Maximum Covering Subtrees for Phylogenetic Networks

Tree-based phylogenetic networks, which may be roughly defined as leaf-labeled networks built by adding arcs only between the original tree edges, have elegant properties for modeling evolutionary histories. We answer an open question of Francis, Semple, and Steel about the complexity of determining how far a phylogenetic network is from being tree-based, including non-binary phylogenetic networks. We show that finding a phylogenetic tree covering the maximum number of nodes in a phylogenetic network can be be computed in polynomial time via an encoding into a minimum-cost maximum flow problem

Couples' voluntary counselling and testing and nevirapine use in antenatal clinics in two African capitals: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>With the accessibility of prevention of mother to child transmission (PMTCT) services in sub-Saharan Africa, more women are being tested for HIV in antenatal care settings. Involving partners in the counselling and testing process could help prevent horizontal and vertical transmission of HIV. This study was conducted to assess the feasibility of couples' voluntary counseling and testing (CVCT) in antenatal care and to measure compliance with PMTCT.</p> <p>Methods</p> <p>A prospective cohort study was conducted over eight months at two public antenatal clinics in Kigali, Rwanda, and Lusaka, Zambia. A convenience sample of 3625 pregnant women was enrolled. Of these, 1054 women were lost to follow up. The intervention consisted of same-day individual voluntary counselling and testing (VCT) and weekend CVCT; HIV-positive participants received nevirapine tablets. In Kigali, nevirapine syrup was provided in the labour and delivery ward; in Lusaka, nevirapine syrup was supplied in pre-measured single-dose syringes. The main outcome measures were nurse midwife-recorded deliveries and reported nevirapine use.</p> <p>Results</p> <p>In eight months, 1940 women enrolled in Kigali (984 VCT, 956 CVCT) and 1685 women enrolled in Lusaka (1022 VCT, 663 CVCT). HIV prevalence was 14% in Kigali, and 27% in Lusaka. Loss to follow up was more common in Kigali than Lusaka (33% vs. 24%, p = 0.000). In Lusaka, HIV-positive and HIV-negative women had significantly different loss-to-follow-up rates (30% vs. 22%, p = 0.002). CVCT was associated with reduced loss to follow up: in Kigali, 31% of couples versus 36% of women testing alone (p = 0.011); and in Lusaka, 22% of couples versus 25% of women testing alone (p = 0.137). Among HIV-positive women with follow up, CVCT had no impact on nevirapine use (86-89% in Kigali; 78-79% in Lusaka).</p> <p>Conclusions</p> <p>Weekend CVCT, though new, was feasible in both capital cities. The beneficial impact of CVCT on loss to follow up was significant, while nevirapine compliance was similar in women tested alone or with their partners. Pre-measured nevirapine syrup syringes provided flexibility to HIV-positive mothers in Lusaka, but may have contributed to study loss to follow up. These two prevention interventions remain a challenge, with CVCT still operating without supportive government policy in Zambia.</p

The perils of project-based work: Attempting resistance to extreme work practices in video game development

This article examines two blogs written by the spouses of game developers about extreme and exploitative working conditions in the video game industry and the associated reader comments. The wives of these video game developers and members of the game community decry these working conditions and challenge dominant ideologies about making games. This article contributes to the work intensification literature by challenging the belief that long hours are necessary and inevitable to make successful games, discussing the negative toll of extreme work on workers and their families, and by highlighting that the project-based structure of game development both creates extreme work conditions and inhibits resistance. It considers how extreme work practices are legitimized through neo-normative control mechanisms made possible through project-based work structures and the perceived imperative of a race or ‘crunch’ to meet project deadlines. The findings show that neo-normative control mechanisms create an insularity within project teams and can make it difficult for workers to resist their own extreme working conditions, and at times to even understand them as extreme

Inflammatory Genital Infections Mitigate a Severe Genetic Bottleneck in Heterosexual Transmission of Subtype A and C HIV-1

The HIV-1 epidemic in sub-Saharan Africa is driven largely by heterosexual transmission of non-subtype B viruses, of which subtypes C and A are predominant. Previous studies of subtype B and subtype C transmission pairs have suggested that a single variant from the chronically infected partner can establish infection in their newly infected partner. However, in subtype A infected individuals from a sex worker cohort and subtype B individuals from STD clinics, infection was frequently established by multiple variants. This study examined over 1750 single-genome amplified viral sequences derived from epidemiologically linked subtype C and subtype A transmission pairs very early after infection. In 90% (18/20) of the pairs, HIV-1 infection is initiated by a single viral variant that is derived from the quasispecies of the transmitting partner. In addition, the virus initiating infection in individuals who were infected by someone other than their spouse was characterized to determine if genital infections mitigated the severe genetic bottleneck observed in a majority of epidemiologically linked heterosexual HIV-1 transmission events. In nearly 50% (3/7) of individuals infected by someone other than their spouse, multiple genetic variants from a single individual established infection. A statistically significant association was observed between infection by multiple genetic variants and an inflammatory genital infection in the newly infected individual. Thus, in the vast majority of HIV-1 transmission events in cohabiting heterosexual couples, a single genetic variant establishes infection. Nevertheless, this severe genetic bottleneck can be mitigated by the presence of inflammatory genital infections in the at risk partner, suggesting that this restriction on genetic diversity is imposed in large part by the mucosal barrier

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy

Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual

Genome of the Asian Longhorned Beetle (\u3cem\u3eAnoplophora glabripennis\u3c/em\u3e), a Globally Significant Invasive Species, Reveals Key Functional and Evolutionary Innovations at the Beetle-Plant Interface

Background: Relatively little is known about the genomic basis and evolution of wood-feeding in beetles. We undertook genome sequencing and annotation, gene expression assays, studies of plant cell wall degrading enzymes, and other functional and comparative studies of the Asian longhorned beetle, Anoplophora glabripennis, a globally significant invasive species capable of inflicting severe feeding damage on many important tree species. Complementary studies of genes encoding enzymes involved in digestion of woody plant tissues or detoxification of plant allelochemicals were undertaken with the genomes of 14 additional insects, including the newly sequenced emerald ash borer and bull-headed dung beetle. Results: The Asian longhorned beetle genome encodes a uniquely diverse arsenal of enzymes that can degrade the main polysaccharide networks in plant cell walls, detoxify plant allelochemicals, and otherwise facilitate feeding on woody plants. It has the metabolic plasticity needed to feed on diverse plant species, contributing to its highly invasive nature. Large expansions of chemosensory genes involved in the reception of pheromones and plant kairomones are consistent with the complexity of chemical cues it uses to find host plants and mates. Conclusions: Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle, certain other phytophagous beetles, and to a lesser degree, other phytophagous insects. Our results thus begin to establish a genomic basis for the evolutionary success of beetles on plants

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes