimetric studies of a high-affinity consensus peptide (CP-1; Blasie, C. A., and Berg, J. (2002) Biochemistry 41, 15068-73). Despite its elegance, the general predominance of LFSE is unclear as (i) the magnitude by which CP-1 prefers Zn(2+) is greater than that expected and (ii) the analogous metal ion selectivity of a zinc metalloenzyme (carbonic anhydrase) is driven by changes in entropy rather than enthalpy. Because CP-1 was designed to optimize zinc binding, we have investigated the NMR structure and metal ion selectivity of a natural finger of lower stability derived from human tumor-suppressor protein WT1. Raman spectroscopy suggests that the structure of the WT1 domain is unaffected by interchange of Zn(2+) and Co(2+). As in CP-1, preferential binding of Zn(2+) (relative to Co(2+)) is driven predominantly by differences in enthalpy, but in this case the enthalpic advantage is less than that predicted by LFSE. A theoretical framework is presented to define the relationship between LFSE and other thermodynamic factors, such as metal ion electroaffinities, enthalpies of hydration, and the topography of the underlying folding landscape. The contribution of environmental coupling to entropy-enthalpy compensation is delineated in a formal thermodynamic cycle. Together, these considerations indicate that LFSE provides an important but incomplete description of the stringency and thermodynamic origin of metal-ion selectivity.

Solvation and the Hidden Thermodynamics of a Zinc Finger Probed by Nonstandard Repair of a Protein Crevice

Protein Science : a Publication of the Protein Society. Dec, 2004  |  Pubmed ID: 15557258

The classical Zn finger contains a phenylalanine at the crux of its three architectural elements: a beta-hairpin, an alpha-helix, and a Zn(2+)-binding site. Surprisingly, phenylalanine is not required for high-affinity Zn2+ binding, but instead contributes to the specification of a precise DNA-binding surface. Substitution of phenylalanine by leucine leads to a floppy but native-like structure whose Zn affinity is maintained by marked entropy-enthalpy compensation (DeltaDeltaH -8.3 kcal/mol and -TDeltaDeltaS 7.7 kcal/mol). Phenylalanine and leucine differ in shape, size, and aromaticity. To distinguish which features correlate with dynamic stability, we have investigated a nonstandard finger containing cyclohexanylalanine at this site. The structure of the nonstandard finger is similar to that of the native domain. The cyclohexanyl ring assumes a chair conformation, and conformational fluctuations characteristic of the leucine variant are damped. Although the nonstandard finger exhibits a lower affinity for Zn2+ than does the native domain (DeltaDeltaG -1.2 kcal/mol), leucine-associated perturbations in enthalpy and entropy are almost completely attenuated (DeltaDeltaH -0.7 kcal/mol and -TDeltaDeltaS -0.5 kcal/mol). Strikingly, global changes in entropy (as inferred from calorimetry) are in each case opposite in sign from changes in configurational entropy (as inferred from NMR). This seeming paradox suggests that enthalpy-entropy compensation is dominated by solvent reorganization rather than nominal molecular properties. Together, these results demonstrate that dynamic and thermodynamic perturbations correlate with formation or repair of a solvated packing defect rather than type of physical interaction (aromatic or aliphatic) within the core.

Huntingtin-interacting Protein HIP14 is a Palmitoyl Transferase Involved in Palmitoylation and Trafficking of Multiple Neuronal Proteins

Neuron. Dec, 2004  |  Pubmed ID: 15603740

In neurons, posttranslational modification by palmitate regulates the trafficking and function of signaling molecules, neurotransmitter receptors, and associated synaptic scaffolding proteins. However, the enzymatic machinery involved in protein palmitoylation has remained elusive. Here, using biochemical assays, we show that huntingtin (htt) interacting protein, HIP14, is a neuronal palmitoyl transferase (PAT). HIP14 shows remarkable substrate specificity for neuronal proteins, including SNAP-25, PSD-95, GAD65, synaptotagmin I, and htt. Conversely, HIP14 is catalytically invariant toward paralemmin and synaptotagmin VII. Exogenous HIP14 enhances palmitoylation-dependent vesicular trafficking of several acylated proteins in both heterologous cells and neurons. Moreover, interference with endogenous expression of HIP14 reduces clustering of PSD-95 and GAD65 in neurons. These findings define HIP14 as a mammalian palmitoyl transferase involved in the palmitoylation and trafficking of multiple neuronal proteins.

Enhancing the Activity of Insulin at the Receptor Interface: Crystal Structure and Photo-cross-linking of A8 Analogues

Biochemistry. Dec, 2004  |  Pubmed ID: 15610006

The receptor-binding surface of insulin is broadly conserved, reflecting its evolutionary optimization. Neighboring positions nevertheless offer an opportunity to enhance activity, through either transmitted structural changes or introduction of novel contacts. Nonconserved residue A8 is of particular interest as Thr(A8) --> His substitution (a species variant in birds and fish) augments the potency of human insulin. Diverse A8 substitutions are well tolerated, suggesting that the hormone-receptor interface is not tightly packed at this site. To resolve whether enhanced activity is directly or indirectly mediated by the variant A8 side chain, we have determined the crystal structure of His(A8)-insulin and investigated the photo-cross-linking properties of an A8 analogue containing p-azidophenylalanine. The structure, characterized as a T(3)R(3)(f) zinc hexamer at 1.8 A resolution, is essentially identical to that of native insulin. The photoactivatable analogue exhibits efficient cross-linking to the insulin receptor. The site of cross-linking lies within a 14 kDa C-terminal domain of the alpha-subunit. This contact, to our knowledge the first to be demonstrated from the A chain, is inconsistent with a recent model of the hormone-receptor complex derived from electron microscopy. Optimizing the binding interaction of a nonconserved side chain on the surface of insulin may thus enhance its activity.

Neuroligins Mediate Excitatory and Inhibitory Synapse Formation: Involvement of PSD-95 and Neurexin-1beta in Neuroligin-induced Synaptic Specificity

The Journal of Biological Chemistry. Apr, 2005  |  Pubmed ID: 15723836

The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1beta. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.

Diabetes-associated Mutations in Human Insulin: Crystal Structure and Photo-cross-linking Studies of A-chain Variant Insulin Wakayama

Biochemistry. Apr, 2005  |  Pubmed ID: 15794638

Naturally occurring mutations in insulin associated with diabetes mellitus identify critical determinants of its biological activity. Here, we describe the crystal structure of insulin Wakayama, a clinical variant in which a conserved valine in the A chain (residue A3) is substituted by leucine. The substitution occurs within a crevice adjoining the classical receptor-binding surface and impairs receptor binding by 500-fold, an unusually severe decrement among mutant insulins. To resolve whether such decreased activity is directly or indirectly mediated by the variant side chain, we have determined the crystal structure of Leu(A3)-insulin and investigated the photo-cross-linking properties of an A3 analogue containing p-azidophenylalanine. The structure, characterized in a novel crystal form as an R(6) zinc hexamer at 2.3 A resolution, is essentially identical to that of the wild-type R(6) hexamer. The variant side chain remains buried in a nativelike crevice with small adjustments in surrounding side chains. The corresponding photoactivatable analogue, although of low affinity, exhibits efficient cross-linking to the insulin receptor. The site of photo-cross-linking lies within a 14 kDa C-terminal domain of the alpha-subunit. This domain, unrelated in sequence to the major insulin-binding region in the N-terminal L1 beta-helix, is also contacted by photoactivatable probes at positions A8 and B25. Packing of Val(A3) at this interface may require a conformational change in the B chain to expose the A3-related crevice. The structure of insulin Wakayama thus evokes the reasoning of Sherlock Holmes in "the curious incident of the dog in the night": the apparent absence of structural perturbations (like the dog that did not bark) provides a critical clue to the function of a hidden receptor-binding surface.

Modulation of Neuronal Protein Trafficking and Function by Palmitoylation

Current Opinion in Neurobiology. Oct, 2005  |  Pubmed ID: 16125924

Modification of proteins with the lipid palmitate regulates targeting to specific vesicular compartments and synaptic membranes. Mounting evidence indicates that this lipid modification modulates diverse aspects of neuronal development and synaptic transmission. In particular, palmitoylation regulates the function of proteins that control neuronal differentiation, axonal pathfinding and filopodia formation. In addition, trafficking of numerous proteins associated with synaptic vesicle release machinery requires protein palmitoylation. Remarkably, reversible palmitoylation of specific scaffolding proteins and signaling molecules dynamically regulates ion channel clustering and synaptic strength. The recent discovery of enzymes that palmitoylate specific subsets of synaptic proteins suggests that this process is tightly controlled in neurons.

Proinsulin is Refractory to Protein Fibrillation: Topological Protection of a Precursor Protein from Cross-beta Assembly

The Journal of Biological Chemistry. Dec, 2005  |  Pubmed ID: 16239223

Insulin is susceptible to fibrillation, a misfolding process leading to well ordered cross-beta assembly. Protection from fibrillation in beta cells is provided by sequestration of the susceptible monomer within zinc hexamers. We demonstrate that proinsulin is refractory to fibrillation under conditions that promote the rapid fibrillation of zinc-free insulin. Proinsulin fibrils, as probed by Raman microscopy, are nonetheless similar in structure to insulin fibrils. The connecting peptide, although not well ordered in native proinsulin, participates in a fibril-specific beta-sheet. Native insulin and proinsulin exhibit similar free energies of unfolding as inferred from guanidine denaturation studies: relative amyloidogenicities are thus not correlated with global stability. Strikingly, the susceptibility of proinsulin to fibrillation is increased by scission of the connecting peptide at single sites. We thus propose that the connecting peptide constrains a large scale conformational change in the misfolded protein. A tethering mechanism is proposed based on a model of an insulin protofilament derived from electron-microscopic image reconstruction. The proposed relationship between cross-beta assembly and protein topology is supported by studies of single-chain analogs (mini-proinsulin and insulin-like growth factor I) in which foreshortened connecting peptides further retard fibrillation. In addition to its classic function to facilitate disulfide pairing, the connecting peptide may protect beta cells from toxic protein misfolding in the endoplasmic reticulum.

Virtual Mouse Placenta: Tissue Layer Segmentation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2005  |  Pubmed ID: 17282903

Microscopic imaging is an important phenotyping tool to characterize the phenotype (e.g., morphology and behavior) change caused by genotype manipulation such as mutation and gene knockout. Recently we use high resolution microscopic imaging to study the morphological change on mouse placenta induced by retinoblast (Rb) gene knockout. In order to assess the morphological change we first segment each microscopic image into regions corresponding to different tissue types. Due to the complex structure of these tissues and large variation among the more than 2,000 images, we design a Bayesian supervised segmentation method which utilizing image features of all levels. The method has been applied to the entire data set and generated satisfactory results that is essential for further analysis on 3-D morphological change of the tissue types.

Determinants of Variation in Analgesic and Opioid Prescribing Practice in an Emergency Department

Journal of Opioid Management. Nov-Dec, 2006  |  Pubmed ID: 17326595

Adequate treatment of patients' pain is a top priority for the World Health Organization (WHO), American Medical Association (AMA), and American College of Emergency Physicians (ACEP), but "adequate" is not clearly defined. Most previous studies of emergency department (ED) pain treatments have centered on musculoskeletal pain in terms of rates of analgesia and disparities in treatment based on race and age. This study will examine complaints of pain other than musculoskeletal and will focus on treatment disparities that may result from differences inpatient and physician characteristics.

Preparation of Highly Conductive, Self-assembled Gold/polyaniline Nanocables and Polyaniline Nanotubes

Chemistry (Weinheim an Der Bergstrasse, Germany). Jul, 2006  |  Pubmed ID: 16628760

One-dimensional gold/polyaniline (Au/PANI-CSA) coaxial nanocables with an average diameter of 50-60 nm and lengths of more than 1 mum were successfully synthesized by reacting aniline monomer with chlorauric acid (HAuCl(4)) through a self-assembly process in the presence of D-camphor-10-sulfonic acid (CSA), which acts as both a dopant and surfactant. It was found that the formation probability and the size of the Au/PANI-CSA nanocables depends on the molar ratio of aniline to HAuCl(4) and the concentration of CSA, respectively. A synergistic growth mechanism was proposed to interpret the formation of the Au/PANI-CSA nanocables. The directly measured conductivity of a single gold/polyaniline nanocable was found to be high (approximately 77.2 S cm(-1)). Hollow PANI-CSA nanotubes, with an average diameter of 50-60 nm, were also obtained successfully by dissolving the Au nanowire core of the Au/PANI-CSA nanocables.

Palmitoylation of Huntingtin by HIP14 is Essential for Its Trafficking and Function

Nature Neuroscience. Jun, 2006  |  Pubmed ID: 16699508

Post-translational modification by the lipid palmitate is crucial for the correct targeting and function of many proteins. Here we show that huntingtin (htt) is normally palmitoylated at cysteine 214, which is essential for its trafficking and function. The palmitoylation and distribution of htt are regulated by the palmitoyl transferase huntingtin interacting protein 14 (HIP14). Expansion of the polyglutamine tract of htt, which causes Huntington disease, results in reduced interaction between mutant htt and HIP14 and consequently in a marked reduction in palmitoylation. Mutation of the palmitoylation site of htt, making it palmitoylation resistant, accelerates inclusion formation and increases neuronal toxicity. Downregulation of HIP14 in mouse neurons expressing wild-type and mutant htt increases inclusion formation, whereas overexpression of HIP14 substantially reduces inclusions. These results suggest that the expansion of the polyglutamine tract in htt results in decreased palmitoylation, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity.

Disparities in Analgesia and Opioid Prescribing Practices for Patients with Musculoskeletal Pain in the Emergency Department

Journal of Emergency Nursing: JEN : Official Publication of the Emergency Department Nurses Association. Jun, 2006  |  Pubmed ID: 16730276

Healthy People 2010 seeks to eliminate racial and ethnic disparities in health care; however, disparities due to age and race have been described in emergency department pain treatment. Although pain is a common patient complaint in emergency departments, many people receive no analgesia. This study examined the influence of patient and provider characteristics on ED and discharge analgesia and opioid prescribing practices.

[Smoking and Subjective Life Qualities in Middle School Students]

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi. Feb, 2006  |  Pubmed ID: 16749994

To understand the tendency of smoking in middle school students during the last 5 years and to identify the relationship between subjective life qualities and different smoking behaviors in order to determine the possible effects on tobacco use.

[Impact of Childhood Abuses on the Psychology and Behaviors Regarding Harmful Dietary Pattern in Adolescents]

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi. Apr, 2006  |  Pubmed ID: 16875536

To examine the effect of childhood abuses on adolescents' psychology and behaviors related to harmful dietary pattern.

Structure-specific Effects of Protein Topology on Cross-beta Assembly: Studies of Insulin Fibrillation

Biochemistry. Aug, 2006  |  Pubmed ID: 16922503

Systemic amyloidoses, an important class of protein misfolding diseases, are often due to fibrillation of disulfide-cross-linked globular proteins otherwise unrelated in sequence or structure. Although cross-beta assembly is regarded as a universal property of polypeptides, it is not understood how such amyloids accommodate diverse disulfide connectivities. Does amyloidogenicity depend on protein topology? A model is provided by insulin, a two-chain protein containing three disulfide bridges. The importance of chain topology is demonstrated by mini-proinsulin (MP), a single-chain analogue in which the C-terminus of the B chain (residue B30) is tethered to the N-terminus of the A chain (A1). The B30-A1 tether impedes the fiber-specific alpha --> beta transition, leading to slow formation of a structurally nonuniform amorphous precipitate. Conversely, fibrillation is robust to interchange of disulfide bridges. Whereas native insulin exhibits pairings [A6-A11, A7-B7, and A20-B19], metastable isomers with alternative pairings [A6-B7, A7-A11, A20-B19] or [A6-A7, A11-B7, A20-B1] readily undergo fibrillation with essentially identical alpha --> beta transitions. Respective pairing schemes are in each case retained. Isomeric fibrils and the amorphous MP precipitate are each able to seed the fibrillation of wild-type insulin, suggesting a structural correspondence between respective nuclei or modes of assembly. Together, our results demonstrate that effects of polypeptide topology on amyloidogenicity depend on structural context. Although the native structures and stabilities of single-chain insulin analogues are similar to those of wild-type insulin, the interchain tether constrains the extent of conformational distortion at elevated temperature, retards initial non-native aggregation, and is apparently incompatible with the mature structure of an insulin protofilament. We speculate that the general danger of fibrillation has imposed a constraint in protein evolution, selecting for topologies unfavorable to amyloid formation.

Highly Enantioselective Alpha-aminoxylation of Aldehydes and Ketones in Ionic Liquids

The Journal of Organic Chemistry. Oct, 2006  |  Pubmed ID: 17025337

As the first example for the synthesis of optically active alpha-hydroxyaldehydes and alpha-hydroxyketones in ionic liquids, we applied RTILs into L-proline catalyzed direct enantioselective alpha-aminoxylation of both aldehydes and ketones successfully. This protocol features a number of advantages, such as recycling of green solvents and chiral organocatalyst, high yields, excellent enantioselectivities, short reaction times, and broad substrate scope.

Alterations in Cerebral Potentials Evoked by Rectal Distention and Drinking Ice Water in Patients with Irritable Bowel Syndrome

Journal of Gastroenterology and Hepatology. Dec, 2006  |  Pubmed ID: 17074024

Visceral hypersensitivity has been found to be present in irritable bowel syndrome (IBS). The current study sought to study visceral afferent hypersensitivity in IBS patients and obtain further objective evidence of alterations in intestinal afferent pathways in IBS patients by cerebral evoked potentials (CEP).

Multiscale Hybrid Linear Models for Lossy Image Representation

IEEE Transactions on Image Processing : a Publication of the IEEE Signal Processing Society. Dec, 2006  |  Pubmed ID: 17153941

In this paper, we introduce a simple and efficient representation for natural images. We view an image (in either the spatial domain or the wavelet domain) as a collection of vectors in a high-dimensional space. We then fit a piece-wise linear model (i.e., a union of affine subspaces) to the vectors at each downsampling scale. We call this a multiscale hybrid linear model for the image. The model can be effectively estimated via a new algebraic method known as generalized principal component analysis (GPCA). The hybrid and hierarchical structure of this model allows us to effectively extract and exploit multimodal correlations among the imagery data at different scales. It conceptually and computationally remedies limitations of many existing image representation methods that are based on either a fixed linear transformation (e.g., DCT, wavelets), or an adaptive uni-modal linear transformation (e.g., PCA), or a multimodal model that uses only cluster means (e.g., VQ). We will justify both quantitatively and experimentally why and how such a simple multiscale hybrid model is able to reduce simultaneously the model complexity and computational cost. Despite a small overhead of the model, our careful and extensive experimental results show that this new model gives more compact representations for a wide variety of natural images under a wide range of signal-to-noise ratios than many existing methods, including wavelets. We also briefly address how the same (hybrid linear) modeling paradigm can be extended to be potentially useful for other applications, such as image segmentation.

[Correlation Between Psychopathological Symptoms, Coping Style in Adolescent and Childhood Repeated Physical, Emotional Maltreatment]

Zhonghua Er Ke Za Zhi. Chinese Journal of Pediatrics. Sep, 2006  |  Pubmed ID: 17217665

To study possible relationship between psychopathological symptoms, positive and negative coping styles in adolescents who experienced repeated serious childhood physical abuse (CPA), moderate CPA, and childhood emotional abuse (CEA).

Salicylate-based Anti-inflammatory Drugs Inhibit the Early Lesion of Diabetic Retinopathy

Diabetes. Feb, 2007  |  Pubmed ID: 17259377

It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.

[Study on the Relations Between Psycho-behaviors and Weight Control in Adolescents]

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi. Nov, 2007  |  Pubmed ID: 18396661

To describe the different sex, age and grade distribution of coping behavior and its psychological effects on weight, and to analyze the correlation between overweight, obesity and unhealthy psycho-behaviors related to weight control in adolescents.

Rb is Critical in a Mammalian Tissue Stem Cell Population

Genes & Development. Jan, 2007  |  Pubmed ID: 17210791

The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5). Here we show that the specific loss of Rb in trophoblast stem (TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb(-/-) embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.

Asymmetric Synthesis of Primary Amines Via the Spiroborate-catalyzed Borane Reduction of Oxime Ethers

Organic Letters. Apr, 2007  |  Pubmed ID: 17397177

[reaction: see text] The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0 degrees C resulting in complete conversion to the corresponding primary amine in up to 99% ee.

The A-chain of Insulin Contacts the Insert Domain of the Insulin Receptor. Photo-cross-linking and Mutagenesis of a Diabetes-related Crevice

The Journal of Biological Chemistry. Nov, 2007  |  Pubmed ID: 17884811

The contribution of the insulin A-chain to receptor binding is investigated by photo-cross-linking and nonstandard mutagenesis. Studies focus on the role of Val(A3), which projects within a crevice between the A- and B-chains. Engineered receptor alpha-subunits containing specific protease sites ("midi-receptors") are employed to map the site of photo-cross-linking by an analog containing a photoactivable A3 side chain (para-azido-Phe (Pap)). The probe cross-links to a C-terminal peptide (residues 703-719 of the receptor A isoform, KTFEDYLHNVVFVPRPS) containing side chains critical for hormone binding (underlined); the corresponding segment of the holoreceptor was shown previously to cross-link to a Pap(B25)-insulin analog. Because Pap is larger than Val and so may protrude beyond the A3-associated crevice, we investigated analogs containing A3 substitutions comparable in size to Val as follows: Thr, allo-Thr, and alpha-aminobutyric acid (Aba). Substitutions were introduced within an engineered monomer. Whereas previous studies of smaller substitutions (Gly(A3) and Ser(A3)) encountered nonlocal conformational perturbations, NMR structures of the present analogs are similar to wild-type insulin; the variant side chains are accommodated within a native-like crevice with minimal distortion. Receptor binding activities of Aba(A3) and allo-Thr(A3) analogs are reduced at least 10-fold; the activity of Thr(A3)-DKP-insulin is reduced 5-fold. The hormone-receptor interface is presumably destabilized either by a packing defect (Aba(A3)) or by altered polarity (allo-Thr(A3) and Thr(A3)). Our results provide evidence that Val(A3), a site of mutation causing diabetes mellitus, contacts the insert domain-derived tail of the alpha-subunit in a hormone-receptor complex.

Detection and Visualization of Surface-pockets to Enable Phenotyping Studies

IEEE Transactions on Medical Imaging. Sep, 2007  |  Pubmed ID: 17896599

In this paper, we propose a technique for detecting pockets on a surface-of-interest. A sequence of propagating fronts converging to the target surface is used as the basis for inspection. We compute a correspondence function between the initial and the target surface. This leads to a natural definition of the local feature size measured as the evolution distance between mapped points. Surface pockets are then extracted as salient clusters embedded in the feature space. The level-set initialization also determines the scale-space of the extracted pockets. Results are presented on a case-study in which the focus is to chronicle the phenotyping differences in genetically modified mouse placenta. Our results are validated based on manually verified ground-truth.

Physical Activity Might Not Be the Protective Factor for Health Risk Behaviours and Psychopathological Symptoms in Adolescents

Journal of Paediatrics and Child Health. Nov, 2007  |  Pubmed ID: 17924938

This study aims to examine the effect of physical activity (PA) intensity on tobacco or alcohol abuse, suicide behaviours and psychopathological symptoms in junior and senior high school students in China.

[Psychological Well-being Among Adolescents of Parents Living with AIDS or HIV]

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi. Jun, 2007  |  Pubmed ID: 17939385

To investigate the psychological well-being among adolescents of HIV-positive parents.

The Expression of Interleukin-22 and S100A7, A8, A9 MRNA in Patients with Psoriasis Vulgaris

Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban. Oct, 2007  |  Pubmed ID: 18060647

In order to study the expression of interleukin-22 (IL-22) and S100A7, A8, A9 mRNA in the skin lesions of patients with psoriasis vulgaris and their relationship, the biopsies were taken from skin lesions in 35 patients with psoriasis vulgaris and the skin of 16 normal controls, and the expression levels of IL-22 and S100A7, A8 and A9 mRNA were detected by semi-quantitative RT-PCR. The results showed that (1) IL-22 and S100A8, A9 mRNA were positively expressed in the psoriatic skin lesions but negatively expressed in the normal controls; The expression level of S100A7 was (1.133+/-0.040) in the psoriatic skin lesions, significantly higher than that in the normal controls (0.744+/-0.037, P<0.01). (2) There were significantly positive correlations between the expression of IL-22/S100A7 mRNA, IL-22/S100A8 mRNA, IL-22/S100A9 mRNA in the psoriasis vulgaris (r(1)=0.543, r (2)=0.774, r(3)=0.621, P<0.01). It was concluded that IL-22 and S100A7, A8, A9 might play important roles in the occurrence and progression of psoriasis.

Orthogonal Sample Design Scheme for Two-dimensional Synchronous Spectroscopy and Its Application in Probing Intermolecular Interactions

Applied Spectroscopy. Dec, 2007  |  Pubmed ID: 18198029

This paper introduces a new approach to probing intermolecular interactions based on a framework of two-dimensional (2D) synchronous spectroscopy. Mathematical analysis performed on 2D synchronous spectra using variable concentration as an external perturbation shows that the cross-peaks are composed of two parts. The first part reflects intermolecular interactions that manifest in the form of deviation from the Beer-Lambert law. The second part is related simply to the concentration variations of the solutes and is responsible for the generation of interfering cross-peaks not related to the intermolecular interactions in the system. It is the second part that prevents the reliable identification of intermolecular interactions. We propose a way of selecting the concentrations of solutes so that the resultant dynamic concentration vectors of different solutes become orthogonal to one another. Therefore, the contribution of the second part to the cross-peaks can be effectively removed by the dot product of orthogonal vectors. Our new approach has been tested on a simulated chemical system and a real chemical system. The results demonstrate that interfering cross-peaks can be successfully removed from a 2D synchronous spectrum so that the cross-peaks can be used as a reliable tool to characterize or probe intermolecular interactions.

Paralemmin-1, a Modulator of Filopodia Induction is Required for Spine Maturation

Molecular Biology of the Cell. May, 2008  |  Pubmed ID: 18287537

Dendritic filopodia are thought to participate in neuronal contact formation and development of dendritic spines; however, molecules that regulate filopodia extension and their maturation to spines remain largely unknown. Here we identify paralemmin-1 as a regulator of filopodia induction and spine maturation. Paralemmin-1 localizes to dendritic membranes, and its ability to induce filopodia and recruit synaptic elements to contact sites requires protein acylation. Effects of paralemmin-1 on synapse maturation are modulated by alternative splicing that regulates spine formation and recruitment of AMPA-type glutamate receptors. Paralemmin-1 enrichment at the plasma membrane is subject to rapid changes in neuronal excitability, and this process controls neuronal activity-driven effects on protrusion expansion. Knockdown of paralemmin-1 in developing neurons reduces the number of filopodia and spines formed and diminishes the effects of Shank1b on the transformation of existing filopodia into spines. Our study identifies a key role for paralemmin-1 in spine maturation through modulation of filopodia induction.

Design of an Active Ultrastable Single-chain Insulin Analog: Synthesis, Structure, and Therapeutic Implications

The Journal of Biological Chemistry. May, 2008  |  Pubmed ID: 18332129

Single-chain insulin (SCI) analogs provide insight into the inter-relation of hormone structure, function, and dynamics. Although compatible with wild-type structure, short connecting segments (<3 residues) prevent induced fit upon receptor binding and so are essentially without biological activity. Substantial but incomplete activity can be regained with increasing linker length. Here, we describe the design, structure, and function of a single-chain insulin analog (SCI-57) containing a 6-residue linker (GGGPRR). Native receptor-binding affinity (130 +/- 8% relative to the wild type) is achieved as hindrance by the linker is offset by favorable substitutions in the insulin moiety. The thermodynamic stability of SCI-57 is markedly increased (DeltaDeltaG(u) = 0.7 +/- 0.1 kcal/mol relative to the corresponding two-chain analog and 1.9 +/- 0.1 kcal/mol relative to wild-type insulin). Analysis of inter-residue nuclear Overhauser effects demonstrates that a native-like fold is maintained in solution. Surprisingly, the glycine-rich connecting segment folds against the insulin moiety: its central Pro contacts Val(A3) at the edge of the hydrophobic core, whereas the final Arg extends the A1-A8 alpha-helix. Comparison between SCI-57 and its parent two-chain analog reveals striking enhancement of multiple native-like nuclear Overhauser effects within the tethered protein. These contacts are consistent with wild-type crystal structures but are ordinarily attenuated in NMR spectra of two-chain analogs, presumably due to conformational fluctuations. Linker-specific damping of fluctuations provides evidence for the intrinsic flexibility of an insulin monomer. In addition to their biophysical interest, ultrastable SCIs may enhance the safety and efficacy of insulin replacement therapy in the developing world.

An Indicator of Cancer: Downregulation of Monoamine Oxidase-A in Multiple Organs and Species

BMC Genomics. 2008  |  Pubmed ID: 18366702

Identifying consistent changes in cellular function that occur in multiple types of cancer could revolutionize the way cancer is treated. Previous work has produced promising results such as the identification of p53. Recently drugs that affect serotonin reuptake were shown to reduce the risk of colon cancer in man. Here, we analyze an ensemble of cancer datasets focusing on genes involved in the serotonergic pathway. Genechip datasets consisting of cancerous tissue from human, mouse, rat, or zebrafish were extracted from the GEO database. We first compared gene expression between cancerous tissues and normal tissues for each type of cancer and then identified changes that were common to a variety of cancer types.

Highly Enantioselective Borane Reduction of Heteroaryl and Heterocyclic Ketoxime Ethers Catalyzed by Novel Spiroborate Ester Derived from Diphenylvalinol: Application to the Synthesis of Nicotine Analogues

The Journal of Organic Chemistry. Jun, 2008  |  Pubmed ID: 18447392

An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from ( S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10 degrees C. ( S)- N-ethylnornicotine ( 3) was also successfully synthesized from the TIPS-protected ( S)-2-amino-2-pyridylethanol in 97% ee.

Reconstruction of Cellular Biological Structures from Optical Microscopy Data

IEEE Transactions on Visualization and Computer Graphics. Jul-Aug, 2008  |  Pubmed ID: 18467760

Developments in optical microscopy imaging have generated large high-resolution data sets that have spurred medical researchers to conduct investigations into mechanisms of disease, including cancer at cellular and subcellular levels. The work reported here demonstrates that a suitable methodology can be conceived that isolates modality-dependent effects from the larger segmentation task and that 3D reconstructions can be cognizant of shapes as evident in the available 2D planar images. In the current realization, a method based on active geodesic contours is first deployed to counter the ambiguity that exists in separating overlapping cells on the image plane. Later, another segmentation effort based on a variant of Voronoi tessellations improves the delineation of the cell boundaries using a Bayesian formulation. In the next stage, the cells are interpolated across the third dimension thereby mitigating the poor structural correlation that exists in that dimension. We deploy our methods on three separate data sets obtained from light, confocal, and phase-contrast microscopy and validate the results appropriately.

The Structure of a Mutant Insulin Uncouples Receptor Binding from Protein Allostery. An Electrostatic Block to the TR Transition

The Journal of Biological Chemistry. Jul, 2008  |  Pubmed ID: 18492668

The zinc insulin hexamer undergoes allosteric reorganization among three conformational states, designated T(6), T(3)R(3)(f), and R(6). Although the free monomer in solution (the active species) resembles the classical T-state, an R-like conformational change is proposed to occur upon receptor binding. Here, we distinguish between the conformational requirements of receptor binding and the crystallographic TR transition by design of an active variant refractory to such reorganization. Our strategy exploits the contrasting environments of His(B5) in wild-type structures: on the T(6) surface but within an intersubunit crevice in R-containing hexamers. The TR transition is associated with a marked reduction in His(B5) pK(a), in turn predicting that a positive charge at this site would destabilize the R-specific crevice. Remarkably, substitution of His(B5) (conserved among eutherian mammals) by Arg (occasionally observed among other vertebrates) blocks the TR transition, as probed in solution by optical spectroscopy. Similarly, crystallization of Arg(B5)-insulin in the presence of phenol (ordinarily a potent inducer of the TR transition) yields T(6) hexamers rather than R(6) as obtained in control studies of wild-type insulin. The variant structure, determined at a resolution of 1.3A, closely resembles the wild-type T(6) hexamer. Whereas Arg(B5) is exposed on the protein surface, its side chain participates in a solvent-stabilized network of contacts similar to those involving His(B5) in wild-type T-states. The substantial receptor-binding activity of Arg(B5)-insulin (40% relative to wild type) demonstrates that the function of an insulin monomer can be uncoupled from its allosteric reorganization within zinc-stabilized hexamers.

An Imaging Workflow for Characterizing Phenotypical Change in Large Histological Mouse Model Datasets

Journal of Biomedical Informatics. Dec, 2008  |  Pubmed ID: 18502696

This paper presents a workflow designed to quantitatively characterize the 3D structural attributes of macroscopic tissue specimens acquired at a micron level resolution using light microscopy. The specific application is a study of the morphological change in a mouse placenta induced by knocking out the retinoblastoma gene.

[Studies on Coordination and Hydrogen Bond Intermolecular Interaction Using 1D & 2D FTIR Spectroscopy]

Guang Pu Xue Yu Guang Pu Fen Xi = Guang Pu. Mar, 2008  |  Pubmed ID: 18536407

Two-dimensional (2D) correlation spectroscopy is a powerful method to study the intermolecular interactions between different molecules/functional groups. In the present paper, variable concentrations were selected to construct 2D synchronous spectrum for studying the weak intermolecular interactions in solutions. Mathematical analysis performed on 2D synchronous spectra using variable concentration as an external perturbation shows that the "Orthogonal Sample Design Scheme" is necessary for eliminating the interfering cross peaks in 2D synchronous spectra. The authors prepared four mixed-solutes-solutions whose concentration series satisfy the "Orthogonal Sample Design Scheme" for each chemical system and the consequent 2D synchronous spectrum was calculated from the corresponding four 1D spectra. Thus, by 1D & 2D FTIR spectra together with solid grinding reaction, the intermolecular interactions in two chemical systems (Sodium 2-Aminobenzoate/NdCl3 in aqueous solution, and 2-ethylhexyl phosphonic acid mono 2-ethylhexyl ester (PC88A)/Naphthenic Acid (NA) in heptane solution) were studied, where the intermolecular interactions only induce subtle spectral variations in conventional 1D spectra. First, the cross peaks between f-f transition bands of Nd3+ ion at 521, 574, 741, 795 and 865 nm and pi-pi transition band of Sodium 2-Aminobenzoate at 308 nm in 2D synchronous spectrum confirm the coordination interaction between Sodium 2-Aminobenzoate and Nd3+. Solid grinding reaction between Sodium 2-Aminobenzoate and NdCl3 and FTIR spectra of the product indicate that the vibration bands of amino, carboxyl groups from sodium 2-aminobenzoate show considerable changes. Based on the spectral result above, a conclusion is drawn that Nd3+ can coordinate with Sodium 2-Aminobenzoate by amino and carboxyl groups. Second, the cross peaks between POH stretching band of PC88A at 983 cm(-1) and COOH stretching band of NA at 1 710 cm(-1) in 2D spectra confirm the interaction between PC88A and NA. Subtraction spectrum demonstrates that when PC88A is mixed with NA in heptane solution, and P=O stretching band of PC88A shifts from 1 199 to 1161 cm(-1), and POH stretching band shifts from 983 to 965 cm(-1). Based on the spectral result above, a conclusion was made that PC88A and NA can interact with each other by forming new assemblies with POH and COOH groups.

A Practical and Efficient Route for the Highly Enantioselective Synthesis of Mexiletine Analogues and Novel Beta-thiophenoxy and Pyridyl Ethers

The Journal of Organic Chemistry. Sep, 2008  |  Pubmed ID: 18690744

A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues with use of 10% of spiroborate ester 6 as chirality transfer agent is presented. A variety of mexiletine analogues were prepared in good yield with excellent enantioselectivities (91-97% ee) from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel beta-amino ethers containing thiophenyl and pyridyl fragments.

ErbB4-neuregulin Signaling Modulates Synapse Development and Dendritic Arborization Through Distinct Mechanisms

The Journal of Biological Chemistry. Nov, 2008  |  Pubmed ID: 18819924

Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.

Neural Palmitoyl-proteomics Reveals Dynamic Synaptic Palmitoylation

Nature. Dec, 2008  |  Pubmed ID: 19092927

Palmitoylation regulates diverse aspects of neuronal protein trafficking and function. Here a global characterization of rat neural palmitoyl-proteomes identifies most of the known neural palmitoyl proteins-68 in total, plus more than 200 new palmitoyl-protein candidates, with further testing confirming palmitoylation for 21 of these candidates. The new palmitoyl proteins include neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins, as well as SNAREs and other vesicular trafficking proteins. Of particular interest is the finding of palmitoylation for a brain-specific Cdc42 splice variant. The palmitoylated Cdc42 isoform (Cdc42-palm) differs from the canonical, prenylated form (Cdc42-prenyl), both with regard to localization and function: Cdc42-palm concentrates in dendritic spines and has a special role in inducing these post-synaptic structures. Furthermore, assessing palmitoylation dynamics in drug-induced activity models identifies rapidly induced changes for Cdc42 as well as for other synaptic palmitoyl proteins, suggesting that palmitoylation may participate broadly in the activity-driven changes that shape synapse morphology and function.

[Formation of W/O Microemulsions in TBP-Pd(II)-HCl Extraction System and Spectroscopic Research on the Evolution of Solution Aggregation Structure]

Guang Pu Xue Yu Guang Pu Fen Xi = Guang Pu. Sep, 2008  |  Pubmed ID: 19093556

The formation of W/O microemulsions in the extraction system TBP-Pd(II)-HCl was investigated. The solution structural evolution of the palladium loaded organic phases, with the variation in the content of acid into the organic phases, was characterized by various spectroscopic techniques such as DLS, FTIR and 31P-/1H NMR. The results indicated that (1) the extraction behaviors of palladium was related to the formation of W/O microemulsion structure in the loaded organic solutions. Because of the co-extraction of hydrochloric acid, there formed the microscopic aggregates in the loaded organic phases. (2) The variation in the HCl content in organic phase resulted in corresponding changes in solution structure. With the increase in the HCl content, the average radii of nanoscopic aggregates in the organic phases increased and then decreased. The extraction of HCl into the organic phase exhibited a distinct impact on the O-H stretching vibration and O-H-O bending vibration of water molecules in the microscopic W/O micelles. FTIR spectra of the organic phase saturated with acids show that the broad band of O-H stretching vibration of water extended to a very wide range and overlaped with the C-H stretching vibration bands. The higher the acid concentration in the organic phase was, the greater the overlapping. On the other hand, it was also observed that a remarkable change appeared in the O-H-O bending vibration of water and the stretching vibration of P=O in TBP molecules shifted to lower frequency. With the increase in acid content in the TBP organic phases, the observed 31P NMR chemical shifts decreased and varied to up-field; whereas the 1H NMR chemical shift of H+ increased and even became larger than that of deuterium chloride-d at a lower frequency field. The changes in delta 31P to opposite direction of delta H+ means that TBP molecules were associated with acid protons and water molecules in microemulsion pools to form RP=O x H+ or RP=O x H3O+, and then interacted with PdCl4(2-) complex ions, which finally led to the extraction of palladium into the organic phase. (3) When forming the W/O reversed micelles/microemulsions, the concentration of acid within the microscopic micelles was even higher than that of saturated concentrated hydrochloric acid. It was the microscopic structural changes in organic phase microemulsion "water pool" that resulted in the corresponding variations in the palladium extraction behaviors.

New Bioinformatics Approach to Analyze Gene Expressions and Signaling Pathways Reveals Unique Purine Gene Dysregulation Profiles That Distinguish Between CD and UC

Inflammatory Bowel Diseases. Jul, 2009  |  Pubmed ID: 19253308

Expression of purine genes is modulated by inflammation or experimental colitis and altered expression leads to disrupted gut function. We studied purine gene dysregulation profiles in inflammatory bowel disease (IBD) and determined whether they can distinguish between Crohn's disease (CD) and ulcerative colitis (UC) using Pathway Analysis and a new Comparative Analysis of Gene Expression and Selection (CAGES) method.

Neuronal Palmitoyl Acyl Transferases Exhibit Distinct Substrate Specificity

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Aug, 2009  |  Pubmed ID: 19299482

Palmitoylation, a post-translational modification of cysteine residues with the lipid palmitate, has recently emerged as an important mechanism for regulating protein trafficking and function. With the identification of 23 DHHC mammalian palmitoyl acyl transferases (PATs), a key question was the nature of substrate-enzyme specificity for these PATs. Using the acyl-biotin exchange palmitoylation assay, we compared the substrate specificity of four neuronal PATs, namely DHHC-3, DHHC-8, HIP14L (DHHC-13), and HIP14 (DHHC-17). Exogenous expression of enzymes and substrates in COS cells reveals that HIP14L and HIP14 modulate huntingtin palmitoylation, DHHC-8 modulates paralemmin-1 palmitoylation, and DHHC-3 shows the least substrate specificity. These in vitro data were validated by lentiviral siRNA-mediated knockdown of endogenous HIP14 and DHHC-3 in cultured rat cortical neurons. PATs require the presence of palmitoylated cysteines in order to interact with their substrates. To understand the elements that influence enzyme/substrate specificity further, we fused the HIP14 ankryin repeat domain to the N terminus of DHHC-3, which is not a PAT for huntingtin. This modification enabled DHHC-3 to behave similarly to HIP14 by modulating palmitoylation and trafficking of huntingtin. Taken together, this study indicates that individual PATs have specific substrate preference, determined by regulatory domains outside the DHHC domain of the enzymes.

Decoding the Cryptic Active Conformation of a Protein by Synthetic Photoscanning: Insulin Inserts a Detachable Arm Between Receptor Domains

The Journal of Biological Chemistry. May, 2009  |  Pubmed ID: 19321435

Proteins evolve in a fitness landscape encompassing a complex network of biological constraints. Because of the interrelation of folding, function, and regulation, the ground-state structure of a protein may be inactive. A model is provided by insulin, a vertebrate hormone central to the control of metabolism. Whereas native assembly mediates storage within pancreatic beta-cells, the active conformation of insulin and its mode of receptor binding remain elusive. Here, functional surfaces of insulin were probed by photocross-linking of an extensive set of azido derivatives constructed by chemical synthesis. Contacts are circumferential, suggesting that insulin is encaged within its receptor. Mapping of photoproducts to the hormone-binding domains of the insulin receptor demonstrated alternating contacts by the B-chain beta-strand (residues B24-B28). Whereas even-numbered probes (at positions B24 and B26) contact the N-terminal L1 domain of the alpha-subunit, odd-numbered probes (at positions B25 and B27) contact its C-terminal insert domain. This alternation corresponds to the canonical structure of abeta-strand (wherein successive residues project in opposite directions) and so suggests that the B-chain inserts between receptor domains. Detachment of a receptor-binding arm enables photo engagement of surfaces otherwise hidden in the free hormone. The arm and associated surfaces contain sites also required for nascent folding and self-assembly of storage hexamers. The marked compression of structural information within a short polypeptide sequence rationalizes the diversity of diabetes-associated mutations in the insulin gene. Our studies demonstrate that photoscanning mutagenesis can decode the active conformation of a protein and so illuminate cryptic constraints underlying its evolution.

Enhancing the Activity of a Protein by Stereospecific Unfolding: Conformational Life Cycle of Insulin and Its Evolutionary Origins

The Journal of Biological Chemistry. May, 2009  |  Pubmed ID: 19321436

A central tenet of molecular biology holds that the function of a protein is mediated by its structure. An inactive ground-state conformation may nonetheless be enjoined by the interplay of competing biological constraints. A model is provided by insulin, well characterized at atomic resolution by x-ray crystallography. Here, we demonstrate that the activity of the hormone is enhanced by stereospecific unfolding of a conserved structural element. A bifunctional beta-strand mediates both self-assembly (within beta-cell storage vesicles) and receptor binding (in the bloodstream). This strand is anchored by an invariant side chain (Phe(B24)); its substitution by Ala leads to an unstable but native-like analog of low activity. Substitution by d-Ala is equally destabilizing, and yet the protein diastereomer exhibits enhanced activity with segmental unfolding of the beta-strand. Corresponding photoactivable derivatives (containing l- or d-para-azido-Phe) cross-link to the insulin receptor with higher d-specific efficiency. Aberrant exposure of hydrophobic surfaces in the analogs is associated with accelerated fibrillation, a form of aggregation-coupled misfolding associated with cellular toxicity. Conservation of Phe(B24), enforced by its dual role in native self-assembly and induced fit, thus highlights the implicit role of misfolding as an evolutionary constraint. Whereas classical crystal structures of insulin depict its storage form, signaling requires engagement of a detachable arm at an extended receptor interface. Because this active conformation resembles an amyloidogenic intermediate, we envisage that induced fit and self-assembly represent complementary molecular adaptations to potential proteotoxicity. The cryptic threat of misfolding poses a universal constraint in the evolution of polypeptide sequences.

TSC-22 Contributes to Hematopoietic Precursor Cell Proliferation and Repopulation and is Epigenetically Silenced in Large Granular Lymphocyte Leukemia

Blood. May, 2009  |  Pubmed ID: 19329776

Aberrant methylation of tumor suppressor genes can lead to their silencing in many cancers. TSC-22 is a gene silenced in several solid tumors, but its function and the mechanism(s) responsible for its silencing are largely unknown. Here we demonstrate that the TSC-22 promoter is methylated in primary mouse T or natural killer (NK) large granular lymphocyte (LGL) leukemia and this is associated with down-regulation or silencing of TSC-22 expression. The TSC-22 deregulation was reversed in vivo by a 5-aza-2'-deoxycytidine therapy of T or NK LGL leukemia, which significantly increased survival of the mice bearing this disease. Ectopic expression of TSC-22 in mouse leukemia or lymphoma cell lines resulted in delayed in vivo tumor formation. Targeted disruption of TSC-22 in wild-type mice enhanced proliferation and in vivo repopulation efficiency of hematopoietic precursor cells (HPCs). Collectively, our data suggest that TSC-22 normally contributes to the regulation of HPC function and is a putative tumor suppressor gene that is hypermethylated and silenced in T or NK LGL leukemia.

Well-defined Organic Nanotubes from Multicomponent Bottlebrush Copolymers

Journal of the American Chemical Society. May, 2009  |  Pubmed ID: 19397329

Bottlebrush copolymers are comblike macromolecules with densely grafted polymeric branches that adopt a cylindrical shape in solutions. We demonstrate a new method for the preparation of organic nanotubes by single molecule templating of core-shell bottlebrush copolymers. Multicomponent bottlebrush copolymers with well-defined structural parameters are synthesized by a combination of different living polymerization methods. Tubular structures can be prepared by cross-linking the shell layer and selectively etching out the core. The shape and size of original bottlebrush macromolecules are preserved during these transformations, which leads to the formation of well-defined organic nanotubes. The length and diameter of nanotubes are dictated by the length of the backbones and branches of the polymeric precursors, respectively. Water-soluble nanotubes with a hydrophobic interior can be prepared from bottlebrush copolymers with triblock copolymer branches. Herein, we outline molecular design strategies to fabricate nanotubes with controlled lengths, open pores, and different solubility characteristics.

Spiroborate Ester-mediated Asymmetric Synthesis of Beta-hydroxy Ethers and Its Conversion to Highly Enantiopure Beta-amino Ethers

The Journal of Organic Chemistry. Jun, 2009  |  Pubmed ID: 19413288

Borane-mediated reduction of aryl and alkyl ketones with alpha-aryl- and alpha-pyridyloxy groups affords beta-hydroxy ethers in high enantiomeric purity (up to 99% ee) and in good yield, using as catalyst 10 mol % of spiroborate ester 1 derived from (S)-diphenylprolinol. Representative beta-hydroxy ethers are successfully converted to beta-amino ethers, with minor epimerization, by phthalimide substitution under Mitsunobu's conditions followed by hydrazinolysis to obtain primary amino ethers or by imide reduction with borane to afford beta-2,3-dihydro-1H-isoindol ethers. Nonracemic Mexiletine and nAChR analogues with potential biological activity are also synthesized in excellent yield by mesylation of key beta-hydroxy pyridylethers and substitution with five-, six-, and seven-membered ring heterocyclic amines.

Feature-based Registration of Histopathology Images with Different Stains: an Application for Computerized Follicular Lymphoma Prognosis

Computer Methods and Programs in Biomedicine. Dec, 2009  |  Pubmed ID: 19487043

Follicular lymphoma (FL) is the second most common type of non-Hodgkin's lymphoma. Manual histological grading of FL is subject to remarkable inter- and intra-reader variations. A promising approach to grading is the development of a computer-assisted system that improves consistency and precision. Correlating information from adjacent slides with different stain types requires establishing spatial correspondences between the digitized section pair through a precise non-rigid image registration. However, the dissimilar appearances of the different stain types challenges existing registration methods. This study proposes a method for the automatic non-rigid registration of histological section images with different stain types. This method is based on matching high level features that are representative of small anatomical structures. This choice of feature provides a rich matching environment, but also results in a high mismatch probability. Matching confidence is increased by establishing local groups of coherent features through geometric reasoning. The proposed method is validated on a set of FL images representing different disease stages. Statistical analysis demonstrates that given a proper feature set the accuracy of automatic registration is comparable to manual registration.

Overexpression of Mitogen-activated Protein Kinase Kinase 4 and Nuclear Factor-kappaB in Laryngeal Squamous Cell Carcinoma: a Potential Indicator for Poor Prognosis

Oncology Reports. Jul, 2009  |  Pubmed ID: 19513509

This study aimed to investigate the expression and clinical significance of mitogen-activated protein kinase kinase 4 MKK4 and nuclear factor-kappaB (NF-kappaB) in patients with laryngeal squamous cell carcinoma (LSCC). We used immunohistochemistry (IHC) to examine the expression of MKK4 and NF-kappaB in 78 LSCCs and their adjacent normal tissues. To clarify the validity of MKK4 and NF-kappaB as determined by the IHC analysis, RT-PCR was performed on 21 tissues randomly selected from the 78 LSCCs. The positive expression rates of MKK4 and NF-kappaB in patients with LSCC were 67.9% (53/78) and 60.3% (47/78) respectively, which were significantly higher than those in the adjacent normal tissue (both P<0.01). The positive expression of MKK4 and NF-kappaB tended to be associated positively with lymph node metastasis (both P<0.01) as well as T stage (both P<0.01). The Spearman analysis indicated that the expression level of MKK4 was positively correlated with that of NF-kappaB significantly (rs=0.368, P<0.01). Overall survival curves estimated by Kaplan-Meier showed that tumor patients with low MKK4 and NF-kappaB expression in their tumor cells survive significantly longer than patients with high MKK4 and NF-kappaB levels (P=0.027, and P<0.01, respectively). In addition, multivariate Cox regression analysis showed that N stage, T stage and NF-kappaB expression are significant independent prognostic factors for overall survival (P<0.01, P=0.014, and P=0.027, respectively). These findings suggested that the expression of MKK4 and NF-kappaB may be considered as a useful prognostic marker of LSCC after surgical resection.

Comparative Study on ChIP-seq Data: Normalization and Binding Pattern Characterization

Bioinformatics (Oxford, England). Sep, 2009  |  Pubmed ID: 19561022

Antibody-based Chromatin Immunoprecipitation assay followed by high-throughput sequencing technology (ChIP-seq) is a relatively new method to study the binding patterns of specific protein molecules over the entire genome. ChIP-seq technology allows scientist to get more comprehensive results in shorter time. Here, we present a non-linear normalization algorithm and a mixture modeling method for comparing ChIP-seq data from multiple samples and characterizing genes based on their RNA polymerase II (Pol II) binding patterns.

[Fluorescence Spectra and Protonation of Ofloxacin in Strong Acidic Solutions]

Guang Pu Xue Yu Guang Pu Fen Xi = Guang Pu. May, 2009  |  Pubmed ID: 19650478

Fluorescence and UV-Vis spectra of ofloxacin (OFL) in sulfuric acid were studied. In the present paper, a new protonation state of OFL was observed. In hydrochloric acid, OFL produced bright green fluorescence upon excitation by UV radiation. The maximal emission wavelength of OFL is about 505 nm. However, OFL produces violet fluorescence when dissolved in concentrated sulfuric acid. The maximal emission wavelength changes into 400 nm. Further analysis demonstrated that the above changes arise from the variation of protonation states of OFL molecule. In dilute sulfuric acid, OFL accepted one proton, resulting in a protonation state that is similar to the OFL molecule dissolved HCl solution. The corresponding fluorescence band occurs at 505 nm. In concentrated sulfuric acid solution, OFL might accept additional protons. As a result, the size of the conjugated system is reduced and the fluorescence band exhibits a blue shift. In sulfuric acid of moderate concentrations, two bands at 505 and 400 nm respectively were found in the fluorescence emission spectra, indicating that OFL in two different protonation states coexists in the solution. In addition, both excitation band in excitation spectra and absorption bands in UV-Vis spectra exhibit red-shifted with the decrease in the concentration of sulfuric acid. Based on the above result, OFL can be used as a spectral probe to reflect the variation of H+ in strong acid environment.

Synthesis of 1,1-[1-naphthyloxy-2-thiophenyl]-2-methylaminomethylcyclopropanes and Their Evaluation As Inhibitors of Serotonin, Norepinephrine, and Dopamine Transporters

Journal of Medicinal Chemistry. Oct, 2009  |  Pubmed ID: 19791802

Stereodefined trisubstituted cyclopropanes bearing naphthyloxy, thiophenyl, and (N-methylamino)methyl groups were synthesized in enantiopure form employing asymmetric cyclopropanation of (E)- and (Z)-allylic alcohols as the key step. In vitro assays of the synthesized cyclopropanes revealed that the K(i) of one of the enantiomers as a dual inhibitor of serotonin and norepinephrine transporters is in the low nanomolar range and is comparable to that of duloxetine.

Double Orthogonal Sample Design Scheme and Corresponding Basic Patterns in Two-dimensional Correlation Spectra for Probing Subtle Spectral Variations Caused by Intermolecular Interactions

The Journal of Physical Chemistry. A. Nov, 2009  |  Pubmed ID: 19817427

This paper introduces a new approach named double orthogonal sample design scheme (DOSD) to probe intermolecular interactions based on a framework of two-dimensional (2D) correlated spectroscopy. In this approach, specifically designed concentration series are selected according to the mathematical analysis on orthogonal vectors to generate useful 2D correlated spectra. As a result, the interfering portion can be completely removed from both synchronous and asynchronous spectra, and complementary information concerning intermolecular interactions can be obtained from the set of 2D spectra. A model system, where intermolecular interactions occur between two solutes in a solution, is used to investigate the behavior of 2D correlated spectra generated by using the DOSD approach. Simulation results demonstrate that the resultant spectral patterns can reflect subtle spectral variation in bandwidths, peak positions, and absorptivities brought about by intermolecular interaction, which are hardly visualized in conventional 1D spectra because of the severe band-overlapping problem. The ability to reveal a subtle variation in a characteristic peak in detail by using the DOSD approach provides a new opportunity to understand the nature of intermolecular interactions from a molecular structural point of view. Intermolecular interactions between iodine and benzene in CCl(4) solutions were investigated by using the proposed DOSD approach to prove the applicability of the DOSD method in real chemical systems.

A 90-day Toxicology Study of Transgenic Lysine-rich Maize Grain (Y642) in Sprague-Dawley Rats

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. Feb, 2009  |  Pubmed ID: 19073230

The gene for a lysine-rich protein (sb401) obtained from potatoes (Solanum berthaultii) was inserted into maize seed to produce Y642 transgenic maize. Compositional analysis of Y642 grain demonstrated that the concentrations of lysine and total protein were higher than those observed in maize grain from a near-isogenic non-genetically modified (non-GM) commercially available control quality protein maize (Nongda 108). The safety of Y642 maize grain was assessed by comparison of toxicology response variables in Sprague-Dawley (SD) rats consuming diets containing Y642 maize grain with those containing Nongda 108 maize grain. Maize grains from Y642 or Nongda 108 were incorporated into rodent diets at low (30%) or high concentrations (76%) and administered to SD rats (n=10/sex/group) for 90 days. An additional group of negative control group of rats (n=10/sex/group) were fed AIN93G diets. No adverse diet-related differences in body weights, feed consumption/utilization, clinical chemistry, hematology, absolute and relative organ weights were observed. Further, no differences in gross or microscopic pathology were observed between rats consuming diets with Y642 maize grain compared with rats consuming diets containing Nongda 108 maize grain. These results demonstrated that Y642 lysine-rich maize is as safe and nutritious as conventional quality protein maize.

Tensor Classification of N-point Correlation Function Features for Histology Tissue Segmentation

Medical Image Analysis. Feb, 2009  |  Pubmed ID: 18762444

In this paper, we utilize the N-point correlation functions (N-pcfs) to construct an appropriate feature space for achieving tissue segmentation in histology-stained microscopic images. The N-pcfs estimate microstructural constituent packing densities and their spatial distribution in a tissue sample. We represent the multi-phase properties estimated by the N-pcfs in a tensor structure. Using a variant of higher-order singular value decomposition (HOSVD) algorithm, we realize a robust classifier that provides a multi-linear description of the tensor feature space. Validated results of the segmentation are presented in a case-study that focuses on understanding the genetic phenotyping differences in mouse placentae.

Robust 3D Reconstruction and Identification of Dendritic Spines from Optical Microscopy Imaging

Medical Image Analysis. Feb, 2009  |  Pubmed ID: 18819835

In neurobiology, the 3D reconstruction of neurons followed by the identification of dendritic spines is essential for studying neuronal morphology, function and biophysical properties. Most existing methods suffer from problems of low reliability, poor accuracy and require much user interaction. In this paper, we present a method to reconstruct dendrites using a surface representation of the neuron. The skeleton of the dendrite is extracted by a procedure based on the medial geodesic function that is robust and topology preserving, and it is used to accurately identify spines. The sensitivity of the algorithm on the various parameters is explored in detail and the method is shown to be robust.

Enabling Data Analysis on High-Throughput Data in Large Data Depository Using Web-Based Analysis Platform - A Case Study on Integrating QUEST with GenePattern in Epigenetics Research

Proceedings. IEEE International Conference on Bioinformatics and Biomedicine. Nov, 2009  |  Pubmed ID: 21151835

Enabling data analysis in large data depositories for high throughput experimental data such as gene microarrays and ChIP-seq is challenging. In this paper, we discuss three methods for integrating QUEST, a data depository for epigenetic experiments, with a web-based data analysis platform GenePattern. These methods are universal and can serve as an exemplary implementation resolving the dilemma facing many similar database systems in integrating data analysis tools.

9-Benzamido-acridinium Chloride

Acta Crystallographica. Section E, Structure Reports Online. 2009  |  Pubmed ID: 21578238

In the title compound, C(20)H(15)N(2)O(+)·Cl(-), the dihedral angle between the fused-ring system and the benzene ring is 63.10 (7)°. In the crystal, N-H⋯Cl hydrogen bonds link the components and aromatic π-π stacking [shortest centroid-centroid distance = 3.6421 (12) Å] occurs.

N-(2-Amino-phen-yl)-2-anilinobenzamide

Acta Crystallographica. Section E, Structure Reports Online. 2009  |  Pubmed ID: 21583922

In the title compound, C(19)H(17)N(3)O, the planes of the aromatic substituents attached to the benzamide moiety are almost perpendicular to one another, making a dihedral angle of 88.16 (7)°. The observed conformation of the mol-ecule is produced by an intra-molecular N-H⋯O hydrogen bond.

Proliferative Effects of Chishao on Schwann Cells Are FGF-uPA, and ERK- and JNK-dependent

The American Journal of Chinese Medicine. 2009  |  Pubmed ID: 19938226

This study evaluated the proliferative effects of chishao on RSC96, Schwann cells. A dose-dependent proliferative effect of chishao was obtained by methylthiazol tetrazolium (MTT), proliferating cell nuclear antigen (PCNA) Western blotting, and wound healing assays in Schwann cells administered with chishao (0-500 mg/ml), except at 500 mg/ml concentration. The chishao-treated cells also showed a dose-dependent activated fibroblast growth factor-2 (FGF-2) signaling with increased urokinase plasminogen activator (uPA) and decreased plasminogen activator inhibitor-1 (PAI-1), enhanced proliferative proteins, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)-signaling. Using mitogen-actvated protein kinase (MAPK)-signaling chemical inhibitors, U0126, SB203580, and SP600125, the proliferative effects of chishao on RSC cells were identified to be ERK- and JNK- signaling dependent. Based on the results, applying appropriate doses of chishao to Schwann cells would be a potential approach for enhancing neuron regeneration.

A New Model-based Estimation of Ellipses for Object Representation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964084

Fitting geometric models to objects of interest in images is one of the most classical problems studied in computer vision field. As a result of its strong representation power and flexibility, conic is one of the geometric primitives widely used in a large number of image analysis applications, in practice. As opposed to most existing conic fitting methods minimizing the fitting error with the use of the second order polynomial representation, in this paper, we propose a new method that formulates the geometric fitting problem as a process of seeking for the optimal mapping to a bivariate normal distribution model. As a result, some critical disadvantages tightly coupled with those methods following the routine polynomial representation can be well overcome. To demonstrate this, a set of carefully designed comparison experiments is conducted to show the superiority of the newly proposed method to a representative method using the polynomial representation. Additionally, the practical effectiveness of the proposed method is further manifested using a set of real image data with a promising accuracy.

Association of ADAM33 Gene Polymorphisms with COPD in a Northeastern Chinese Population

BMC Medical Genetics. 2009  |  Pubmed ID: 20003279

Chronic obstructive pulmonary disease (COPD) is influenced by both environmental and genetic factors. ADAM33 (a disintegrin and metalloproteinase 33) has been one of the most exciting candidate genes for asthma since its first association with the disease in Caucasian populations. Recently, ADAM33 was shown to be associated with excessive decline of lung function and COPD. The aim of this study was to evaluate the potential relationship between polymorphisms of ADAM33 and COPD in a Han population in northeastern China.

A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues

Journal of Heterocyclic Chemistry. Nov, 2009  |  Pubmed ID: 20161612

A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.

Supramolecular Protein Engineering: Design of Zinc-stapled Insulin Hexamers As a Long Acting Depot

The Journal of Biological Chemistry. Apr, 2010  |  Pubmed ID: 20181952

Bottom-up control of supramolecular protein assembly can provide a therapeutic nanobiotechnology. We demonstrate that the pharmacological properties of insulin can be enhanced by design of "zinc staples" between hexamers. Paired (i, i+4) His substitutions were introduced at an alpha-helical surface. The crystal structure contains both classical axial zinc ions and novel zinc ions at hexamer-hexamer interfaces. Although soluble at pH 4, the combined electrostatic effects of the substitutions and bridging zinc ions cause isoelectric precipitation at neutral pH. Following subcutaneous injection in a diabetic rat, the analog effected glycemic control with a time course similar to that of long acting formulation Lantus. Relative to Lantus, however, the analog discriminates at least 30-fold more stringently between the insulin receptor and mitogenic insulin-like growth factor receptor. Because aberrant mitogenic signaling may be associated with elevated cancer risk, such enhanced specificity may improve safety. Zinc stapling provides a general strategy to modify the pharmacokinetic and biological properties of a subcutaneous protein depot.

Dramatic Increase of Cesarean Deliveries in the Midst of Health Reforms in Rural China

Social Science & Medicine (1982). May, 2010  |  Pubmed ID: 20219278

Cesarean delivery (CD) rates were until recently low in rural China where the population lacked health insurance. In July 2003 the New Cooperative Medical Scheme (NCMS) was introduced. We report findings from a health systems study carried out in the EC-funded project "Structural hinders to and promoters of good maternal care in rural China" in central and western China. The purpose was to analyze how CD rates changed with the increased level of funding of the NCMS. The research design was a natural experiment. Quantitative demographic, administrative and accounts data for 2001-2007 were collected in five counties from the county public health bureaux, the county NCMS offices, the county statistical offices and the Maternal and Child Health (MCH) hospitals, using a structured data collection form. We found that the CD rates increased in four of the five counties in the period 2004-2007 by 36%, 53%, 61% and 131% respectively. In the fifth county the CD rate remained high at 60%. The revenue from CD made up 72-85% of total delivery fee revenue. CD fee revenue increased by 97%, 239% and 408% in the three counties with available data; a higher increase than in general health care revenue. Our conclusion is that the design of NCMS, the provider payment systems, and the revenue-related bonus systems for doctors need to be studied to rein in the unhealthy increases in rural CD rates.

Allergy and Inflammatory Transcriptome is Predominantly Negatively Correlated with CD133 Expression in Glioblastoma

Neuro-oncology. Apr, 2010  |  Pubmed ID: 20308310

Allergies and the use of anti-inflammatory medication appear to be associated with reduced glioblastoma risk. However, these observations may merely reflect systemic immunosuppression induced by the tumor. To better understand the effect of this tumor on allergies and inflammation, we used CD133 mRNA expression as an indicator of tumor aggressiveness and systematically examined its relation to mRNA expression levels of 919 allergy- and inflammation-related genes in 142 glioblastoma tissue samples. We found that 69% of these genes are negatively correlated with CD133 expression including allergy-related (eg, interleukin [IL]-4R-alpha; Pearson correlation coefficient [r] = - 0.40; 95% confidence interval [CI] = - 0.53, -0.25) and immunoregulatory genes (eg, TGF-beta1; r = - 0.35; 95% CI = - 0.49, -0.20). Exceptions to this negative trend include the proinflammatory cytokine IL-17-beta (r = 0.22; 95% CI = 0.06, 0.37) and 2 IL-17 receptors. Also positively related to CD133 expression are NCAM-1 (r = 0.45; 95% CI = 0.31, 0.57) and PDGFR-alpha (r = 0.45; 95% CI = 0.30, 0.57). Previous literature suggests that NCAM-1(+) T cells infiltrate glioblastoma and may cause suppression of antitumor immunity, whereas PDGFR-alpha is involved in neurogenesis and amplified in glioblastoma. Ours is the first study to document down-regulation of the majority of allergy- and inflammation-related genes with glioblastoma progression. However, IL-17 and NCAM-1 may play proinflammatory and immunosuppressive roles, respectively, during the late stage of glioblastoma progression. Our findings suggest that immune function continues to change as the tumor progresses.

Structural Resolution of a Tandem Hormone-binding Element in the Insulin Receptor and Its Implications for Design of Peptide Agonists

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2010  |  Pubmed ID: 20348418

The C-terminal segment of the human insulin receptor alpha-chain (designated alphaCT) is critical to insulin binding as has been previously demonstrated by alanine scanning mutagenesis and photo-cross-linking. To date no information regarding the structure of this segment within the receptor has been available. We employ here the technique of thermal-factor sharpening to enhance the interpretability of the electron-density maps associated with the earlier crystal structure of the human insulin receptor ectodomain. The alphaCT segment is now resolved as being engaged with the central beta-sheet of the first leucine-rich repeat (L1) domain of the receptor. The segment is alpha-helical in conformation and extends 11 residues N-terminal of the classical alphaCT segment boundary originally defined by peptide mapping. This tandem structural element (alphaCT-L1) thus defines the intact primary insulin-binding surface of the apo-receptor. The structure, together with isothermal titration calorimetry data of mutant alphaCT peptides binding to an insulin minireceptor, leads to the conclusion that putative "insulin-mimetic" peptides in the literature act at least in part as mimics of the alphaCT segment as well as of insulin. Photo-cross-linking by novel bifunctional insulin derivatives demonstrates that the interaction of insulin with the alphaCT segment and the L1 domain occurs in trans, i.e., these components of the primary binding site are contributed by alternate alpha-chains within the insulin receptor homodimer. The tandem structural element defines a new target for the design of insulin agonists for the treatment of diabetes mellitus.

Experimental Generation of Laguerre-Gaussian Beam Using Digital Micromirror Device

Applied Optics. Apr, 2010  |  Pubmed ID: 20357867

A digital micromirror device (DMD) modulates laser intensity through computer control of the device. We experimentally investigate the performance of the modulation property of a DMD and optimize the modulation procedure through image correction. Furthermore, Laguerre-Gaussian (LG) beams with different topological charges are generated by projecting a series of forklike gratings onto the DMD. We measure the field distribution with and without correction, the energy of LG beams with different topological charges, and the polarization property in sequence. Experimental results demonstrate that it is possible to generate LG beams with a DMD that allows the use of a high-intensity laser with proper correction to the input images, and that the polarization state of the LG beam differs from that of the input beam.

Design of DOE for Generating a Needle of a Strong Longitudinally Polarized Field

Optics Letters. Apr, 2010  |  Pubmed ID: 20364185

A needle of strong longitudinally polarized field with homogeneous intensity along the optical axis, long depth of focus, and subdiffraction beam size can be generated by focusing a radially polarized light with a high-NA lens and a diffractive optical element (DOE) with belts. A method combining the global-search-optimization algorithm and the tight focusing properties of the radially polarized light is proposed to design the DOE. Based on the tight focusing properties, the light incident on the lens is divided into two parts: areas A and B. We discover that the longitudinal field in the focal region is mainly dependent on the number of belts in area B but not the total number of belts in the DOE.

Creation of Large Band Gap with Anisotropic Annular Photonic Crystal Slab Structure

Optics Express. Mar, 2010  |  Pubmed ID: 20389535

A two-dimensional anisotropic annular photonic crystal slab structure composed of circular air holes and dielectric rods with finite thickness in a triangular lattice is presented to achieve an absolute photonic band gap. Positive uniaxial crystal Tellurium is introduced to the structure with the extraordinary axis parallel to the extension direction of rods. The role of each geometric parameter is investigated by employing the conjugate-gradient method. A large mid-gap ratio is realized by the parameter optimization. A flat band called as anomalous group velocity within two large gaps is discovered and can be widely applied in many fields. A hybrid structure with GaAs slab and Te rods is designed to achieve a large gap and demonstrates that the annular structure can improve the gap effectively.

Contributions of Conserved TPLH Tetrapeptides to the Conformational Stability of Ankyrin Repeat Proteins

Journal of Molecular Biology. May, 2010  |  Pubmed ID: 20398677

Ankyrin repeat (AR) proteins are one of the most abundant classes of repeat proteins and are involved in numerous physiological processes. These proteins are composed of various numbers of AR motifs stacked in a nearly linear fashion to adopt an elongated and nonglobular architecture. One salient feature prevalent in such a structural unit is the TPLH tetrapeptide or a close variant, T/SxxH, which initiates the helix-turn-helix conformation and presumably contributes to conformational stability through a hydrogen-bonding network. In the present study, we investigated the roles of T/SxxH motif in the stability, structure, and function of AR proteins by a systematic and rationalized mutagenic study on, followed by biochemical and biophysical characterization of, gankyrin, an oncogenic protein composed of seven ARs and six T/SxxH tetrapeptides, and P16, a tumor suppressor with four ARs but no TPLH tetrapeptide. Our results showed that this tetrapeptide is ineffectual on global structure and function, but contributes significantly to conformational stability when its stabilizing potentials are fully realized in the local conformation, including (1) the intra-AR hydrogen bonding involving the hydroxyl group; (2) the intra-AR and inter-AR hydrogen bonds involving the imidazole ring; and (3) the hydrophobic interaction associated with the Thr-methyl group. Considering that the capping and close-to-capping units tend to have more sequence diversity and more conformational variation, it could be also generally true that a T/SxxH motif close to the terminal repeats contributes little or even negatively to stability with respect to Ala substitution, but substantially stabilizes the global conformation when located in the middle of a long stretch of ARs.

Synaptic Activity Controls Dendritic Spine Morphology by Modulating EEF2-dependent BDNF Synthesis

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Apr, 2010  |  Pubmed ID: 20427644

Activity-dependent changes in synaptic structure and spine morphology are required for learning and memory, and depend on protein translation. We show that the kinase for eukaryotic elongation factor 2 (eEF2K) regulates dendritic spine stability and synaptic structure by modulating activity-dependent dendritic BDNF synthesis. Specifically RNAi knockdown of eEF2K reduces dendritic spine stability and inhibits dendritic BDNF protein expression; whereas overexpression of a constitutively activated eEF2K induces spine maturation and increases expression of dendritic BDNF. Furthermore, BDNF overexpression rescues the spine stability reduced by RNAi knockdown of eEF2K. We also show that synaptic activity-dependent spine maturation and dendritic BDNF protein expression depend on mGluR/EF2K-induced eEF2 phosphorylation. We propose that the eEF2K/eEF2 pathway is a key biochemical sensor that couple neuronal activity to spine plasticity, by controlling the dendritic translation of BDNF.

Palmitoylation and Function of Glial Glutamate Transporter-1 is Reduced in the YAC128 Mouse Model of Huntington Disease

Neurobiology of Disease. Oct, 2010  |  Pubmed ID: 20685337

Excitotoxicity plays a key role in the selective vulnerability of striatal neurons in Huntington disease (HD). Decreased glutamate uptake by glial cells could account for the excess glutamate at the synapse in patients as well as animal models of HD. The major molecule responsible for clearing glutamate at the synapses is glial glutamate transporter GLT-1. In this study, we show that GLT-1 is palmitoylated at cysteine38 (C38) and further, that this palmitoylation is drastically reduced in HD models both in vitro and in vivo. Palmitoylation is required for normal GLT-1 function. Blocking palmitoylation either with the general palmitoylation inhibitor, 2-bromopalmitate, or with a GLT-1 C38S mutation, severely impairs glutamate uptake activity. In addition, GLT-1-mediated glutamate uptake is indeed impaired in the YAC128 HD mouse brain, with the defect in the striatum evident as early as 3 months prior to obvious neuropathological findings, and in both striatum and cortex at 12 months. These phenotypes are not a result of changes in GLT1 protein expression, suggesting a crucial role of palmitoylation in GLT-1 function. Thus, it appears that impaired GLT-1 palmitoylation is present early in the pathogenesis of HD, and may influence decreased glutamate uptake, excitotoxicity, and ultimately, neuronal cell death in HD.

SYNTHESIS OF SPIROBORATE ESTERS FROM 1,2-AMINOALCOHOLS, ETHYLENE GLYCOL AND TRIISOPROPYL BORATE: PREPARATION OF (S)-1-(1,3,2-DIOXABOROLAN-2-YLOXY)-3-METHYL-1,1-DIPHENYLBUTAN-2-AMINE

Organic Syntheses; an Annual Publication of Satisfactory Methods for the Preparation of Organic Chemicals. 2010  |  Pubmed ID: 20694191

Ursolic Acid Inhibits Early Lesions of Diabetic Nephropathy

International Journal of Molecular Medicine. Oct, 2010  |  Pubmed ID: 20818497

The present study sought to investigate the effects of ursolic acid (UA) on the development of glomerular hypertrophy and type IV collagen accumulation, two early lesions associated with diabetic nephropathy (DN). By treating streptozotocin (STZ)-induced diabetic mice with low-dose UA (0.01% in food) for three months, the diabetes-induced glomerular hypertrophy and type IV collagen accumulation in the kidneys were found to be markedly ameliorated. Further studies identified that UA treatment suppressed diabetes-induced activations of STAT-3, ERK1/2 and JNK pathways, but not the diabetes-induced activation of the p38 pathway. Furthermore, diabetes-induced overexpression of iNOS in the renal cortex was also significantly suppressed by the treatment. UA may thus be considered as a potential therapeutic agent in treating DN.

An Achilles' Heel in an Amyloidogenic Protein and Its Repair: Insulin Fibrillation and Therapeutic Design

The Journal of Biological Chemistry. Apr, 2010  |  Pubmed ID: 20106984

Insulin fibrillation provides a model for a broad class of amyloidogenic diseases. Conformational distortion of the native monomer leads to aggregation-coupled misfolding. Whereas beta-cells are protected from proteotoxicity by hexamer assembly, fibrillation limits the storage and use of insulin at elevated temperatures. Here, we have investigated conformational distortions of an engineered insulin monomer in relation to the structure of an insulin fibril. Anomalous (13)C NMR chemical shifts and rapid (15)N-detected (1)H-(2)H amide-proton exchange were observed in one of the three classical alpha-helices (residues A1-A8) of the hormone, suggesting a conformational equilibrium between locally folded and unfolded A-chain segments. Whereas hexamer assembly resolves these anomalies in accordance with its protective role, solid-state (13)C NMR studies suggest that the A-chain segment participates in a fibril-specific beta-sheet. Accordingly, we investigated whether helicogenic substitutions in the A1-A8 segment might delay fibrillation. Simultaneous substitution of three beta-branched residues (Ile(A2) --> Leu, Val(A3) --> Leu, and Thr(A8) --> His) yielded an analog with reduced thermodynamic stability but marked resistance to fibrillation. Whereas amide-proton exchange in the A1-A8 segment remained rapid, (13)Calpha chemical shifts exhibited a more helical pattern. This analog is essentially without activity, however, as Ile(A2) and Val(A3) define conserved receptor contacts. To obtain active analogs, substitutions were restricted to A8. These analogs exhibit high receptor-binding affinity; representative potency in a rodent model of diabetes mellitus was similar to wild-type insulin. Although (13)Calpha chemical shifts remain anomalous, significant protection from fibrillation is retained. Together, our studies define an "Achilles' heel" in a globular protein whose repair may enhance the stability of pharmaceutical formulations and broaden their therapeutic deployment in the developing world.

An Ets2-driven Transcriptional Program in Tumor-associated Macrophages Promotes Tumor Metastasis

Cancer Research. Feb, 2010  |  Pubmed ID: 20145133

Tumor-associated macrophages (TAM) are implicated in breast cancer metastasis, but relatively little is known about the underlying genes and pathways that are involved. The transcription factor Ets2 is a direct target of signaling pathways involved in regulating macrophage functions during inflammation. We conditionally deleted Ets in TAMs to determine its function at this level on mouse mammary tumor growth and metastasis. Ets2 deletion in TAMs decreased the frequency and size of lung metastases in three different mouse models of breast cancer metastasis. Expression profiling and chromatin immunoprecipitation assays in isolated TAMs established that Ets2 repressed a gene program that included several well-characterized inhibitors of angiogenesis. Consistent with these results, Ets2 ablation in TAMs led to decreased angiogenesis and decreased growth of tumors. An Ets2-TAM expression signature consisting of 133 genes was identified within human breast cancer expression data which could retrospectively predict overall survival of patients with breast cancer in two independent data sets. In summary, we identified Ets2 as a central driver of a transcriptional program in TAMs that acts to promote lung metastasis of breast tumors.

CATALYTIC ENANTIOSELECTIVE BORANE REDUCTION OF BENZYL OXIMES: PREPARATION OF (S)-1-PYRIDIN-3-YL-ETHYLAMINE BIS HYDROCHLORIDE

Organic Syntheses; an Annual Publication of Satisfactory Methods for the Preparation of Organic Chemicals. Jan, 2010  |  Pubmed ID: 20526458

[Two-dimensional Synchronous Correlation Spectroscopy for Probing Fluorescence Energy Transfer]

Guang Pu Xue Yu Guang Pu Fen Xi = Guang Pu. May, 2010  |  Pubmed ID: 20672597

In the present paper, the authors developed a new approach by constructing two-dimensional (2D) UV-Vis/fluorescence heterogeneous synchronous spectrum based on the orthogonal sample design scheme (OSD) developed in our previous works to characterize energy transfer among different lanthanide ions during the luminescence process. The authors use the EuCl3-NdCl3 system as an example. The preliminary experimental results on the 2D synchronous spectra of EuCl3-NdCl3 mixture solutions have demonstrated that cross peaks can be observed among the UV-Vis absorption bands from Nd3+ and fluorescence emission bands from Eu3+. The cross peaks in the 2D synchronous spectra of EuCl3-NdCl3 mixture solutions manifested the interaction between the fluorescence emission from Eu3+ and UV-Vis absorbance from Nd3+, and therefore gives out experimental evidences for the occurrence of energy transfer between Eu3+ and Nd3+ ions. The cross peaks are not from the interaction between the solvent, water, and the solute, Eu3+ or Nd3+ ions. Mathematical analysis performed on 2D synchronous spectra using variable concentration as an external perturbation shows that the orthogonal sample design scheme is indispensable in removing the interfering cross peaks in 2D synchronous spectra. In fact, if the authors detect, respectively, the fluorescence emission spectra of pure Eu3+ solutions and the UV-Vis absorbance spectra of pure Nd3+ solutions, then use these spectra data to construct a series of synthesized spectra of an assumed mixture solution in which Eu3+ and Nd3+ are not mixed together, because Eu3+ and Nd3+ ions are spatially separated, there are no intermolecular interactions that should have occurred. Therefore, there are no cross-peaks that can be observed in the comparative 2D synchronous spectra. The cross peaks in 2D synchronous correlation spectra gives out a new approach to characterizing energy transfer among different lanthanide ions during the luminescence process.

Organosoluble Polypyrrole Nanotubes from Core-shell Bottlebrush Copolymers

Chemical Communications (Cambridge, England). Sep, 2010  |  Pubmed ID: 20683520

Well-defined, organosoluble polypyrrole nanotubes were synthesized by single-molecule templating of multicomponent bottlebrush copolymers with triblock terpolymer side chains.

Space-time Latent Component Modeling of Geo-referenced Health Data

Statistics in Medicine. Aug, 2010  |  Pubmed ID: 20683893

Latent structure models have been proposed in many applications. For space-time health data it is often important to be able to find the underlying trends in time, which are supported by subsets of small areas. Latent structure modeling is one such approach to this analysis. This paper presents a mixture-based approach that can be applied to component selection. The analysis of a Georgia ambulatory asthma county-level data set is presented and a simulation-based evaluation is made.

3,3'-Dimethyl-1,1'-(methyl-enedi-p-phenyl-ene)diimidazolium Bis-(hexa-fluoro-phosphate)

Acta Crystallographica. Section E, Structure Reports Online. 2010  |  Pubmed ID: 21588575

The title N-heterocyclic carbene compound, C(21)H(22)N(4) (2+)·2PF(6) (-), crystallizes as an inversion twin. There are two independent N-heterocyclic carbene dications (A and B) and four independent hexa-fluoro-phosphate anions in the asymmetric unit. The cations are L-shaped with the benzene rings being inclined to one another by 88.82 (16)° in cation A and 87.03 (16)° in cation B. The imidazole rings make dihedral angles of 35.7 (2) and 32.83 (18)° with the attached benzene rings in cation A, and 30.14 (19) and 31.96 (18)° in cation B. In the crystal, the cations are linked via C-H⋯F hydrogen bonds, forming a three-dimensional network. π-π inter-actions involving the benzene and imidazole rings [centroid-centroid distances = 3.602 (2) and 3.723 (2) Å] and C-H⋯π inter-actions are also present.

[Mental Health and Risk Behavior of Married Adult HIV/AIDS Subjects Derived from Paid Blood Donation in the Rural of Anhui Province]

Wei Sheng Yan Jiu = Journal of Hygiene Research. Nov, 2010  |  Pubmed ID: 21351644

To investigate the mental health and risk behavior of married adult HIV/AIDS subjects derived from paid blood donation in the rural of Anhui Province and explore the risk factors for formulation intervention measures.

Borylation of Aryl and Alkenyl Carbamates Through Ni-Catalyzed C--O Activation

Chemistry (Weinheim an Der Bergstrasse, Germany). Dec, 2010  |  Pubmed ID: 21161955

[Lamivudine and Entecavir Significantly Improved the Prognosis of Early-to-mid Stage Hepatitis B Related Acute on Chronic Liver Failure]

Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi = Zhonghua Shiyan He Linchuang Bingduxue Zazhi = Chinese Journal of Experimental and Clinical Virology. Jun, 2010  |  Pubmed ID: 21186528

To clinically study the antiviral effects of lamivudine and entecavir on patients with early-to-mid stage Hepatitis B related acute on chronic liver failure (HBV-ACLF). METHODS; A prospective, randomized, open and parallel controlled clinical trial was designed to observe the antiviral effects of nucleoside analogues on patients with early-to-mid stage HBV-ACLF. Three groups were set for controlled study, i. e. basic treatment group, lamivudine plus basic treatment group and entecavir plus basic treatment group.

DNA Repair Deficiency in a Newly Identified Neurological Disease

Clinical Genetics. Jul, 2010  |  Pubmed ID: 21204791

M/S: Mutations in PNKP cause microcephaly, seizures and defects in DNA repair Shen et al., 2010 Nature Genetics, 42(3): 245-249.

Utilisation, Contents and Costs of Prenatal Care Under a Rural Health Insurance (New Co-operative Medical System) in Rural China: Lessons from Implementation

BMC Health Services Research. 2010  |  Pubmed ID: 21040560

In China, the New Co-operative Medical System (NCMS), a rural health insurance system, has expanded nationwide since 2003. This study aims to describe prenatal care use, content and costs of care in one county where prenatal care is included in the NCMS and two counties where it is not. It also explores the perceptions of stakeholders of the prenatal care benefit package in order to understand the strengths and weaknesses of the approach in the context of rural China and to draw lessons from early implementation.

Multi-dimensional Discovery of Biomarker and Phenotype Complexes

BMC Bioinformatics. 2010  |  Pubmed ID: 21044361

Given the rapid growth of translational research and personalized healthcare paradigms, the ability to relate and reason upon networks of bio-molecular and phenotypic variables at various levels of granularity in order to diagnose, stage and plan treatments for disease states is highly desirable. Numerous techniques exist that can be used to develop networks of co-expressed or otherwise related genes and clinical features. Such techniques can also be used to create formalized knowledge collections based upon the information incumbent to ontologies and domain literature. However, reports of integrative approaches that bridge such networks to create systems-level models of disease or wellness are notably lacking in the contemporary literature.

Using Gene Co-expression Network Analysis to Predict Biomarkers for Chronic Lymphocytic Leukemia

BMC Bioinformatics. 2010  |  Pubmed ID: 21044363

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is a highly heterogeneous disease, and can be divided roughly into indolent and progressive stages based on classic clinical markers. Immunoglobin heavy chain variable region (IgVH) mutational status was found to be associated with patient survival outcome, and biomarkers linked to the IgVH status has been a focus in the CLL prognosis research field. However, biomarkers highly correlated with IgVH mutational status which can accurately predict the survival outcome are yet to be discovered.

RNA Polymerase II Binding Patterns Reveal Genomic Regions Involved in MicroRNA Gene Regulation

PloS One. 2010  |  Pubmed ID: 21072189

MicroRNAs are small non-coding RNAs involved in post-transcriptional regulation of gene expression. Due to the poor annotation of primary microRNA (pri-microRNA) transcripts, the precise location of promoter regions driving expression of many microRNA genes is enigmatic. This deficiency hinders our understanding of microRNA-mediated regulatory networks. In this study, we develop a computational approach to identify the promoter region and transcription start site (TSS) of pri-microRNAs actively transcribed using genome-wide RNA Polymerase II (RPol II) binding patterns derived from ChIP-seq data. Based upon the assumption that the distribution of RPol II binding patterns around the TSS of microRNA and protein coding genes are similar, we designed a statistical model to mimic RPol II binding patterns around the TSS of highly expressed, well-annotated promoter regions of protein coding genes. We used this model to systematically scan the regions upstream of all intergenic microRNAs for RPol II binding patterns similar to those of TSS from protein coding genes. We validated our findings by examining the conservation, CpG content, and activating histone marks in the identified promoter regions. We applied our model to assess changes in microRNA transcription in steroid hormone-treated breast cancer cells. The results demonstrate many microRNA genes have lost hormone-dependent regulation in tamoxifen-resistant breast cancer cells. MicroRNA promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription, and therefore allows comparison of transcription activities between different conditions, such as normal and disease states.

An Efficient Organocatalytic Method for Constructing Biaryls Through Aromatic C-H Activation

Nature Chemistry. Dec, 2010  |  Pubmed ID: 21107368

The direct functionalization of C-H bonds has drawn the attention of chemists for almost a century. C-H activation has mainly been achieved through four metal-mediated pathways: oxidative addition, electrophilic substitution, σ-bond metathesis and metal-associated carbene/nitrene/oxo insertion. However, the identification of methods that do not require transition-metal catalysts is important because methods involving such catalysts are often expensive. Another advantage would be that the requirement to remove metallic impurities from products could be avoided, an important issue in the synthesis of pharmaceutical compounds. Here, we describe the identification of a cross-coupling between aryl iodides/bromides and the C-H bonds of arenes that is mediated solely by the presence of 1,10-phenanthroline as catalyst in the presence of KOt-Bu as a base. This apparently transition-metal-free process provides a new strategy with which to achieve direct C-H functionalization.

A Personalized MicroRNA Microarray Normalization Method Using a Logistic Regression Model

Bioinformatics (Oxford, England). Jan, 2010  |  Pubmed ID: 19933824

MicroRNA (miRNA) is a set of newly discovered non-coding small RNA molecules. Its significant effects have contributed to a number of critical biological events including cell proliferation, apoptosis development, as well as tumorigenesis. High-dimensional genomic discovery platforms (e.g. microarray) have been employed to evaluate the important roles of miRNAs by analyzing their expression profiling. However, because of the small total number of miRNAs and the absence of well-known endogenous controls, the traditional normalization methods for messenger RNA (mRNA) profiling analysis could not offer a suitable solution for miRNA analysis. The need for the establishment of new adaptive methods has come to the forefront.

[Preliminary Investigation on the Formation Mechanism of CCL4-water-cetyl Trimethyl Ammonium Bromide (CTAB) Gel]

Guang Pu Xue Yu Guang Pu Fen Xi = Guang Pu. Oct, 2010  |  Pubmed ID: 21137404

Gels are gaining extensive interest owing to their versatile applications in fields such as drug delivery, tissue engineering, cosmetics, templated materials and food industry. Surfactants have an ability to self-assemble into a variety of supramolecular aggregate structures and morphologies. Of particular interest in resent years are surfactant-based gels, one special class of materials due to surfactant assemblies resulting in viscoelastic solid-like rheological behaviors. Up to now, there is only limited understanding on the mechanism of gel formation, especially on the interaction among water, organic solvents and surfactant during thegel formation. In this study we prepare a Low-molecule-gel that is composed of cetyl trimethyl ammonium bromide (CTAB), water and carbon tetrachloride. Based on the experimental result of XRD and titration, the authors find that CTAB in gel are more than in saturated CTAB solution but CTAB is not solide in gel. CTAB is not solvented in CCl4. The solubility of CTAB in saturated CTAB solution is limited. So the authors suppose that CTAB is a synergistically solubilized by water and CCl4 in the gel. In addition, both NMR and FTIR spectroscopic results demonstrate that CTAB cations form a quasi-ordered structure in the gel.

Andreev and Single-particle Tunneling Spectra of Underdoped Cuprate Superconductors

Physical Review Letters. Oct, 2010  |  Pubmed ID: 21230999

We study tunneling spectroscopy between a normal metal and an underdoped cuprate superconductor modeled by a phenomenological theory in which the pseudogap is a precursor to the undoped Mott insulator. In the low barrier tunneling limit, the spectra are enhanced by Andreev reflection only within a voltage region of the small superconducting energy gap. In the high barrier tunneling limit, the spectra show a large energy pseudogap associated with single particle tunneling. Our theory semiquantitatively describes the two gap behavior observed in tunneling experiments.

A 90-day Safety Study in Sprague-Dawley Rats Fed Milk Powder Containing Recombinant Human Lactoferrin (rhLF) Derived from Transgenic Cloned Cattle

Drug and Chemical Toxicology. Oct, 2011  |  Pubmed ID: 21714769

Transgenic cloned animals expressing beneficial human nutritional traits offer a new strategy for large-scale production of some kinds of functional substances. In some cases, the required safety testing for genetically modified (GM) foods do not seem appropriate for human food safety, though regulations do not seem to provide alternatives. A 90-day rat feeding study is the core study for the safety assessment of GM foods. The test material in this 90-day study was prepared nonfat milk powder containing recombinant human lactoferrin (rhLF), which was expressed in transgenic cloned cattle. Groups of 10 male and female Sprague-Dawley rats were given a nutritionally balanced purified diet containing 7.5, 15, or 30% transgenic or conventional milk powder for 90 days. A commercial AIN93G diet was used as an additional control group. Clinical, biological, and pathological parameters were compared between groups. The only significant effect of treatment was higher mean ferritin and Fe(+) concentrations for both male and female rats fed the transgenic milk powder diets, as compared to rats fed nontransgenic milk diets or the commercial diet. The results of the present study are consistent with previous research, which indicates that milk powder containing rhLF derived from healthy transgenic cloned cattle is as safe as conventional milk powder.

Block Copolymer Micellization Induced Microphase Mass Transfer: Partition of Pd(II), Pt(IV) and Rh(III) in Three-liquid-phase Systems of S201-EOPO-Na2SO4-H2O

Journal of Colloid and Interface Science. Oct, 2011  |  Pubmed ID: 21723561

Three-liquid-phase partitioning of Pd(II), Pt(IV) and Rh(III) in systems of S201(diisoamyl sulfide)/nonane-EOPO(polyethylene oxide-polypropylene oxide random block copolymer)-Na(2)SO(4)-H(2)O was investigated. Experimental results indicated that the selective enrichment of Pd(II), Pt(IV) and Rh(III) respectively into the S201 organic top phase, EOPO-based middle phase and Na(2)SO(4) bottom phase was achieved by control over the phase behavior of the three-liquid-phase systems (TLPS). The microphase mass transfer behavior of Pt(IV), Pd(II) and Rh(III) was closely related to the micellization of EOPO molecules. A suggested micro-mechanism model and a mass transfer model describe the micellization of EOPO molecules and the effect on mass transfer of platinum ions across the microphase interfaces. The salting-out induced continuous dehydration and ordered arrangement of the hydrophilic PEO segments in amphiphilic EOPO micelle, and these are the main driving forces for mass transfer of platinum metal ions onto the exposed activity sites of the dehydrated PEO segments. The differences in microphase interfacial structure of EOPO micelles are crucial for the efficient separation between Pt(IV), Pd(II) and Rh(III).

Apelin Alleviates Diabetes-associated Endoplasmic Reticulum Stress in the Pancreas of Akita Mice

Peptides. Aug, 2011  |  Pubmed ID: 21762740

Apelin, a newly identified bioactive adipokine, has been found to play important roles in multiple diseases, including diabetes, hypertension and cardiovascular diseases with unclear molecular mechanisms. The present study aimed to investigate the effects of apelin on endoplasmic reticulum (ER) stress in the pancreas of Akita mice, a well-established type 1 diabetic model. Apelin-13 (400 pmol/kg) was injected from tail vein for 10 weeks. The physiological characters of experimental animals were evaluated, pancreatic islet morphology and insulin content were assessed by immunohistochemistry, and ER stress markers in the pancreas were examined by Western blots. Our results indicate apelin treatment significantly ameliorates diabetes-induced reduction in pancreatic islet mass and insulin content. Further studies suggested apelin treatment alleviates ER stress by inhibiting the diabetes induced up-regulation of PERK and IRE1α and chaperones (GRP78, calnexin and Hsp70) levels in Akita mice. We also demonstrated that apelin treatment normalizes the diabetes induced alteration of AKT and ERK activations in the pancreas of Akita mice. Taken together, these results suggest a novel physiological role of apelin in alleviating ER stress in the pancreas of type 1 diabetes.

Altered Palmitoylation and Neuropathological Deficits in Mice Lacking HIP14

Human Molecular Genetics. Oct, 2011  |  Pubmed ID: 21775500

Huntingtin interacting protein 14 (HIP14, ZDHHC17) is a huntingtin (HTT) interacting protein with palmitoyl transferase activity. In order to interrogate the function of Hip14, we generated mice with disruption in their Hip14 gene. Hip14-/- mice displayed behavioral, biochemical and neuropathological defects that are reminiscent of Huntington disease (HD). Palmitoylation of other HIP14 substrates, but not Htt, was reduced in the Hip14-/- mice. Hip14 is dysfunctional in the presence of mutant htt in the YAC128 mouse model of HD, suggesting that altered palmitoylation mediated by HIP14 may contribute to HD.

A New Oncolytic Adenoviral Vector Carrying Dual Tumor Suppressor Genes Shows Potent Antitumor Effect

Journal of Cellular and Molecular Medicine. Jul, 2011  |  Pubmed ID: 21794078

Cancer Targeting Gene-Viro-Therapy (CTGVT) is a promising cancer therapeutical strategy that strengthens the antitumor effect of the oncolytic virus by expressing inserted foreign antitumor genes. In this work, we constructed a novel adenoviral vector controlled by the tumor specific survivin promoter on the basis of the ZD55 vector, an E1B55KD gene deleted vector that we have previously constructed. Compared with the original ZD55 vector, this new adenoviral vector (ZD55SP/E1A) showed signficantly improved ability of replication and reporter gene expression. We then inserted the expression cassettes of antitumor gene interleukine-24 (IL-24) and an RNA polymerase III-dependent U6 promoter driving short hairpin RNA (shRNA) that targets M-phase phosphoprotein 1 (MPHOSPH1, a newly identified oncogene) into the ZD55SP/E1A vector. The resulted construct, named ZD55SP/E1A-IL-24-shMPP1, shows excellent antitumor effects in vitro on multiple cancer cell lines, including lung cancer, liver cancer and ovarian cancer. At a high multiplicity of infection (MOI), ZD55SP/E1A-IL-24-shMPP1 triggers postmitotic apoptosis in cancer cells by inducing prolonged mitotic arrest, while at a low MOI, it induces senescence. More remarkably, ZD55SP/E1A-IL-24-shMPP1 shows excellent antitumor effects in vivo on SW620 xenograft nude mice. In conclusion, our strategy of constructing an IL-24 and shMPP1 dual gene expressing oncolytic adenoviral vector, which is regulated by survivin promoter and E1B55KD-deletion, could be a promising method of cancer gene therapy.

Asynchronous Orthogonal Sample Design Scheme for Two-dimensional Correlation Spectroscopy (2D-COS) and Its Application in Probing Intermolecular Interactions from Overlapping Infrared (IR) Bands

Applied Spectroscopy. Aug, 2011  |  Pubmed ID: 21819780

This paper introduces a new approach to analysis of spectra called asynchronous orthogonal sample design (AOSD). Specifically designed concentration series are selected according to mathematical analysis of orthogonal vectors. Based on the AOSD approach, the interfering portion of the spectra arising strictly from the concentration effect can be completely removed from the asynchronous spectra. Thus, two-dimensional (2D) asynchronous spectra can be used as an effective tool to characterize intermolecular interactions that lead to apparent deviations from the Beer-Lambert law, even if the characteristic peaks of two compounds are substantially overlapped. A model solution with two solutes is used to investigate the behavior of the 2D asynchronous spectra under different extents of overlap of the characteristic peaks. Simulation results demonstrate that the resulting spectral patterns can reflect subtle spectral variations in bandwidths, peak positions, and absorptivities brought about by intermolecular interaction, which are barely visualized in the conventional one-dimensional (1D) spectra. Intermolecular interactions between butanone and dimethyl formamide (DMF) in CCl(4) solutions were investigated using the proposed AOSD approach to prove the applicability of the AOSD method in real chemical systems.

Maternal Thyroid Function in the First Twenty Weeks of Pregnancy and Subsequent Fetal and Infant Development: a Prospective Population-based Cohort Study in China

The Journal of Clinical Endocrinology and Metabolism. Oct, 2011  |  Pubmed ID: 21832110

There are a few prospective population-based cohort studies evaluating the effects of maternal thyroid dysfunctions on fetal and infant developments, but they are inconsistent.

Curcumin Inhibits Neuronal and Vascular Degeneration in Retina After Ischemia and Reperfusion Injury

PloS One. 2011  |  Pubmed ID: 21858029

Neuron loss, glial activation and vascular degeneration are common sequelae of ischemia-reperfusion (I/R) injury in ocular diseases. The present study was conducted to explore the ability of curcumin to inhibit retinal I/R injury, and to investigate underlying mechanisms of the drug effects.

Survival and Prognostic Factors in Hepatitis B Virus-related Acute-on-chronic Liver Failure

World Journal of Gastroenterology : WJG. Aug, 2011  |  Pubmed ID: 21876637

To investigate the survival rates and prognostic factors in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).

Realization of a Subwavelength Focused Spot Without a Longitudinal Field Component in a Solid Immersion Lens-based System

Optics Letters. Sep, 2011  |  Pubmed ID: 21931382

In a solid immersion lens (SIL)-based system, we predict theoretically that, by using the illumination of an azimuthally polarized beam with helical phase (APH), the subwavelength focusing can be simultaneously realized both in SIL and the third medium in spite of the presence of an air gap between the SIL and the third medium, which is not easily achieved in the case of the illumination of linearly, circularly, and radially polarized beams. For the APH illumination, the field in the focal region of the multilayered medium has no longitudinal component, and the on-axis intensity of the focused spot is nonzero. The APH illumination extends the capacity of SIL in realizing a supersmall focused spot, which is useful in microscopy, near-field optics, recording optics, and lithographic optics.

Automatic Detection of Stent Struts with Thick Neointimal Growth in Intravascular Optical Coherence Tomography Image Sequences

Physics in Medicine and Biology. Oct, 2011  |  Pubmed ID: 21946129

To assist cardiologists investigating neointimal tissue growth on stents during follow-up with optical coherence tomography (OCT), we developed an automatic algorithm to locate deeply buried stent struts and to quantify the restenosis burden. The technique is based on an improved steerable filter for computing the local ridge strength and orientation. It also uses an ellipsoid fitting algorithm and continuity criteria to obtain globally optimal stent localization. The restenosis burden calculations were compared to manual assessment of OCT coronary artery image data obtained from in vivo human clinical studies. Compared to manual assessment by expert readers, the algorithm operated with > 97% accuracy in the measurement of mean and maximum restenosis burden. The results indicated that the technique yielded comparable accuracy in measuring restenosis burden, and significantly reduced user interaction time.

Charge and Size Selective Molecular Transport by Amphiphilic Organic Nanotubes

Journal of the American Chemical Society. Oct, 2011  |  Pubmed ID: 21961797

Amphiphilic constructs with accessible, nanometer-size cavities can enable selective encapsulation, separation, and purification of nanomaterials and biomacromolecules on a similar length scale. We have developed a new method for the fabrication of amphiphilic organic nanotubes from multicomponent bottlebrush copolymers with triblock terpolymer side chains. The obtained nanotubes were demonstrated to be very effective and highly selective carriers for positively charged molecules and nanometer-size macromolecules by means of liquid-liquid extractions. Unprecedented discrimination between dendrimers with about 2 nm size differential was achieved.

Suppression of Plant-generated Reactive Oxygen Species is Required for Successful Infection by the Rice Blast Fungus

Virulence. Nov-Dec, 2011  |  Pubmed ID: 21971181

Magnaporthe oryzae is a filamentous ascomycete that continuously threatens global rice production. The infection cycle of this pathogen commences with the attachment of conidia to rice plants, followed by the formation and maturation of a specialized infection structure-the appressorium. Melanized appressoria generate immense turgor pressure, which allows the fungus to break through the plant cuticle and cell wall by means of a penetration peg. These stages occur within the first twenty-four hours after which time the penetration peg gives rise to and subsequent primary and secondary infection hyphae. Upon infection, the plant recognizes the pathogen, triggering a series of defense responses and signaling events including the secretion of reactive oxygen species (ROS). In a recent paper, we showed that barley plants generate ROS and cell wall appositions (CWAs) around infection sites and that a fungal gene we termed MoHYR1 is necessary for ameliorating these defense reactions and ensuring successful infection and colonization. When this gene is deleted from the M. oryzae genome, the plant oxidative responses are stronger and disease is reduced.

Subwavelength Imaging by a Graded-index Photonic-crystal Flat Lens in a Honeycomb Lattice

Journal of the Optical Society of America. A, Optics, Image Science, and Vision. Oct, 2011  |  Pubmed ID: 21979524

The left-handed behavior of a photonic-crystal flat lens with a graded index in a honeycomb lattice is proposed and theoretically studied. The performance of the flat superlens imaging of this structure has been demonstrated by finite-difference time-domain simulations. The full width at half-maximum of the image decreases to 62% compared to that of the image of a photonic-crystal slab without a graded index. The evanescent waves can be amplified and propagate to the far-field range. The image is not limited to be near the interface. The canalization effect of this structure is analyzed, and the tolerance of the edge cut of the graded-index structure is pretty good.

Microarray Analysis of Genes Associated with Cell Surface NIS Protein Levels in Breast Cancer

BMC Research Notes. 2011  |  Pubmed ID: 21989294

ABSTRACT:

Non-parametric Population Analysis of Cellular Phenotypes

Medical Image Computing and Computer-assisted Intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention. 2011  |  Pubmed ID: 21995047

Methods to quantify cellular-level phenotypic differences between genetic groups are a key tool in genomics research. In disease processes such as cancer, phenotypic changes at the cellular level frequently manifest in the modification of cell population profiles. These changes are hard to detect due the ambiguity in identifying distinct cell phenotypes within a population. We present a methodology which enables the detection of such changes by generating a phenotypic signature of cell populations in a data-derived feature-space. Further, this signature is used to estimate a model for the redistribution of phenotypes that was induced by the genetic change. Results are presented on an experiment involving deletion of a tumor-suppressor gene dominant in breast cancer, where the methodology is used to detect changes in nuclear morphology between control and knockout groups.

Periconceptional Folic Acid Supplementation Among Women Attending Antenatal Clinic in Anhui, China: Data from a Population-based Cohort Study

Midwifery. Oct, 2011  |  Pubmed ID: 22015219

OBJECTIVES: to examine the rate of periconceptional and optimal folic acid supplementation, and to characterise their patterns and determinants among antenatal women in central China. DESIGN: data from 4290 women in the Anhui Birth Defects and Child Development Cohort Study recruited between October 2008 and September 2009 were analysed. SETTING: seven Maternal and Child Health Centres of two cities (Hefei and Maanshan) in Anhui province of central China. PARTICIPANTS: women initiating prenatal care were included and asked to complete a structured questionnaire regarding folic acid supplementation. FINDINGS: sixty-eight per cent (2905/4290) of pregnant women reported taking folic acid supplementation periconceptionally (i.e. at some point before or during early pregnancy), and 32.8% (1405/4290) and 65.2% (2797/4290) had taken it before or during early pregnancy, respectively. However, only 16.1% (690/4290) used it optimally (i.e. regularly from four weeks before pregnancy throughout four weeks after pregnancy). Use of periconceptional folic acid was significantly associated with educational level, household income, registered residence, age, gestational age at recruitment, and planning of pregnancy. CONCLUSION: optimal folic acid supplementation was relatively low. IMPLICATIONS FOR PRACTICE: further efforts are needed to inform the population and promote the use of folic acid supplementation.

Does Delivery Mode Affect Women's Postpartum Quality of Life in Rural China?

Journal of Clinical Nursing. Oct, 2011  |  Pubmed ID: 22023714

Aims and objectives.  To explore the impact of delivery mode on women's postpartum quality of life in rural China and probe factors influencing postnatal quality of life. Background.  Childbirth significantly affects puerpera's physical, psychological and social domains of quality of life. Under the circumstance of increasing high caesarean section rate in rural China, the impact of delivery mode on postnatal quality of life remains unclear. Design.  Cross-sectional study design. Methods.  Women residing in rural areas and in their 0-12 months after childbirth from 30 rural townships participated in a household survey. A structured questionnaire was used to evaluate women's socio-demographic characteristics, previous pregnant experiences, foetal characteristics and use of maternal health services. The scale for rural postnatal quality of life was adopted to assess postnatal quality of life from six dimensions: physical complaints and pain, sleep and energy, sex satisfaction, interpersonal communication, self-evaluated living stress and perceived life satisfaction. Results.  The overall caeserean section rate was 70·0% (962/1375), and most of them (59·7%) were selected by maternal request. None of six dimensions and total score of quality of life displayed significant difference between women with normal delivery and cesaerean section. It was found that postnatal home visit related to good postnatal quality of life and lower husband education level, male gender of infant were associated with poor quality of life. Conclusions.  Delivery mode did not affect postpartum quality of life in rural China. Socio-cultural determinants may contribute more in influencing postnatal quality of life. Relevance to clinical practice.  Null findings in impact of delivery mode on postpartum quality of life may cause more difficulties in maternal decision-making for vaginal delivery in rural China. The importance of postnatal home visit could justify available and quality postnatal care in improving postpartum quality of life. Further research needs to explore the effective prevention programmes, especially attention for parenting boys.

Clonal Production and Organization of Inhibitory Interneurons in the Neocortex

Science (New York, N.Y.). Oct, 2011  |  Pubmed ID: 22034427

The neocortex contains excitatory neurons and inhibitory interneurons. Clones of neocortical excitatory neurons originating from the same progenitor cell are spatially organized and contribute to the formation of functional microcircuits. In contrast, relatively little is known about the production and organization of neocortical inhibitory interneurons. We found that neocortical inhibitory interneurons were produced as spatially organized clonal units in the developing ventral telencephalon. Furthermore, clonally related interneurons did not randomly disperse but formed spatially isolated clusters in the neocortex. Individual clonal clusters consisting of interneurons expressing the same or distinct neurochemical markers exhibited clear vertical or horizontal organization. These results suggest that the lineage relationship plays a pivotal role in the organization of inhibitory interneurons in the neocortex.

Coffee Components Inhibit Amyloid Formation of Human Islet Amyloid Polypeptide in Vitro: Possible Link Between Coffee Consumption and Diabetes Mellitus

Journal of Agricultural and Food Chemistry. Dec, 2011  |  Pubmed ID: 22059381

Global epidemic studies have suggested that coffee consumption is reversely correlated with the incidence of type 2 diabetes mellitus (T2DM), a metabolic disease. The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of T2DM. Coffee extracts have three major active components: caffeine, caffeic acid (CA), and chlorogenic acid (CGA). In this study, the effects of these major coffee components, as well as dihydrocaffeic acid (DHCA) (a major metabolite of CGA and CA), on the amyloidogenicity of hIAPP were investigated by thioflavin-T based fluorescence emission, transmission electronic microscopy, circular dichroism, light-induced cross-linking, dynamic light scattering, and MTT-based cell viability assays. The results suggest that all components show varied inhibitory effects on the formation of toxic hIAPP amyloids, in which CA shows the highest potency in delaying the conformational transition of the hIAPP molecule with the most prolonged lag time, whereas caffeine shows the lowest potency. At a 5-fold excess molar ratio of compound to hIAPP, all coffee-derived compounds affect the secondary structures of incubated hIAPP as suggested by the circular dichroism spectra and CDPro deconvolution analysis. Further photoinduced cross-linking based oligomerization and dynamic light scattering studies suggested CA and CGA significantly suppressed the formation of hIAPP oligomers, whereas caffeine showed no significant effect on oligomerization. Cell protection effects were also observed for all three compounds, with the protection efficiency being greatest for CA and least for CGA. These findings suggest that the beneficial effects of coffee consumption on T2DM may be partly due to the ability of the major coffee components and metabolites to inhibit the toxic aggregation of hIAPP.

3,3'-Dibenzyl-1,1'-[naphthalene-1,4-diylbis(methyl-ene)]di(1H-imidazol-3-ium) Bis-(hexa-fluoro-phosphate)

Acta Crystallographica. Section E, Structure Reports Online. Sep, 2011  |  Pubmed ID: 22064506

In the title N-heterocyclic carbene compound, C(32)H(30)N(4) (2+)·2PF(6) (-), the mean plane of the naphthalene ring system makes dihedral angles of 79.15 (15) and 76.85 (16) with the imidazole rings and 56.15 (19) and 80.56 (16)° with the benzene rings. An intra-molecular C-H⋯N hydrogen bond occurs. The crystal structure is stabilized by C-H⋯F inter-actions. In addition, π-π inter-actions [centroid-centroid distances = 3.848 (1) and 3.574 (3) Å] are observed. The nine equatorial F atoms in the two PF(6) (-) anions were disordered over two positions with occupancy ratios of 0.545 (10):0.455 (10) and 0.793 (11):0.207 (11) in the two anions.

Bis[1-benzyl-3-(4-methyl-phen-yl)imidazol-2-yl-idene]silver(I) Hexa-fluorido-phosphate

Acta Crystallographica. Section E, Structure Reports Online. Aug, 2011  |  Pubmed ID: 22090884

The title silver N-heterocyclic carbene compound, [Ag(C(17)H(16)N(2))(2)]PF(6), crystallizes as a mononuclear salt. The two imidazole rings, which are almost coplanar [maximum deviation from the least squares plane of 0.05 (2) Å], are linked by the Ag atom with a C-Ag-C angle of 178.60 (9)°. In the crystal, C-H⋯F hydrogen bonds, weak π-π inter-actions [centroid-centroid distances = 3.921 (1) and 3.813 (3) Å] and C-H⋯π inter-actions lead to a supermolecular structure.

1-Benzyl-3-[3-(naphthalen-2-yl-oxy)prop-yl]imidazolium Hexa-fluoro-phosphate

Acta Crystallographica. Section E, Structure Reports Online. Aug, 2011  |  Pubmed ID: 22091087

In the title salt, C(23)H(23)N(2)O(+)·PF(6) (-), the PF(6) (-) anion is highly disordered (occupancy ratios of 0.35:0.35:0.3, 0.7:0.15:0.15, 0.7:0.3 and 0.35:0.35:0.15:0.15) with the four F atoms in the equatorial plane rotating about the axial F-P-F bond. The mean plane of the imidazole ring makes dihedral angles of 82.44 (17) and 14.39 (16)°, respectively, with the mean planes of the benzene ring and the naphthalene ring system. The crystal structure is stabilized by C-H⋯F hydrogen bonds. In addition, π-π [centroid-centroid distances = 3.7271 (19)-3.8895 (17) Å] and C-H⋯π inter-actions are observed.

K-Neighborhood Decentralization: A Comprehensive Solution to Index the UMLS for Large Scale Knowledge Discovery

Journal of Biomedical Informatics. Dec, 2011  |  Pubmed ID: 22154838

The Unified Medical Language System (UMLS) is the largest thesaurus in the biomedical informatics domain. Previous works have shown that knowledge constructs comprised of transitively-associated UMLS concepts are effective for discovering potentially novel biomedical hypotheses. However, the extremely large size of the UMLS becomes a major challenge for these applications. To address this problem, we designed a k-neighborhood Decentralization Labeling Scheme (kDLS) for the UMLS, and the corresponding method to effectively evaluate the kDLS indexing results. kDLS provides a comprehensive solution for indexing the UMLS for very efficient large scale knowledge discovery. We demonstrated that it is highly effective to use kDLS paths to prioritize disease-gene relations across the whole genome, with extremely high fold-enrichment values. To our knowledge, this is the first indexing scheme capable of supporting efficient large scale knowledge discovery on the UMLS as a whole. Our expectation is that kDLS will become a vital engine for retrieving information and generating hypotheses from the UMLS for future medical informatics applications.

Maternal Socio-economic Indices for Prenatal Care Research in Rural China

European Journal of Public Health. Dec, 2011  |  Pubmed ID: 22158993

BACKGROUND: The conceptualization and measurement of socio-economic status (SES) is difficult in developing settings. In the absence of SES indices for women in rural China, we constructed SES indices for prenatal care research, and examined their relation to perinatal care and outcomes. METHODS: This study utilized data of 4364 rural women having recently given birth, collected by a cross-sectional survey in three rural Chinese provinces in 2007. Principal component analysis (PCA) was used to construct the SES indices and multilevel logistic regression was use to relate the indices to low birthweight, short exclusive breastfeeding (≤4 months), childbirth at the county or higher level health facility, caesarean section, inadequate prenatal care and no postnatal care. RESULTS: Three separate SES indices (wealth, occupational and educational indices) were obtained from the PCA analysis, capturing maternal, paternal and household SES characteristics. After adjusting for individual level factors, village and township wealth, higher levels of the indices were inversely associated with inadequate prenatal care. Higher occupational status was positively associated with short exclusive breastfeeding and childbirth at the county or higher level health facility, but inversely associated with no postnatal care. Higher educational status was positively associated with no postnatal care. CONCLUSION: Three SES indices (wealth, occupational and educational) were obtained from this study for prenatal care research. The indices gave mostly varying results on their associations with perinatal care and outcomes, indicating that SES measures may be outcome-specific.

Accumulation of Endoplasmic Reticulum Stress and Lipogenesis in the Liver Through Generational Effects of High Fat Diets

Journal of Hepatology. Dec, 2011  |  Pubmed ID: 22173165

BACKGROUND & AIMS: The dramatic rise of nonalcoholic fatty liver disease (NAFLD) among children in the past decade cannot be solely explained by the increased high fat diet (HFD) intake in kids. Recent studies suggest that the offspring of HFD-fed mothers develop a worse form of NAFLD when weaned on the HFD than when weaned on the normal chow (NC), indicating that a feed-forward circle may exacerbate the syndromes throughout multiple generations. In the present study, the aforementioned feed-forward circle was investigated in mice by employing continuous HFD feeding for three generations. METHODS: C57BL/6 mice were fed with either a HFD or NC for three consecutive generations (F0, F1, and F2). Body weight, food intake, hepatic histology; levels of insulin, leptin, and triglycerides; expression of factors involved in lipogenesis and endoplasmic reticulum (ER) stress pathways; and histone methylation status were investigated in male offspring. RESULTS: Obesity occurred earlier, became more severe through generations (F2>F1>F0), and was accompanied by a gradual increase of histological scoring of steatosis in male mice with transgenerational HFD feeding. The highest degree of steatosis occurred in HFD-treated F2 mice and was associated with the highest levels of insulin and leptin. The latter mice were characterized by enhanced lipogenesis and ER stress with a trend of transgenerational changes was detected for LXRα, ERO1-α, histone methylations, and H3K9 histone methyltransferase. Furthermore, chromatin immunoprecipitation (CHIP) assay demonstrated a significantly reduced accumulation of methylated histones in LXRα and ERO1-α gene promoters. CONCLUSIONS: Under HFD feeding stress, the male offspring of the F2 generation (derived from both grand-maternal and maternal obesity) are extremely susceptible to developing obesity and hepatic steatosis. This is presumably a consequence of transgenerational accumulation of epigenetic modifications leading to up-regulation of lipogenesis and ER stress pathways in the liver.

Porcine Islet Amyloid Polypeptide Fragments Are Refractory to Amyloid Formation

FEBS Letters. Jan, 2011  |  Pubmed ID: 21130765

Of 10 variation sites between sequences of amyloid-resistant porcine islet amyloid polypeptide (pIAPP) and amyloid-prone human IAPP (hIAPP), seven locate within residues 17-29, the most amyloidogenic fragment within hIAPP. To investigate how these variations affect amyloidogenicity, 26 IAPP(17-29) or IAPP(20-29) variants were synthesized and their secondary structures, amyloidogenicity, oligomerization and cytotoxicity were studied. Our results indicated that pIAPP fragments are refractory to amyloid formation and significantly less cytotoxic compared with hIAPP fragments. A novel stable dimer was observed in pIAPP(20-29) solution, whereas hIAPP(20-29) exists mostly as monomers and trimers. Among all human to porcine substitutions, S20R caused the most prolonged lag time and significantly attenuated cytotoxicity. The different oligomerization and amyloidogenic properties of hIAPP and pIAPP fragments are discussed.

Borylation of Aryl and Alkenyl Carbamates Through Ni-catalyzed C-O Activation

Chemistry (Weinheim an Der Bergstrasse, Germany). Jan, 2011  |  Pubmed ID: 21226092

Non-invasive Tumor Detection in Small Animals Using Novel Functional Pluronic Nanomicelles Conjugated with Anti-mesothelin Antibody

Nanoscale. Apr, 2011  |  Pubmed ID: 21365120

In this study QDs were encapsulated in carboxylated PluronicF127 (F127COOH) triblock polymeric micelles and conjugated with anti-mesothelin antibody for the purpose of alleviating potential toxicity, enhancing the stability and improving targeting efficiency of CdTe/ZnS quantum dots (QDs) in tumors. The amphiphilic triblock polymer of F127COOH contains hydrophilic carboxylated poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) units. After encapsulating QDs into carboxylated F127 (F127COOH-QD) micelles, the particles were conjugated with anti-mesothelin antibodies to allow targeting of cancerous areas. The size of the monodispersed spherical QD-containing micelles was determined to be ∼120 nm by dynamic light scattering (DLS). The critical micelle concentration (CMC) was estimated to be 4.7 × 10(-7) M. In an in vitro study, the anti-methoselin antibody conjugated F127COOH (Me-F127COOH-QD) nanomicelles showed negligible cytotoxicity to pancreatic cancer cells (Panc-1). Confocal microscopy demonstrated that the Me-F127COOH-QD nanomicelles were taken up more efficiently by Panc-1 cells, due to antibody mediated targeting. An in vivo imaging study showed that Me-F127COOH-QD nanomicelles accumulated at the pancreatic tumor site 15 min after intravenous injection. In addition, the low in vivo toxicity of the nanomicellar formulation was evaluated by pathological assays. These results suggest that anti-mesothein antibody conjugated carboxylated F127 nanomicelles may serve as a promising nanoscale platform for early human pancreatic cancer detection and targeted drug delivery.

Transition-metal-catalyzed C-C Bond Formation Through the Fixation of Carbon Dioxide

Chemical Society Reviews. May, 2011  |  Pubmed ID: 21387036

Carbon dioxide is an important carbon source in the atmosphere and is "problematic" toward the activities of human beings. Although carbon dioxide is a cheap, abundant and relatively nontoxic C1 source, its chemical transformations have not been widely developed so far and are still far from synthetic applications, especially in the construction of the C-C bond. This critical review summarizes the recent advances on transition-metal-catalyzed C-C bond formation through the fixation of carbon dioxide and their synthetic applications (124 references).

Vector-vortex Bessel-Gauss Beams and Their Tightly Focusing Properties

Optics Letters. Mar, 2011  |  Pubmed ID: 21403718

We demonstrate that the amplitude of vector-vortex beams has a Bessel-Gauss (BG) distribution through a rigorous vector electromagnetic analysis. We also investigate the intensity profiles in the focal plane of vector-vortex beams that are focused by a high numerical-aperture lens obeying the Helmholtz condition. Although the intensity of a vector-vortex BG beam with a topological charge n=1 is nonzero along the axis in the focal plane, the beams with n≠1 show discrete multiple spots which can be useful for optical trapping.

Proteins That Promote Filopodia Stability, but Not Number, Lead to More Axonal-dendritic Contacts

PloS One. 2011  |  Pubmed ID: 21408225

Dendritic filopodia are dynamic protrusions that are thought to play an active role in synaptogenesis and serve as precursors to spine synapses. However, this hypothesis is largely based on a temporal correlation between filopodia formation and synaptogenesis. We investigated the role of filopodia in synapse formation by contrasting the roles of molecules that affect filopodia elaboration and motility, versus those that impact synapse induction and maturation. We used a filopodia inducing motif that is found in GAP-43, as a molecular tool, and found this palmitoylated motif enhanced filopodia number and motility, but reduced the probability of forming a stable axon-dendrite contact. Conversely, expression of neuroligin-1 (NLG-1), a synapse inducing cell adhesion molecule, resulted in a decrease in filopodia motility, but an increase in the number of stable axonal contacts. Moreover, RNAi knockdown of NLG-1 reduced the number of presynaptic contacts formed. Postsynaptic scaffolding proteins such as Shank1b, a protein that induces the maturation of spine synapses, increased the rate at which filopodia transformed into spines by stabilization of the initial contact with axons. Taken together, these results suggest that increased filopodia stability and not density, may be the rate-limiting step for synapse formation.

Transactional Database Transformation and Its Application in Prioritizing Human Disease Genes

IEEE/ACM Transactions on Computational Biology and Bioinformatics / IEEE, ACM. Mar, 2011  |  Pubmed ID: 21422495

Binary (0/1) matrices, commonly known as transactional databases, can represent many application data, including gene-phenotype data where '1' represents a confirmed gene-phenotype relation and '0' represents an unknown relation. It is natural to ask what information is hidden behind these '0's and '1's. Unfortunately, recent matrix completion methods, though very effective in many cases, are less likely to infer something interesting from these 0/1 matrices. To answer this challenge, we propose \textsc{IndEvi}, a very succinct and effective algorithm to perform independent-evidence-based transactional database transformation. Each entry of a 0/1 matrix is evaluated by "independent evidence" (maximal supporting patterns) extracted from the whole matrix for this entry. The value of an entry, no matter 0 or 1, has completely no effect for its independent evidence. The experiment on a gene-phenotype database shows that our method is highly promising in ranking candidate genes and predicting unknown disease genes.

Synthesis of Spirocyclic β-keto-lactams: Copper Catalyzed Process

Chemical Communications (Cambridge, England). May, 2011  |  Pubmed ID: 21437335

In the presence of catalytic amount of copper salt, an efficient and flexible synthetic method towards the synthesis of a structurally new type of spirocyclic lactams was developed.

Comparing Multiple ChIP-sequencing Experiments

Journal of Bioinformatics and Computational Biology. Apr, 2011  |  Pubmed ID: 21523932

New high-throughput sequencing technologies can generate millions of short sequences in a single experiment. As the size of the data increases, comparison of multiple experiments on different cell lines under different experimental conditions becomes a big challenge. In this paper, we investigate ways to compare multiple ChIP-sequencing experiments. We specifically studied epigenetic regulation of breast cancer and the effect of estrogen using 50 ChIP-sequencing data from Illumina Genome Analyzer II. First, we evaluate the correlation among different experiments focusing on the total number of reads in transcribed and promoter regions of the genome. Then, we adopt the method that is used to identify the most stable genes in RT-PCR experiments to understand background signal across all of the experiments and to identify the most variable transcribed and promoter regions of the genome. We observed that the most variable genes for transcribed regions and promoter regions are very distinct. Gene ontology and function enrichment analysis on these most variable genes demonstrate the biological relevance of the results. In this study, we present a method that can effectively select differential regions of the genome based on protein-binding profiles over multiple experiments using real data points without any normalization among the samples.

HYR1-mediated Detoxification of Reactive Oxygen Species is Required for Full Virulence in the Rice Blast Fungus

PLoS Pathogens. Apr, 2011  |  Pubmed ID: 21533213

During plant-pathogen interactions, the plant may mount several types of defense responses to either block the pathogen completely or ameliorate the amount of disease. Such responses include release of reactive oxygen species (ROS) to attack the pathogen, as well as formation of cell wall appositions (CWAs) to physically block pathogen penetration. A successful pathogen will likely have its own ROS detoxification mechanisms to cope with this inhospitable environment. Here, we report one such candidate mechanism in the rice blast fungus, Magnaporthe oryzae, governed by a gene we refer to as MoHYR1. This gene (MGG_07460) encodes a glutathione peroxidase (GSHPx) domain, and its homologue in yeast was reported to specifically detoxify phospholipid peroxides. To characterize this gene in M. oryzae, we generated a deletion mutantΔhyr1 which showed growth inhibition with increased amounts of hydrogen peroxide (H₂O₂). Moreover, we observed that the fungal mutants had a decreased ability to tolerate ROS generated by a susceptible plant, including ROS found associated with CWAs. Ultimately, this resulted in significantly smaller lesion sizes on both barley and rice. In order to determine how this gene interacts with other (ROS) scavenging-related genes in M. oryzae, we compared expression levels of ten genes in mutant versus wild type with and without H₂O₂. Our results indicated that the HYR1 gene was important for allowing the fungus to tolerate H₂O₂ in vitro and in planta and that this ability was directly related to fungal virulence.

Photon-number-resolving Detection at 1.04 μm Via Coincidence Frequency Upconversion

Optics Letters. May, 2011  |  Pubmed ID: 21540981

We demonstrate photon-number-resolving detection based on coincidence frequency upconversion. Pumped by synchronized pulses, the photon signal of the coherent state at 1.04 μm was upconverted into visible replicas with preserved photon number distribution. The upconverted photons were then registered by a silicon multipixel photon counter. The photon-number-resolving performance was improved by reducing the background counts with a synchronous pump as the coincidence gate and reducing the intrinsic parametric fluorescence influence with long-wavelength pumping. A total detection efficiency of 3.7% was achieved with a quite low noise probability per pulse of 0.0002.

Completeness and Utility of Interview Data from Proxy Respondents in Prenatal Care Research in Rural China

Maternal and Child Health Journal. May, 2011  |  Pubmed ID: 21553083

In household surveys, the use of data provided by relatives can increase response rates and generalisability of research findings. This study assessed the quality of data from relatives and the impact of the data source on the association between the use of prenatal care and pregnancy outcomes. Data for 3,673 new mothers and 293 proxy respondents were available from a house-hold survey in 2008-2009 in rural China. Analyses were performed using chi-square test, ANOVA, Kruskal-Wallis test, and logistic regression models. Differences in the studied variables were small, but proxy respondents were slightly more likely to have missing data than the new mothers. Differences and missing data were more common for the use of prenatal care and outcome variables (mode of delivery, place of delivery, birth weight, use of postnatal care, and gestational age at birth) than for the background characteristics of the participants. Husbands' reports were closer to the index reports than that of the other proxies. The associations between the exposures and outcomes were mostly similar between the proxy and index respondents. Relatives can be interviewed instead of women to study prenatal care without a substantial negative impact on study results. Studies using proxy respondents should stratify the analysis by type of respondents.

De Novo Synthesis and Cellular Uptake of Organic Nanocapsules with Tunable Surface Chemistry

Biomacromolecules. Jun, 2011  |  Pubmed ID: 21563757

Water-soluble organic nanocapsules were prepared from bottlebrush copolymers with triblock terpolymer side chains composed of a degradable inner block (polylactide), a cross-linkable middle block (poly(4-butenylstyrene)), and a functional outer block (poly(styrene-co-maleic anhydride)). Bottlebrush copolymers are macromolecules with a long linear backbone and shorter polymeric side chains densely grafted onto the backbone. Hollow cylindrical nanoparticles were prepared by peripheral cross-linking of the bottlebrush copolymers and subsequent selective removal of the core. Reactive anhydride groups of the outer functional layer allowed for the preparation of nanocapsules with tunable surface characteristics. Cellular uptake of negatively charged organic nanocapsules showed strong surface chemistry dependence. The presence of hydrophobic groups on the nanocapsule surface was necessary for their nonspecific association with the cell membrane and subsequent internalization by endocytosis. The length of surface grafted oligoethylene glycol chains also had a dramatic influence on the intracellular accumulation of nanocapsules. Macropinocytosis was shown to be the predominant pathway for the cellular uptake of organic nanocapsules.

Inflammatory Gene Regulatory Networks in Amnion Cells Following Cytokine Stimulation: Translational Systems Approach to Modeling Human Parturition

PloS One. 2011  |  Pubmed ID: 21655103

A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs) in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs) stimulated with interleukin-1β, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-κB were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP) signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals.

KIAA0101 Interacts with BRCA1 and Regulates Centrosome Number

Molecular Cancer Research : MCR. Aug, 2011  |  Pubmed ID: 21673012

To find genes and proteins that collaborate with BRCA1 or BRCA2 in the pathogenesis of breast cancer, we used an informatics approach and found a candidate BRCA interactor, KIAA0101, to function like BRCA1 in exerting a powerful control over centrosome number. The effect of KIAA0101 on centrosomes is likely direct, as its depletion does not affect the cell cycle, KIAA0101 localizes to regions coincident with the centrosomes, and KIAA0101 binds to BRCA1. We analyzed whether KIAA0101 protein is overexpressed in breast cancer tumor samples in tissue microarrays, and we found that overexpression of KIAA0101 correlated with positive Ki67 staining, a biomarker associated with increased disease severity. Furthermore, overexpression of the KIAA0101 gene in breast tumors was found to be associated with significantly decreased survival time. This study identifies KIAA0101 as a protein important for breast tumorigenesis, and as this factor has been reported as a UV repair factor, it may link the UV damage response to centrosome control.

Superconcentrated Hydrochloric Acid

The Journal of Physical Chemistry. B. Jun, 2011  |  Pubmed ID: 21615094

We report the discovery of a potentially useful superconcentrated HCl at ambient temperature and pressure by using a simple surfactant-based reversed micelle system. Surprisingly, the molar ratios of H(+) to H(2)O (denoted as n(H+)/n(H2O)) in superconcentrated HCl can be larger than 5, while the maximum achievable n(H+)/n(H2O) value for conventional saturated HCl aqueous solution (37 wt %) is only about 0.28. Furthermore, both NMR and FT-IR results indicate that a significant amount of HCl remains in the molecular form rather than being ionized into H(+) and Cl(-). The superconcentrated HCl may promote some organic reactions that are not feasible by using conventional 37 wt % HCl solution. For example, addition reaction between C═C and HCl occurs in superconcentrated HCl solution without using catalysts.

Arylation of α-pivaloxyl Ketones with Arylboronic Reagents Via Ni-catalyzed Sp3 C-O Activation

Chemical Communications (Cambridge, England). Jul, 2011  |  Pubmed ID: 21623433

A Suzuki-Miyaura coupling of α-pivaloxyl ketones via Ni-catalyzed sp(3) C-O activation to produce α-aryl ketones is developed. This study offers a convenient method to construct α-arylation products from readily available α-hydroxyl carbonyl compounds.

Wild-type HTT Modulates the Enzymatic Activity of the Neuronal Palmitoyl Transferase HIP14

Human Molecular Genetics. Sep, 2011  |  Pubmed ID: 21636527

Huntington disease (HD) is caused by polyglutamine expansion in the huntingtin (HTT) protein. Huntingtin-interacting protein 14 (HIP14), one of 23 DHHC domain-containing palmitoyl acyl transferases (PATs), binds to HTT and robustly palmitoylates HTT at cysteine 214. Mutant HTT exhibits reduced palmitoylation and interaction with HIP14, contributing to the neuronal dysfunction associated with HD. In this study, we confirmed that, among 23 DHHC PATs, HIP14 and its homolog DHHC-13 (HIP14L) are the two major PATs that palmitoylate HTT. Wild-type HTT, in addition to serving as a palmitoylation substrate, also modulates the palmitoylation of HIP14 itself. In vivo, HIP14 palmitoylation is decreased in the brains of mice lacking one HTT allele (hdh+/-) and is further reduced in mouse cortical neurons treated with HTT antisense oligos (HTT-ASO) that knockdown HTT expression by ∼95%. Previously, it has been shown that palmitoylation of DHHC proteins may affect their enzymatic activity. Indeed, palmitoylation of SNAP25 by HIP14 is potentiated in vitro in the presence of wild-type HTT. This influence of HTT on HIP14 activity is lost in the presence of CAG expansion. Furthermore, in both brains of hdh+/- mice and neurons treated with HTT-ASO, we observe a significant reduction in palmitoylation of endogenous SNAP25 and GluR1, synaptic proteins that are substrates of HIP14, suggesting wild-type HTT also influences HIP14 enzymatic activity in vivo. This study describes an important biochemical function for wild-type HTT modulation of HIP14 palmitoylation and its enzymatic activity.

A Multinational Study of the Influence of Health-related Quality of Life on In-hospital Outcome After Coronary Artery Bypass Graft Surgery

American Heart Journal. Jun, 2011  |  Pubmed ID: 21641366

The effect of health-related quality of life on in-hospital outcomes after coronary artery bypass grafting surgery has not been investigated in international multicenter studies. We hypothesized that poor preoperative health status is associated with mortality and length of hospital stay.

Enoyl Acyl Carrier Protein Reductase Inhibitors: a Patent Review (2006 - 2010)

Expert Opinion on Therapeutic Patents. Jul, 2011  |  Pubmed ID: 21651455

INTRODUCTION: Bacterial enoyl acyl carrier protein reductase (ENR) specificity reduces the double bond in enoyl thioester substrates in the final enzymatic step of the elongation cycle of the fatty acid synthase-II pathway. Its function is essential for bacterial organism survival, making it an attractive target for the development of novel antibiotics. The structural features and therapeutic potential of this enzyme have stimulated the rational design of ENR inhibitors, and important progress has been achieved to date. AREAS COVERED: This review describes recent advances made in the search for ENR inhibitors, as reflected by patent applications filed from 2006 to 2010, together with an overview of the relevant literature. The first section of this paper provides a background of the biology of ENR, followed by a description of its structure and function. The main section describes the substrate specificities for ENR, and the structure-based rational design of patent inhibitors originating from different companies and academic groups. EXPERT OPINION: The increase in the number of ENR inhibitors bodes well for the development of new therapeutics against multidrug-resistant bacteria. The challenge is now to improve the pharmacokinetic parameters of these inhibitors and translate them into clinical studies.

Chiral Epoxides Via Borane Reduction of 2-haloketones Catalyzed by Spiroborate Ester: Application to the Synthesis of Optically Pure 1,2-hydroxy Ethers and 1,2-azido Alcohols

The Journal of Organic Chemistry. Mar, 2011  |  Pubmed ID: 21294519

An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield.

Gene Network and Pathway Generation and Analysis

International Journal of Computational Biology and Drug Design. 2011  |  Pubmed ID: 21339552

Zinc Deficiency Activates S100A8 Inflammation in the Absence of COX-2 and Promotes Murine Oral-esophageal Tumor Progression

International Journal of Cancer. Journal International Du Cancer. Jul, 2011  |  Pubmed ID: 20857495

Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2(-/-) mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2(-/-) and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2(-/-) mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2(-/-) vs. ZS:Cox-2(-/-) forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2(-/-) forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2(-/-) mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy.

Low Postnatal Care Rates in Two Rural Counties in Anhui Province, China: Perceptions of Key Stakeholders

Midwifery. Oct, 2011  |  Pubmed ID: 20850212

to explore the perceptions of stakeholders on postnatal care and to describe the rate of postnatal home visits in two rural counties in Anhui Province, China.

Enhance the Resolution of Photonic Crystal Negative Refraction Imaging by Metal Grating

Optics Letters. Feb, 2012  |  Pubmed ID: 22297352

The resolution of imaging is limited by the missing of high-frequencies information. The superlens employing negative refraction can compensate for these components. But for the directional coupling of Bloch waves and the low coupling efficiency of large-angle waves, the resolution of subwavelength imaging is not satisfactory. However, the subwavelength metallic grating can produce high-order diffracted waves carrying a lot of high-frequencies information. Therefore, this structure is used to inhibit the zero-order diffraction and enhance the high-order diffraction to achieve super-resolution.

Analyzing ChIP-seq Data: Preprocessing, Normalization, Differential Identification, and Binding Pattern Characterization

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22130887

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is a high-throughput antibody-based method to study genome-wide protein-DNA binding interactions. ChIP-seq technology allows scientist to obtain more accurate data providing genome-wide coverage with less starting material and in shorter time compared to older ChIP-chip experiments. Herein we describe a step-by-step guideline in analyzing ChIP-seq data including data preprocessing, nonlinear normalization to enable comparison between different samples and experiments, statistical-based method to identify differential binding sites using mixture modeling and local false discovery rates (fdrs), and binding pattern characterization. In addition, we provide a sample analysis of ChIP-seq data using the steps provided in the guideline.

Photon Correlation in Single-photon Frequency Upconversion

Optics Express. Jan, 2012  |  Pubmed ID: 22330478

We experimentally investigated the intensity cross-correlation between the upconverted photons and the unconverted photons in the single-photon frequency upconversion process with multi-longitudinal mode pump and signal sources. In theoretical analysis, with this multi-longitudinal mode of both signal and pump sources system, the properties of the signal photons could also be maintained as in the single-mode frequency upconversion system. Experimentally, based on the conversion efficiency of 80.5%, the joint probability of simultaneously detecting at upconverted and unconverted photons showed an anti-correlation as a function of conversion efficiency which indicated the upconverted photons were one-to-one from the signal photons. While due to the coherent state of the signal photons, the intensity cross-correlation function g(2)(0) was shown to be equal to unity at any conversion efficiency, agreeing with the theoretical prediction. This study will benefit the high-speed wavelength-tunable quantum state translation or photonic quantum interface together with the mature frequency tuning or longitudinal mode selection techniques.