Effect of phytase on intestinal phytate breakdown, plasma inositol concentrations and glucose transporter type 4 abundance in muscle membranes of weanling pigs

The objective of this current study was to determine the effects of phytase dosing on growth performance, mineral digestibility, phytate breakdown and the level of glucose transporter type 4 (GLUT4) in muscle plasma membranes of weanling pigs. A total of 160 barrows were used in a randomized completely block design and assigned to four treatments for a 7-week study. Depending on the feeding phase, diets differed in dietary calcium (Ca) and phosphorus (P) levels (PC:8 to 6.8g/kg Ca; 7.3 to 6.3 g/kg P; negative control (NC):5.5 to 5.2 g/kg Ca; 5.4 to 4.7 g/kg P). NC diets were supplemented with phytase at 0 (NC); 500 (NC+500 FTU) or 2000 FTU/kg (NC+2000 FTU) phytase units/kg. Blood was collected after fasting (d 48) or feeding (d 49) for measurement of plasma inositol concentrations. On d 49, two pigs per pen were euthanized, duodenal and ileal digesta samples were collected to determine inositol phosphates (InsP6-2) concentrations. High phytase supplementation increased body weight (BW) on d 21, 35 and 49 (P <0.05). Over the entire feeding period, average daily gain (ADG), average daily feed intake (ADFI) and feed efficiency were increased by NC+2000 FTU compared to the other treatments (P <0.05). Postprandial plasma inositol concentration was increased in NC+2000 (P < 0.01), but there was only a tendency (P = 0.06) of a higher fasting plasma inositol concentration in this group. Inositol concentrations in the portal vein plasma (d 49) were not different among treatments. Duodenal digesta InsP5 and InsP6 concentrations were similar in PC and NC, but higher in these two treatments (P < 0.05) than those supplemented with phytase. Phytase supplementation decreased InsP6-4, resulting in increased InsP3-2 and myo-inositol concentrations. Similar effects were found in ileal contents. Compared to NC, phytase supplementation resulted in greater cumulative InsP6-2 disappearance (93.6% vs. 72.8% vs. 25.0%, for NC+2000 FTU, NC +500 FTU and NC, respectively, P < 0.01) till the the distal ileum. Longissimus dorsi muscle plasma membrane GLUT4 concentration was increased by NC+2000 FTU (P < 0.01) compared to NC. In summary, high phytase supplementation increased growth performance of nursery pigs. The higher myo-inositol release from phytate could contribute to the increased expression of GLUT4 in muscle plasma membranes. Further investigation is needed to determine if this is associated with enhanced cellular glucose uptake and utilization

Joining the dots Global Challenges and the Valuing Nature Agenda

The Valuing Nature Network aims to improve understanding of the value of nature in both economic and non-economic terms, and improve the use of these valuations in decision making. It funds interdisciplinary research and builds links between researchers and people who make decisions that affect nature in business, policy-making, and in practice. The Global Challenges Research Fund aims to support research that directly contributes to the sustainable development and welfare of people in developing countries. • A review of the United Nations Sustainable Development Goals (see Annex I) and their targets revealed a number of themes that have links to the Valuing Nature Network research agenda, specifically: the governance of natural resources; conservation of natural capital and sustainable use of ecosystems; environmentally, socially and economically sustainable agro-forestry systems; and knowledge exchange at the science-policy interface. Assessing the extent and depth of existing research in these areas, and identifying networks of current research collaboration, can enable the identification of key opportunities for advancing research into the natural environment that also seeks to address the challenges associated with international development

Effect of phytase supplementation on plasma and organ myo-inositol content and erythrocyte inositol phosphates in chickens

‘Woody breast’ (WB) and ‘white striping’ in broiler meat is a global problem. With unknown etiology, WB negatively impacts bird health, welfare and is a significant economic burden to the poultry industry. New evidence has shown that WB is associated with dysregulation in systemic and breast muscle-oxygen homeostasis, resulting in hypoxia and anaemia. However, it has been observed that phytase (Quantum Blue (QB) a modified, E. coli-derived 6-phytase) super dosing can reverse dysregulation of muscle-oxygen homeostasis and reduces WB severity by ~5%. The objective of this study was to assess whether levels of Ins(1,3,4,5,6)P5, the main allosteric regulator of haemoglobin, are influenced by changes in plasma myo-inositol arising from super dosing with phytase. To enable this, methods suitable for measurement of myo-inositol in tissues and inositol phosphates in blood were developed. Data were collected from independent trials, including male Ross 308 broilers fed low and adequate calcium/available phosphate (Ca/AvP) diets supplemented with QB at 1,500 phytase units (FTU)/kg, which simultaneously decreased gizzard InsP6 (P<0.001) and increased gizzard myo-inositol (P<0.001). Similarly, male Cobb 500 broiler chicks fed a negative control (NC) diet deficient in AvP, Ca and sodium or diet supplemented with the QB phytase at 500, 1000 or 2,000 FTU/kg increased plasma (P<0.001) and liver (P=0.007) myo-inositol of 18d-old birds at 2,000 FTU/kg. Finally, QB supplementation of Cobb 500 breeder flock diet at 1,250 FTU/kg increased blood myo-inositol (P<0.001) and erythrocyte Ins(1,3,4,5,6)P5 (P=0.011) of their 1d-old hatchlings. These data confirmed the ability of phytase to modulate inositol phosphate pathways by provision of metabolic precursors of important signalling molecules. The ameliorations of WB afforded by super doses of phytase may include modulation of hypoxia pathways that also involve inositol signalling molecules. Elevations of erythrocyte Ins(1,3,4,5,6)P5 by phytase supplementation may enhance systemic oxygen carrying capacity, an important factor in the amelioration of WB and WS myopathy

Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC) : a pragmatic, cluster randomised controlled trial

BACKGROUND: Mechanical chest compression devices have the potential to help maintain high-quality cardiopulmonary resuscitation (CPR), but despite their increasing use, little evidence exists for their effectiveness. We aimed to study whether the introduction of LUCAS-2 mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest. METHODS: The pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial was a pragmatic, cluster-randomised open-label trial including adults with non-traumatic, out-of-hospital cardiac arrest from four UK Ambulance Services (West Midlands, North East England, Wales, South Central). 91 urban and semi-urban ambulance stations were selected for participation. Clusters were ambulance service vehicles, which were randomly assigned (1:2) to LUCAS-2 or manual CPR. Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. The primary outcome was survival at 30 days following cardiac arrest and was analysed by intention to treat. Ambulance dispatch staff and those collecting the primary outcome were masked to treatment allocation. Masking of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. The study is registered with Current Controlled Trials, number ISRCTN08233942. FINDINGS: We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 group, 2819 assigned to the control group) between April 15, 2010 and June 10, 2013. 985 (60%) patients in the LUCAS-2 group received mechanical chest compression, and 11 (<1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30 day survival was similar in the LUCAS-2 group (104 [6%] of 1652 patients) and in the manual CPR group (193 [7%] of 2819 patients; adjusted odds ratio [OR] 0·86, 95% CI 0·64-1·15). No serious adverse events were noted. Seven clinical adverse events were reported in the LUCAS-2 group (three patients with chest bruising, two with chest lacerations, and two with blood in mouth). 15 device incidents occurred during operational use. No adverse or serious adverse events were reported in the manual group. INTERPRETATION: We noted no evidence of improvement in 30 day survival with LUCAS-2 compared with manual compressions. On the basis of ours and other recent randomised trials, widespread adoption of mechanical CPR devices for routine use does not improve survival

Global analysis of gene expression in NGF-deprived sympathetic neurons identifies molecular pathways associated with cell death

Developing sympathetic neurons depend on nerve growth factor (NGF) for survival and die by apoptosis after NGF withdrawal. This process requires de novo gene expression but only a small number of genes induced by NGF deprivation have been identified so far, either by a candidate gene approach or in mRNA differential display experiments. This is partly because it is difficult to obtain large numbers of sympathetic neurons for in vitro studies. Here, we describe for the first time, how advances in gene microarray technology have allowed us to investigate the expression of all known genes in sympathetic neurons cultured in the presence and absence of NGF

Pre-hospital assessment of the role of adrenaline : measuring the effectiveness of drug administration in cardiac arrest (PARAMEDIC-2) : trial protocol

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest. This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant. 8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes). Trial registration (ISRCTN73485024)

Taxonomy of the order Bunyavirales : second update 2018

In October 2018, the order Bunyavirales was amended by inclusion of the family Arenaviridae, abolishment of three families, creation of three new families, 19 new genera, and 14 new species, and renaming of three genera and 22 species. This article presents the updated taxonomy of the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).Non peer reviewe

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD