Public health risk of foodborne pathogens in edible African land snails, Cameroon

In tropical countries, land snails are an important food source; however, foodborne disease risks are poorly quantified. We detected Campylobacter spp., Yersinia spp., Listeria spp., Salmonella spp., or Shiga-toxigenic Escherichia coli in 57%–86% of snails in Cameroon. Snail meat is a likely vector for enteric diseases in sub-Saharan Africa countries

Unraveling the B. pseudomallei Heptokinase WcbL: from structure to drug discovery

Journal ArticleOpen Access funded by Biotechnology and Biological Sciences Research Council under a Creative Commons Attribution 4.0 International Public LicenseGram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.Biotechnology and Biological Sciences Research Counci

Structural insights into WcbI, a novel polysaccharide-biosynthesis enzyme

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. Available at: http://journals.iucr.org/m/ Copyright © 2013 International Union of CrystallographyCapsular polysaccharides (CPSs) are protective structures on the surfaces of many Gram-negative bacteria. The principal CPS of the human pathogen and Tier 1 select agent Burkholderia pseudomallei consists of a linear repeat of -­3)-­2-O-acetyl-6-deoxy-[beta]-D-manno-heptopyranose-(1-. This CPS is critical to the virulence of this emerging pathogen and represents a key target for the development of novel therapeutics. wcbI is one of several genes in the CPS biosynthetic cluster whose deletion leads to significant attenuation of the pathogen; unlike most others, it has no homologues of known function and no detectable sequence similarity to any protein with an extant structure. Here, the crystal structure of WcbI bound to its proposed product, coenzyme A, is reported at 1.38 Å resolution, solved using the halide-soak method with multiple anomalous dispersion. This structure reveals that WcbI incorporates a previously described 100-amino-acid subdomain into a novel, principally helical fold (310 amino acids). This fold adopts a cradle-like structure, with a deep binding pocket for CoA in the loop-rich cradle. Structural analysis and biophysical assays suggest that WcbI functions as an acetyltransferase enzyme, whilst biochemical tests suggest that another functional module might be required to assist its activity in forming the mature B. pseudomallei capsule.Biotechnology and Biological Sciences Research Council (BBSRC

Targeted Mutation Detection in Advanced Breast Cancer Using MammaSeq Identifies RET as a Potential Contributor to Breast Cancer Metastasis

The lack of any reported breast cancer specific diagnostic NGS tests inspired the development of MammaSeq, an amplicon based NGS panel built specifically for use in advanced breast cancer. In a pilot study to define the clinical utility of the panel, 46 solid tumor samples, plus an additional 14 samples of circulating-free DNA (cfDNA) from patients with advanced breast cancer were sequenced and analyzed using the OncoKB precision oncology database. We identified 26 clinically actionable variants (levels 1-3) annotated by the OncoKB precision oncology database, distributed across 20 out of 46 solid tumor cases (40%), and 4 clinically actionable mutations distributed across 4 samples in the 14 cfDNA sample cohort (29%). The mutation allele (MAF) frequencies of ESR1-D538G and FOXA1-Y175C mutations correlated with CA.27.29 levels in patient-matched blood, indicating that MAF may be a reliable marker for disease burden. Interestingly, 4 of the mutations found in metastatic samples occurred in the gene RET, an oncogenic receptor tyrosine kinase. In an orthogonal study, the lab has recently identified RET as one of the most recurrently upregulated genes in breast cancer brain metastases. Interestingly, the ligand for RET is the family of glial-cell derived neurotrophic factors (GDNF), a growth factor secreted by glial cells of the central nervous system. This lead to the hypothesis that RET overexpression facilitates breast cancer brain metastasis in response to the high levels of GDNF, while RET activating point mutations increase metastatic capacity without specific organ tropism. While the effect of GDNF treatment on proliferation in 2D was limited, in ultra-low attachment (ULA) plates we saw a significant increase in anchorage independent growth of MCF-7 cells. To determine if GDNF acts as a chemoattractant for RET positive BrCa cells, we utilized a transwell migration assay, with GDNF as the sole chemoattractant. When RET was overexpressed, there was a visual increase in cell migration. Together, these studies demonstrate the clinical feasibility of using MammaSeq to detect clinically actionable mutations in breast cancer patients, and provides provisional data supporting the investigation of RET signaling as a potentially targetable mediator of breast cancer brain metastasis

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series

Background - The causes of phenotypic heterogeneity in familial Alzheimer’s disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer’s disease (ADAD). Methods - We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Findings - Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1’s first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. Interpretation - ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Funding - Medical Research Council and National Institute for Health Research

Self-management of chronic pain in Malaysian patients: effectiveness trial with 1-year follow-up

Self-management of chronic illnesses has been widely recognised as an important goal on quality of life, health service utilisation and cost grounds. This study describes the first published account on the application of this approach to people suffering from chronic pain conditions in a Southeast Asian country, Malaysia. A heterogeneous sample of chronic pain patients in Malaysia attended a 2-week cognitive–behavioural pain management programme (PMP) aimed at improving daily functional activities and general psychological well-being. Complete datasets from 70 patients out of 102 patients who attended 11 programmes conducted from 2002 to 2007, as well as the 1-month and 1-year follow-up sessions at the hospital clinic, are reported. The pre- to post-treatment results on self-report measures indicate that significant gains were achieved on the dimensions of pain, disability and psychological well-being. These gains were maintained at both 1-month and 1-year follow-ups. The results mirror those reported from similar interventions in Europe and North America and indicate the concept of self-management of a chronic illness is acceptable and meaningful to Asian patients. Importantly, the achieved outcomes were independent of gender and ethnic group status

Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics

Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network

Objective: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Methods: Among two subsets of the DIAN cohort (age range 19.6–66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009–2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. Results: There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope − 0.365, 95% CI: −0.958 to −0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. Interpretation: We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD

Reciprocity as a foundation of financial economics

This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice

Elementary sensory-motor transformations underlying olfactory navigation in walking fruit-flies.

Odor attraction in walking Drosophila melanogaster is commonly used to relate neural function to behavior, but the algorithms underlying attraction are unclear. Here, we develop a high-throughput assay to measure olfactory behavior in response to well-controlled sensory stimuli. We show that odor evokes two behaviors: an upwind run during odor (ON response), and a local search at odor offset (OFF response). Wind orientation requires antennal mechanoreceptors, but search is driven solely by odor. Using dynamic odor stimuli, we measure the dependence of these two behaviors on odor intensity and history. Based on these data, we develop a navigation model that recapitulates the behavior of flies in our apparatus, and generates realistic trajectories when run in a turbulent boundary layer plume. The ability to parse olfactory navigation into quantifiable elementary sensori-motor transformations provides a foundation for dissecting neural circuits that govern olfactory behavior