Mitochondrial genome of an Allegheny Woodrat (\u3ci\u3eNeotoma magister\u3c/i\u3e)

The Allegheny woodrat (Neotoma magister) is endemic to the eastern United States. Population numbers have decreased rapidly over the last four decades due to habitat fragmentation, disease-related mortality, genetic isolation and inbreeding depression; however, effective management is hampered by limited genetic resources. To begin addressing this need, we sequenced and assembled the entire Allegheny woodrat mitochondrial genome. The genome assembly is 16,310 base pairs in length, with an overall base composition of 34% adenine, 27% thymine, 26% cytosine and 13% guanine. This resource will facilitate our understanding of woodrat population genetics and behavioral ecology

Tissue Plasminogen Activator Mediates Deleterious Complement Cascade Activation in Stroke

The use of intravenous tissue plasminogen activator (tPA) in the treatment of ischemic stroke is limited by its propensity to exacerbate brain edema and hemorrhage. The mechanisms underlying these deleterious effects of tPA remain incompletely understood. The purpose of this study was to delineate a pathway of tPA-mediated complement cascade activation in stroke and to determine whether complement inhibition ameliorates the adverse effects of post-ischemic tPA administration. We found that tPA promotes C3 cleavage both in vitro and in ischemic brain through a plasmin-mediated extrinsic pathway. Using cell culture models, we then showed that the C3a-receptor is strongly expressed on ischemic endothelium and that exogenous C3a dramatically enhances endothelial cell permeability. Next, we assessed the effect of tPA administration on brain edema and hemorrhage in a transient model of focal cerebral ischemia in C57BL/6 mice. We found that intravenous tPA exacerbates brain edema and hemorrhage in stroke, and that these effects are abrogated by a small-molecule antagonist of the C3a receptor. These findings establish for the first time that intravenous tPA dramatically upregulates complement cascade activation in ischemic brain and that pharmacologic complement inhibition protects against the adverse effects of tPA-mediated thrombolysis in stroke

Public health surveillance in the UK revolutionises our understanding of the invasive Salmonella Typhimurium epidemic in Africa

Background:The ST313 sequence type ofSalmonellaTyphimurium causes invasive non-typhoidal salmonellosis and wasthought to be confined to sub-Saharan Africa. Two distinct phylogenetic lineages of African ST313 have been identified.Methods:We analysed the whole genome sequences ofS. Typhimurium isolates from UK patients that weregenerated following the introduction of routine whole-genome sequencing (WGS) ofSalmonella entericabyPublic Health England in 2014.Results:We found that 2.7% (84/3147) ofS. Typhimurium from patients in England and Wales were ST313 and wereassociated with gastrointestinal infection. Phylogenetic analysis revealed novel diversity of ST313 that distinguishedUK-linked gastrointestinal isolates from African-associated extra-intestinal isolates. The majority of genome degradationof African ST313 lineage 2 was conserved in the UK-ST313, but the African lineages carried a characteristic prophageand antibiotic resistance gene repertoire. These findings suggest that a strong selection pressure exists for certainhorizontally acquired genetic elements in the African setting. One UK-isolated lineage 2 strain that probably originatedin Kenya carried a chromosomally locatedblaCTX-M-15, demonstrating the continual evolution of this sequence type inAfrica in response to widespread antibiotic usage.Conclusions:The discovery of ST313 isolates responsible for gastroenteritis in the UK reveals new diversity in thisimportant sequence type. This study highlights thepower of routine WGS by public health agencies to makeepidemiologically significant deductions that would be missed by conventional microbiological methods. Wespeculate that the niche specialisation of sub-Saharan African ST313 lineages is driven in part by the acquisitionof accessory genome elements

(13) C magnetic resonance spectroscopy measurements with hyperpolarized [1-(13) C] pyruvate can be used to detect the expression of transgenic pyruvate decarboxylase activity in vivo.

PURPOSE: Dissolution dynamic nuclear polarization can increase the sensitivity of the (13) C magnetic resonance spectroscopy experiment by at least four orders of magnitude and offers a novel approach to the development of MRI gene reporters based on enzymes that metabolize (13) C-labeled tracers. We describe here a gene reporter based on the enzyme pyruvate decarboxylase (EC 4.1.1.1), which catalyzes the decarboxylation of pyruvate to produce acetaldehyde and carbon dioxide. METHODS: Pyruvate decarboxylase from Zymomonas mobilis (zmPDC) and a mutant that lacked enzyme activity were expressed using an inducible promoter in human embryonic kidney (HEK293T) cells. Enzyme activity was measured in the cells and in xenografts derived from the cells using (13) C MRS measurements of the conversion of hyperpolarized [1-(13) C] pyruvate to H(13) CO3-. RESULTS: Induction of zmPDC expression in the cells and in the xenografts derived from them resulted in an approximately two-fold increase in the H(13) CO3-/[1-(13) C] pyruvate signal ratio following intravenous injection of hyperpolarized [1-(13) C] pyruvate. CONCLUSION: We have demonstrated the feasibility of using zmPDC as an in vivo reporter gene for use with hyperpolarized (13) C MRS. Magn Reson Med 76:391-401, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.PD was in receipt of a studentship funded by CRUK and S.-S.T. a Yousef Jameel studentship. TBR was in receipt of an Intra-European Marie Curie (FP7-PEOPLE- 2009-IEF, Imaging Lymphoma) and Long-term EMBO (EMBO-ALT-1145-2009) fellowships and E.M.S. and I.M.R were recipients of fellowships from the European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Initial Training Network METAFLUX (project number 264780). E.M.S. also acknowledges the educational support of Programme for Advanced Medical Education from Calouste Gulbenkian Foundation, Champalimaud Foundation, Ministerio de Saude and Fundacao para a Ciencia e Tecnologia, Portugal. The work was supported by a CRUK Programme Grant (17242) to KMB. The polarizer and related materials were provided by GE-Healthcare.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/mrm.2587

The InfraRed Imaging Spectrograph (IRIS) for TMT: latest science cases and simulations

The Thirty Meter Telescope (TMT) first light instrument IRIS (Infrared Imaging Spectrograph) will complete its preliminary design phase in 2016. The IRIS instrument design includes a near-infrared (0.85 - 2.4 micron) integral field spectrograph (IFS) and imager that are able to conduct simultaneous diffraction-limited observations behind the advanced adaptive optics system NFIRAOS. The IRIS science cases have continued to be developed and new science studies have been investigated to aid in technical performance and design requirements. In this development phase, the IRIS science team has paid particular attention to the selection of filters, gratings, sensitivities of the entire system, and science cases that will benefit from the parallel mode of the IFS and imaging camera. We present new science cases for IRIS using the latest end-to-end data simulator on the following topics: Solar System bodies, the Galactic center, active galactic nuclei (AGN), and distant gravitationally-lensed galaxies. We then briefly discuss the necessity of an advanced data management system and data reduction pipeline.Comment: 15 pages, 7 figures, SPIE (2016) 9909-0

Different atmospheric moisture divergence responses to extreme and moderate El Niños

On seasonal and inter-annual time scales, vertically integrated moisture divergence provides a useful measure of the tropical atmospheric hydrological cycle. It reflects the combined dynamical and thermodynamical effects, and is not subject to the limitations that afflict observations of evaporation minus precipitation. An empirical orthogonal function (EOF) analysis of the tropical Pacific moisture divergence fields calculated from the ERA-Interim reanalysis reveals the dominant effects of the El Niño-Southern Oscillation (ENSO) on inter-annual time scales. Two EOFs are necessary to capture the ENSO signature, and regression relationships between their Principal Components and indices of equatorial Pacific sea surface temperature (SST) demonstrate that the transition from strong La Niña through to extreme El Niño events is not a linear one. The largest deviation from linearity is for the strongest El Niños, and we interpret that this arises at least partly because the EOF analysis cannot easily separate different patterns of responses that are not orthogonal to each other. To overcome the orthogonality constraints, a self-organizing map (SOM) analysis of the same moisture divergence fields was performed. The SOM analysis captures the range of responses to ENSO, including the distinction between the moderate and strong El Niños identified by the EOF analysis. The work demonstrates the potential for the application of SOM to large scale climatic analysis, by virtue of its easier interpretation, relaxation of orthogonality constraints and its versatility for serving as an alternative classification method. Both the EOF and SOM analyses suggest a classification of “moderate” and “extreme” El Niños by their differences in the magnitudes of the hydrological cycle responses, spatial patterns and evolutionary paths. Classification from the moisture divergence point of view shows consistency with results based on other physical variables such as SST

Multimodal MRI characteristics of the glioblastoma infiltration beyond contrast enhancement.

Our inability to identify the invasive margin of glioblastomas hampers attempts to achieve local control. Diffusion tensor imaging (DTI) has been implemented clinically to delineate the margin of the tumor infiltration, its derived anisotropic (q) values can extend beyond the contrast-enhanced area and correlates closely with the tumor. However, its correlation with tumor infiltration shown on multivoxel proton magnetic resonance spectroscopy1 (MRS) and perfusion magnetic resonance imaging (MRI) should be investigated. In this study, we aimed to show tissue characteristics of the q-defined peritumoral invasion on MRS and perfusion MRI. Patients with a primary glioblastoma were included (n = 51). Four regions of interest were analyzed; the contrast-enhanced lesion, peritumoral abnormal q region, peritumoral normal q region, and contralateral normal-appearing white matter. MRS, including choline (Cho)/creatinine (Cr), Cho/N-acetyl-aspartate (NAA) and NAA/Cr ratios, and the relative cerebral blood volume (rCBV) were analyzed. Our results showed an increase in the Cho/NAA (p = 0.0346) and Cho/Cr (p = 0.0219) ratios in the peritumoral abnormal q region, suggestive of tumor invasion. The rCBV was marginally elevated (p = 0.0798). Furthermore, the size of the abnormal q regions was correlated with survival; patients with larger abnormal q regions showed better progression-free survival (median 287 versus 53 days, p = 0.001) and overall survival (median 464 versus 274 days, p = 0.006) than those with smaller peritumoral abnormal q regions of interest. These results support how the DTI q abnormal area identifies tumor activity beyond the contrast-enhanced area, especially correlating with MRS.This study is funded by the UK National Institute of Health Research Clinician Scientist Fellowship (SJP) and grants from Chang Gung Medical Foundation and Chang Gung Memorial Hospital (JLY), Cambridge Trust and China Scholarship Council (CL), the Remmert Adriaan Laan Fund and the René Vogels Fund (AH), and the Commonwealth Scholarship Commission and Cambridge Commonwealth Overseas Trust (NRB)

ANDES: Statistical tools for the ANalyses of DEep Sequencing

<p>Abstract</p> <p>Background</p> <p>The advancements in DNA sequencing technologies have allowed researchers to progress from the analyses of a single organism towards the deep sequencing of a sample of organisms. With sufficient sequencing depth, it is now possible to detect subtle variations between members of the same species, or between mixed species with shared biomarkers, such as the 16S rRNA gene. However, traditional sequencing analyses of samples from largely homogeneous populations are often still based on multiple sequence alignments (MSA), where each sequence is placed along a separate row and similarities between aligned bases can be followed down each column. While this visual format is intuitive for a small set of aligned sequences, the representation quickly becomes cumbersome as sequencing depths cover loci hundreds or thousands of reads deep.</p> <p>Findings</p> <p>We have developed ANDES, a software library and a suite of applications, written in Perl and R, for the statistical ANalyses of DEep Sequencing. The fundamental data structure underlying ANDES is the position profile, which contains the nucleotide distributions for each genomic position resultant from a multiple sequence alignment (MSA). Tools include the root mean square deviation (RMSD) plot, which allows for the visual comparison of multiple samples on a position-by-position basis, and the computation of base conversion frequencies (transition/transversion rates), variation (Shannon entropy), inter-sample clustering and visualization (dendrogram and multidimensional scaling (MDS) plot), threshold-driven consensus sequence generation and polymorphism detection, and the estimation of empirically determined sequencing quality values.</p> <p>Conclusions</p> <p>As new sequencing technologies evolve, deep sequencing will become increasingly cost-efficient and the inter and intra-sample comparisons of largely homogeneous sequences will become more common. We have provided a software package and demonstrated its application on various empirically-derived datasets. Investigators may download the software from Sourceforge at <url>https://sourceforge.net/projects/andestools</url>.</p

Metformin is a metabolic modulator and radiosensitiser in rectal cancer

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer

Reduced Risk of Malaria Parasitemia Following Household Screening and Treatment: A Cross-Sectional and Longitudinal Cohort Study

BACKGROUND: In regions of declining malaria transmission, new strategies for control are needed to reduce transmission and achieve elimination. Artemisinin-combination therapy (ACT) is active against immature gametocytes and can reduce the risk of transmission. We sought to determine whether household screening and treatment of infected individuals provides protection against infection for household members. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted in two areas in Southern Province, Zambia in 2007 and 2008/2009. To determine the impact of proactive case detection, households were randomly selected either to join a longitudinal cohort, in which participants were repeatedly screened throughout the year and those infected treated with artemether-lumefantrine, or a cross-sectional survey, in which participants were visited only once. Cross-sectional surveys were conducted throughout the year. The prevalence of RDT positivity was compared between the longitudinal and cross-sectional households at baseline and during follow-up using multilevel logistic regression. In the 2007 study area, 174 and 156 participants enrolled in the cross-sectional and longitudinal groups, respectively. In the 2008/2009 study area, 917 and 234 participants enrolled in the cross-sectional and longitudinal groups, respectively. In both study areas, participants and households in the longitudinal and cross-sectional groups were similar on demographic characteristics and prevalence of RDT positivity at baseline (2007: OR = 0.97; 95% CI:0.46, 2.03 | 2008/2009: OR = 1.28; 95% CI:0.44, 3.79). After baseline, the prevalence of RDT positivity was significantly lower in longitudinal compared to cross-sectional households in both study areas (2007: OR = 0.44; 95% CI:0.20, 0.96 | 2008/2009: OR = 0.16; 95% CI:0.05, 0.55). CONCLUSIONS/SIGNIFICANCE: Proactive case detection, consisting of screening household members with an RDT and treating those positive with ACT, can reduce transmission and provide indirect protection to household members. A targeted test and treat strategy could contribute to the elimination of malaria in regions of low transmission