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Find video protocols related to scientific articles indexed in Pubmed.
Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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Background In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. Methods We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. Results A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. Conclusions In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238 .).
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Biomimetic transparent and superhydrophobic coatings: from nature and beyond nature.
Chem. Commun. (Camb.)
PUBLISHED: 11-20-2014
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It is well known that high optical transparency is one of the most crucial criteria for the overwhelming majority of optical devices and correlative functions, including smart windows, camera lenses, solar cell systems and optoelectronic devices. With the frequent exposure of this equipment to all sorts of environments, such as outdoor conditions, a surface with self-cleaning properties can guard against fouling, humidity, bacterial growth and so forth. That is one type of application of the big family of superhydrophobic coatings. Therefore, integrating high transparency with self-cleaning characteristics is of great importance for such applications. In this review, the recent developments in designing, synthesizing and manufacturing transparent and superhydrophobic surfaces are reviewed. Firstly, the established theoretical aspects of surface wetting properties are summarized and then several natural and bio-inspired superhydrophobic surfaces of diverse microcosmic structures are presented as representative examples. With a focus on distinctively employed materials and the corresponding fabrication of superhydrophobic coatings with high transparency, the promising research directions and application prospects of this rapidly developing field are briefly addressed as well.
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Development of 107 SSR markers from whole genome shotgun sequences of Chinese bayberry (Myrica rubra) and their application in seedling identification.
J Zhejiang Univ Sci B
PUBLISHED: 11-05-2014
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Chinese bayberry (Myrica rubra Sieb. et Zucc.) is one of the important subtropical fruit crops native to the South of China and Asian countries. In this study, 107 novel simple sequence repeat (SSR) molecular markers, a powerful tool for genetic diversity studies, cultivar identification, and linkage map construction, were developed and characterized from whole genome shotgun sequences. M13 tailing for forward primers was applied as a simple method in different situations. In total, 828 alleles across 45 accessions were detected, with an average of 8 alleles per locus. The number of effective alleles ranged from 1.22 to 10.41 with an average of 4.08. The polymorphic information content (PIC) varied from 0.13 to 0.89, with an average of 0.63. Moreover, these markers could also be amplified in their related species Myrica cerifera (syn. Morella cerifera) and Myrica adenophora. Seventy-eight SSR markers can be used to produce a genetic map of a cross between 'Biqi' and 'Dongkui'. A neighbor-joining (NJ) tree was constructed to assess the genetic relationships among accessions, and the elite accessions 'Y2010-70', 'Y2012-140', and 'Y2012-145', were characterized as potential new genotypes for cultivation.
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Chronic Stress Impairs ?1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus.
J. Neurosci.
PUBLISHED: 10-31-2014
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Alpha 1-adrenergic receptors (?1-ARs) control the activity of dorsal raphe nucleus (DRn) serotonin (5-HT) neurons and play crucial role in the regulation of arousal and stress homoeostasis. However, the precise role of these receptors in regulating glutamate synapses of rat DRn 5-HT neurons and whether chronic stress exposure alters such regulation remain unknown. In the present study, we examined the impact of chronic restraint stress on ?1-AR-mediated regulation of glutamate synapses onto DRn 5-HT neurons. We found that, in the control condition, activation of ?1-ARs induced an inward current and long-term depression (LTD) of glutamate synapses of DRn 5-HT neurons. The ?1-AR LTD was initiated by postsynaptic ?1-ARs but mediated by a decrease in glutamate release. The presynaptic expression of the ?1-AR LTD was signaled by retrograde endocannabinoids (eCBs). Importantly, we found that chronic exposure to restraint stress profoundly reduced the magnitude of ?1-AR LTD but had no effect on the amplitude of ?1-AR-induced inward current. Chronic restraint stress also reduced the CB1 receptor-mediated inhibition of EPSC and the eCB-mediated depolarization-induced suppression of excitation. Collectively, these results indicate that chronic restraint stress impairs the ?1-AR LTD by reducing the function of presynaptic CB1 receptors and reveal a novel mechanism by which noradrenaline controls synaptic strength and plasticity in the DRn. They also provide evidence that chronic stress impairs eCB signaling in the DRn, which may contribute, at least in part, to the dysregulation of the stress homeostasis.
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Triphenyltin chloride induces spindle microtubule depolymerisation and inhibits meiotic maturation in mouse oocytes.
Reprod. Fertil. Dev.
PUBLISHED: 10-29-2014
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Meiosis produces haploid gametes for sexual reproduction. Triphenyltin chloride (TPTCL) is a highly bioaccumulated and toxic environmental oestrogen; however, its effect on oocyte meiosis remains unknown. We examined the effect of TPTCL on mouse oocyte meiotic maturation in vitro and in vivo. In vitro, TPTCL inhibited germinal vesicle breakdown (GVBD) and first polar body extrusion (PBE) in a dose-dependent manner. The spindle microtubules completely disassembled and the chromosomes condensed after oocytes were exposed to 5 or 10?gmL(-1) TPTCL. ?-Tubulin protein was abnormally localised near chromosomes rather than on the spindle poles. In vivo, mice received TPTCL by oral gavage for 10 days. The general condition of the mice deteriorated and the ovary coefficient was reduced (P<0.05). The number of secondary and mature ovarian follicles was significantly reduced by 10mgkg(-1) TPTCL (P<0.05). GVBD decreased in a non-significant, dose-dependent manner (P>0.05). PBE was inhibited with 10mgkg(-1) TPTCL (P<0.05). The spindles of in vitro and in vivo metaphase II oocytes were disassembled with 10mgkg(-1) TPTCL. These results suggest that TPTCL seriously affects meiotic maturation by disturbing cell-cycle progression, disturbing the microtubule cytoskeleton and inhibiting follicle development in mouse oocytes.
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Porous Ice Phases with VI and Distorted VII Structures Constrained in Nanoporous Silica.
Nano Lett.
PUBLISHED: 10-27-2014
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High-pressure compression of water contained in nanoporous silica allowed fabrication of novel porous ice phases as a function of pressure. The starting liquid nanoporous H2O transformed to ice VI and VII at 1.7 and 2.5 GPa, respectively, which are 0.6 and 0.4 GPa higher than commonly accepted pressures for bulk H2O. The continuous increase of pressure drives the formation of a tetragonally distorted VII structure with the space group I4mm, rather than a cubic Pn3m phase in bulk ice. The enhanced incompressibility of the tetragonal ice is related to the unique nanoporous configuration, and the distortion ratio c/a gradually increases with increasing pressure. The structural changes and enhanced thermodynamic stability may be interpreted by the two-dimensional distribution of silanol groups on the porous silica surfaces and the associated anisotropic interactions with H2O at the interfaces.
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Octadecanuclear Macrocycles and Nonanuclear Bowl-Shaped Structures Based on Two Analogous Pyridyl-Substituted Imidazole-4,5-dicarboxylate Ligands.
J. Am. Chem. Soc.
PUBLISHED: 10-27-2014
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Two types of unprecedented Cp*Rh-based (Cp* = ?(5)-C5Me5) complexes, two octadecanuclear macrocycles, and a nonanuclear bowl-shaped complex have been synthesized from two analogous pyridyl-functionalized imidazole-4,5-dicarboxylate ligands, 2-(pyridin-4-yl)-1H-imidazole-4,5-dicarboxylate ligand and 2-(pyridin-3-yl)-1H-imidazole-4,5-dicarboxylate ligand, respectively.
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Construction of iridium and rhodium cyclometalated macrocycles based on p-carborane and N,N'-donor bridging ligands.
Dalton Trans
PUBLISHED: 10-22-2014
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Six tetranuclear half-sandwich iridium and rhodium complexes bridged by neutral N,N'-donor pyridyl-imine ligands and 1,12-dicarbadodecaborane(12)-1,12-dicarboxylate (p-CDC) were controllably synthesized and fully characterized. The results revealed that the precursors, binuclear complexes [(Cp*M)2{1,4-bis(2-pyridylmethyleneamino)benzene}Cl2][OTf]2 (Cp* = ?(5)-pentamethylcyclopentadienyl, M = Ir (), Rh ()), have different preferential configurations, and tetranuclear complexes [(Cp*M)4{1,4-bis(2-pyridylmethyleneamino)benzene}2(p-CDC)2][OTf]4 (M = Ir (), Rh ()), which were prepared using monodentate p-carborane dicarboxylate and or , showed highly twisted backbones. Likewise, homologous regular rectangular compounds [(Cp*M)4{1,4-{(2-C5H4N)HC[double bond, length as m-dash]N}2-2,3,5,6-Me4C6}2(p-CDC)2][OTf]4 (M = Ir (), Rh ()) and [(Cp*M)4{1,4-{(2-C5H4N)HC[double bond, length as m-dash]N}2-1,5-naphthalene}2(p-CDC)2][OTf]4 (M = Ir (), Rh ()) were obtained following a similar synthetic route. X-ray determination confirmed that and have stacking channels as well.
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Antiphospholipid antibodies attenuate endothelial repair and promote neointima formation in mice.
J Am Heart Assoc
PUBLISHED: 10-16-2014
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Antiphospholipid syndrome patients have antiphospholipid antibodies (aPLs) that promote thrombosis, and they have increased cardiovascular disease risk. Although the basis for the thrombosis has been well delineated, it is not known why antiphospholipid syndrome patients also have an increased prevalence of nonthrombotic vascular occlusion. The aims of this work were to determine if aPLs directly promote medial hypertrophy or neointima formation in mice and to identify the underlying mechanisms.
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EOL-1, the homolog of the mammalian Dom3Z, regulates olfactory learning in C. elegans.
J. Neurosci.
PUBLISHED: 10-03-2014
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Learning is an essential function of the nervous system. However, our understanding of molecular underpinnings of learning remains incomplete. Here, we characterize a conserved protein EOL-1 that regulates olfactory learning in Caenorhabditis elegans. A recessive allele of eol-1 (enhanced olfactory learning) learns better to adjust its olfactory preference for bacteria foods and eol-1 acts in the URX sensory neurons to regulate learning. The mammalian homolog of EOL-1, Dom3Z, which regulates quality control of pre-mRNAs, can substitute the function of EOL-1 in learning regulation, demonstrating functional conservation between these homologs. Mutating the residues of Dom3Z that are critical for its enzymatic activity, and the equivalent residues in EOL-1, abolishes the function of these proteins in learning. Together, our results provide insights into the function of EOL-1/Dom3Z and suggest that its activity in pre-mRNA quality control is involved in neural plasticity.
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Granulation of increasingly hydrophobic formulations using a twin screw granulator.
Int J Pharm
PUBLISHED: 08-12-2014
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The application of twin screw granulation in the pharmaceutical industry has generated increasing interest due to its suitability for continuous processing. However, an understanding of the impact of formulation properties such as hydrophobicity on intermediate and finished product quality has not yet been established. Hence, the current work investigated the granulation behaviour of three formulations containing increasing amounts of hydrophobic components using a Consigma™-1 twin screw granulator. Process conditions including powder feed rate, liquid to solid ratio, granulation liquid composition and screw configuration were also evaluated. The size of the wet granules was measured in order to enable exploration of granulation behaviour in isolation without confounding effects from downstream processes such as drying. The experimental observations indicated that the granulation process was not sensitive to the powder feed rate. The hydrophobicity led to heterogeneous liquid distribution and hence a relatively large proportion of un-wetted particles. Increasing numbers of kneading elements led to high shear and prolonged residence time, which acted to enhance the distribution of liquid and feeding materials. The bimodal size distributions considered to be characteristic of twin screw granulation were primarily ascribed to the breakage of relatively large granules by the kneading elements.
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High Environmental Stress Yields Greater Tocotrienol Content While Changing Vitamin E Profiles of Wild Emmer Wheat Seeds.
J Med Food
PUBLISHED: 08-08-2014
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Abstract Vitamin E is an essential human nutrient that was first isolated from wheat. Emmer wheat, the cereal of Old World agriculture and a precursor to durum wheat, grows wild in the Fertile Crescent. Evolution Canyon, Israel, provides a microsite that models effects of contrasting environments. The north-facing and south-facing slopes exhibit low and high stress environments, respectively. Wild emmer wheat seeds were collected from both slopes and seed tocochromanol contents measured to test the hypothesis that high stress alters emmer wheat seed tocol-omics. Seeds from high stress areas contained more total vitamin E (108±15?nmol/g) than seeds from low stress environments (80±17?nmol/g, P=.0004). Vitamin E profiles within samples from these different environments revealed significant differences in isoform concentrations. Within each region, ?- plus ?-tocotrienols represented the highest concentration of wheat tocotrienols (high stress, P<.0001; low stress, P<.0001), while ?-tocopherol represented the highest concentration of the tocopherols (high stress, P=.0002; low stress, P<.0001). Percentages of both ?-tocotrienol and ?-tocopherol increased in high stress conditions. Changes under higher stress apparently are due to increased pathway flux toward more tocotrienol production. The production of more ?-isoforms suggests increased flow through a divergent path controlled by the VTE1 gene. Hence, stress conditions alter plant responses such that vitamin E profiles are changed, likely an attempt to provide additional antioxidant activity to promote seed viability and longevity.
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Lithocarpic Acids A-N, 3,4-seco-Cycloartane Derivatives from the Cupules of Lithocarpus polystachyus.
J. Nat. Prod.
PUBLISHED: 08-08-2014
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Fourteen new 3,4-seco-cycloartane-type triterpenes, lithocarpic acids A-N (1-14), together with one known compound, coccinetane E (15), were identified from the cupules of Lithocarpus polystachyus. The structures of 1-14 were determined by spectroscopic data analysis and chemical methods, and the absolute configurations of 1 and 4 were defined unequivocally by X-ray crystallography using Cu K? radiation. Compounds 1-15 are the first examples of 3,4-seco-cycloartane derivatives isolated from the genus Lithocarpus. Among them, compounds 1 and 2, 9 and 10, and 11 and 12 were found to be three pairs of C-24 epimers, while compounds 7 and 8 represent the first examples of 3,4-seco-norcycloartane-type triterpenes. Compound 1, as the major component of the plant extract, showed potent antibacterial activity against Micrococcus luteus and Bacillus subtilis, with MIC values of 3.1 and 6.3 ?g/mL, respectively, as well as inhibitory activity against human and mouse 11?-hydroxysteroid dehydrogenase type 1, with IC50 values of 1.9 and 0.24 ?M, respectively.
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Sample size calculations for prevalent cohort designs.
Stat Methods Med Res
PUBLISHED: 08-06-2014
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Cross-sectional prevalent cohort design has drawn considerable interests in the studies of association between risk factors and time-to-event outcome. The sampling scheme in such design gives rise to length-biased data that require specialized analysis strategy but can improve study efficiency. The power and sample size calculation methods are however lacking for studies with prevalent cohort design, and using the formula developed for traditional survival data may overestimate sample size. We derive the sample size formulas that are appropriate for the design of cross-sectional prevalent cohort studies, under the assumptions of exponentially distributed event time and uniform follow-up for cross-sectional prevalent cohort design. We perform numerical and simulation studies to compare the sample size requirements for achieving the same power between prevalent cohort and incident cohort designs. We also use a large prospective prevalent cohort study to demonstrate the procedure. Using rigorous designs and proper analysis tools, the prospective prevalent cohort design can be more efficient than the incident cohort design with the same total sample sizes and study durations.
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Preparation of two flavonoid glycosides with unique structures from barley seedlings by membrane separation technology and preparative high-performance liquid chromatography.
J Sep Sci
PUBLISHED: 07-23-2014
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Barley seedlings are rich in flavones that can have positive effects on people with antihypoxia and antifatigue. Lutonarin and saponarin are two major flavonoid glycosides that have unique structures in barley seedlings. This study presents a new approach for the preparation of lutonarin and saponarin from barely seedlings by membrane separation technology and preparative high-performance liquid chromatography. Preparative conditions of these two flavonoid glycosides by membrane separation technology were studied using response surface methodology. Under the optimized conditions, the total contents of these two flavonoid glycosides amounts to 17.0%.
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Regulation of Saccharomyces cerevisiae MEF1 by Hda1p affects salt resistance of bdf1? mutant.
FEMS Yeast Res.
PUBLISHED: 07-19-2014
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Bromodomain factor 1 (Bdf1p) is a transcriptional regulator. The absence of Bdf1p causes salt sensitivity with abnormal nucleus and mitochondrial dysfunction. In this study, we reported that the salt sensitivity, mitochondrial dysfunction, and nuclear instability of bdf1? mutant were suppressed by HDA1 deletion or MEF1 overexpression. Hda1p overexpression inhibited the relieving effects of low-copy overexpression of MEF1. Further analysis showed that Bdf1p regulated HDA1 transcription positively by binding to its promoter at ?201 to +6 bp, whereas Hda1p modulated MEF1 expression negatively by binding to its promoter at ?201 to +6 bp. These results suggested that Bdf1p likely regulated MEF1 expression negatively by regulating HDA1 positively. Mitochondrial proteomics analysis showed that the expression levels of six mitochondrial proteins were significantly changed by MEF1 overexpression. Among the six genes, over-expression of PDB1, ILV5, or ATP2 partially recovered the salt stress sensitivity of bdf1?. However, none of these mitochondrial proteins could recover mitochondrial respiration indicating that the individual functional proteins could not replace Mef1p activity. It indicated that positive regulation of MEF1 was important in recovering the salt sensitivity of bdf1? mutant.
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Physician variation in management of low-risk prostate cancer: a population-based cohort study.
JAMA Intern Med
PUBLISHED: 07-16-2014
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Up-front treatment of older men with low-risk prostate cancer can cause morbidity without clear survival benefit; however, most such patients receive treatment instead of observation. The impact of physicians on the management approach is uncertain.
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Metformin decreases lung cancer risk in diabetic patients in a dose-dependent manner.
Lung Cancer
PUBLISHED: 07-11-2014
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Higher risk of lung cancer has been noted in patients with type 2 diabetes mellitus (DM). Some observational studies have shown a reduced risk of lung cancer in DM patients taking metformin, but a dose-response relationship has never been reported. The aim of this study is to exam the association between the dose of metformin and the incidence of lung cancer in a Chinese population.
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Dissecting the signaling mechanisms underlying recognition and preference of food odors.
J. Neurosci.
PUBLISHED: 07-11-2014
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Food is critical for survival. Many animals, including the nematode Caenorhabditis elegans, use sensorimotor systems to detect and locate preferred food sources. However, the signaling mechanisms underlying food-choice behaviors are poorly understood. Here, we characterize the molecular signaling that regulates recognition and preference between different food odors in C. elegans. We show that the major olfactory sensory neurons, AWB and AWC, play essential roles in this behavior. A canonical G?-protein, together with guanylate cyclases and cGMP-gated channels, is needed for the recognition of food odors. The food-odor-evoked signal is transmitted via glutamatergic neurotransmission from AWC and through AMPA and kainate-like glutamate receptor subunits. In contrast, peptidergic signaling is required to generate preference between different food odors while being dispensable for the recognition of the odors. We show that this regulation is achieved by the neuropeptide NLP-9 produced in AWB, which acts with its putative receptor NPR-18, and by the neuropeptide NLP-1 produced in AWC. In addition, another set of sensory neurons inhibits food-odor preference. These mechanistic logics, together with a previously mapped neural circuit underlying food-odor preference, provide a functional network linking sensory response, transduction, and downstream receptors to process complex olfactory information and generate the appropriate behavioral decision essential for survival.
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Rad23 interaction with the proteasome is regulated by phosphorylation of its ubiquitin-like (UbL) domain.
J. Mol. Biol.
PUBLISHED: 06-27-2014
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Rad23 was identified as a DNA repair protein; although a role in protein degradation has been described. The protein degradation function of Rad23 contributes to cell cycle progression, stress response, ER proteolysis, DNA repair. Rad23 binds the proteasome through a ubiquitin-like (UbL) domain, and contains ubiquitin-associated (UBA) motifs that bind multiubiquitin chains. These domains allow Rad23 to function as a substrate shuttle-factor. This property is shared by structurally similar proteins (Dsk2 and Ddi1), and is conserved among the human and mouse counterparts of Rad23. Despite much effort, the regulation of Rad23 interactions with ubiquitinated substrates and the proteasome is unknown. We report here that Rad23 is extensively phosphorylated in vivo and in vitro. Serine residues in UbL are phosphorylated, and influence Rad23 interaction with proteasomes. Replacement of these serine residues with acidic residues, to mimic phosphorylation, reduced proteasome binding. We reported that when UbL is overexpressed, it can compete with Rad23 for proteasome interaction and inhibit substrate turnover. This effect is not observed with UbL containing acidic substitutions, consistent with results that phosphorylation inhibits interaction with the proteasome. Loss of both Rad23 and Rpn10 caused pleiotropic defects that were suppressed by overexpressing either Rad23 or Rpn10. Rad23 bearing a UbL domain with acidic substitutions failed to suppress rad23? rpn10?, confirming the importance of regulated Rad23/proteasome binding. Strikingly, Threonine-75 in human HR23B also regulates interaction with the proteasome, suggesting that phosphorylation is a conserved mechanism for controlling Rad23/proteasome interaction.
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One-pot synthesis of fluorescent BSA-Ce/Au nanoclusters as ratiometric pH probes.
Chem. Commun. (Camb.)
PUBLISHED: 06-24-2014
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A facile, one-pot synthetic approach has been developed for the preparation of BSA-Ce/Au NCs. The fluorescence intensities of BSA-Ce/Au NCs at 410 and 650 nm are pH dependent and independent, respectively. The fluorescence intensity ratio (I410/I650) is linear against pH values from 6.0 to 9.0. These stable and biocompatible BSA-Ce/Au NCs have been used as ratiometric probes for monitoring local pH values inside HeLa cells.
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Surgeon influence on use of needle biopsy in patients with breast cancer: a national medicare study.
J. Clin. Oncol.
PUBLISHED: 06-09-2014
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Use of needle biopsy is a proposed quality measure in the diagnosis and treatment of breast cancer, yet prior literature documents underuse. Nationally, little is known regarding the contribution of a patient's surgeon to needle biopsy use, and knowledge regarding downstream impact of needle biopsy on breast cancer care is incomplete.
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Underuse of trimodality treatment affects survival for patients with inflammatory breast cancer: an analysis of treatment and survival trends from the National Cancer Database.
J. Clin. Oncol.
PUBLISHED: 06-02-2014
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To analyze factors that predict the use of trimodality treatment (chemotherapy, surgery, and radiation therapy [RT]) and evaluate the impact that trimodality treatment use has on survival for patients with inflammatory breast cancer (IBC).
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Dammarane-type triterpenoids as 11?-HSD1 inhibitors from Homonoia riparia.
Org. Biomol. Chem.
PUBLISHED: 05-30-2014
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An exploration for 11?-HSD1 inhibitors from Homonoia riparia returned eight new dammarane-type triterpenoids, horipenoids A–H (1–8), and a known oleanane-type triterpenoid (9). Their structures were elucidated on the basis of comprehensive analysis of spectroscopic data, and the absolute configuration of horipenoid E (5) was established by single crystal X-ray crystallography. Compounds 1–4 represent a rare class of octanortriterpenoids. Horipenoids C (3) and E (5) showed potent inhibition against mouse 11?-HSD1 with IC50 values of 0.810 ± 0.058 and 0.898 ± 0.215 ?M, respectively.
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Heavy metal and organic contaminants in mangrove ecosystems of China: a review.
Environ Sci Pollut Res Int
PUBLISHED: 05-26-2014
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China's rapid economic growth has been accompanied by increasing environmental pollution. Mangrove ecosystems are now facing greater pollution pressures due to elevated chemical discharges from various land-based sources. Data on the levels of heavy metals and organic pollutants in mangrove compartments (sediments, plants, zoobenthos, and fish) in China over the past 20 years have been summarized to evaluate the current pollution status of the mangrove ecosystem. Overall, the Pearl River and Jiulong River estuaries were severely polluted spots. Concentrations of Cu, Zn, Cd, and Pb in mangrove sediments of Guangdong, Fujian, and Hong Kong were higher than those from Guangxi and Hainan. The pollution status was closely linked to industrialization and urbanization. The highest concentrations of polycyclic aromatic hydrocarbons (PAHs) were found in mangrove sediments from Hong Kong, followed by Fujian and Guangdong. Mangrove plants tend to have low-enriched ability for heavy metals and organic pollutants. Much higher levels of Pb, Cd, and Hg were observed in mollusks.
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Start-Up of a Combined Anaerobic/Partial Nitritation/ANAMMOX Process for High-Salt Mustard Wastewater Treatment.
Appl. Biochem. Biotechnol.
PUBLISHED: 05-23-2014
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To treat high salinity wastewater from the mustard pickling industry, a combined anaerobic, partial nitritation (PN), and anammox process was employed using three connected reactors: an anaerobic sequencing batch biofilm reactor (ASBBR) for anaerobic treatment, a sequencing batch reactor (SBR) for PN, and an upflow anaerobic sludge blanket (UASB) for anammox. The start-up of the three individual reactors was investigated. Results showed that each reactor started up successfully, notwithstanding the stepwise increase of influent salinity to about 16.1 g NaCl/L. In the ASBBR, 89.7 % of chemical oxygen demand in the influent was removed and organic nitrogen was converted to ammonium (NH4 (+)-N). The SBR performed well with NO3 (-)-N concentration of 4.9 mg/L and ratio of NO2 (-)-N to NH4 (+)-N at the range of 1.0 to 1.3 in the effluent, which favored the anammox process. After the start-up of the UASB, the anammox process also showed stability and efficiency with a high total nitrogen removal efficiency of 86.2 % under high salinity of 12.0 g NaCl/L and nitrogen loading rate of 258 mg/(L?·?day).
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Ingol-type diterpenes from Euphorbia antiquorum with mouse 11?-hydroxysteroid dehydrogenase type 1 inhibition activity.
J. Nat. Prod.
PUBLISHED: 05-19-2014
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Eighteen new ingol-type diterpenes, euphorantins A-R (1-18), along with four known analogues (19-22), were isolated from the aerial parts of Euphorbia antiquorum. Compounds 1-3 are the first examples of C-17-oxygenated ingol-type diterpenes, and compounds 16-18 represent a rare class of 2,3-di-epimers of ingols. Diterpenes 1, 14, and 22 exhibited inhibitory activities against mouse 11?-HSD1 with IC50 values of 12.0, 6.4, and 0.41 ?M, respectively.
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High vanillin tolerance of an evolved Saccharomyces cerevisiae strain owing to its enhanced vanillin reduction and antioxidative capacity.
J. Ind. Microbiol. Biotechnol.
PUBLISHED: 04-16-2014
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The phenolic compounds present in hydrolysates pose significant challenges for the sustainable lignocellulosic materials refining industry. Three Saccharomyces cerevisiae strains with high tolerance to lignocellulose hydrolysate were obtained through ethyl methanesulfonate mutation and adaptive evolution. Among them, strain EMV-8 exhibits specific tolerance to vanillin, a phenolic compound common in lignocellulose hydrolysate. The EMV-8 maintains a specific growth rate of 0.104 h(-1) in 2 g L(-1) vanillin, whereas the reference strain cannot grow. Physiological studies revealed that the vanillin reduction rate of EMV-8 is 1.92-fold higher than its parent strain, and the Trolox equivalent antioxidant capacity of EMV-8 is 15 % higher than its parent strain. Transcriptional analysis results confirmed an up-regulated oxidoreductase activity and antioxidant activity in this strain. Our results suggest that enhancing the antioxidant capacity and oxidoreductase activity could be a strategy to engineer S. cerevisiae for improved vanillin tolerance.
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Excitatory Synaptic Function and Plasticity Is Persistently Altered in Ventral Tegmental Area Dopamine Neurons after Prenatal Ethanol Exposure.
Neuropsychopharmacology
PUBLISHED: 04-02-2014
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Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, is impacted by PE. Pregnant rats were exposed to ethanol (0 or 6?g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2-12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to increased excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhanced amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders.Neuropsychopharmacology accepted article preview online, 06 October 2014. doi:10.1038/npp.2014.265.
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Comparison of laser induced thermal fracture between polycrystalline ceramic and crystal Nd:YAG.
Opt Lett
PUBLISHED: 04-02-2014
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Continuous wave 808 nm pump laser-induced thermal damage of polycrystalline transparent ceramic and crystalline Nd:YAG materials was investigated both experimentally and theoretically. The measured temperature agrees well with the theoretical simulation, and the maximum hoop stresses occur on the incident facet of the end-pumped rod at about ?2 times of the pump beam radius w0, where the temperature gradient is the highest and the damage occurs first at this location. The fracture-limited laser intensity of ceramics was experimentally measured to be 6.4±0.6??kW/cm2, nearly 64% higher than that of the crystals (3.9±0.3??kW/cm2). The deduced thermal fracture stress for ceramic was 386±50??MPa, which is 64% higher than that of the crystals (235±16??MPa).
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Mercury contamination in fish and human hair from Hainan Island, South China Sea: Implication for human exposure.
Environ. Res.
PUBLISHED: 03-26-2014
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Hair has long been recognized as a good biomarker for human exposure to Hg. The mercury concentrations in 14 species of marine fish and hair samples from 177 coastal residents in Hainan, South China Sea were investigated to assess the status of mercury exposure associated with marine fish consumption. Concentrations of total Hg (THg) and methylmercury (MeHg) in the fish muscles were 0.094±0.008 and 0.066±0.006?g/gww, respectively, which were far below the limit considered safe for consumption (0.5?g/g). The average THg concentrations in hair of adults (1.02±0.92?g/g) were lower than the provisional tolerable weekly intake (PTWI) level of 2.2?g/g. However, 23.7% of children had a hair THg level exceeding the RfD level of 1?g/g, indicating a great risk of Hg exposure to children via fish consumption. The concentration of THg in hair was significantly correlated with fish consumption but not with gender-specific fish intake. With higher fish consumption frequency, the fishermen had significantly elevated hair Hg levels compared to the students and the other general public, who had similar hair THg levels but different fish consumption patterns, indicating the existence of other sources of Hg exposure to the residents of Hainan Island.
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Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report.
Transfusion
PUBLISHED: 03-24-2014
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Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine?A are the most frequently used.
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The logistic growth of duckweed (Lemna minor) and kinetics of ammonium uptake.
Environ Technol
PUBLISHED: 03-21-2014
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Mathematical models have been developed to describe nitrogen uptake and duckweed growth experimentally to study the kinetics of ammonium uptake under various concentrations. The kinetics of duckweed ammonium uptake was investigated using the modified depletion method after plants were grown for two weeks at different ammonium concentrations (0.5-14 mg/L) in the culture medium. The maximum uptake rate and Michaelis-Menten constant for ammonium were estimated as 0.082 mg/(g fresh weight x h) and 1.877 mg/L, respectively. Duckweed growth was assessed when supplied at different total nitrogen (TN) concentrations (1-5 mg/L) in the culture medium. The results showed that the intrinsic growth rate was from 0.22 to 0.26 d(-1), and TN concentrations had no significant influence on the duckweed growth rate.
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Anthropogenic land uses elevate metal levels in stream water in an urbanizing watershed.
Sci. Total Environ.
PUBLISHED: 03-17-2014
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Land use/cover change is a dominant factor affecting surface water quality in rapidly developing areas of Asia. In this study we examined relationships between land use and instream metal loadings in a rapidly developing mixed land use watershed in southeastern China. Five developing subwatersheds and one forested reference site (head water) were instrumented with timing- and rainfall-triggered autosampler and instream loadings of anthropogenic metals (Cu, Zn, Pb, Cr, Cd, and Mn) were monitored from March 2012 to December 2013. Farm land and urban land were positively, and forest and green land were negatively associated with metal loadings (except Cr) in stream water. All developing sites had higher loadings than the reference head water site. Assessed by Chinese surface water quality standard (GB3830-2002), instream loadings of Cu and Zn occasionally exceeded the Class I thresholds at monitoring points within farmland dominated subwatersheds while Mn loadings were greater than the limit for drinking water sources at all monitoring points. Farm land use highly and positively contributed to statistical models of instream loadings of Cu, Zn, Cd, and Mn while urban land use was the dominant contributor to models of Pb and Cd loadings. Rainfall played a crucial role in metal loadings in stream water as a direct source (there were significant levels of Cu and Zn in rain water) and as a driver of watershed processes (loadings were higher in wet years and seasons). Urbanization effects on metal loadings in this watershed are likely to change rapidly with development in future years. Further monitoring to characterize these changes is clearly warranted and should help to develop plans to avoid conflicts between economic development and water quality degradation in this watershed and in watersheds throughout rapidly developing areas of Asia.
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Adsorption behavior of tightly bound extracellular polymeric substances on model organic surfaces under different pH and cations with surface plasmon resonance.
Water Res.
PUBLISHED: 03-07-2014
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Tightly bound extracellular polymeric substances (TB-EPS) play a substantial role on microbial aggregates, which can promote microbial cells to aggregate and adhere onto the carrier in bioreactor. However, the attachment and adsorption of TB-EPS on different surfaces were awaited to be elucidated. In this study, four self-assembled monolayers (SAMs) carrying methyl (CH3-SAM), amino (NH2-SAM), hydroxyl (OH-SAM), and carboxyl (COOH-SAM) terminal groups were prepared to model different surfaces. TB-EPS adsorption on these surfaces under different pH conditions and additional cations were investigated using surface plasmon resonance. The adsorption of TB-EPS dramatically decreased with the decreasing pH values. CH3-SAM surface achieved the maximum adsorption at the same condition. Na(+) promoted the TB-EPS adsorbed on COOH-SAM surface. The Ca(2+)-mediated complexes were attracted by COOH-SAM and repelled by NH2-SAM, respectively. The adsorptions of TB-EPS on the four SAM surfaces were significantly increased by adding Fe(3+). These results demonstrated that the TB-EPS adsorption on the organic surfaces were dependent on the pH and cation of solution.
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An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
PLoS Genet.
PUBLISHED: 03-01-2014
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Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.
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Asymmetric epoxidation of cis/trans-?-methylstyrene catalysed by immobilised Mn(salen) with different linkages: heterogenisation of homogeneous asymmetric catalysis.
Chemistry
PUBLISHED: 02-12-2014
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Immobilised Mn(salen) catalysts with two different linkages were studied in the asymmetric epoxidation of cis/trans-?-methylstyrene using NaClO as oxidant. The immobilised Mn(salen) complexes inside nanopores can lead to different catalytic behaviour compared with that of homogeneous Jacobsen catalyst. The rigidity of the linkage was found to be a key factor affecting the catalytic performance of immobilised catalysts. The immobilised catalyst with a rigid linkage exhibited comparable chemical selectivity, enantioselectivity and cis/trans ratio of product formation to that obtained with homogeneous Jacobsen catalysts. In contrast, the immobilised catalyst with a flexible linkage gave remarkably lower chemical selectivity, enantioselectivity and inverted cis/trans ratio compared with the results obtained with the homogeneous Jacobsen catalyst and the immobilised catalyst with rigid linkage. Thus, for immobilised Mn(salen) catalysts, a rigid linkage connecting active centres to the support is essential to obtain activity and enantioselectivity as high as those obtained in homogeneous systems.
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Characterization of protein marker expression, tumorigenicity, and doxorubicin chemoresistance in two new canine mammary tumor cell lines.
BMC Vet. Res.
PUBLISHED: 02-10-2014
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BackgroundCanine mammary tumors (CMTs) are the most common type of cancer found in female dogs. Establishment and evaluation of tumor cell lines can facilitate investigations of the biological mechanisms of cancer. Different cell models are used to investigate genetic, epigenetic, and cellular pathways, cancer progression, and cancer therapeutics. Establishment of new cell models will greatly facilitate research in this field. In the present study, we established and characterized two new CMT cell lines derived from a single CMT.ResultsWe established two cell lines from a single malignant CMT specimen: DTK-E and DTK-SME. Morphologically, the DTK-E cells were large, flat, and epithelial-like, whereas DTK-SME cells were round and epithelial-like. Doubling times were 24 h for DTK-E and 18 h for DTK-SME. On western blots, both cell lines expressed cytokeratin AE1, vimentin, cytokeratin 7 (CK7), and heat shock protein 27 (HSP27). Moreover, investigation of chemoresistance revealed that DTK-SME was more resistant to doxorubicin-induced apoptosis than DTK-E was. After xenotransplantation, both DTK-E and DTK-SME tumors appeared within 14 days, but the average size of DTK-SME tumors was greater than that of DTK-E tumors after 56 days.ConclusionWe established two new cell lines from a single CMT, which exhibit significant diversity in cell morphology, protein marker expression, tumorigenicity, and chemoresistance. The results of this study revealed that the DTK-SME cell line was more resistant to doxorubicin-induced apoptosis and exhibited higher tumorigenicity in vivo than the DTK-E cell line. We anticipate that the two novel CMT cell lines established in this study will be useful for investigating the tumorigenesis of mammary carcinomas and for screening anticancer drugs.
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Mercury pollution in fish from South China Sea: levels, species-specific accumulation, and possible sources.
Environ. Res.
PUBLISHED: 02-09-2014
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Both total mercury (THg) and methylmercury (MeHg) levels in fish collected from South China Sea (SCS) were studied to understand Hg pollution in Chinese tropical marine ecosystems. The average THg concentrations in fish species ranged from 39.6 ?g/kg for rabbitfish (Siganus fuscessens) to 417 ?g/kg for thornfish (Terapon jarbua), while those of MeHg varied from 13 ?g/kg (rabbitfish) to 176 ?g/kg (thornfish). The median values of MeHg/THg ratios in different fish species ranged from 36 to 85%. Significant inter-species differences of THg and MeHg in fish were observed due to feeding habits and fish sizes. Overall, carnivorous fish had higher levels of THg, MeHg and MeHg/THg ratios than omnivorous and herbivorous fish. High Hg levels in fish of the SCS were probably related to Hg input from atmospheric deposition and anthropogenic activities.
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Fine-tuning of NADH oxidase decreases byproduct accumulation in respiration deficient xylose metabolic Saccharomyces cerevisiae.
BMC Biotechnol.
PUBLISHED: 02-08-2014
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Efficiently utilizing all available carbon from lignocellulosic feedstock presents a major barrier to the production of economically feasible biofuel. Previously, to enable xylose utilization, we introduced a cofactor-dependent xylose reductase (XR) and xylitol dehydrogenase (XDH) pathway, or a cofactor-independent xylose isomerase (XI) pathway, into Saccharomyces cerevisiae. The resulting strains metabolized xylose with high efficiency. However, in both pathway recombinant strains, the cofactor imbalance caused accumulation of the byproducts glycerol and/or xylitol and reduced the ethanol production efficiency.
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First do no harm: population-based study shows non-evidence-based trastuzumab prescription may harm elderly women with breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 02-07-2014
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Trastuzumab, although cardiotoxic, is associated with improved survival in HER2-positive breast cancer. Non-compliance with HER2 testing guidelines before prescribing trastuzumab occurs in practice; however, the clinical consequences are unclear. Using SEER-Medicare database (2000-2009), we assessed differences in baseline characteristics between women ? 65 with breast cancer who received and did not receive HER2 testing prior to trastuzumab prescription. We used propensity score matched-pair analysis to balance the confounders between these two groups. We assessed the differences in overall survival and 3-year rates of avoiding congestive heart failure (CHF) between women who received trastuzumab without HER2 testing (trastuzumab group) and women who had chemotherapy but did not receive trastuzumab (irrespective of testing) (chemo-only group). Based on the matched data, we used Cox regression in these assessments with double robust estimation or with stratification. Among women who received trastuzumab, 140 (4.7 %) had no documentation of HER2 testing. Breast surgery, south residential region, and an earlier year of diagnosis were predictive of no HER2 testing in multivariate logistic regression. Women in the chemo-only group had similar overall survival (HR = 1.28; P = 0.108) over an 8-year follow-up post-diagnosis and significantly higher likelihood of avoiding CHF over 3 years after the first administration of chemotherapy or trastuzumab (HR = 1.66, P = 0.036) compared to women in the trastuzumab group, using the propensity score-matched data. Non-evidence-based prescription of trastuzumab is associated with increased rates of CHF with no additional survival benefit among older women with breast cancer. Inappropriate prescriptions of targeted therapies agent can lead to detrimental health and financial consequences.
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Cost of contralateral prophylactic mastectomy.
Ann. Surg. Oncol.
PUBLISHED: 02-04-2014
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To compare the healthcare costs of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) with those of women who did not.
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Semiparametric Accelerated Failure Time Model for Length-biased Data with Application to Dementia Study.
Stat Sin
PUBLISHED: 01-31-2014
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A semiparametric accelerated failure time (AFT) model is proposed to evaluate the effects of risk factors on the unbiased failure times for the target population given the observed length-biased data. The analysis of length-biased data is complicated by informative right censoring due to the biased sampling mechanism, and consequently the techniques for conventional survival analysis are not applicable. We propose estimating equation methods for estimation and show the asymptotic properties of the proposed estimators. The small sample performance of the estimating methods are investigated and compared with that of existing methods under various underlying distributions and censoring mechanisms. We apply the proposed model and estimating methods to a prevalent cohort study, the Canadian Study of Health and Aging (CSHA), to evaluate the survival duration according to diagnosis of subtype of dementia.
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Composition of EPS fractions from suspended sludge and biofilm and their roles in microbial cell aggregation.
Chemosphere
PUBLISHED: 01-28-2014
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The adhesion and aggregation properties of microbial cell are closely related to extracellular polymeric substances (EPS). In this work, the composition and physicochemical characteristics of EPS in biofilm and suspended sludge (S-sludge) were determined to evaluate their roles in microbial cell aggregation. Raman spectroscopy and three-dimensional fluorescence spectra have been employed to reveal each EPS fraction in different composition. The flocculating capacity of each EPS fraction in the S-sludge shows extraordinary activity, comparing its counterpart in biofilm. Microbial cell surfaces present high hydrophobicity and increased zeta potentials upon EPS extraction. In addition, the respective contribution of EPS to cell aggregating was elucidated. The contribution of combined SEPS and LB-EPS was 23% for S-sludge sample, whereas that was negligible for biofilm sample. The contribution of LB-EPS and TB-EPS were 16% and 30% for S-sludge sample, and -6% and negligible for biofilm sample, respectively. Therefore, EPS promoted the S-sludge cells to aggregate, while in contrast, they showed a negligible or negative effect on the biofilm cells aggregating.
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A Promoter Region Polymorphism in PDCD-1 Gene Is Associated with Risk of Rheumatoid Arthritis in the Han Chinese Population of Southeastern China.
Int J Genomics
PUBLISHED: 01-21-2014
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Objective. Programmed cell death 1 (PD-1) induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the association of PDCD-1 polymorphisms with the risk of RA among Chinese patients and healthy controls. Methods. Using the PCR-direct sequencing analysis, 4 PDCD-1 SNPs (rs36084323, rs11568821, rs2227982, and rs2227981) were genotyped in 320?RA patients and 309 matched healthy controls. Expression of PD-1 was determined in peripheral blood lymphocytes by flow cytometry and quantitative real-time reverse transcriptase polymerase chain reaction. Results. We observed that the GG genotype of rs36084323 was associated with a increased risk for developing RA (OR 1.70, 95% 1.11-2.61, P = 0.049). Patients carrying G/G genotype displayed an increased mRNA level of PD-1 (P = 0.04) compared with A/A genotype and healthy controls. Meanwhile, patients homozygous for rs36084323 had induced basal PD-1 expression on activated CD4+ T cells. Conclusion. The PDCD-1 polymorphism rs36084323 was significantly associated with RA risk in Han Chinese population. This SNP, which effectively influenced the expression of PD-1, may be a biomarker of early diagnosis of RA and a suitable indicator of utilizing PD-1 inhibitor for treatment of RA.
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Reversible cross-linking, microdomain structure, and heterogeneous dynamics in thermally reversible cross-linked polyurethane as revealed by solid-state NMR.
J Phys Chem B
PUBLISHED: 01-17-2014
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Polyurethane material is widely utilized in industry and daily life due to its versatile chemistry and relatively easy handling. Here, we focused on a novel thermally reversible cross-linked polyurethane with comprehensive remarkable mechanical properties as reported in our recent work (Adv. Mater. 2013, 25, 4912). The microphase-separated structure and heterogeneous segmental dynamics were well revealed by T2 relaxometry experiments, which was also first utilized to in situ monitor the reversible cross-linking associated with Diels-Alder (DA) and retro-Diels-Alder (RDA) reactions. On the basis of T2 relaxometry results, we determined the actual temperature of the (R)DA reaction as well as the corresponding activation energies of the motion of soft segments. Besides, the roles of the temperature and cross-linker contents on the microdomain structure and dynamics are discussed in detail. It is found that the microphase separation is enhanced by the increase of temperature as well as the incorporation of cross-linkers. Also, the polyurethane samples are still thermal-stable even at a high temperature beyond the disassociation of the cross-linkages. Furthermore, Baum-Pines and three-pulse multiple-quantum NMR experiments are utilized to investigate the heterogeneous structures and dynamics of the mobile and rigid segments, respectively. Both the results obtained from the T2 relaxometry and multiple-quantum NMR experiments are in good agreement with the macroscopic mechanical properties of the polyurethane. Finally, it is also well demonstrated that proton T2 relaxometry combined with multiple-quantum NMR is a powerful method to study the heterogeneous structures and dynamics of a multiphase polymer system.
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Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting.
Cancer Med
PUBLISHED: 01-06-2014
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We evaluated the efficacy of using standard radiologic and histologic criteria to guide the follow-up of patients with lobular carcinoma in situ (LCIS), lobular neoplasia (LN), or atypical lobular hyperplasia (ALH). Patients with high-risk benign lesions diagnosed on biopsy were presented and reviewed in a multidisciplinary clinical management conference from 1 November 2003 through September 2011. Associations between patient characteristics and rates of upgrade were determined by univariate and multivariate logistic models, and times to diagnosis carcinoma were calculated. Of 853 cases reviewed, 124 (14.5%) were lobular neoplasms. In all, 104 patients were clinically and/or radiographically monitored. In 20 patients, who were found to have LN on core biopsy and were recommended to have immediate surgical excision, a more significant lesion was identified in 8 (40%) of the excised specimens. Factors associated with a more significant lesion on excisional biopsy included whether the lobular lesion had been targeted for biopsy and whether the extent of disease involved three or more terminal duct lobular units. Of the 104 patients radiographically and clinically monitored, the median follow-up time was 3.4 years with a range of 0.44-8.6 years. Five patients under surveillance were subsequently diagnosed with breast malignancy (three of the five at a site unrelated to the initial biopsy). Patients with incidental lobular lesions identified on percutaneous core needle biopsy have a small risk of upgrade and may not require an excisional biopsy. Clinical management of low-volume lobular lesions in a multidisciplinary setting is an efficacious alternative to surgical excision when radiologic and histologic characteristics are well-defined.
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Fibrinogen Dusart presenting as recurrent thromboses in the hepatic portal system.
Blood Coagul. Fibrinolysis
PUBLISHED: 01-04-2014
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Dysfibrogenemias are characterized by the production of abnormally functioning fibrinogen, occurring in the presence of liver disease, medication toxicity, malignancy, or genetic mutation. Here, we report a patient with multiple, separate episodes of hepatic portal system thromboses associated with dysfibrinogenemia. Molecular studies identified the presence of a 554Arg?Cys mutation in the fibrinogen A? gene, previously identified as Fibrinogen Dusart (also known as Fibrinogen Paris V and Fibrinogen Chapel Hill). This case further illustrates the association of this dysfibrinogenemia with a unique thrombophilic manifestation.
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Numerical analysis of the relationship between nasal structure and its function.
ScientificWorldJournal
PUBLISHED: 01-01-2014
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The functions of the nasal cavity are closely related to its structure. In this study the three-dimensional finite element models were established based on the clinical data of twenty-four volunteers to study the influence of nasal structure on nasal functions of heating the inhaled airflow. Numerical simulations mainly concerning the airflow distribution and the airflow temperature are performed. The character of airflow heating process in these models is gained from the simulation results of these nasal cavities. The parameters describing the geometry of nasal cavity, such as the surface area of nasal airway and the volume of nasal cavity, are considered to be related to the nasal function of heating the inhaled airflow. The approximate function describing the relationship between the geometric parameters of the nasal airway and the nasal functions is gotten. This study can provide a numerical platform for studying some clinical problems and will contribute to the further research on the relationship between nasal structure and nasal functions.
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[Clinical outcomes of percutaneous kyphoplasty under local anesthesia for osteoporotic vertebral compression fractures].
Zhonghua Yi Xue Za Zhi
PUBLISHED: 12-24-2013
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To analyze the clinical outcomes of percutaneous kyphoplasty under local anesthesia for osteoporotic vertebral compression fractures.
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Immediate Reduction Under General Anesthesia and Single-staged Anteroposterior Spinal Reconstruction for Fracture-Dislocation of Lower Cervical Spine.
J Spinal Disord Tech
PUBLISHED: 12-17-2013
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Fracture-dislocation of the lower cervical spine is a severe traumatic lesion, most frequently resulting in tetraplegia. Treatment is usually painful and time consuming. This retrospective study evaluated the clinical curative effect of immediate reduction under general anesthesia and single-staged anteroposterior spinal reconstruction for fracture-dislocation of the lower cervical spine. Twelve cases of traumatic lower cervical spinal fracture-dislocation were retrospectively analyzed from January 2006 to December 2011. The injury level was C4/C5 in 4, C5/C6 in 5, and C6/C7 in 3 patients. The spinal cord function grades according to the American Spinal Injury Association impairment scale (2000 edition amended) before operation were as follows: grade A in 2 cases, grade B in 2 cases, grade C in 5 cases, grade D in 2 cases, and grade E in 1 case. On admission, all patients underwent immediate reduction under general anesthesia and single-staged anteroposterior spinal reconstruction by circumferential fixation/fusion. The spinal cord function grades according to American Spinal Injury Association after operation were as follows: grade A in 1 case, grade B in 1 case, grade C in 3 cases, grade D in 3 cases, and grade E in 4 cases. All 12 patients showed evidence of stability at the instrumented level on the final follow-up examination (mean follow-up, 3.7 y). Immediate reduction under general anesthesia followed by a single-stage combined anteroposterior spinal reconstruction is a safe and reliable way of treating patients with lower cervical spine fracture-dislocations.
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[Variation of nitrogen during the high suspended sediments concentration water supply in an artificial shallow lake].
Huan Jing Ke Xue
PUBLISHED: 12-03-2013
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The effect of water quality and suspended sediments in the process of water supply is of an increasing concern recently in an artificial shallow lake. The water supply from the Yellow River to Dongchang Lake happened on April 23rd to 25th, 2012. The synchronous monitoring of flow velocity, suspended sediment concentration, dissolved nitrogen and particulate nitrogen concentration was conducted during the three days in five monitoring sites of the longitudinal profile from inlet to outlet. The spatio-temporal variation of nitrogen and the relationship between nitrogen concentration and suspended sediment concentration was analyzed. Moreover, the analysis of different nitrogen forms in surface water and bottom sediment was also made in the whole lake before and after the water supply. Results showed that the process of water supplement had an obvious effect on flow velocities and suspended sediment concentrations around the inlet area. The influence area was a limited scope. The spatial distribution of nitrogen presented a certain concentration gradient along the flow direction. Around the water inlet, concentrations of all nitrogen forms in water and bottom sediment was higher than those in other lake zones. The amplitude of variation of all nitrogen concentrations in surface water, suspended sediments showed a decreasing trend from water inlet to outlet. And concentrations of total dissolved and particulate nitrogen increased at different ratios after water supply in the lake. Total particulate nitrogen concentration increase was higher. It revealed the water supply of the Yellow River had a great influence on lake water. The dissolved nitrogen was the main nitrogen form in water supply. The ratio of total dissolved nitrogen to particulate nitrogen was 7.3 : 1. Nitrate was the primary form in dissolved nitrogen, and ammonium was the primary form in particulate nitrogen, respectively. The correlation between concentration of suspended sediments and ammonium, total nitrogen were notable during te water supply, the correlation coefficient were 0.868 and 0.876. Ammonium was mainly influenced by water supply and adsorption and precipitation of suspended sediments. However, the concentration of nitrate was not influenced. Organic nitrogen was the main form in bottom sediment. It meant that the Yellow River water and suspended sediments were the input sources of nitrogen to Dongehang Lake.
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Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice.
ACS Nano
PUBLISHED: 10-28-2013
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Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-? signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-? inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.
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Re-examining the Size/Charge Paradigm: Differing in Vivo Characteristics of Size- and Charge-Matched Mesoporous Silica Nanoparticles.
J. Am. Chem. Soc.
PUBLISHED: 10-16-2013
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The combination of nanoparticle (NP) size, charge, and surface chemistry (e.g., extent of modification with polyethylene glycol (PEG)) is accepted as a key determinant of NP/cellular interactions. However, the influence of spatial arrangement and accessibility of the charged molecules on the NP surface vis-à-vis the average surface charge (zeta (?) potential) is incompletely understood. Here we demonstrate that two types of mesoporous silica nanoparticles (MSNP) that are matched in terms of primary and hydrodynamic particle size, shape, pore structure, colloidal stability, and ? potential, but differ in surface chemistry, viz. the spatial arrangement and relative exposure of surface amines, have profoundly different interactions with cells and tissues when evaluated in vitro and in vivo. While both particles are ?50 nm in diameter, PEGylated, and positively charged (? = +40 mV), PEG-PEI (MSNPs modified with exposed polyamines), but not PEG-NMe3(+) (MSNP modified with distributed, obstructed amines) rapidly bind serum proteins, diverse cells types in vitro, and endothelial and white blood cells in vivo (ex ovo chick embryo model). This finding helps elucidate the relative role of surface exposure of charged molecules vs ? potential in otherwise physicochemically matched MSNP and highlights protein corona neutrality as an important design consideration when synthesizing cationic NPs for biological applications.
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Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: A critical role for heme oxygenase-1.
Free Radic. Biol. Med.
PUBLISHED: 08-23-2013
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Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE(-/-)) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE(-/-) mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE(-/-) mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE(-/-) mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE(-/-) mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE (-/-)mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE(-/-) mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1.
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Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.
Mol. Cancer Ther.
PUBLISHED: 08-13-2013
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Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.
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High ?-Glucosidase Secretion in Saccharomyces cerevisiae Improves the Efficiency of Cellulase Hydrolysis and Ethanol Production in Simultaneous Saccharification and Fermentation.
J. Microbiol. Biotechnol.
PUBLISHED: 08-10-2013
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Bioethanol production from lignocellulose is considered as a sustainable biofuel supply. However, the low cellulose hydrolysis efficiency limits the cellulosic ethanol production. The cellulase is strongly inhibited by the major end product cellobiose, which can be relieved by the addition of ?-glucosidase. In this study, three ?-glucosidases from different organisms were respectively expressed in Saccharomyces cerevisiae and the ?-glucosidase from Saccharomycopsis fibuligera showed the best activity (5.2 U/ml). The recombinant strain with S. fibuligera ?-glucosidase could metabolize cellobiose with a specific growth rate similar to the control strain in glucose. This recombinant strain showed higher hydrolysis efficiency in the cellulose simultaneous saccharification and fermentation, when using the Trichoderma reesei cellulase, which is short of the ?-glucosidase activity. The final ethanol concentration was 110% (using Avicel) and 89% (using acid-pretreated corncob) higher than the control strain. These results demonstrated the effect of ?-glucosidase secretion in the recombinant S. cerevisiae for enhancing cellulosic ethanol conversion.
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Guanidine alkaloids from Plumbago zeylanica.
J. Nat. Prod.
PUBLISHED: 07-12-2013
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Eleven new guanidine alkaloids, plumbagines A-G (2-8) and plumbagosides A-D (9-12), as well as two known analogues (1, 13), were isolated from the aerial parts of Plumbago zeylanica. Their structures were elucidated by spectroscopic analyses including 1D and 2D NMR, MS, IR, and CD methods. The absolute configuration of 1 was determined by single-crystal X-ray diffraction of its derivative (1a).
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Effects of Mesoporous Silica Coating and Post-Synthetic Treatment on the Transverse Relaxivity of Iron Oxide Nanoparticles.
Chem Mater
PUBLISHED: 07-02-2013
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Mesoporous silica nanoparticles have the capacity to load and deliver therapeutic cargo and incorporate imaging modalities, making them prominent candidates for theranostic devices. One of the most widespread imaging agents utilized in this and other theranostic platforms is nanoscale superparamagnetic iron oxide. Although several core-shell magnetic mesoporous silica nanoparticles presented in the literature have provided high T 2 contrast in vitro and in vivo, there is ambiguity surrounding which parameters lead to enhanced contrast. Additionally, there is a need to understand the behavior of these imaging agents over time in biologically relevant environments. Herein, we present a systematic analysis of how the transverse relaxivity (r 2) of magnetic mesoporous silica nanoparticles is influenced by nanoparticle diameter, iron oxide nanoparticle core synthesis, and the use of a hydrothermal treatment. This work demonstrates that samples which did not undergo a hydrothermal treatment experienced a drop in r 2 (75% of original r 2 within 8 days of water storage), while samples with hydrothermal treatment maintained roughly the same r 2 for over 30 days in water. Our results suggest that iron oxide oxidation is the cause of the r 2 loss, and this oxidation can be prevented both during synthesis and storage by the use of deoxygenated conditions during nanoparticle synthesis. The hydrothermal treatment also provides colloidal stability, even in acidic and highly salted solutions, and a resistance against acid degradation of the iron oxide nanoparticle core. The results of this study show the promise of multifunctional mesoporous silica nanoparticles but will also likely inspire further investigation into multiples types of theranostic devices, taking into consideration their behavior over time and in relevant biological environments.
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Enhanced xylose fermentation capacity related to an altered glucose sensing and repression network in a recombinant Saccharomyces cerevisiae.
Bioengineered
PUBLISHED: 06-26-2013
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The co-fermentation of glucose and xylose is one of the issues in decreasing the price of biofuel or chemicals produced from lignocellulosic materials. A glucose and xylose co-utilizing Saccharomyces cerevisiae was obtained through rational genetic manipulation. Non-rational evolution in xylose was performed, and the xylose utilization efficiency of the engineered strain was significantly enhanced. The results of transcriptome study suggested that Snf1/Mig1-mediated regulation, a part of glucose sensing and repression network, was altered in the evolved strain and might be related to the enhancement of xylose utilization.
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T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation.
J. Exp. Med.
PUBLISHED: 06-26-2013
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ROR?t is necessary for the generation of TH17 cells but the molecular mechanisms for the regulation of TH17 cells are still not fully understood. We show that activation of CD4? T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced TH17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dosedependently reduced the percentage of IL-17–producing CD4? T cells. NO mediates nitration of tyrosine residues in ROR?t, leading to the suppression of ROR?t-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses.
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11?-HSD1 inhibitors from Walsura cochinchinensis.
J. Nat. Prod.
PUBLISHED: 06-25-2013
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A search for inhibitors of 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) from Walsura cochinchinensis yielded 10 new limonoids, cochinchinoids A-J (1-10), and two new triterpenoids, 3-epimesendanin S (11) and cochinchinoid K (12). Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of 1 and 12 being established by X-ray diffraction analysis. Of these compounds, cochinchinoid K (12) displayed inhibitory activity against mouse 11?-HSD1 with an IC50 value of 0.82 ?M.
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Improvement of L-arabinose fermentation by modifying the metabolic pathway and transport in Saccharomyces cerevisiae.
Biomed Res Int
PUBLISHED: 06-18-2013
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The L-arabinose utilization pathway was established in Saccharomyces cerevisiae, by expressing the codon-optimized araA, araB, and araD genes of Lactobacillus plantarum. After overexpressing the TAL1, TKL1, RPE1, RKI1, and GAL2 genes and adaptive evolution, the L-arabinose utilization of the recombinant strain became efficient. The resulting strain displayed a maximum specific growth rate of 0.075?h(-1), a maximum specific L-arabinose consumption rate of 0.61?g?h(-1)?g(-1) dry cell weight, and a promising ethanol yield of 0.43?g?g(-1) from L-arabinose fermentation.
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The expression of Heparanase mRNA and its clinical significance in Hepatocellular carcinoma.
J Cancer Res Ther
PUBLISHED: 06-18-2013
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To investigate the clinico-pathologic importance of Heparanase mRNA expression in hepatocellular carcinoma and its relationship with prognosis.
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Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP).
Br. J. Haematol.
PUBLISHED: 06-04-2013
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The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as other microangiopathies (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.
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The nuclear import of oncoprotein hepatitis B X-interacting protein depends on interacting with c-Fos and phosphorylation of both proteins in breast cancer cells.
J. Biol. Chem.
PUBLISHED: 05-10-2013
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Aberrant nuclear localization of oncogenic transcription factors and coactivators always leads to the development of cancer. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating the nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP interacted with c-Fos through their leucine zipper domains in vitro and in vivo. Interestingly, the leucine zipper mutant of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the nuclear import of HBXIP was required for phosphorylation of c-Fos at Thr(232), Thr(325), Thr(331), and Ser(374) by ERK1/2. In addition, the mutant of HBXIP at the Ser(108) phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser(108). The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of the oncoprotein HBXIP requires interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our findings provide new insights into the mechanism of the nuclear import of HBXIP. Therapeutically, the block of the nuclear import of HBXIP is significant in breast cancer.
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Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11?-HSD1 inhibitors: potential impact in diabetes.
Eur J Med Chem
PUBLISHED: 05-08-2013
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The biological screening of a collection of nature occurring diterpenoids against 11?-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11?-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11?-HSD1) = 9.4 nM and selectivity index (human 11?-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11?-HSD1 were generated using docking simulations. Based on the results, the structural-activity relationships (SARs) of compounds 1b and 2 were also discussed.
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Increases in both acute and chronic temperature potentiate tocotrienol concentrations in wild barley at Evolution Canyon.
Chem. Biodivers.
PUBLISHED: 04-21-2013
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Biosynthesis of tocols (vitamin E isoforms) is linked to response to temperature in plants. Evolution Canyon, an ecogeographical microcosm extending over an average of 200 meters (range 100-400) wide area in the Carmel Mountains of northern Israel, has been suggested as a model for studying global warming. Both domestic (Hordeum vulgare) and wild (Hordeum spontaneum) barley compared with wheat, oat, corn, rice, and rye show high tocotrienol/tocopherol ratios. Therefore, we hypothesized that tocol distribution might change in response to global warming. ?-, ?-, ?-, and ?-tocopherol, and ?-, ?-, ?-, and ?-tocotrienol concentrations were measured in wild barley (H. spontaneum) seeds harvested from the xeric (African) and mesic (European) slopes of Evolution Canyon over a six-year period from 2005-2011. Additionally, we examined seeds from areas contiguous to and distant from the part of the Canyon severely burned during the Carmel Fire of December 2010. Increased ?-tocotrienol (p<0.01) was correlated with 1) temperature increases, 2) to the hotter African slope in contrast to the cooler European slope, and 3) to propinquity to the fire. The study illustrates the role of ?-tocotrienol in both chronic and acute temperature adaptation in wild barley and suggests future research into thermoregulatory mechanisms in plants.
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An assay for functional xylose transporters in Saccharomyces cerevisiae.
Anal. Biochem.
PUBLISHED: 04-20-2013
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It has been considered that more efficient uptake of xylose could promote increased xylose metabolic capacity of several microorganisms. In this study, an assay to screen xylose transporters was established in the Saccharomyces cerevisiae strain, which expresses the xylosidase gene of Bacillus pumilus intracellularly. The absorbed xylose analog p-nitrophenyl-?-d-xylopyranoside (pNPX) rapidly hydrolyzed to p-nitrophenol (pNP), which displayed a yellow tint when exposed to xylosidase in vivo. The xylose transporter activities of the strain were computed using the pNP production rate, which was detected extracellularly. This method could be used for both high-throughput screening and smaller scale investigations. AraEp, which is a pentose transporter of Corynebacterium glutamicum, was expressed in S. cerevisiae and exhibited better transport capacity than the endogenous transporters Hxt7p and Gal2p. Moreover, a mutant of AraEp with 103% greater transport capacity was screened out, and the computer simulation suggested that transmembrane domain 5 was an important factor for the transport capacity of AraEp in S. cerevisiae.
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