Draft Genome Sequences of Strains of Pasteurella multocida Isolated from the United Kingdom and the United States

Pasteurella multocida is a major pathogen of farm animals and has worldwide distribution. Here we report the draft genome sequences of four strains that were isolated from animals in the United Kingdom and the United States and represent pathogenic and commensal presentation of the bacterium

Does acute exercise affect the performance of whole-body, psychomotor skills in an inverted-U fashion?:a meta-analytic investigation

The primary purpose of this study was to examine, using meta-analytical measures, whether research into the performance of whole-body, psychomotor tasks following moderate and heavy exercise demonstrates an inverted-U effect. A secondary purpose was to compare the effects of acute exercise on tasks requiring static maintenance of posture versus dynamic, ballistic skills. Moderate intensity exercise was determined as being between 40% and 79% maximum power output (ẆMAX) or equivalent, while ≥ 80% ẆMAX was considered to be heavy. There was a significant difference (Zdiff = 4.29, p = 0.001, R2 = 0.42) between the mean effect size for moderate intensity exercise (g = 0.15) and that for heavy exercise size (g = − 0.86). These data suggest a catastrophe effect during heavy exercise. Mean effect size for static tasks (g = − 1.24) was significantly different (Zdiff = 3.24, p = 0.001, R2 = 0.90) to those for dynamic/ballistic tasks (g = − 0.30). The result for the static versus dynamic tasks moderating variables point to perception being more of an issue than peripheral fatigue for maintenance of static posture. The difference between this result and those found in meta-analyses examining the effects of acute exercise on cognition shows that, when perception and action are combined, the complexity of the interaction induces different effects to when cognition is detached from motor performance

Recruitment of hypothalamic orexin neurons after formalin injections in adult male rats exposed to a neonatal immune challenge

Exposure to early life physiological stressors, such as infection, is thought to contribute to the onset of psychopathology in adulthood. In animal models, injections of the bacterial immune challenge, lipopolysaccharide (LPS), during the neonatal period has been shown to alter both neuroendocrine function and behavioural pain responses in adulthood. Interestingly, recent evidence suggests a role for the lateral hypothalamic peptide orexin in stress and nociceptive processing. However, whether neonatal LPS exposure affects the reactivity of the orexin system to formalin-induced inflammatory pain in later life remains to be determined. Male Wistar rats (n=13) were exposed to either LPS or saline (0.05mg/kg, i.p) on postnatal days (PND) 3 and 5. On PND 80-97, all rats were exposed to a subcutaneous hindpaw injection of 2.25% formalin. Following behavioural testing, animals were perfused and brains processed for Fos-protein and orexin immunohistochemistry. Rats treated with LPS during the neonatal period exhibited decreased licking behaviours during the interphase of the formalin test, the period typically associated with the active inhibition of pain, and increased grooming responses to formalin in adulthood. Interestingly, these behavioural changes were accompanied by an increase in the percentage of Fos-positive orexin cells in the dorsomedial and perifornical hypothalamus in LPS-exposed animals. Similar increases in Fos-protein were also observed in stress and pain sensitive brain regions that receive orexinergic inputs. These findings highlight a potential role for orexin in the behavioural responses to pain and provide further evidence that early life stress can prime the circuitry responsible for these responses in adulthood

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MRC Epidemiology Unit programme: MC_UU_12015/4.OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease

Transformation in a changing climate: a research agenda

The concept of transformation in relation to climate and other global change is increasingly receiving attention. The concept provides important opportunities to help examine how rapid and fundamental change to address contemporary global challenges can be facilitated. This paper contributes to discussions about transformation by providing a social science, arts and humanities perspective to open up discussion and set out a research agenda about what it means to transform and the dimensions, limitations and possibilities for transformation. Key focal areas include: (1) change theories, (2) knowing whether transformation has occurred or is occurring; (3) knowledge production and use; (4), governance; (5) how dimensions of social justice inform transformation; (6) the limits of human nature; (7) the role of the utopian impulse; (8) working with the present to create new futures; and (9) human consciousness. In addition to presenting a set of research questions around these themes the paper highlights that much deeper engagement with complex social processes is required; that there are vast opportunities for social science, humanities and the arts to engage more directly with the climate challenge; that there is a need for a massive upscaling of efforts to understand and shape desired forms of change; and that, in addition to helping answer important questions about how to facilitate change, a key role of the social sciences, humanities and the arts in addressing climate change is to critique current societal patterns and to open up new thinking. Through such critique and by being more explicit about what is meant by transformation, greater opportunities will be provided for opening up a dialogue about change, possible futures and about what it means to re-shape the way in which people live

