Characterisation of the Ugandan HIV epidemic with full-length genome sequence data from 1986 to 2016

Presented here are two large Ugandan HIV genome datasets, one from the modern period (by the MRC/UVRI & LSHTM group and PANGEA), and another generated from stored 1986 serum samples using target-capture next generation sequencing. Uganda uniquely has two HIV subtypes at similar proportions, and although subtype A1 is older than subtype D, both subtypes are well established in all cohorts and risk groups, which has facilitated comparison of the two. Previously, HIV sequence data from East Africa has typically been short gene sequences, thus the full-length genome data here has presented an opportunity to compare the evolutionary histories of the two subtypes across the genome, and carry out an examination of inter-subtype recombination patterns. The majority of the modern HIV genomes are unique recombinant forms (URFs), representing a large number of independent superinfection events, which is consistent with the size and age of the epidemic. There are wide scale patterns of recombination along the genome, which are described. Specifically, the region of envelope from C2 of gp120 to the transmembrane region of gp41 is almost always found intact since disruption of these protein interactions is expected to be highly detrimental. Re-discovered serum samples from 1986 yielded 109 full-length HIV ’historical’ genomes. The subtype distribution is shown to significantly change over time: subtype D fell from 67% in 1986 to 17% in the modern PANGEA sample. Furthermore, co-receptor tropism (CXCR4 or CCR5) was predicted with geno2pheno and a significant difference between the historical subtypes was observed: 63% of subtype D genomes are X4 tropic (known to be associated with faster progression to AIDS) whilst 0% of A1 sequences are X4 tropic. Therefore, co-receptor tropism may have reduced the effective reproductive number of subtype D by reducing the duration of potential onward exposure (due to faster time to death) compared with A1, and can explain a drop in subtype D prevalence over time. Finally, BEAST1 methods are applied to reconstruct the demographic histories of the two subtypes over time using gag, pol, and env gene data, and place the subtypes in their wider East African context. These findings characterise a highly diverse and complex epidemic in Uganda that has shifted from predominantly sub-type D to predominantly subtype A1 between 1986 and 2016, whilst pervasive and ongoing recombination has generated a wide variety of URFs

A large population sample of African HIV genomes from the 1980s reveals a reduction in subtype D over time associated with propensity for CXCR4 tropism

We present 109 near full-length HIV genomes amplified from blood serum samples obtained during early 1986 from across Uganda, which to our knowledge is the earliest and largest population sample from the initial phase of the HIV epidemic in Africa. Consensus sequences were made from paired-end Illumina reads with a target-capture approach to amplify HIV material following poor success with standard approaches. In comparisons with a smaller 'intermediate' genome dataset from 1998 to 1999 and a 'modern' genome dataset from 2007 to 2016, the proportion of subtype D was significantly higher initially, dropping from 67% (73/109), to 57% (26/46) to 17% (82/465) respectively (p < 0.0001). Subtype D has previously been shown to have a faster rate of disease progression than other subtypes in East African population studies, and to have a higher propensity to use the CXCR4 co-receptor ("X4 tropism"); associated with a decrease in time to AIDS. Here we find significant differences in predicted tropism between A1 and D subtypes in all three sample periods considered, which is particularly striking the 1986 sample: 66% (53/80) of subtype D env sequences were predicted to be X4 tropic compared with none of the 24 subtype A1. We also analysed the frequency of subtype in the envelope region of inter-subtype recombinants, and found that subtype A1 is over-represented in env, suggesting recombination and selection have acted to remove subtype D env from circulation. The reduction of subtype D frequency over three decades therefore appears to be a result of selective pressure against X4 tropism and its higher virulence. Lastly, we find a subtype D specific codon deletion at position 24 of the V3 loop, which may explain the higher propensity for subtype D to utilise X4 tropism

Radiative Corrections to the ZbbˉZ b \bar{b} Vertex and Constraints on Extended Higgs Sectors

We explore the radiative corrections to the process $Z \to b \bar b$ in models with extended Higgs sectors. The observables $R_b = \Gamma(Z \to b \bar b)/\Gamma(Z \to \rm{hadrons})$ and the $Z b \bar b$ coupling asymmetry, $A_b = (g_L^2 - g_R^2)/(g_L^2 + g_R^2)$, are sensitive to these corrections. We present general formulae for the one-loop corrections to $R_b$ and $A_b$ in an arbitrary extended Higgs sector, and derive explicit results for a number of specific models. We find that in models containing only doublets, singlets, or larger multiplets constrained by a custodial $SU(2)_{c}$ symmetry so that $M_W = M_Z \cos\theta_W$ at tree level, the one-loop corrections due to virtual charged Higgs bosons always worsen agreement with experiment. The $R_{b}$ measurement can be used to set lower bounds on the charged Higgs masses. Constraints on models due to the one-loop contributions of neutral Higgs bosons are also examined.Comment: 54 pages, 11 figure

Evolutionary Dead End in the Galápagos: Divergence of Sexual Signals in the Rarest of Darwin's Finches

Understanding the mechanisms underlying speciation remains a challenge in evolutionary biology. The adaptive radiation of Darwin's finches is a prime example of species formation, and their study has revealed many important insights into evolutionary processes. Here, we report striking differences in mating signals (songs), morphology and genetics between the two remnant populations of Darwin's mangrove finch Camarhynchus heliobates, one of the rarest species in the world. We also show that territorial males exhibited strong discrimination of sexual signals by locality: in response to foreign songs, males responded weaker than to songs from their own population. Female responses were infrequent and weak but gave approximately similar results. Our findings not only suggest speciation in the mangrove finch, thereby providing strong support for the central role of sexual signals during speciation, but they have also implications for the conservation of this iconic bird. If speciation is complete, the eastern species will face imminent extinction, because it has a population size of only 5–10 individuals

Shirt sponsorship by gambling companies in the English and Scottish Premier Leagues: global reach and public health concerns

While the nature of gambling practices is contested, a strong evidence base demonstrates that gambling can become a serious disorder and have a range of detrimental effects for individuals, communities and societies. Over the last decade, football in the UK has become visibly entwined with gambling marketing. To explore this apparent trend, we tracked shirt sponsors in both the English and Scottish Premier Leagues since 1992 and found a pronounced increase in the presence of sponsorship by gambling companies. This increase occurred at the same time the Gambling Act 2005, which liberalized rules, was introduced. We argue that current levels of gambling sponsorship in UK football, and the global visibility it provides to gambling brands, is a public health concern that needs to be debated and addressed. We recommend that legislators revisit the relationship between football in the UK and the sponsorship it receives from the gambling industry

Evidence for Secretion of a Netrin-1-like Protein by Tetrahymena thermophila

Netrin-1 is a pleiotropic signaling molecule with targets in many mammalian cell types. Though first characterized as a chemotactic signal involved in neuronal guidance during development, netrin-1 has since been found to have a regulatory role in angiogenesis, and is also used as a biomarker in certain cancers. Tetrahymena thermophila are free-living protists that rely on chemotactic signals to find food, as well as to escape predators. Chemoattractants cause the cells to swim faster in the forward direction, while chemorepellents cause ciliary reversal, resulting in movement of the cell away from the noxious stimulus. We have previously found that netrin-1 is a chemorepellent in T. thermophila. More recently, we have detected netrin-1 by ELISA in both whole cell extract and secreted protein samples obtained from T. thermophila. In addition, we have immunolocalized netrin-1 staining to the cytosol of T. thermophila using an anti-netrin-1 antibody. We are currently running Western blots to determine the molecular weight of this protein and compare it to its vertebrate counterparts. Further experimentation is needed to determine the physiological role of this protein in T. thermophila

Integrated collaborative care teams to enhance service delivery to youth with mental health and substance use challenges : Protocol for a pragmatic randomised controlled trial

Introduction: Among youth, the prevalence of mental health and addiction (MHA) disorders is roughly 20%, yet youth are challenged to access evidence-based services in a timely fashion. To address MHA system gaps, this study tests the benefits of an Integrated Collaborative Care Team (ICCT) model for youth with MHA challenges. A rapid, stepped-care approach geared to need in a youth-friendly environment is expected to result in better youth MHA outcomes. Moreover, the ICCT approach is expected to decrease service wait-times, be more youth-friendly and familyfriendly, and be more cost-effective, providing substantial public health benefits. Methods and analysis: In partnership with four community agencies, four adolescent psychiatry hospital departments, youth and family members with lived experience of MHA service use, and other stakeholders, we have developed an innovative model of collaborative, community-based service provision involving rapid access to needs-based MHA services. A total of 500 youth presenting for hospital-based, outpatient psychiatric service will be randomised to ICCT services or hospital-based treatment as usual, following a pragmatic randomised controlled trial design. The primary outcome variable will be the youth's functioning, assessed at intake, 6 months and 12 months. Secondary outcomes will include clinical change, youth/family satisfaction and perception of care, empowerment, engagement and the incremental cost-effectiveness ratio (ICER). Intent-to-treat analyses will be used on repeated-measures data, along with cost-effectiveness and cost-utility analyses, to determine intervention effectiveness. Ethics and dissemination: Research Ethics Board approval has been received from the Centre for Addiction and Mental Health, as well as institutional ethical approval from participating community sites. This study will be conducted according to Good Clinical Practice guidelines. Participants will provide informed consent prior to study participation and data confidentiality will be ensured. A data safety monitoring panel will monitor the study. Results will be disseminated through community and peer-reviewed academic channels

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited