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981.
Background
Many problems in protein modeling require obtaining a discrete representation of the protein conformational space as an ensemble of conformations. In ab-initio structure prediction, in particular, where the goal is to predict the native structure of a protein chain given its amino-acid sequence, the ensemble needs to satisfy energetic constraints. Given the thermodynamic hypothesis, an effective ensemble contains low-energy conformations which are similar to the native structure. The high-dimensionality of the conformational space and the ruggedness of the underlying energy surface currently make it very difficult to obtain such an ensemble. Recent studies have proposed that Basin Hopping is a promising probabilistic search framework to obtain a discrete representation of the protein energy surface in terms of local minima. Basin Hopping performs a series of structural perturbations followed by energy minimizations with the goal of hopping between nearby energy minima. This approach has been shown to be effective in obtaining conformations near the native structure for small systems. Recent work by us has extended this framework to larger systems through employment of the molecular fragment replacement technique, resulting in rapid sampling of large ensembles.Methods
This paper investigates the algorithmic components in Basin Hopping to both understand and control their effect on the sampling of near-native minima. Realizing that such an ensemble is reduced before further refinement in full ab-initio protocols, we take an additional step and analyze the quality of the ensemble retained by ensemble reduction techniques. We propose a novel multi-objective technique based on the Pareto front to filter the ensemble of sampled local minima.Results and conclusions
We show that controlling the magnitude of the perturbation allows directly controlling the distance between consecutively-sampled local minima and, in turn, steering the exploration towards conformations near the native structure. For the minimization step, we show that the addition of Metropolis Monte Carlo-based minimization is no more effective than a simple greedy search. Finally, we show that the size of the ensemble of sampled local minima can be effectively and efficiently reduced by a multi-objective filter to obtain a simpler representation of the probed energy surface.982.
B cells are believed to be central to the disease process in systemic lupuserythematosus (SLE), making them a target for new therapeutic intervention. In recentyears there have been many publications regarding the experience in SLE of B-celldepletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use.However, the two large randomised controlled trials in extra-renal lupus (EXPLORERstudy) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.Based on the clinical experience with rituximab this failure was somewhat unexpectedand raised a number of questions and concerns, not only into the true level ofbenefit of B-cell depletion in a broad population but also how to test the true levelof effectiveness of an investigational agent as we seek to improve the design oftherapeutic trials in SLE. A better understanding of what went wrong in these trialsis essential to elucidate the underlying reasons for the disparate observations notedin open studies and controlled trials. In this review, we focus on various factorsthat may affect the ability to accurately and confidently establish the level oftreatment effect of the investigational agent, in this case rituximab, in the twostudies and explore hurdles faced in the randomised controlled trials investigatingthe efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based onthe lessons learned from the clinical trials, we make suggestions that could beimplemented in future clinical trial design to overcome the hurdles faced. 相似文献
983.
Background
Membrane proteins perform essential roles in diverse cellular functions and are regarded as major pharmaceutical targets. The significance of membrane proteins has led to the developing dozens of resources related with membrane proteins. However, most of these resources are built for specific well-known membrane protein groups, making it difficult to find common and specific features of various membrane protein groups.Methods
We collected human membrane proteins from the dispersed resources and predicted novel membrane protein candidates by using ortholog information and our membrane protein classifiers. The membrane proteins were classified according to the type of interaction with the membrane, subcellular localization, and molecular function. We also made new feature dataset to characterize the membrane proteins in various aspects including membrane protein topology, domain, biological process, disease, and drug. Moreover, protein structure and ICD-10-CM based integrated disease and drug information was newly included. To analyze the comprehensive information of membrane proteins, we implemented analysis tools to identify novel sequence and functional features of the classified membrane protein groups and to extract features from protein sequences.Results
We constructed HMPAS with 28,509 collected known membrane proteins and 8,076 newly predicted candidates. This system provides integrated information of human membrane proteins individually and in groups organized by 45 subcellular locations and 1,401 molecular functions. As a case study, we identified associations between the membrane proteins and diseases and present that membrane proteins are promising targets for diseases related with nervous system and circulatory system. A web-based interface of this system was constructed to facilitate researchers not only to retrieve organized information of individual proteins but also to use the tools to analyze the membrane proteins.Conclusions
HMPAS provides comprehensive information about human membrane proteins including specific features of certain membrane protein groups. In this system, user can acquire the information of individual proteins and specified groups focused on their conserved sequence features, involved cellular processes, and diseases. HMPAS may contribute as a valuable resource for the inference of novel cellular mechanisms and pharmaceutical targets associated with the human membrane proteins. HMPAS is freely available at http://fcode.kaist.ac.kr/hmpas.984.
James M Scheiman 《Arthritis research & therapy》2013,15(Z3):S5
NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks. 相似文献
985.
Pain affects the quality of life for millions of individuals and is a major reason for healthcare utilization. As populations age, medical personnel will need to manage more and more patients suffering from pain associated with degenerative and inflammatory musculoskeletal disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment for both acute and chronic musculoskeletal pain; however, their use is associated with potentially significant gastrointestinal (GI) toxicity. Guidelines suggest various strategies to prevent problems in those at risk for NSAID-associated GI complications. In this article, we review the data supporting one such strategy - the use of histamine type-2 receptor antagonists (H2RAs) - for the prevention of GI adverse events in NSAID users. Older studies suggest that high-dose H2RAs are effective in preventing upper GI ulcers and dyspepsia. This suggestion was recently confirmed during clinical trials with a new ibuprofen/famotidine combination that reduced the risk of ulcers by 50% compared with ibuprofen alone. 相似文献
986.
Alok Kumar Gupta Vikram Singh Gaur Sanjay Gupta Anil Kumar 《Functional & integrative genomics》2013,13(2):179-190
In order to understand the molecular basis of high nitrogen use efficiency of finger millet, five genes (EcHNRT2, EcLNRT1, EcNADH-NR, EcGS, and EcFd-GOGAT) involved in nitrate uptake and assimilation were isolated using conserved primer approaches. Expression profiles of these five genes along with the previously isolated EcDof1 was studied under increased KNO3 concentrations (0.15 to 1,500 μM) for 2 h as well as at 1.5 μM for 24 h in the roots and shoots of 25 days old nitrogen deprived two contrasting finger millet genotypes (GE-3885 and GE-1437) differing in grain protein content (13.76 and 6.15 %, respectively). Time kinetics experiment revealed that, all the five genes except EcHNRT2 in the leaves of GE-3885 were induced within 30 min of nitrate exposure indicating that there might be a greater nitrogen deficit in leaves and therefore quick transportation of nitrate signals to the leaves. Exposing the plants to increasing nitrate concentrations for 2 h showed that in roots of GE-3885, NR was strongly induced while GS was repressed; however, the pattern was found to be reversed in leaves of GE-1437 indicating that in GE-3885, most of the nitrate might be reduced in the roots but assimilated in leaves and vice-versa. Furthermore, compared with the low-protein genotype, expression of HNRT2 was strongly induced in both roots and shoots of high-protein genotype at the least nitrate concentration supplied. This further indicates that GE-3885 is a quick sensor of nitrogen compared with the low-protein genotype. Furthermore, expression of EcDof1 was also found to overlap the expression of NR, GS, and GOGAT indicating that Dof1 probably regulates the expression of these genes under different conditions by sensing the nitrogen fluctuations around the root zone. 相似文献
987.
Aim Small (< 1 km2) alpine glaciers are likely to disappear in this century, resulting in decreased regional habitat heterogeneity in associated streams. Both heterogeneity within and spatial isolation among glacier‐influenced streams can enhance beta diversity of stream‐dwelling organisms. We measured beta at both community and population‐genetic levels within and among streams currently influenced by small Pyrenean glaciers. We aimed to evaluate whether patterns are analogous between the two levels, to apply various approaches for characterizing beta, and to infer the outcome of future glacier loss on regional biodiversity. Location Four glacier‐fed basins in the Parc National des Pyrénées, France. Methods We classified each of 18 stream reaches across the basins into either high‐, mid‐ or low‐‘glaciality’ (glacial influence) groups according to four physicochemical characteristics. At each reach, we collected macroinvertebrate communities and evaluated mitochondrial DNA haplotypes for 11–13 individuals of Baetis alpinus Pictet. Using taxa/haplotypes as basic units, we evaluated community and population‐genetic beta diversity simultaneously. We measured beta diversity in three major ways: as multivariate (Sørensen's dissimilarity, Jost D) and ‘classical’ (gamma/alpha) variation to compare among glaciality groups, and as turnover along the glaciality gradient within each basin. Results For most approaches at both organizational levels, beta was greatest among high‐glaciality reaches, absolute values of variation of beta in high‐glaciality streams were strikingly similar between levels, and the steepest turnover within basins occurred between high‐ and mid‐glaciality reaches. Therefore, high‐glaciality reaches contained assemblages and populations that were unique both within that stream type (among basins) and compared with other stream types within basins. Main conclusions Parallel beta diversity patterns at population‐genetic and community levels suggested that environmental drivers influence these levels analogously. Extreme conditions (e.g. low temperature, high instability, isolation) in high‐glaciality streams probably enhance beta at both levels. Stream beta diversity is likely to decrease substantially with continued glacial reduction in this system. 相似文献
988.
David Leaper Christian Münter Sylvie Meaume Alessandro Scalise Nacho Blanes Mompó Birte Petersen Jakobsen Finn Gottrup 《PloS one》2013,8(7)
Background
Venous leg ulcers are common, troublesome, and their failure to heal is often related to a heavy bio-burden. Ionized silver has both anti-inflammatory and antimicrobial properties. The ulcer healing properties of the silver releasing foam dressing Biatain Ag has been examined in 4 randomized controlled trials (RCTs).Aim
To evaluate ulcer healing through a meta-analytic approach after treatment with either Biatain Ag or a non-active dressing.Patients and Methods
685 subjects with pure or mixed hard-to-heal venous leg ulcers were included in the meta-analysis.Results
Biatain Ag showed a significant treatment effect (p<0.0001), responder rate (p<0.001), and healing rate (p = 0.002).Conclusion
The meta-analysis of the 4 RCTs provided statistical significant evidence to support the use of Biatain Ag dressing in treatment of hard-to-heal venous leg ulcers. 相似文献989.
Mikaela Willmer Daniel Berglind Thorkild I. A. S?rensen Erik N?slund Per Tynelius Finn Rasmussen 《PloS one》2013,8(12)