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71.
Men and women differ in susceptibility to many diseases and in responses to treatment. Recent advances in genome-wide association
studies (GWAS) provide a wealth of data for associating genetic profiles with disease risk; however, in general, these data
have not been systematically probed for sex differences in gene-disease associations. Incorporating sex into the analysis
of GWAS results can elucidate new relationships between single nucleotide polymorphisms (SNPs) and human disease. In this
study, we performed a sex-differentiated analysis on significant SNPs from GWAS data of the seven common diseases studied
by the Wellcome Trust Case Control Consortium. We employed and compared three methods: logistic regression, Woolf’s test of
heterogeneity, and a novel statistical metric that we developed called permutation method to assess sex effects (PMASE). After
correction for false discovery, PMASE finds SNPs that are significantly associated with disease in only one sex. These sexually
dimorphic SNP-disease associations occur in Coronary Artery Disease and Crohn’s Disease. GWAS analyses that fail to consider
sex-specific effects may miss discovering sexual dimorphism in SNP-disease associations that give new insights into differences
in disease mechanism between men and women. 相似文献
72.
Phylogenetic footprinting is a method for the discovery of regulatory elements in a set of homologous regulatory regions, usually collected from multiple species. It does so by identifying the best conserved motifs in those homologous regions. There are two popular sets of methods-alignment-based and motif-based, which are generally employed for phylogenetic methods. However, serious efforts have lacked to develop a tool exclusively for phylogenetic footprinting, based on either of these methods. Nevertheless, a number of software and tools exist that can be applied for prediction of phylogenetic footprinting with variable degree of success. The output from these tools may get affected by a number of factors associated with current state of knowledge, techniques and other resources available. We here present a critical apprehension of various phylogenetic approaches with reference to prokaryotes outlining the available resources and also discussing various factors affecting footprinting in order to make a clear idea about the proper use of this approach on prokaryotes. 相似文献
73.
Dubey A Boukouvala F Keyvan G Hsia R Saranteas K Brone D Misra T Ierapetritou MG Muzzio FJ 《AAPS PharmSciTech》2012,13(1):231-246
A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design
(QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability
in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were
analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability
component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in
a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging
method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate,
pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard
deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the
tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments
predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed
at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic
application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by
more than half. 相似文献
74.
A growing literature supports a role for sleep after training in long-term memory consolidation and enhancement. Consequently, interrupted sleep should result in cognitive deficits. Recent evidence from an animal study indeed showed that optimal memory consolidation during sleep requires a certain amount of uninterrupted sleep.Sleep continuity is disrupted in various medical disorders. We compared performance on a motor sequence learning task (MST) in relatively young subjects with obstructive sleep apnea (n = 16; apnea-hypopnea index 17.1±2.6/h [SEM]) to a carefully matched control group (n = 15, apnea-hypopnea index 3.7±0.4/h, p<0.001. Apart from AHI, oxygen nadir and arousal index, there were no significant differences between groups in total sleep time, sleep efficiency and sleep architecture as well as subjective measures of sleepiness based on standard questionnaires. In addition performance on the psychomotor vigilance task (reaction time and lapses), which is highly sensitive to sleep deprivation showed no differences as well as initial learning performance during the training phase. However there was a significant difference in the primary outcome of immediate overnight improvement on the MST between the two groups (controls = 14.7±4%, patients = 1.1±3.6%; P = 0.023) as well as plateau performance (controls = 24.0±5.3%, patients = 10.1±2.0%; P = 0.017) and this difference was predicted by the arousal index (p = 0.02) rather than oxygen saturation (nadir and time below 90% saturation. Taken together, this outcome provides evidence that there is a clear minimum requirement of sleep continuity in humans to ensure optimal sleep dependent memory processes. It also provides important new information about the cognitive impact of obstructive sleep apnea and challenges its current definitions. 相似文献
75.
76.
