Evidence for a Positive Cosmological Constant from Flows of Galaxies and Distant Supernovae

Recent observations of high-redshift supernovae seem to suggest that the global geometry of the Universe may be affected by a `cosmological constant', which acts to accelerate the expansion rate with time. But these data by themselves still permit an open universe of low mass density and no cosmological constant. Here we derive an independent constraint on the lower bound to the mass density, based on deviations of galaxy velocities from a smooth universal expansion. This constraint rules out a low-density open universe with a vanishing cosmological constant, and together the two favour a nearly flat universe in which the contributions from mass density and the cosmological constant are comparable. This type of universe, however, seems to require a degree of fine tuning of the initial conditions that is in apparent conflict with `common wisdom'.Comment: 8 pages, 1 figure. Slightly revised version. Letter to Natur

Optimal search strategies for identifying sound clinical prediction studies in EMBASE

BACKGROUND: Clinical prediction guides assist clinicians by pointing to specific elements of the patient's clinical presentation that should be considered when forming a diagnosis, prognosis or judgment regarding treatment outcome. The numbers of validated clinical prediction guides are growing in the medical literature, but their retrieval from large biomedical databases remains problematic and this presents a barrier to their uptake in medical practice. We undertook the systematic development of search strategies ("hedges") for retrieval of empirically tested clinical prediction guides from EMBASE. METHODS: An analytic survey was conducted, testing the retrieval performance of search strategies run in EMBASE against the gold standard of hand searching, using a sample of all 27,769 articles identified in 55 journals for the 2000 publishing year. All articles were categorized as original studies, review articles, general papers, or case reports. The original and review articles were then tagged as 'pass' or 'fail' for methodologic rigor in the areas of clinical prediction guides and other clinical topics. Search terms that depicted clinical prediction guides were selected from a pool of index terms and text words gathered in house and through request to clinicians, librarians and professional searchers. A total of 36,232 search strategies composed of single and multiple term phrases were trialed for retrieval of clinical prediction studies. The sensitivity, specificity, precision, and accuracy of search strategies were calculated to identify which were the best. RESULTS: 163 clinical prediction studies were identified, of which 69 (42.3%) passed criteria for scientific merit. A 3-term strategy optimized sensitivity at 91.3% and specificity at 90.2%. Higher sensitivity (97.1%) was reached with a different 3-term strategy, but with a 16% drop in specificity. The best measure of specificity (98.8%) was found in a 2-term strategy, but with a considerable fall in sensitivity to 60.9%. All single term strategies performed less well than 2- and 3-term strategies. CONCLUSION: The retrieval of sound clinical prediction studies from EMBASE is supported by several search strategies

Simulations of atmospheric methane for Cape Grim, Tasmania, to constrain southeastern Australian methane emissions

This study uses two climate models and six scenarios of prescribed methane emissions to compare modelled and observed atmospheric methane between 1994 and 2007, for Cape Grim, Australia (40.7° S, 144.7° E). The model simulations follow the TransCom-CH4 protocol and use the Australian Community Climate and Earth System Simulator (ACCESS) and the CSIRO Conformal-Cubic Atmospheric Model (CCAM). Radon is also simulated and used to reduce the impact of transport differences between the models and observations. Comparisons are made for air samples that have traversed the Australian continent. All six emission scenarios give modelled concentrations that are broadly consistent with those observed. There are three notable mismatches, however. Firstly, scenarios that incorporate interannually varying biomass burning emissions produce anomalously high methane concentrations at Cape Grim at times of large fire events in southeastern Australia, most likely due to the fire methane emissions being unrealistically input into the lowest model level. Secondly, scenarios with wetland methane emissions in the austral winter overestimate methane concentrations at Cape Grim during wintertime while scenarios without winter wetland emissions perform better. Finally, all scenarios fail to represent a~methane source in austral spring implied by the observations. It is possible that the timing of wetland emissions in the scenarios is incorrect with recent satellite measurements suggesting an austral spring (September–October–November), rather than winter, maximum for wetland emissions. © Author(s) 2015

EMBASE search strategies for identifying methodologically sound diagnostic studies for use by clinicians and researchers

BACKGROUND: Accurate diagnosis by clinicians is the cornerstone of decision making for recommending clinical interventions. The current best evidence from research concerning diagnostic tests changes unpredictably as science advances. Both clinicians and researchers need dependable access to published evidence concerning diagnostic accuracy. Bibliographic databases such as EMBASE provide the most widely available entrée to this literature. The objective of this study was to develop search strategies that optimize the retrieval of methodologically sound diagnostic studies from EMBASE for use by clinicians. METHODS: An analytic survey was conducted, comparing hand searches of 55 journals with retrievals from EMBASE for 4,843 candidate search terms and 6,574 combinations. All articles were rated using purpose and quality indicators, and clinically relevant diagnostic accuracy articles were categorized as 'pass' or 'fail' according to explicit criteria for scientific merit. Candidate search strategies were run in EMBASE, the retrievals being compared with the hand search data. The proposed search strategies were treated as "diagnostic tests" for sound studies and the manual review of the literature was treated as the "gold standard." The sensitivity, specificity, precision and accuracy of the search strategies were calculated. RESULTS: Of the 433 articles about diagnostic tests, 97 (22.4%) met basic criteria for scientific merit. Combinations of search terms reached peak sensitivities of 100% with specificity at 70.4%. Compared with best single terms, best multiple terms increased sensitivity for sound studies by 8.2% (absolute increase), but decreased specificity (absolute decrease 6%) when sensitivity was maximized. When terms were combined to maximize specificity, the single term "specificity.tw." (specificity of 98.2%) outperformed combinations of terms. CONCLUSION: Empirically derived search strategies combining indexing terms and textwords can achieve high sensitivity and specificity for retrieving sound diagnostic studies from EMBASE. These search filters will enhance the searching efforts of clinicians

A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes

A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health

Contribution of proteasome-catalyzed peptide cis-splicing to viral targeting by CD8⁺ T cells in HIV-1 infection

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8⁺ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I–bound peptides on HIV-infected cells. We demonstrate that HIV-1–derived spliced peptides comprise a relatively minor component of the HLA-I–bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8⁺ T cell responses relatively infrequently during infection, CD8⁺ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs. © 2013 Song et al

Optimizing search strategies to identify randomized controlled trials in MEDLINE

BACKGROUND: The Cochrane Highly Sensitive Search Strategy (HSSS), which contains three phases, is widely used to identify Randomized Controlled Trials (RCTs) in MEDLINE. Lefebvre and Clarke suggest that reviewers might consider using four revisions of the HSSS. The objective of this study is to validate these four revisions: combining the free text terms volunteer, crossover, versus, and the Medical Subject Heading CROSS-OVER STUDIES with the top two phases of the HSSS, respectively. METHODS: We replicated the subject search for 61 Cochrane reviews. The included studies of each review that were indexed in MEDLINE were pooled together by review and then combined with the subject search and each of the four proposed search strategies, the top two phases of the HSSS, and all three phases of the HSSS. These retrievals were used to calculate the sensitivity and precision of each of the six search strategies for each review. RESULTS: Across the 61 reviews, the search term versus combined with the top two phases of the HSSS was able to find 3 more included studies than the top two phases of the HSSS alone, or in combination with any of the other proposed search terms, but at the expense of missing 56 relevant articles that would be found if all three phases of the HSSS were used. The estimated time needed to finish a review is 1086 hours for all three phases of the HSSS, 823 hours for the strategy versus, 818 hours for the first two phases of the HSSS or any of the other three proposed strategies. CONCLUSION: This study shows that compared to the first two phases of the HSSS, adding the term versus to the top two phases of the HSSS balances the sensitivity and precision in the reviews studied here to some extent but the differences are very small. It is well known that missing relevant studies may result in bias in systematic reviews. Reviewers need to weigh the trade-offs when selecting the search strategies for identifying RCTs in MEDLINE

Pilot study of an interactive voice response system to improve medication refill compliance

<p>Abstract</p> <p>Background</p> <p>Sub-optimal adherence to prescribed medications is well documented. Barriers to medication adherence include medication side effects, cost, and forgetting to take or refill medications. Interactive Voice Response (IVR) systems show promise as a tool for reminding individuals to take or refill medications. This pilot study evaluated the feasibility and acceptability of using an IVR system for prescription refill and daily medication reminders. We tested two novel features: personalized, medication-specific reminder messages and communication via voice recognition.</p> <p>Methods</p> <p>Patients enrolled in a study of electronic prescribing and medication management in Quebec, Canada who were taking chronic disease-related drugs were eligible to participate. Consenting patients had their demographic, telephone, and medication information transferred to an IVR system, which telephoned patients to remind them to take mediations and/or refill their prescriptions. Facilitators and barriers of the IVR system use and acceptability of the IVR system were assessed through a structured survey and open-ended questions administered by telephone interview.</p> <p>Results</p> <p>Of the 528 eligible patients who were contacted, 237 refused and 291 consented; 99 participants had started the pilot study when it was terminated because of physician and participant complaints. Thirty-eight participants completed the follow-up interview. The majority found the IVR system's voice acceptable, and did not have problems setting up the time and location of reminder calls. However, many participants experienced technical problems when called for reminders, such as incorrect time of calls and voice recognition difficulties. In addition, most participants had already refilled their prescriptions when they received the reminder calls, reporting that they did not have difficulties remembering to refill prescriptions on their own. Also, participants were not receptive to speaking to an automated voice system.</p> <p>Conclusion</p> <p>IVR systems designed to improve medication compliance must address key technical and performance issues and target those individuals with reported memory difficulties or complex medication regimens in order to improve the utility of the system. Future research should also identify characteristics of medication users who are more likely to be receptive to IVR technology.</p

Protective Coupling of Mitochondrial Function and Protein Synthesis via the eIF2α Kinase GCN-2

Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2–dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2–dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPRmt