Associations of Infant Nutrition with Insulin Resistance Measures in Early Adulthood: Evidence from the Barry-Caerphilly Growth (BCG) Study

Background: Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance. Objective: To assess the association of breast milk and quantity of infant formula and cows ’ milk intake during infancy with insulin resistance measures in early adulthood. Design: Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows ’ milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30). Results: 573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows ’ milk feeding or of increasing quartiles of formula/cows’ milk consumption during infancy (,3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows ’ milk feeding at 3 months were: fasting glucose (20.07 mmol/l; 95 % CI: 20.19, 0.05); fasting insulin (8.0%; 28.7, 27.6); ISI0 (26.1%; 211.3, 12.1) and CIR30 (3.8%; 219.0, 32.8). There was also little evidence that increasing intakes of formula/cows ’ milk at 3 months were associated with fastin

Spatial co‐localisation of extreme weather events: a clear and present danger

Extreme weather events have become a dominant feature of the narrative surrounding changes in global climate with large impacts on ecosystem stability, functioning and resilience; however, understanding of their risk of co‐occurrence at the regional scale is lacking. Based on the UK Met Office’s long‐term temperature and rainfall records, we present the first evidence demonstrating significant increases in the magnitude, direction of change and spatial co‐localisation of extreme weather events since 1961. Combining this new understanding with land‐use data sets allowed us to assess the likely consequences on future agricultural production and conservation priority areas. All land‐uses are impacted by the increasing risk of at least one extreme event and conservation areas were identified as the hotspots of risk for the co‐occurrence of multiple event types. Our findings provide a basis to regionally guide land‐use optimisation, land management practices and regulatory actions preserving ecosystem services against multiple climate threats

Resilience of ecosystem service delivery in grasslands in response to single and compound extreme weather events

Extreme weather events are increasing in frequency and magnitude with profound effects on ecosystem functioning. Further, there is now a greater likelihood that multiple extreme events are occurring within a single year. Here we investigated the effect of a single drought, flood or compound (flood + drought) extreme event on temperate grassland ecosystem processes in a field experiment. To assess system resistance and resilience, we studied changes in a wide range of above- and below-ground indicators (plant diversity and productivity, greenhouse gas emissions, soil chemical, physical and biological metrics) during the 8 week stress events and then for 2 years post-stress. We hypothesized that agricultural grasslands would have different degrees of resistance and resilience to flood and drought stress. We also investigated two alternative hypotheses that the combined flood + drought treatment would either, (A) promote ecosystem resilience through more rapid recovery of soil moisture conditions or (B) exacerbate the impact of the single flood or drought event. Our results showed that flooding had a much greater effect than drought on ecosystem processes and that the grassland was more resistant and resilient to drought than to flood. The immediate impact of flooding on all indicators was negative, especially for those related to production, and climate and water regulation. Flooding stress caused pronounced and persistent shifts in soil microbial and plant communities with large implications for nutrient cycling and long-term ecosystem function. The compound flood + drought treatment failed to show a more severe impact than the single extreme events. Rather, there was an indication of quicker recovery of soil and microbial parameters suggesting greater resilience in line with hypothesis (A). This study clearly reveals that contrasting extreme weather events differentially affect grassland ecosystem function but that concurrent events of a contrasting nature may promote ecosystem resilience to future stress

Causal inference for heritable phenotypic risk factors using heterogeneous genetic instruments.

Over a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that "all genes affect every complex trait" complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and potential pleiotropic pathways involved

Impacts of abiotic stresses on the physiology and metabolism of cool-season grasses:A review

Grasslands cover more than 70% of the world's agricultural land playing a pivotal role in global food security, economy, and ecology due to their flexibility and functionality. Climate change, characterized by changes in temperature and precipitation patterns, and by increased levels of greenhouse gases in the atmosphere, is anticipated to increase both the frequency and severity of extreme weather events, such as drought, heat waves, and flooding. Potentially, climate change could severely compromise future forage crop production and should be considered a direct threat to food security. This review aimed to summarize our current understanding of the physiological and metabolic responses of temperate grasses to those abiotic stresses associated with climate change. Primarily, substantial decreases in photosynthetic rates of cool‐season grasses occur as a result of high temperatures, water‐deficit or water‐excess, and elevated ozone, but not CO2 concentrations. Those decreases are usually attributed to stomatal and non‐stomatal limitations. Additionally, while membrane instability and reactive oxygen species production was a common feature of the abiotic stress response, total antioxidant capacity showed a stress‐specific response. Furthermore, climate change‐related stresses altered carbohydrate partitioning, with implications for biomass production. While water‐deficit stress, increased CO2, and ozone concentrations resulted in higher carbohydrate content, the opposite occurred under conditions of heat stress and flooding. The extent of damage is greatly dependent on location, as well as the type and intensity of stress. Fortunately, temperate forage grass species are highly heterogeneous. Consequently, through intra‐ and in particular inter‐specific plant hybridization (e.g., Festuca x Lolium hybrids) new opportunities are available to harness, within single genotypes, gene combinations capable of combating climate change

Empirically driven transdiagnostic stages in the development of mood, anxiety and psychotic symptoms in a cohort of youth followed from birth

Staging models with transdiagnostic validity across mood, psychotic, and anxiety disorders could advance early intervention efforts as well as our understanding of the common underpinnings of such psychopathology. However, there are few well-supported operationalisations for such transdiagnostic models, particularly in community-based samples. We aimed to explore the inter-relationships among mood, psychotic, and anxiety symptom stages, and their common risk factors to develop data-informed transdiagnostic stages. We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective ongoing birth cohort study. We developed operational thresholds for stages of depressive, hypomanic, anxiety, and psychotic symptoms based on the existing literature, refined further by expert consensus. We selected 1b level as the primary stage or outcome of interest. This represents moderate symptoms that are likely to be associated with the onset of the need for clinical mental health care. We used questionnaire and clinic data completed by young people ages 18 and 21 years. We used descriptive methods and network analyses to examine the overlap among Stage 1b psychopathology. We then examined the patterns of relationships between several risk factors and 1b stages using logistic regressions. Among 3269 young people with data available to determine all symptom stages, 64.3% were female and 96% Caucasian. Descriptive and network analyses indicated that 1b level depressive, anxiety, and psychotic symptom stages were inter-related while hypomania was not. Similarly, anxiety, depressive, and psychotic 1b stages were associated with the female sex, more emotional and behavioral difficulties in early adolescence, and life events in late adolescence. Hypomania was not related to any of these risk factors. Given their inter-relationships and similar risk factors, anxiety, psychotic and depressive, symptoms could be combined to form a transdiagnostic stage in this cohort. Such empirical transdiagnostic stages could help with prognostication and indicated prevention in youth mental health

Breeding progress and preparedness for mass‐scale deployment of perennial lignocellulosic biomass crops switchgrass, miscanthus, willow and poplar

UK: The UK‐led miscanthus research and breeding was mainly supported by the Biotechnology and Biological Sciences Research Council (BBSRC), Department for Environment, Food and Rural Affairs (Defra), the BBSRC CSP strategic funding grant BB/CSP1730/1, Innovate UK/BBSRC “MUST” BB/N016149/1, CERES Inc. and Terravesta Ltd. through the GIANT‐LINK project (LK0863). Genomic selection and genomewide association study activities were supported by BBSRC grant BB/K01711X/1, the BBSRC strategic programme grant on Energy Grasses & Bio‐refining BBS/E/W/10963A01. The UK‐led willow R&D work reported here was supported by BBSRC (BBS/E/C/00005199, BBS/E/C/00005201, BB/G016216/1, BB/E006833/1, BB/G00580X/1 and BBS/E/C/000I0410), Defra (NF0424) and the Department of Trade and Industry (DTI) (B/W6/00599/00/00). IT: The Brain Gain Program (Rientro dei cervelli) of the Italian Ministry of Education, University, and Research supports Antoine Harfouche. US: Contributions by Gerald Tuskan to this manuscript were supported by the Center for Bioenergy Innovation, a US Department of Energy Bioenergy Research Center supported by the Office of Biological and Environmental Research in the DOE Office of Science, under contract number DE‐AC05‐00OR22725. Willow breeding efforts at Cornell University have been supported by grants from the US Department of Agriculture National Institute of Food and Agriculture. Contributions by the University of Illinois were supported primarily by the DOE Office of Science; Office of Biological and Environmental Research (BER); grant nos. DE‐SC0006634, DE‐SC0012379 and DE‐SC0018420 (Center for Advanced Bioenergy and Bioproducts Innovation); and the Energy Biosciences Institute. EU: We would like to further acknowledge contributions from the EU projects “OPTIMISC” FP7‐289159 on miscanthus and “WATBIO” FP7‐311929 on poplar and miscanthus as well as “GRACE” H2020‐EU.3.2.6. Bio‐based Industries Joint Technology Initiative (BBI‐JTI) Project ID 745012 on miscanthus.Peer reviewedPostprintPublisher PD

A rare mutation in SMAD9 associated with high bone mass identifies the SMAD-dependent BMP signalling pathway as a potential anabolic target for osteoporosis

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (P-GWAS = 6 x 10(-16); P-GENE = 8 x 10(-17)). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. (c) 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

Canine Brachycephaly is Associated with a Retrotransposon-Mediated Missplicing of SMOC2

In morphological terms, “form” is used to describe an object’s shape and size. In dogs, facial form is stunningly diverse. Facial retrusion, the proximodistal shortening of the snout and widening of the hard palate is common to brachycephalic dogs and is a welfare concern, as the incidence of respiratory distress and ocular trauma observed in this class of dogs is highly correlated with their skull form. Progress to identify the molecular underpinnings of facial retrusion is limited to association of a missense mutation in BMP3 among small brachycephalic dogs. Here, we used morphometrics of skull isosurfaces derived from 374 pedigree and mixed-breed dogs to dissect the genetics of skull form. Through deconvolution of facial forms, we identified quantitative trait loci that are responsible for canine facial shapes and sizes. Our novel insights include recognition that the FGF4 retrogene insertion, previously associated with appendicular chondrodysplasia, also reduces neurocranium size. Focusing on facial shape, we resolved a quantitative trait locus on canine chromosome 1 to a 188-kb critical interval that encompasses SMOC2. An intronic, transposable element within SMOC2 promotes the utilization of cryptic splice sites, causing its incorporation into transcripts, and drastically reduces SMOC2 gene expression in brachycephalic dogs. SMOC2 disruption affects the facial skeleton in a dose-dependent manner. The size effects of the associated SMOC2 haplotype are profound, accounting for 36% of facial length variation in the dogs we tested. Our data bring new focus to SMOC2 by highlighting its clinical implications in both human and veterinary medicine