The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Effects of rapid urbanisation on the urban thermal environment between 1990 and 2011 in Dhaka Megacity, Bangladesh

This study investigates the influence of land-use/land-cover (LULC) change on land surface temperature (LST) in Dhaka Megacity, Bangladesh during a period of rapid urbanisation. LST was derived from Landsat 5 TM scenes captured in 1990, 2000 and 2011 and compared to contemporaneous LULC maps. We compared index-based and linear spectral mixture analysis (LSMA) techniques for modelling LST. LSMA derived biophysical parameters corresponded more strongly to LST than those produced using index-based parameters. Results indicated that vegetation and water surfaces had relatively stable LST but it increased by around 2 °C when these surfaces were converted to built-up areas with extensive impervious surfaces. Knowledge of the expected change in LST when one land-cover is converted to another can inform land planners of the potential impact of future changes and urges the development of better management strategies

Allosteric Modulation of the HIV-1 gp120-gp41 Association Site by Adjacent gp120 Variable Region 1 (V1) N-Glycans Linked to Neutralization Sensitivity

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/ or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and Cterminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn136 in V1 (T138N mutation) inconjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N139INN sequence, which ablates the overlapping Asn141-Asn142-Ser-Ser potential N-linked glycosylation sequons inV1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu593, Trp596 and Lys601. The 136 and/or 142glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120-gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb selection

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r(2) of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r(2) of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62863/1/nature06258.pd

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Measurement of VH, H → b b ¯ production as a function of the vector-boson transverse momentum in 13 TeV pp collisions with the ATLAS detector

Cross-sections of associated production of a Higgs boson decaying into bottom-quark pairs and an electroweak gauge boson, W or Z, decaying into leptons are measured as a function of the gauge boson transverse momentum. The measurements are performed in kinematic fiducial volumes defined in the `simplified template cross-section' framework. The results are obtained using 79.8 fb-1 of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 13 TeV. All measurements are found to be in agreement with the Standard Model predictions, and limits are set on the parameters of an effective Lagrangian sensitive to modifications of the Higgs boson couplings to the electroweak gauge bosons

Measurements of differential cross-sections in four-lepton events in 13 TeV proton-proton collisions with the ATLAS detector

Measurements of four-lepton differential and integrated fiducial cross-sections in events with two same-flavour, opposite-charge electron or muon pairs are presented. The data correspond to 139 fb−1 of s√ = 13 TeV proton-proton collisions, collected by the ATLAS detector during Run 2 of the Large Hadron Collider (2015–2018). The final state has contributions from a number of interesting Standard Model processes that dominate in different four-lepton invariant mass regions, including single Z boson production, Higgs boson production and on-shell ZZ production, with a complex mix of interference terms, and possible contributions from physics beyond the Standard Model. The differential cross-sections include the four-lepton invariant mass inclusively, in slices of other kinematic variables, and in different lepton flavour categories. Also measured are dilepton invariant masses, transverse momenta, and angular correlation variables, in four regions of four-lepton invariant mass, each dominated by different processes. The measurements are corrected for detector effects and are compared with state-of-the-art Standard Model calculations, which are found to be consistent with the data. The Z → 4ℓ branching fraction is extracted, giving a value of (4.41 ± 0.30) × 10−6. Constraints on effective field theory parameters and a model based on a spontaneously broken B − L gauge symmetry are also evaluated. Further reinterpretations can be performed with the provided information

Search for pair production of third-generation scalar leptoquarks decaying into a top quark and a τ-lepton in pp collisions at s√ = 13 TeV with the ATLAS detector

A search for pair production of third-generation scalar leptoquarks decaying into a top quark and a τ-lepton is presented. The search is based on a dataset of pp collisions at s√ = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Events are selected if they have one light lepton (electron or muon) and at least one hadronically decaying τ -lepton, or at least two light leptons. In addition, two or more jets, at least one of which must be identified as containing b-hadrons, are required. Six final states, defined by the multiplicity and flavour of lepton candidates, are considered in the analysis. Each of them is split into multiple event categories to simultaneously search for the signal and constrain several leading backgrounds. The signal-rich event categories require at least one hadronically decaying τ-lepton candidate and exploit the presence of energetic final-state objects, which is characteristic of signal events. No significant excess above the Standard Model expectation is observed in any of the considered event categories, and 95% CL upper limits are set on the production cross section as a function of the leptoquark mass, for different assumptions about the branching fractions into tτ and bν. Scalar leptoquarks decaying exclusively into tτ are excluded up to masses of 1.43 TeV while, for a branching fraction of 50% into tτ, the lower mass limit is 1.22 TeV

Measurements of differential cross-sections in top-quark pair events with a high transverse momentum top quark and limits on beyond the Standard Model contributions to top-quark pair production with the ATLAS detector at √s = 13 TeV

Cross-section measurements of top-quark pair production where the hadronically decaying top quark has transverse momentum greater than 355 GeV and the other top quark decays into ℓνb are presented using 139 fb−1 of data collected by the ATLAS experiment during proton-proton collisions at the LHC. The fiducial cross-section at s = 13 TeV is measured to be σ = 1.267 ± 0.005 ± 0.053 pb, where the uncertainties reflect the limited number of data events and the systematic uncertainties, giving a total uncertainty of 4.2%. The cross-section is measured differentially as a function of variables characterising the tt¯ system and additional radiation in the events. The results are compared with various Monte Carlo generators, including comparisons where the generators are reweighted to match a parton-level calculation at next-to-next-to-leading order. The reweighting improves the agreement between data and theory. The measured distribution of the top-quark transverse momentum is used to search for new physics in the context of the effective field theory framework. No significant deviation from the Standard Model is observed and limits are set on the Wilson coefficients of the dimension-six operators OtG and Otq(8), where the limits on the latter are the most stringent to date. [Figure not available: see fulltext.]