The Study of Hepatitis B Virus Using Bioinformatics

Hepatitis refers to the inflammation of the liver. A major cause of hepatitis is the hepatotropic virus, hepatitis B virus (HBV). Annually, more than 786,000 people die as a result of the clinical manifestations of HBV infection, which include cirrhosis and hepatocellular carcinoma. Sequence heterogeneity is a feature of HBV, because the viral-encoded polymerase lacks proof-reading ability. HBV has been classified into nine genotypes, A to I, with a putative 10th genotype, “J,” isolated from a single individual. Comparative analysis of HBV strains from various geographic regions of the world and from different eras can shed light on the origin, evolution, transmission and response to anti-HBV preventative, and treatment measures. Bioinformatics tools and databases have been used to better understand HBV mutations and how they develop, especially in response to antiviral therapy and vaccination. Despite its small genome size of ~3.2 kb, HBV presents several bioinformatic challenges, which include the circular genome, the overlapping open reading frames, and the different genome lengths of the genotypes. Thus, bioinformatics tools and databases have been developed to facilitate the study of HBV

A taxonomic and phylogenetic study of Nephroselmis Stein (Prasinophyceae, Chlorophyta)

The Prasinophycean genus Nephroselmis Stein is a group of largely marine, photosynthetic,scaly biflagellates which has undergone several taxonomic changes since its erection in 1878. The taxonomy and phylogeny of the genus was investigated in the present study using separate and combined morphological and molecular maximum parsimony cladistic analyses. New data from light and electron microscopy were combined with data from the literature. Partial 18S gene molecular data from fresh material and from GenBank were included. Seven species of Nephroselmis were confirmed as discrete entities: N. anterostigmatica, N. astigmatica, N. olivacea, N. pyriformis, N. rotunda, N. spinosa and N. viridis. The existing generic and specific descriptions are emended. Samples of N. fissa, N. gaoae, N. marina and N. minuta could not be sourced from culture collections or opportunistic sampling, and as no detailed and reliable electron microscopic work is available for these species, they were not included and could not be confirmed by this study. The cladistic analyses undertaken in this study confirmed that the genus Nephroselmis is monophyletic. Reweighted morphological cladistic analysis yielded distinct clades within the genus, grouped predominantly by body scale number and scale complexity. Partial 18S molecular cladistic analysis agreed well with the morphological analysis, as did the combined analysis. N. pyriformis, which shows the greatest number of plesiomorphic features and possesses the simplest scale morphology, was placed in a basal position in all three analyses. The greatest scale complexity is found in N. anterostigmatica and N. astigmatica, which occured as sister species in all three analyses. Eyespot modifications are found in these two species only: N. astigmatica lacks an eyespot and the eyespot of N. anterostigmatica is atypically located on the anterior surface of the cell. N. olivacea and N. viridis show intermediate scale complexity and were placed as sister species in all three analyses. The relationship between N. rotunda and N. spinosa varied between the three analyses. The reweighted morphological cladistic analysis placed N. rotunda, which has three body scale layers, in its own clade, between N. pyriformis, which has two body scale layers, and the clade consisting of all other Nephroselmis species, which possess four or five body scale layers. The partial 18S molecular cladistic analysis grouped N. rotunda and N. spinosa in a clade sister to the N. olivacea / N. viridis clade. The combined analysis grouped N. rotunda and N. spinosa in a clade sister to the remaining Nephroselmis species. The only freshwater species, N. olivacea, occured in a clade with N. viridis (in a more derived position), rather than in a basal position or alone in a clade. This is consistent with N. olivacea having adapted to a freshwater environment as a result of, for example, a marine overwash event. Of the nine other genera included in the molecular analysis, Dolichomastix, Mamiella, Pseudoscourfieldia and Tetraselmis appeared as the sister clade of Nephroselmis

Luminosity Functions of XMM-LSS C1 Galaxy Clusters

CFHTLS optical photometry has been used to study the galaxy luminosity functions of 14 X-ray selected clusters from the XMM-LSS survey. These are mostly groups and poor clusters, with masses (M_{500}) in the range 0.6 to 19x10 ^{13} M_solar and redshifts 0.05-0.61. Hence these are some of the highest redshift X-ray selected groups to have been studied. Lower and upper colour cuts were used to determine cluster members. We derive individual luminosity functions (LFs) for all clusters as well as redshift-stacked and temperature-stacked LFs in three filters, g', r' and z', down to M=-14.5. All LFs were fitted by Schechter functions which constrained the faint-end slope, alpha, but did not always fit well to the bright end. Derived values of alpha ranged from -1.03 to as steep as -2.1. We find no evidence for upturns at faint magnitudes. Evolution in alpha was apparent in all bands: it becomes shallower with increasing redshift; for example, in the z' band it flattened from -1.75 at low redshift to -1.22 in the redshift range z=0.43-0.61. Eight of our systems lie at z~0.3, and we combine these to generate a galaxy LF in three colours for X-ray selected groups and poor clusters at redshift 0.3. We find that at z~0.3 alpha is steeper (-1.67) in the green (g') band than it is (-1.30) in the red (z') band. This colour trend disappears at low redshift, which we attribute to reddening of faint blue galaxies from z~0.3 to z~0. We also calculated the total optical luminosity and found it to correlate strongly with X-ray luminosity (L_X proportional to L_OPT^(2.1)), and also with ICM temperature (L_OPT proportional to T^(1.62)), consistent with expectations for self-similar clusters with constant mass-to-light ratio. We did not find any convincing correlation of Schechter parameters with mean cluster temperature.Comment: 23 pages, 17 figure

Universal IMF vs dark halo response in early-type galaxies: breaking the degeneracy with the fundamental plane

We use the relations between aperture stellar velocity dispersion (\sigma_ap), stellar mass (M_sps), and galaxy size (R_e) for a sample of \sim 150,000 early-type galaxies from SDSS/DR7 to place constraints on the stellar initial mass function (IMF) and dark halo response to galaxy formation. We build LCDM based mass models that reproduce, by construction, the relations between galaxy size, light concentration and stellar mass, and use the spherical Jeans equations to predict \sigma_ap. Given our model assumptions (including those in the stellar population synthesis models), we find that reproducing the median \sigma_ap vs M_sps relation is not possible with {\it both} a universal IMF and a universal dark halo response. Significant departures from a universal IMF and/or dark halo response are required, but there is a degeneracy between these two solutions. We show that this degeneracy can be broken using the strength of the correlation between residuals of the velocity-mass (\Delta log \sigma_ap) and size-mass (\Delta log R_e) relations. The slope of this correlation, d_vr \equiv \Delta log \sigma_ap/\Delta log R_e, varies systematically with galaxy mass from d_vr \simeq -0.45 at M_sps \sim 10^{10}M_sun, to d_vr \simeq -0.15 at M_sps \sim 10^{11.6} M_sun. The virial fundamental plane (FP) has d_vr=-1/2, and thus we find the tilt of the observed FP is mass dependent. Reproducing this tilt requires {\it both} a non-universal IMF and a non-universal halo response. Our best model has mass-follows-light at low masses (Msps < 10^{11.2}M_sun) and unmodified NFW haloes at M_sps \sim 10^{11.5} M_sun. The stellar masses imply a mass dependent IMF which is "lighter" than Salpeter at low masses and "heavier" than Salpeter at high masses.Comment: 19 pages, 16 figures, accepted to MNRAS. More extensive discussion, 4 new figures, conclusions unchange

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead