Accounting for the biological complexity of pathogenic fungi in phylogenetic dating

In the study of pathogen evolution, temporal dating of phylogenies provides information on when species and lineages may have diverged in the past. When combined with spatial and epidemiological data in phylodynamic models, these dated phylogenies can also help infer where and when outbreaks occurred, how pathogens may have spread to new geographic locations and/or niches, and how virulence or drug resistance has developed over time. Although widely applied to viruses and, increasingly, to bacterial pathogen outbreaks, phylogenetic dating is yet to be widely used in the study of pathogenic fungi. Fungi are complex organisms with several biological processes that could present issues with appropriate inference of phylogenies, clock rates, and divergence times, including high levels of recombination and slower mutation rates although with potentially high levels of mutation rate variation. Here, we discuss some of the key methodological challenges in accurate phylogeny reconstruction for fungi in the context of the temporal analyses conducted to date and make recommendations for future dating studies to aid development of a best practices roadmap in light of the increasing threat of fungal outbreaks and antifungal drug resistance worldwide

Cross-Disciplinary Genomics Approaches to Studying Emerging Fungal Infections

Emerging fungal pathogens pose a serious, global and growing threat to food supply systems, wild ecosystems, and human health. However, historic chronic underinvestment in their research has resulted in a limited understanding of their epidemiology relative to bacterial and viral pathogens. Therefore, the untargeted nature of genomics and, more widely, -omics approaches is particularly attractive in addressing the threats posed by and illuminating the biology of these pathogens. Typically, research into plant, human and wildlife mycoses have been largely separated, with limited dialogue between disciplines. However, many serious mycoses facing the world today have common traits irrespective of host species, such as plastic genomes; wide host ranges; large population sizes and an ability to persist outside the host. These commonalities mean that -omics approaches that have been productively applied in one sphere and may also provide important insights in others, where these approaches may have historically been underutilised. In this review, we consider the advances made with genomics approaches in the fields of plant pathology, human medicine and wildlife health and the progress made in linking genomes to other -omics datatypes and sets; we identify the current barriers to linking -omics approaches and how these are being underutilised in each field; and we consider how and which -omics methodologies it is most crucial to build capacity for in the near future

Association of comorbidity and health service usage among patients with dementia in the UK: a population-based study

$\textbf{BACKGROUND}$: The majority of people with dementia have other long-term diseases, the presence of which may affect the progression and management of dementia. This study aimed to identify subgroups with higher healthcare needs, by analysing how primary care consultations, number of prescriptions and hospital admissions by people with dementia varies with having additional long-term diseases (comorbidity). $\textbf{METHODS}$: A retrospective cohort study based on health data from the Clinical Practice Research Datalink (CPRD) was conducted. Incident cases of dementia diagnosed in the year starting 1/3/2008 were selected and followed for up to 5 years. The number of comorbidities was obtained from a set of 34 chronic health conditions. Service usage (primary care consultations, hospitalisations and prescriptions) and time-to-death were determined during follow-up. Multilevel negative binomial regression and Cox regression, adjusted for age and gender, were used to model differences in service usage and death between differing numbers of comorbidities. $\textbf{RESULTS}$: Data from 4999 people (14 866 person-years of follow-up) were analysed. Overall, 91.7% of people had 1 or more additional comorbidities. Compared with those with 2 or 3 comorbidities, people with ≥6 comorbidities had higher rates of primary care consultations (rate ratio (RR) 1.31, 95% CI 1.25 to 1.36), prescriptions (RR 1.68, 95% CI 1.57 to 1.81), and hospitalisation (RR 1.62, 95% CI 1.44 to 1.83), and higher risk of death (HR 1.56, 95% CI 1.37 to 1.78). $\textbf{DISCUSSION}$: In the UK, people with dementia with higher numbers of comorbidities die earlier and have considerably higher health service usage in terms of primary care consultations, hospital admissions and prescribing. This study provides strong evidence that comorbidity is a key factor that should be considered when allocating resources and planning care for people with dementia

Sun exposure behaviour, seasonal vitamin D deficiency, and relationship to bone health in adolescents

YesContext: Vitamin D is essential for bone health in adolescence, where there is rapid bone mineral content accrual. As cutaneous sun-exposure provides vitamin D, there is no recommended oral intake for UK adolescents. Objective: Assess seasonal vitamin D status and its contributors in white Caucasian adolescents, and examine bone health in those found deficient. Design: Prospective cohort study. Setting: Six schools in Greater Manchester, UK. Participants: 131 adolescents, 12–15 years. Intervention(s): Seasonal assessment of circulating 25-hydroxyvitamin D (25OHD), personal sunexposure and dietary vitamin D. Adolescents deficient (25OHD <10 ng/mL/25 nmol/L) in ≥one season underwent dual-energy X-ray absorptiometry (lumbar spine, femoral neck), with bone mineral apparent density (BMAD) correction for size, and peripheral quantitative computed tomography (distal radius) for volumetric (v)BMD. Main Outcome Measure: Serum 25OHD; BMD. Results: Mean 25OHD was highest in September: 24.1 (SD 6.9) ng/mL and lowest in January: 15.5 (5.9) ng/mL. Over the year, 16% were deficient in ≥one season and 79% insufficient (25OHD <20 ng/mL/50 nmol/L) including 28% in September. Dietary vitamin D was low year-round while personal sun-exposure was seasonal and predominantly across the school week. Holidays accounted for 17% variation in peak 25OHD (p<0.001). Nineteen adolescents underwent bone assessment, which showed low femoral neck BMAD versus matched reference data (p=0.0002), 3 with Z≤ -2.0 distal radius trabecular vBMD. Conclusions: Sun-exposure levels failed to provide adequate vitamin D, ~one-quarter adolescents insufficient even at summer-peak. Seasonal vitamin D deficiency was prevalent and those affected had low BMD. Recommendations on vitamin D acquisition are indicated in this age-group.The Bupa Foundation (Grant number TBF-M10-017)

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Local artifacts in ice core methane records caused by layered bubble trapping and in situ production: A multi-site investigation

Advances in trace gas analysis allow localised, non-atmospheric features to be resolved in ice cores, superimposed on the coherent atmospheric signal. These high-frequency signals could not have survived the low-pass filter effect that gas diffusion in the firn exerts on the atmospheric history and therefore do not result from changes in the atmospheric composition at the ice sheet surface. Using continuous methane (CH$_{4}$) records obtained from five polar ice cores, we characterise these non-atmospheric signals and explore their origin. Isolated samples, enriched in CH$_{4}$ in the Tunu13 (Greenland) record are linked to the presence of melt layers. Melting can enrich the methane concentration due to a solubility effect, but we find that an additional in situ process is required to generate the full magnitude of these anomalies. Furthermore, in all the ice cores studied there is evidence of reproducible, decimetre-scale CH$_{4}$ variability. Through a series of tests, we demonstrate that this is an artifact of layered bubble trapping in a heterogeneous-density firn column; we use the term "trapping signal" for this phenomenon. The peak-to-peak amplitude of the trapping signal is typically 5 ppb, but may exceed 40 ppb. Signal magnitude increases with atmospheric CH$_{4}$ growth rate and seasonal density contrast, and decreases with accumulation rate. Significant annual periodicity is present in the CH$_{4}$ variability of two Greenland ice cores, suggesting that layered gas trapping at these sites is controlled by regular, seasonal variations in the physical properties of the firn. Future analytical campaigns should anticipate high-frequency artifacts at high-melt ice core sites or during time periods with high atmospheric CH$_{4}$ growth rate in order to avoid misinterpretation of such features as past changes in atmospheric composition.Please visit the publisher's website

Author manuscript; available in PMC

Abstract The current study aims to further our understanding of the applicability of the transtheoretical model (TM) to intimate partner violence (IPV), with particular focus on mental health symptoms (depression, posttraumatic stress disorder symptomatology, suicidal ideation) in a sample of lowincome African American women seeking medical services at an inner city emergency department. Results revealed that of the 121 abused African American women, the majority (95%) were in the precontempla-tion and contemplation stages of the change process. Further, contrary to predictions, bivariate analyses revealed those at further stages of change endorsed more severe mental health symptoms. However, a multivariate analysis of variance examining differences in level of mental health symptoms between women high and low on stages of change was inconclusive due to the small number of women at the higher stages of the TM model. These findings contribute to the growing body of literature supporting the TM as applied to IPV. Results are discussed in terms of applicability to intervention design. Keywords intimate partner violence; African American women; transtheoretical model The transtheoretical model (TM), also known as the stages of change model, describes an individual&apos;s readiness to change behavior. The TM suggests that to make a successful behavior change, individuals must go through a process of evaluating and increasing their readiness to change, ultimately making the change and maintaining the behavior. The TM conceptualize

Local artifacts in ice core methane records caused by layered bubble trapping and in situ production: a multi-site investigation

Advances in trace gas analysis allow localised, non-atmospheric features to be resolved in ice cores, superimposed on the coherent atmospheric signal. These high-frequency signals could not have survived the low-pass filter effect that gas diffusion in the firn exerts on the atmospheric history and therefore do not result from changes in the atmospheric composition at the ice sheet surface. Using continuous methane (CH₄) records obtained from five polar ice cores, we characterise these non-atmospheric signals and explore their origin. Isolated samples, enriched in CH₄ in the Tunu13 (Greenland) record are linked to the presence of melt layers. Melting can enrich the methane concentration due to a solubility effect, but we find that an additional in situ process is required to generate the full magnitude of these anomalies. Furthermore, in all the ice cores studied there is evidence of reproducible, decimetre-scale CH₄ variability. Through a series of tests, we demonstrate that this is an artifact of layered bubble trapping in a heterogeneous-density firn column; we use the term “trapping signal” for this phenomenon. The peak-to-peak amplitude of the trapping signal is typically 5 ppb, but may exceed 40 ppb. Signal magnitude increases with atmospheric CH₄ growth rate and seasonal density contrast, and decreases with accumulation rate. Significant annual periodicity is present in the CH₄ variability of two Greenland ice cores, suggesting that layered gas trapping at these sites is controlled by regular, seasonal variations in the physical properties of the firn. Future analytical campaigns should anticipate high-frequency artifacts at high-melt ice core sites or during time periods with high atmospheric CH₄ growth rate in order to avoid misinterpretation of such features as past changes in atmospheric composition.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Copernicus Publications on behalf of the European Geosciences Union. The published article can be found at: http://www.climate-of-the-past.net

Mind the gap? Civil society policy engagement and the pursuit of gender justice: critical discourse analysis of the implementation of the Beijing Declaration and Platform for Action in Africa 2003–2015

This article presents critical discourse analysis of state and civil society organisations’ efforts to implement the gender mainstreaming goals set out in the United Nations’ Beijing Declaration. It is argued that the latter represents a generational opportunity to apply a Feminist Political Economic Framework to development in Africa. However, the research findings show how current practice falls short of the sought-after participative democratic model of mainstreaming. Instead, analysis reveals significant differences in state and civil society organisations’ policy framing, issues over conceptual clarity and a disjuncture in state and civil society prioritisation of key gendered issues such as poverty, economic inequality and conflict resolution. This matters because it indicates that the capacity of the civil sphere to act as a political arena from which NGOs may challenge the traditionally male-dominated power structures is being undermined by a ‘disconnect’ between state and civil society as they pursue contrasting agendas

Facial Skin Coloration Affects Perceived Health of Human Faces

Numerous researchers have examined the effects of skin condition, including texture and color, on the perception of health, age, and attractiveness in human faces. They have focused on facial color distribution, homogeneity of pigmentation, or skin quality. We here investigate the role of overall skin color in determining perceptions of health from faces by allowing participants to manipulate the skin portions of color-calibrated Caucasian face photographs along CIELab color axes. To enhance healthy appearance, participants increased skin redness (a*), providing additional support for previous findings that skin blood color enhances the healthy appearance of faces. Participants also increased skin yellowness (b*) and lightness (L*), suggesting a role for high carotenoid and low melanin coloration in the healthy appearance of faces. The color preferences described here resemble the red and yellow color cues to health displayed by many species of nonhuman animals