Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.

ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation

Shortest Path versus Multi-Hub Routing in Networks with Uncertain Demand

We study a class of robust network design problems motivated by the need to scale core networks to meet increasingly dynamic capacity demands. Past work has focused on designing the network to support all hose matrices (all matrices not exceeding marginal bounds at the nodes). This model may be too conservative if additional information on traffic patterns is available. Another extreme is the fixed demand model, where one designs the network to support peak point-to-point demands. We introduce a capped hose model to explore a broader range of traffic matrices which includes the above two as special cases. It is known that optimal designs for the hose model are always determined by single-hub routing, and for the fixed- demand model are based on shortest-path routing. We shed light on the wider space of capped hose matrices in order to see which traffic models are more shortest path-like as opposed to hub-like. To address the space in between, we use hierarchical multi-hub routing templates, a generalization of hub and tree routing. In particular, we show that by adding peak capacities into the hose model, the single-hub tree-routing template is no longer cost-effective. This initiates the study of a class of robust network design (RND) problems restricted to these templates. Our empirical analysis is based on a heuristic for this new hierarchical RND problem. We also propose that it is possible to define a routing indicator that accounts for the strengths of the marginals and peak demands and use this information to choose the appropriate routing template. We benchmark our approach against other well-known routing templates, using representative carrier networks and a variety of different capped hose traffic demands, parameterized by the relative importance of their marginals as opposed to their point-to-point peak demands

Effect of vitamin D supplementation on outcomes in people with early psychosis

Importance People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, −1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, −0.98; 95% CI, −2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, −0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, −1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, −0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, −2.09; 95% CI, −4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, −1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, −4.60 to 4.94); Global Assessment of Function disability score (mean difference, −0.01; 95% CI, −5.25 to 5.23), or Calgary Depression Scale score (mean difference, −0.39; 95% CI, −2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration isrctn.org Identifier: ISRCTN1242484

Operational Research in Education

Operational Research (OR) techniques have been applied, from the early stages of the discipline, to a wide variety of issues in education. At the government level, these include questions of what resources should be allocated to education as a whole and how these should be divided amongst the individual sectors of education and the institutions within the sectors. Another pertinent issue concerns the efficient operation of institutions, how to measure it, and whether resource allocation can be used to incentivise efficiency savings. Local governments, as well as being concerned with issues of resource allocation, may also need to make decisions regarding, for example, the creation and location of new institutions or closure of existing ones, as well as the day-to-day logistics of getting pupils to schools. Issues of concern for managers within schools and colleges include allocating the budgets, scheduling lessons and the assignment of students to courses. This survey provides an overview of the diverse problems faced by government, managers and consumers of education, and the OR techniques which have typically been applied in an effort to improve operations and provide solutions

Probabilistic Model Checking for Energy Analysis in Software Product Lines

In a software product line (SPL), a collection of software products is defined by their commonalities in terms of features rather than explicitly specifying all products one-by-one. Several verification techniques were adapted to establish temporal properties of SPLs. Symbolic and family-based model checking have been proven to be successful for tackling the combinatorial blow-up arising when reasoning about several feature combinations. However, most formal verification approaches for SPLs presented in the literature focus on the static SPLs, where the features of a product are fixed and cannot be changed during runtime. This is in contrast to dynamic SPLs, allowing to adapt feature combinations of a product dynamically after deployment. The main contribution of the paper is a compositional modeling framework for dynamic SPLs, which supports probabilistic and nondeterministic choices and allows for quantitative analysis. We specify the feature changes during runtime within an automata-based coordination component, enabling to reason over strategies how to trigger dynamic feature changes for optimizing various quantitative objectives, e.g., energy or monetary costs and reliability. For our framework there is a natural and conceptually simple translation into the input language of the prominent probabilistic model checker PRISM. This facilitates the application of PRISM's powerful symbolic engine to the operational behavior of dynamic SPLs and their family-based analysis against various quantitative queries. We demonstrate feasibility of our approach by a case study issuing an energy-aware bonding network device.Comment: 14 pages, 11 figure

Understanding the role of omega-3 fatty acid supplementation for human performance

Omega-3 polyunsaturated fatty acids (n-3PUFA) ingestion is associated with multiple health benefits, including improved brain and heart function. Research examining the influence of n-3PUFA supplementation on indices of athletic performance remains limited, with studies administering various dosing strategies in an attempt to improve recovery from muscle damaging exercise, revealing mixed findings. Currently, protein is the most common nutritional strategy to improve recovery from muscle damage however, studies have shown mixed results. As n-3PUFA supplementation is known to exhibit anti-inflammatory properties, combining n-3PUFA with protein in supplement form may promote recovery from muscle damaging exercise. This thesis demonstrates that coingesting n-3PUFA with protein serves to reduce muscle soreness and attenuate the rise in putative blood markers of muscle damage following an intense bout of exercise in soccer players. However, there were no improvements in soccer-skill performance observed with n-3PUFA and protein supplementation. The mechanism(s) underpinning the improvement in recovery with n-3PUFA supplementation is not currently known but may relate to the increase in n-3PUFA composition within skeletal muscle. Dietary n-3PUFA ingestion has been shown to exhibit protective effects on lean tissue during periods of skeletal muscle catabolism such as leg immobilisation and in disease states. This thesis demonstrates that during short-term (2-wk) weight loss, increased dietary n-3PUFA intake fails to attenuate the decline in lean body mass during energy restriction. However, n-3PUFA supplementation improved muscle strength despite the reduction in muscle mass. The explanation for the improvement in muscle strength with n-3PUFA supplementation may be related to a modification of neuromuscular function. This thesis also examined the biological role of the antioxidant, curcumin, to facilitate the incorporation of n-3PUFA into whole blood and the phospholipid membrane of skeletal muscle. However, we demonstrated that the addition of curcumin to an n-3PUFA-based supplement did not facilitate tissue incorporation of n-3PUFA into blood or skeletal muscle. The explanation for this null finding unclear, but may relate to the dose of curcumin and/or n-3PUFA administered in the supplementation regimen. Abstracts containing actual data are included within each experimental chapter