Performance and diarrhoea in piglets following weaning at seven weeks of age: Challenge with E. coli O 149 and effect of dietary factors

Four dietary factors (ad libitum versus feed restriction, control versus protein restriction at ad libitum feeding, control versus inclusion of lupine as a protein source at ad libitum feeding, and control versus extra vitamin E at ad libitum feeding) were tested in four separate experiments for the effect on diarrhoea. To introduce a diarrhoea-like condition, half of the piglets were challenged with an inoculation of an E. coli O 149 dose of 1 x 108 colony forming units on day two and three after weaning (day of weaning = day one). All piglets were susceptible since the dams were tested mono-zygotic susceptible to the attachment site of E. coli O 149 in the intestines. Each of the four experiments included 32 piglets from 4 sows. The design was 2 x 2 factorial with dietary factor and E. coli O 149 challenge as the two factors, each at two levels. The piglets were housed individually during the experiment which lasted for 10 days from weaning at 7 weeks of age. The daily recordings included feed intake, weight and faeces score (from 1 = firm and solid to 6 = yellow and watery). Faeces from days 2 to 5 were tested for E. coli strains. In addition, blood was sampled and serum was analysed for E. coli antibodies, IgG and IgM. Generally the E. coli challenge had no effect on growth and feed intake whereas faeces score and number of faeces haemolytic bacteria increased and faeces dry matter decreased. Feed restriction decreased the weight gain while faeces characteristics were unaffected. An analysis including all four experiments revealed that a feed intake of less than 200 g day one after weaning seems to be associated with a relatively high incidence of a post-weaning diarrhoea-like condition. Protein restriction decreased faeces score and increased faeces dry matter while weight gain tended to decrease. Inclusion of lupine affected neither weight gain nor faeces characteristics. Extra vitamin E did not affect weight gain while faeces dry matter decreased, and faeces score and number of faecal haemolytic bacteria increased. The dietary treatments had no effect on the immunological responses. In conclusion, the studied dietary factors could not alleviate a diarrhoea-like condition and at the same time maintain the growth rate. Furthermore, the results indicate that performance can be improved if piglets achieve a daily feed intake of at least 200 g from day one after weaning

Loss of the Actin Remodeler Eps8 Causes Intestinal Defects and Improved Metabolic Status in Mice

In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan. Here we show that knockout mice for Eps8, a regulator of actin dynamics, display reduced body weight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status. Alteration in the liver gene expression profile, in behavior and metabolism point to a calorie restriction-like phenotype in Eps8 knockout mice. Additionally, and consistent with a calorie restricted metabolism, Eps8 knockout mice show increased lifespan. The metabolic alterations in Eps8 knockout mice correlated with a significant reduction in intestinal fat absorption presumably caused by a 25% reduction in intestinal microvilli length. Our findings implicate actin dynamics as a novel variable in the determination of longevity. Additionally, our observations suggest that subtle differences in energy balance can, over time, significantly affect bodyweight and metabolic status in mice

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients

Soil-Improving Cropping Systems for Sustainable and Profitable Farming in Europe

Soils form the basis for agricultural production and other ecosystem services, and soil management should aim at improving their quality and resilience. Within the SoilCare project, the concept of soil-improving cropping systems (SICS) was developed as a holistic approach to facilitate the adoption of soil management that is sustainable and profitable. SICS selected with stakeholders were monitored and evaluated for environmental, sociocultural, and economic effects to determine profitability and sustainability. Monitoring results were upscaled to European level using modelling and Europe-wide data, and a mapping tool was developed to assist in selection of appropriate SICS across Europe. Furthermore, biophysical, sociocultural, economic, and policy reasons for (non)adoption were studied. Results at the plot/farm scale showed a small positive impact of SICS on environment and soil, no effect on sustainability, and small negative impacts on economic and sociocultural dimensions. Modelling showed that different SICS had different impacts across Europe-indicating the importance of understanding local dynamics in Europe-wide assessments. Work on adoption of SICS confirmed the role economic considerations play in the uptake of SICS, but also highlighted social factors such as trust. The project's results underlined the need for policies that support and enable a transition to more sustainable agricultural practices in a coherent way

Deficiency of the clock gene Bmal1 affects neural progenitor cell migration

We demonstrate the impact of a disrupted molecular clock in Bmal1-deficient (Bmal1−/−) mice on migration of neural progenitor cells (NPCs). Proliferation of NPCs in rostral migratory stream (RMS) was reduced in Bmal1−/− mice, consistent with our earlier studies on adult neurogenesis in hippocampus. However, a significantly higher number of NPCs from Bmal1−/− mice reached the olfactory bulb as compared to wild-type littermates (Bmal1+/+ mice), indicating a higher migration velocity in Bmal1−/− mice. In isolated NPCs from Bmal1−/− mice, not only migration velocity and expression pattern of genes involved in detoxification of reactive oxygen species were affected, but also RNA oxidation of catalase was increased and catalase protein levels were decreased. Bmal1+/+ migration phenotype could be restored by treatment with catalase, while treatment of NPCs from Bmal1+/+ mice with hydrogen peroxide mimicked Bmal1−/− migration phenotype. Thus, we conclude that Bmal1 deficiency affects NPC migration as a consequence of dysregulated detoxification of reactive oxygen species

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Belowground biomass response to nutrient enrichment depends on light limitation across globally distributed grasslands

Anthropogenic activities are increasing nutrient inputs to ecosystems worldwide, with consequences for global carbon and nutrient cycles. Recent meta-analyses show that aboveground primary production is often co-limited by multiple nutrients; however, little is known about how root production responds to changes in nutrient availability. At twenty-nine grassland sites on four continents, we quantified shallow root biomass responses to nitrogen (N), phosphorus (P) and potassium plus micronutrient enrichment and compared below- and aboveground responses. We hypothesized that optimal allocation theory would predict context dependence in root biomass responses to nutrient enrichment, given variation among sites in the resources limiting to plant growth (specifically light versus nutrients). Consistent with the predictions of optimal allocation theory, the proportion of total biomass belowground declined with N or P addition, due to increased biomass aboveground (for N and P) and decreased biomass belowground (N, particularly in sites with low canopy light penetration). Absolute root biomass increased with N addition where light was abundant at the soil surface, but declined in sites where the grassland canopy intercepted a large proportion of incoming light. These results demonstrate that belowground responses to changes in resource supply can differ strongly from aboveground responses, which could significantly modify predictions of future rates of nutrient cycling and carbon sequestration. Our results also highlight how optimal allocation theory developed for individual plants may help predict belowground biomass responses to nutrient enrichment at the ecosystem scale across wide climatic and environmental gradients

Consensus guidelines for lumbar puncture in patients with neurological diseases

Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S

Soil-Improving Cropping Systems for Sustainable and Profitable Farming in Europe

Soils form the basis for agricultural production and other ecosystem services, and soil management should aim at improving their quality and resilience. Within the SoilCare project, the concept of soil-improving cropping systems (SICS) was developed as a holistic approach to facilitate the adoption of soil management that is sustainable and profitable. SICS selected with stakeholders were monitored and evaluated for environmental, sociocultural, and economic effects to determine profitability and sustainability. Monitoring results were upscaled to European level using modelling and Europe-wide data, and a mapping tool was developed to assist in selection of appropriate SICS across Europe. Furthermore, biophysical, sociocultural, economic, and policy reasons for (non)adoption were studied. Results at the plot/farm scale showed a small positive impact of SICS on environment and soil, no effect on sustainability, and small negative impacts on economic and sociocultural dimensions. Modelling showed that different SICS had different impacts across Europe—indicating the importance of understanding local dynamics in Europe-wide assessments. Work on adoption of SICS confirmed the role economic considerations play in the uptake of SICS, but also highlighted social factors such as trust. The project’s results underlined the need for policies that support and enable a transition to more sustainable agricultural practices in a coherent way