Receptor activity modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors

The calcitonin gene-related peptide (CGRP) family of G protein-coupled receptors (GPCRs) is formed through association of the calcitonin receptor-like receptor (CLR) and one of three receptor activitymodifying proteins (RAMPs). Binding of one of the three peptide ligands, CGRP, adrenomedullin (AM) or intermedin/adrenomedullin2 (AM2) is well known to result in a Gαs-mediated increase in cAMP. Here we use modified yeast strains that couple receptor activation to cell growth, via chimeric yeast/Gα subunits, and HEK-293 cells to characterize the effect of different RAMP and ligand combinations on this pathway. We not only demonstrate functional couplings to both Gα$_{s}$ and Gα$_{q}$ but also identify a Gα$_{i}$ component to CLR signaling in both yeast and HEK- 293 cells, which is absent in HEK-293S cells. We show that the CGRP family of receptors displays both ligand and RAMP-dependent signaling bias between Gα$_{s}$, Gα$_{i}$ and Gα$_{q/11}$ pathways. The results are discussed in the context of RAMP interactions probed through molecular modelling and molecular dynamics simulations of the RAMP-GPCR-G protein complexes. This study further highlights the importance of RAMPs to CLR pharmacology, and to bias in general, as well as identifying the importance of choosing an appropriate model system for the study of GPCR pharmacology.This work was supported by the National Heart Foundation of New Zealand (H.W.), the School of Biological Sciences, University of Auckland seed fund (H.W.), the BBSRC (G.L. - BB/M00015X/1), (D.P. - BB/M000176/1), (C.A.R. - BB/M006883/1), a BBSRC Doctoral Training Partnership (M.H. – BB/JO14540/1), an MRC Doctoral Training Partnership (I.W. - MR/J003964/1), a Warwick Impact Fund (C.W., G.L.), a Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Warwick Undergraduate Research Scholarship Scheme (A.S and R.H).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the American Society for Biochemistry and Molecular Biology

A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen

Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that “senescent” mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-α. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP

Retinal Expression of Wnt-Pathway Mediated Genes in Low-Density Lipoprotein Receptor-Related Protein 5 (Lrp5) Knockout Mice

Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout $(Lrp5^{-/-})$ mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing $Lrp5^{−/−}$ mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from $Lrp5^{−/−}$ and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in $Lrp5^{−/−}$ retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in $Lrp5^{−/−}$ retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in $Lrp5^{−/−}$ retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR

A Systematic Review of Individual and Contextual Factors Affecting ART Initiation, Adherence, and Retention for HIV-Infected Pregnant and Postpartum Women

BACKGROUND: Despite progress reducing maternal mortality, HIV-related maternal deaths remain high, accounting, for example, for up to 24 percent of all pregnancy-related deaths in sub-Saharan Africa. Antiretroviral therapy (ART) is effective in improving outcomes among HIV-infected pregnant and postpartum women, yet rates of initiation, adherence, and retention remain low. This systematic literature review synthesized evidence about individual and contextual factors affecting ART use among HIV-infected pregnant and postpartum women. METHODS: Searches were conducted for studies addressing the population (HIV-infected pregnant and postpartum women), intervention (ART), and outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. Individual and contextual enablers and barriers to ART use were extracted and organized thematically within a framework of individual, interpersonal, community, and structural categories. RESULTS: Thirty-four studies were included in the review. Individual-level factors included both those within and outside a woman’s awareness and control (e.g., commitment to child’s health or age). Individual-level barriers included poor understanding of HIV, ART, and prevention of mother-to-child transmission, and difficulty managing practical demands of ART. At an interpersonal level, disclosure to a spouse and spousal involvement in treatment were associated with improved initiation, adherence, and retention. Fear of negative consequences was a barrier to disclosure. At a community level, stigma was a major barrier. Key structural barriers and enablers were related to health system use and engagement, including access to services and health worker attitudes. CONCLUSIONS: To be successful, programs seeking to expand access to and continued use of ART by integrating maternal health and HIV services must identify and address the relevant barriers and enablers in their own context that are described in this review. Further research on this population, including those who drop out of or never access health services, is needed to inform effective implementation