Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes

The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2,3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM {\beta}-lactamase (blaTEM) varied greatly among 15 different {\beta}-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles blaTEM-50 and blaTEM-85, each of which differs from its ancestor blaTEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV

Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance

Reactivated androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC). Novel AR targeting drugs abiraterone and enzalutamide have improved survival of CRPC patients. However, resistance to these agents develops and patients ultimately succumb to CRPC. Potential mechanisms of resistance include the following: 1) Expression of AR splice variants such as the AR-V7 isoform which lacks the ligand-binding domain, 2) AR missense mutations in the ligand-binding domain, such as F876L and T877A, and 3) Mutation or overexpression of androgen biosynthetic enzymes or glucocorticoid receptor. Several novel agents may overcome resistance mechanisms. Galeterone acts through multiple mechanisms that include degradation of AR protein and is being evaluated in CRPC patients positive for AR-V7. EPI-001 and related compounds inhibit AR splice variants by targeting the N-terminal transactivation domain of AR. Promising therapies and novel biomarkers, such as AR-V7, may lead to improved outcomes for CRPC patients

The Gendered Nature of Ecosystem Services

This is the final version. Available from Elsevier via the DOI in this record. This article assesses the extent to which our conceptualisation, understanding and empirical analysis of ecosystem services are inherently gendered; in other words, how they might be biased and unbalanced in terms of their appreciation of gender differences. We do this by empirically investigating how women and men are able to benefit from ecosystem services across eight communities in coastal Kenya and Mozambique. Our results highlight different dimensions of wellbeing affected by ecosystem services, and how these are valued differently by men and women. However, it is not just the division of costs and benefits of ecosystem services that is gendered. Using a heuristic device of the ‘ecosystem-wellbeing chain’ we explain patterns within our primary data as an outcome of gendered knowledge systems, gendered behavioural expectations, gendered access to resources and gendered institutions. We conclude that this holistic, gendered understanding of ecosystem services is important not just for how ecosystem services are conceptualised, but also for the development and implementation of sustainable and equitable policy and interventions.Natural Environment Research Council (NERC)Ecosystem Services for Poverty Alleviation (ESPA)Economic and Social Research Council (ESRC

Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. Significance: Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.Peer reviewe

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer

This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer

Improving understanding of the functional diversity of fisheries by exploring the influence of global catch reconstruction

Functional diversity is thought to enhance ecosystem resilience, driving research focused on trends in the functional composition of fisheries, most recently with new reconstructions of global catch data. However, there is currently little understanding of how accounting for unreported catches (e.g. small-scale and illegal fisheries, bycatch and discards) influences functional diversity trends in global fisheries. We explored how diversity estimates varied among reported and unreported components of catch in 2010, and found these components had distinct functional fingerprints. Incorporating unreported catches had little impact on global-scale functional diversity patterns. However, at smaller, management-relevant scales, the effects of incorporating unreported catches were large (changes in functional diversity of up to 46%). Our results suggest there is greater uncertainty about the risks to ecosystem integrity and resilience from current fishing patterns than previously recognized. We provide recommendations and suggest a research agenda to improve future assessments of functional diversity of global fisheries

DNA building blocks: keeping control of manufacture

Ribonucleotide reductase (RNR) is the only source for de novo production of the four deoxyribonucleoside triphosphate (dNTP) building blocks needed for DNA synthesis and repair. It is crucial that these dNTP pools are carefully balanced, since mutation rates increase when dNTP levels are either unbalanced or elevated. RNR is the major player in this homeostasis, and with its four different substrates, four different allosteric effectors and two different effector binding sites, it has one of the most sophisticated allosteric regulations known today. In the past few years, the structures of RNRs from several bacteria, yeast and man have been determined in the presence of allosteric effectors and substrates, revealing new information about the mechanisms behind the allosteric regulation. A common theme for all studied RNRs is a flexible loop that mediates modulatory effects from the allosteric specificity site (s-site) to the catalytic site for discrimination between the four substrates. Much less is known about the allosteric activity site (a-site), which functions as an on-off switch for the enzyme's overall activity by binding ATP (activator) or dATP (inhibitor). The two nucleotides induce formation of different enzyme oligomers, and a recent structure of a dATP-inhibited α6β2 complex from yeast suggested how its subunits interacted non-productively. Interestingly, the oligomers formed and the details of their allosteric regulation differ between eukaryotes and Escherichia coli Nevertheless, these differences serve a common purpose in an essential enzyme whose allosteric regulation might date back to the era when the molecular mechanisms behind the central dogma evolved

The Gendered Nature of Ecosystem Services

This article assesses the extent to which our conceptualisation, understanding and empirical analysis of ecosystem services are inherently gendered; in other words, how they might be biased and unbalanced in terms of their appreciation of gender differences. We do this by empirically investigating how women and men are able to benefit from ecosystem services across eight communities in coastal Kenya and Mozambique. Our results highlight different dimensions of wellbeing affected by ecosystem services, and how these are valued differently by men and women. However, it is not just the division of costs and benefits of ecosystem services that is gendered. Using a heuristic device of the ‘ecosystem-wellbeing chain’, we explain patterns within our primary data as an outcome of gendered knowledge systems, gendered behavioural expectations, gendered access to resources and gendered institutions. We conclude that this holistic, gendered understanding of ecosystem services is important not just for how ecosystem services are conceptualised, but also for the development and implementation of sustainable and equitable policy and interventions

Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene

<p>Abstract</p> <p>Background</p> <p>While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice.</p> <p>Methods</p> <p>Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot.</p> <p>Results</p> <p>RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT +/- mice.</p> <p>Conclusion</p> <p>These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.</p