MZ Adzemovic J Öckinger M Zeitelhofer S Hochmeister AD Beyeen A Paulson A Gillett M Thessen Hedreul R Covacu H Lassmann T Olsson M Jagodic 《PloS one》2012,7(7):e39794
Multiple sclerosis (MS) is a polygenic disease characterized by inflammation and demyelination in the central nervous system (CNS), which can be modeled in experimental autoimmune encephalomyelitis (EAE). The Eae18b locus on rat chromosome 10 has previously been linked to regulation of beta-chemokine expression and severity of EAE. Moreover, the homologous chemokine cluster in humans showed evidence of association with susceptibility to MS. We here established a congenic rat strain with Eae18b locus containing a chemokine cluster (Ccl2, Ccl7, Ccl11, Ccl12 and Ccl1) from the EAE- resistant PVG rat strain on the susceptible DA background and utilized myelin oligodendrocyte glycoprotein (MOG)-induced EAE to characterize the mechanisms underlying the genetic regulation. Congenic rats developed a milder disease compared to the susceptible DA strain, and this was reflected in decreased demyelination and in reduced recruitment of inflammatory cells to the brain. The congenic strain also showed significantly increased Ccl11 mRNA expression in draining lymph nodes and spinal cord after EAE induction. In the lymph nodes, macrophages were the main producers of CCL11, whereas macrophages and lymphocytes expressed the main CCL11 receptor, namely CCR3. Accordingly, the congenic strain also showed significantly increased Ccr3 mRNA expression in lymph nodes. In the CNS, the main producers of CCL11 were neurons, whereas CCR3 was detected on neurons and CSF producing ependymal cells. This corresponded to increased levels of CCL11 protein in the cerebrospinal fluid of the congenic rats. Increased intrathecal production of CCL11 in congenic rats was accompanied by a tighter blood brain barrier, reflected by more occludin(+) blood vessels. In addition, the congenic strain showed a reduced antigen specific response and a predominant anti-inflammatory Th2 phenotype. These results indicate novel mechanisms in the genetic regulation of neuroinflammation. 相似文献
77.
Petrlova J Kálai T Maezawa I Altman R Harishchandra G Hong HS Bricarello DA Parikh AN Lorigan GA Jin LW Hideg K Voss JC 《PloS one》2012,7(4):e35443
Background
The deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer''s disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species.Methodology/Principal Findings
To achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the Aβ peptide to investigate the binding and influence of fluorene compounds on AβO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species.Conclusions
Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they posses both antioxidant properties and the ability to disrupt AβO species. 相似文献78.
Pathway analysis has become the first choice for gaining insight into the underlying biology of differentially expressed genes and proteins, as it reduces complexity and has increased explanatory power. We discuss the evolution of knowledge base-driven pathway analysis over its first decade, distinctly divided into three generations. We also discuss the limitations that are specific to each generation, and how they are addressed by successive generations of methods. We identify a number of annotation challenges that must be addressed to enable development of the next generation of pathway analysis methods. Furthermore, we identify a number of methodological challenges that the next generation of methods must tackle to take advantage of the technological advances in genomics and proteomics in order to improve specificity, sensitivity, and relevance of pathway analysis. 相似文献
79.
Gautam B Singh G Wadhwa G Farmer R Singh S Singh AK Jain PA Yadav PK 《Bioinformation》2012,8(3):134-141
Toxoplasma gondii is an obligate intracellular apicomplexan parasite that can infect a wide range of warm-blooded animals including humans. In humans and other intermediate hosts, toxoplasma develops into chronic infection that cannot be eliminated by host's immune response or by currently used drugs. In most cases, chronic infections are largely asymptomatic unless the host becomes immune compromised. Thus, toxoplasma is a global health problem and the situation has become more precarious due to the advent of HIV infections and poor toleration of drugs used to treat toxoplasma infection, having severe side effects and also resistance have been developed to the current generation of drugs. The emergence of these drug resistant varieties of T. gondii has led to a search for novel drug targets. We have performed a comparative analysis of metabolic pathways of the host Homo sapiens and the pathogen T. gondii. The enzymes in the unique pathways of T. gondii, which do not show similarity to any protein from the host, represent attractive potential drug targets. We have listed out 11 such potential drug targets which are playing some important work in more than one pathway. Out of these, one important target is Glutamate dehydrogenase enzyme; it plays crucial part in oxidation reduction, metabolic process and amino acid metabolic process. As this is also present in the targets of tropical diseases of TDR (Tropical disease related Drug) target database and no PDB and MODBASE 3D structural model is available, homology models for Glutamate dehydrogenase enzyme were generated using MODELLER9v6. The model was further explored for the molecular dynamics simulation study with GROMACS, virtual screening and docking studies with suitable inhibitors against the NCI diversity subset molecules from ZINC database, by using AutoDock-Vina. The best ten docking solutions were selected (ZINC01690699, ZINC17465979, ZINC17465983, ZINC18141294_03, ZINC05462670, ZINC01572309, ZINC18055497_01, ZINC18141294, ZINC05462674 and ZINC13152284_01). Further the Complexes were analyzed through LIGPLOT. On the basis of Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds, specifically ZINC01690699 (as it has minimum energy score and one of the highest number of interactions with the active site residue), could be promising inhibitors for T. gondii using Glutamate dehydrogenase as Drug target. 相似文献
80.
Bharat Bhusan Patnaik Dong Hyun Kim Seung Han Oh Yong-Su Song Nguyen Dang Minh Chanh Jong Sun Kim Woo-jin Jung Atul Kumar Saha Bharat Bhushan Bindroo Yeon Soo Han 《PloS one》2012,7(12)