Binary image representation of a ligand binding site: its application to efficient sampling of a conformational ensemble

<p>Abstract</p> <p>Background</p> <p>Modelling the ligand binding site of a protein is an important component of understanding protein-ligand interactions and is being actively studied. Even if the side chains are restricted to rotamers, a set of commonly-observed low-energy conformations, the exhaustive combinatorial search of ligand binding site conformers is known as NP-hard. Here we propose a new method, ROTAIMAGE, for modelling the plausible conformers for the ligand binding site given a fixed backbone structure.</p> <p>Results</p> <p>ROTAIMAGE includes a procedure of selecting ligand binding site residues, exhaustively searching rotameric conformers, clustering them by dissimilarities in pocket shape, and suggesting a representative conformer per cluster. Prior to the clustering, the list of conformers generated by exhaustive search can be reduced by pruning the conformers that have near identical pocket shapes, which is done using simple bit operations. We tested our approach by modelling the active-site inhibitor binding pockets of matrix metalloproteinase-1 and -13. For both cases, analyzing the conformers based on their pocket shapes substantially reduced the 'computational complexity' (10 to 190 fold). The subsequent clustering revealed that the pocket shapes of both proteins could be grouped into approximately 10 distinct clusters. At this level of clustering, the conformational space spanned by the known crystal structures was well covered. Heatmap analysis identified a few bit blocks that combinatorially dictated the clustering pattern. Using this analytical approach, we demonstrated that each of the bit blocks was associated with a specific pocket residue. Identification of residues that influenced the shape of the pocket is an interesting feature unique to the ROTAIMAGE algorithm.</p> <p>Conclusions</p> <p>ROTAIMAGE is a novel algorithm that was efficient in exploring the conformational space of the ligand binding site. Its ability to identify 'key' pocket residues also provides further insight into conformational flexibility with specific implications for protein-ligand interactions.</p

Cost-effectiveness of installing barriers at bridge and cliff sites for suicide prevention in Australia

Importance: Installation of barriers has been shown to reduce suicides. To our knowledge, no studies have evaluated the cost-effectiveness of installing barriers at multiple bridge and cliff sites where suicides are known to occur. Objective: To examine the cost-effectiveness of installing barriers at bridge and cliff sites throughout Australia. Design, Setting, and Participants: This economic evaluation used an economic model to examine the costs, costs saved, and reductions in suicides if barriers were installed across identified bridge and cliff sites over 5 and 10 years. Specific and accessible bridge and cliff sites across Australia that reported 2 or more suicides over a 5-year period were identified for analysis. A partial societal perspective (including intervention costs and monetary value associated with preventing suicide deaths) was adopted in the development of the model. Interventions: Barriers installed at bridge and cliff sites. Main Outcomes and Measures: Primary outcome was return on investment (ROI) comparing cost savings with intervention costs. Secondary outcomes included incremental cost-effectiveness ratio (ICER), comprising the difference in costs between installation of barriers and no installation of barriers divided by the difference in reduction of suicide cases. Uncertainty and sensitivity analyses were undertaken to examine the association of changes in suicide rates with barrier installation, adjustments to the value of statistical life, and changes in maintenance costs of barriers. Results: A total of 7 bridges and 19 cliff sites were included in the model. If barriers were installed at bridge sites, an estimated US $145 million (95$90 to $160 million) could be saved in prevented suicides over 5 years, and US$270 million (95% UI, $176 to$298 million) over 10 years. The estimated ROI ratio for building barriers over 10 years at bridges was 2.4 (95% UI, 1.5 to 2.7); the results for cliff sites were not significant (ROI, 2.0; 95% UI, -1.1 to 3.8). The ICER indicated monetary savings due to averted suicides over the intervention cost for bridges, although evidence for similar savings was not significant for cliffs. Results were robust in all sensitivity analyses except when the value of statistical life-year over 5 or 10 years only was used. Conclusions and Relevance: In an economic analysis, barriers were a cost-effective suicide prevention intervention at bridge sites. Further research is required for cliff sites

The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis

BACKGROUND: Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations. METHODS: We did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251. FINDINGS: Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohen's d=1·11; p<0·0001), paranoia (-2·22, -2·98 to -1·45, Cohen's d=0·19; p<0·0001), and hallucinations (-1·58, -1·98 to -1·18, Cohen's d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported. INTERPRETATION: To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision. FUNDING: Wellcome Trust

Suicide trends in the early months of the COVID-19 pandemic: an interrupted time-series analysis of preliminary data from 21 countries

BackgroundThe COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that at its most extreme, this may manifest itself in increased suicide rates.MethodsWe sourced real-time suicide data from around the world via a systematic internet search and recourse to our networks and the published literature. We used interrupted time series analysis to model the trend in monthly suicides prior to COVID-19 in each country/area-within-country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic. Countries/areas-within countries contributed data from at least 1 January 2019 to 31 July 2020 and potentially from as far back as 1 January 2016 until as recently as 31 October 2020. We conducted a primary analysis in which we treated 1 April to 31 July 2020 as the COVID-19 period, and two sensitivity analyses in which we varied its start and end dates (for those countries/areas-within-countries with data beyond July 2020).OutcomesWe sourced data from 21 countries (high income [n=16], upper-middle income [n=5]; whole country [n=10], area(s)-within-the-country [n=11]). In general, there does not appear to have been a significant increase in suicides since the pandemic began in the countries for which we had data. In fact, in a number of countries/areas-within-countries there appears to have been a decrease.InterpretationThis is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. It offers a consistent picture, albeit from high- and upper-middle income countries, of suicide numbers largely remaining unchanged or declining in the early months of the pandemic. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic impacts of the pandemic unfold

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D

Suicide numbers during the first 9-15 months of the COVID-19 pandemic compared with pre-existing trends: An interrupted time series analysis in 33 countries

Background Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally. Methods We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation. Findings We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries’ COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries’ income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well. Interpretation Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue