The structure and oxidation of the eye lens chaperone αA-crystallin

The small heat shock protein αA-crystallin is a molecular chaperone important for the optical properties of the vertebrate eye lens. It forms heterogeneous oligomeric ensembles. We determined the structures of human αA-crystallin oligomers by combining cryo-electron microscopy, cross-linking/mass spectrometry, NMR spectroscopy and molecular modeling. The different oligomers can be interconverted by the addition or subtraction of tetramers, leading to mainly 12-, 16- and 20-meric assemblies in which interactions between N-terminal regions are important. Cross-dimer domain-swapping of the C-terminal region is a determinant of αA-crystallin heterogeneity. Human αA-crystallin contains two cysteines, which can form an intramolecular disulfide in vivo. Oxidation in vitro requires conformational changes and oligomer dissociation. The oxidized oligomers, which are larger than reduced αA-crystallin and destabilized against unfolding, are active chaperones and can transfer the disulfide to destabilized substrate proteins. The insight into the structure and function of αA-crystallin provides a basis for understanding its role in the eye lens

The closest elastic tensor of arbitrary symmetry to an elasticity tensor of lower symmetry

The closest tensors of higher symmetry classes are derived in explicit form for a given elasticity tensor of arbitrary symmetry. The mathematical problem is to minimize the elastic length or distance between the given tensor and the closest elasticity tensor of the specified symmetry. Solutions are presented for three distance functions, with particular attention to the Riemannian and log-Euclidean distances. These yield solutions that are invariant under inversion, i.e., the same whether elastic stiffness or compliance are considered. The Frobenius distance function, which corresponds to common notions of Euclidean length, is not invariant although it is simple to apply using projection operators. A complete description of the Euclidean projection method is presented. The three metrics are considered at a level of detail far greater than heretofore, as we develop the general framework to best fit a given set of moduli onto higher elastic symmetries. The procedures for finding the closest elasticity tensor are illustrated by application to a set of 21 moduli with no underlying symmetry.Comment: 48 pages, 1 figur

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

Chandra reveals a luminous Compton-thick QSO powering a Ly \u3b1 blob in a z = 4 starbursting protocluster

Context. Galaxy clusters in the local universe descend from high-redshift overdense regions known as protoclusters. The large gas reservoirs and high rate of galaxy interaction in protoclusters are expected to enhance star-formation activity and trigger luminous supermassive black-hole accretion in the nuclear regions of the host galaxies. Aims. We investigated the active galactic nucleus (AGN) content of a gas-rich and starbursting protocluster at z = 4.002, known as the Distant Red Core (DRC). In particular, we search for luminous and possibly obscured AGN in 13 identified members of the structure, and compare the results with protoclusters at lower redshifts. We also test whether a hidden AGN can power the Ly\u3b1 blob (LAB) detected with VLT/MUSE in the DRC. Methods. We observed all of the identified members of the structure with 139 ks of Chandra ACIS-S imaging. Being less affected by absorption than optical and IR bands, even in the presence of large column densities of obscuring material, X-ray observations are the best tools to detect ongoing nuclear activity in the DRC galaxies. Results. We detect obscured X-ray emission from the two most gas-rich members of the DRC, named DRC-1 and DRC-2. Both of them are resolved into multiple interacting clumps in high-resolution Atacama Large Millimeter Array and Hubble Space Telescope observations. In particular, DRC-2 is found to host a luminous (L2-10 keV 48 3 7 1045 erg s-1) Compton-thick (NH 1024 cm-2) quasar (QSO) candidate, comparable to the most luminous QSOs known at all cosmic times. The AGN fraction among DRC members is consistent with results found for lower redshift protoclusters. However, X-ray stacking analysis reveals that supermassive black hole (SMBH) accretion is likely also taking place in other DRC galaxies that are not detected individually by Chandra. Conclusions. The luminous AGN detected in the most gas-rich galaxies in the DRC and the widespread SMBH accretion in the other members, which is suggested by stacking analysis, point toward the presence of a strong link between large gas reservoirs, galaxy interactions, and luminous and obscured nuclear activity in protocluster members. The powerful and obscured QSO detected in DRC-2 is likely powering the nearby LAB detected with VLT/MUSE, possibly through photoionization; however, we propose that the diffuse Ly\u3b1 emission may be due to gas shocked by a massive outflow launched by DRC-2 over a 4810 kpc scale

Use of biplots and Partial Least Squares regression in microarray data analysis for assessing association between genes involved in different biological pathways

Microarrays are a widespread technology mostly used to explore expression profiles for thousand of genes simultaneously. On the other hand, considerable efforts to understand inter-relationships between groups of genes were made. To this end, multivariate visualization techniques (e.g. biplots) and Partial Least Squares regression have gained relevance in the field of genomic research. Biplots provide a graphical aid to understand mutual relationships between genes and samples and among gene themselves but no dependency is implied; use of passive projection of variables, however, is helpful for understanding conditional relationships between different sets of genes. Additionally, PLS regression provides a framework for quantitatively evaluating these dependencies and for assessing which are the relevant interactions that should be deeper investigated in further studies. These techniques have been applied on a subset of a microarray study on 49 samples of malignant pleural mesothelioma. 70 genes were selected, 62 involved in cell-cell junctions disruption and 8 involved in Epithelial-Mesenchymal Transition (EMT). Since these latter are supposed to play a role in subsequent loss of apicobasal cell polarity, analysis were performed considering EMT genes as the conditioning (i.e. independent) variables and the polarity genes as conditioned (i.e. dependent) variables. PLS regression provided results consistent with those obtained from graphical visualization of EMT genes principal components and passive projections of polarity genes, and helped in detecting relevant associations between different sets of genes. These associations should be investigated in further studies for validation. Future work will address the differential pattern of expression according to histotype of subjects in the PLS framework. Moreover, PLS path modeling will be considered after the specification of a detailed dependency network