Knowledge-based energy functions for computational studies of proteins

This chapter discusses theoretical framework and methods for developing knowledge-based potential functions essential for protein structure prediction, protein-protein interaction, and protein sequence design. We discuss in some details about the Miyazawa-Jernigan contact statistical potential, distance-dependent statistical potentials, as well as geometric statistical potentials. We also describe a geometric model for developing both linear and non-linear potential functions by optimization. Applications of knowledge-based potential functions in protein-decoy discrimination, in protein-protein interactions, and in protein design are then described. Several issues of knowledge-based potential functions are finally discussed.Comment: 57 pages, 6 figures. To be published in a book by Springe

Characterization of an expressed Triticum monococcum Glu-A1y gene containing a premature termination codon in its C-terminal coding region

Premature termination codons (PTCs) are an important reason for the silence of highmolecular- weight glutenin subunits in Triticum species. Although the Glu-A1y gene is generally silent in common wheat, we here isolated an expressed Glu-A1y gene containing a PTC, named 1Ay8.3, from Triticum monococcum ssp. monococcum (AmAm, 2n = 2x = 14). Despite the presence of a PTC (TAG) at base pair positions 1879–1881 in the C-terminal coding region, this did not obviously affect 1Ay8.3 expression in seeds. This was demonstrated by the fact that when the PTC TAG of 1Ay8.3 was mutated to the CAG codon, the mutant in Escherichia coli bacterial cells expressed the same subunit as in the seeds. However, in E. coli, 1Ay8.3 containing the PTC expressed a truncated protein with faster electrophoretic mobility than that in seeds, suggesting that PTC translation termination suppression probably occurs in vivo (seeds) but not in vitro (E. coli). This may represent one of only a few reports on the PTC termination suppression phenomenon in genes

Roadmap on superoscillations

Superoscillations are band-limited functions with the counterintuitive property that they can vary arbitrarily faster than their fastest Fourier component, over arbitrarily long intervals. Modern studies originated in quantum theory, but there were anticipations in radar and optics. The mathematical understanding—still being explored—recognises that functions are extremely small where they superoscillate; this has implications for information theory. Applications to optical vortices, sub-wavelength microscopy and related areas of nanoscience are now moving from the theoretical and the demonstrative to the practical. This Roadmap surveys all these areas, providing background, current research, and anticipating future developments

Identification of an emphysema- associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts

Murine studies have linked TGF-β signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from TGFB2. Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate TGFB2 expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the TGFB2 promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased TGFB2 expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Search for the doubly heavy baryon Ξbc+\it{\Xi}_{bc}^{+} decaying to J/ψΞc+J/\it{\psi} \it{\Xi}_{c}^{+}

A first search for the $\it{\Xi}_{bc}^{+}\to J/\it{\psi}\it{\Xi}_{c}^{+}$ decay is performed by the LHCb experiment with a data sample of proton-proton collisions, corresponding to an integrated luminosity of $9\,\mathrm{fb}^{-1}$ recorded at centre-of-mass energies of 7, 8, and $13\mathrm{\,Te\kern -0.1em V}$. Two peaking structures are seen with a local (global) significance of $4.3\,(2.8)$ and $4.1\,(2.4)$ standard deviations at masses of $6571\,\mathrm{Me\kern -0.1em V\!/}c^2$ and $6694\,\mathrm{Me\kern -0.1em V\!/}c^2$, respectively. Upper limits are set on the $\it{\Xi}_{bc}^{+}$ baryon production cross-section times the branching fraction relative to that of the $B_{c}^{+}\to J/\it{\psi} D_{s}^{+}$ decay at centre-of-mass energies of 8 and $13\mathrm{\,Te\kern -0.1em V}$, in the $\it{\Xi}_{bc}^{+}$ and in the $B_{c}^{+}$ rapidity and transverse-momentum ranges from 2.0 to 4.5 and 0 to $20\,\mathrm{Ge\kern -0.1em V\!/}c$, respectively. Upper limits are presented as a function of the $\it{\Xi}_{bc}^{+}$ mass and lifetime.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-005.html (LHCb public pages

International workshop on next generation gamma-ray source

A workshop on The Next Generation Gamma-Ray Source sponsored by the Office of Nuclear Physics at the Department of Energy, was held November 17-19, 2016 in Bethesda, Maryland. The goals of the workshop were to identify basic and applied research opportunities at the frontiers of nuclear physics that would be made possible by the beam capabilities of an advanced laser Compton beam facility. To anchor the scientific vision to realistically achievable beam specifications using proven technologies, the workshop brought together experts in the fields of electron accelerators, lasers, and optics to examine the technical options for achieving the beam specifications required by the most compelling parts of the proposed research programs. An international assembly of participants included current and prospective γ-ray beam users, accelerator and light-source physicists, and federal agency program managers. Sessions were organized to foster interactions between the beam users and facility developers, allowing for information sharing and mutual feedback between the two groups. The workshop findings and recommendations are summarized in this whitepaper