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INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

Background Employment is important for physical and mental health and self-esteem and provides financial independence. However, little is known on the prognostic value of employment status prior to admission with acute myocardial infarction (MI). Methods and results Using Danish nationwide registries, all patients between 18 and 60 years with a first-time MI admission (2010–2018) and alive at discharge were included. Rates of all-cause mortality and recurrent MI according to workforce attachment at the time of the event was compared using multivariable Cox regression. Of the 16 060 patients included in the study, 3520 (21.9%) patients were not part of the workforce. Patients who were not part of the workforce were older (52 vs. 51 years), less often men (63% vs. 77%), less likely to have higher education, more often living alone (47% vs. 29%), and more often had comorbidities, including heart failure, atrial fibrillation, hypertension, diabetes, chronic kidney disease, and chronic obstructive pulmonary disease. The absolute 5-year risk of death was 3.3% and 12.8% in the workforce and non-workforce group, respectively. The corresponding rates of recurrent MI were 7.5% and 10.9%, respectively. In adjusted analyses, not being part of the workforce was associated with a significantly higher rate of all-cause mortality [HR: 2.39 (95% CI: 2.01–2.83)] and recurrent MI [1.36 (1.18–1.57)]. Conclusion Among patients of working age who were admitted with MI and alive at discharge, not being part of the workforce was associated with a higher long-term rate of all-cause mortality and recurrent MI.

Objectives Peritoneal dissemination from intraabdominal cancers is associated with poor prognosis and rapid disease progression. Hyperthermic intraperitoneal chemotherapy (HIPEC) is an antineoplastic treatment, which has improved survival and recurrence-free survival, but little is known about the acquired chemotherapy concentrations in local tissues. The aim of this study was to assess concentrations of carboplatin during and after HIPEC treatment dynamically and simultaneously in various abdominal organ tissues by means of microdialysis in a novel porcine model. Methods Eight pigs underwent imitation cytoreductive surgery followed by HIPEC (90 min) using a carboplatin dosage of 800 mg/m2. Microdialysis catheters were placed for sampling of drug concentrations in various solid tissues: peritoneum, liver, bladder wall, mesentery and in different depths of one mm and four mm in the hepatoduodenal ligament and rectum. During and after HIPEC, dialysates and blood samples were collected over 8 h. Results No statistically significant differences in mean AUC0-last (range: 2,657–5,176 min·µg/mL), mean Cmax (range: 10.6–26.0 µg/mL) and mean Tmax (range: 105–206 min) were found between the compartments. In plasma there was a tendency towards lower measures. No difference between compartments was found for tissue penetration. At the last samples obtained (450 min) the mean carboplatin concentrations were 4.9–9.9 µg/mL across the investigated solid tissues. Conclusions Equal carboplatin distribution in abdominal organ tissues, detectable concentrations for at least 6 h after HIPEC completion, and a carboplatin penetration depth of minimum four mm were found. The present study proposes a new HIPEC porcine model for future research.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark.MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers.RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

ADGRL1/latrophilin-1, a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe 10 individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all featuring heterozygous variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities while homozygous mice were non-viable. On a permissive background, the null allele also appeared at sub-Mendelian frequency, but many Adgrl1 null mice survived the gestation and reached adulthood. The Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological and behavioral abnormalities in mice and humans.

Small landholders who grow sweet maize for the fresh produce market often also have cattle with little access to winter forage. Grazing cover crops with sweet maize stover can potentially increase the available nutritive value. A 3-year randomized complete block study with three replicates at New Mexico State University’s Alcalde Sustainable Agriculture Science Center compared sweet maize (Zea mays var. rugosa) with sweet maize relay intercropped at the V7–9 stage with cereal rye (rye: Secale cereale L.) or hairy vetch (vetch: Vicia villosa Roth) for early spring grazing. Intercropping the rye or hairy vetch into sweet maize did not influence the sweet maize stover biomass yield or nutritive value after the winter. The dry matter (DM) yield and crude protein (CP) concentration of hairy vetch biomass was greater (p < 0.01) than rye biomass (1.46 vs. 2.94 Mg DM ha−1 for rye and hairy vetch, respectively, and 145 vs. 193 g CP kg−1 for rye and hairy vetch, respectively). Average daily gains by yearling cattle were not different when grazing maize–rye or maize–vetch. Producers should consider the spring planting timing of the primary crop and the initiation of grazing in the winter or the spring to maximize the utilization of the previous crop’s residue (stover), as well as the cover crop itself.

Background Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal. Methods We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting. Results We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging differential transcriptional profiling, bupivacaine phenocopied genetic targeting of PFKM, and enhanced efficacy of bevacizumab in preclinical GBM models in vivo. Conclusion PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.

Traditionally, biogeography has described the distribution of species. But as plant functional traits and functional diversity underpin ecosystem dynamics, understanding drivers of functional diversity at biogeographical scales is essential to understand spatial variation in ecosystem characteristics, particularly in light of ongoing environmental changes. Here we investigate geographic patterns of functional diversity and -traits of the Norwegian flora. We explore whether climate, land-use or glacial history are important drivers of functional diversity. We combine species occurrence records and assemblage-means of functional traits to assess the spatial distribution of functional traits and -diversity of native vascular plants in Norway in a 20 × 20 km grid. We use multiple-model inference to identify which environmental factors contribute the most in explaining the spatial patterns of trait distributions and functional diversity. Additionally, we use the constructed models to predict potential changes in distributions of traits and functional diversity given different climate change scenarios. Both individual traits and functional diversity display clear geographic patterns, predictable by climate, landscape and glacial history. Traits related to plant size and growth peak in warmer areas and are predicted to increase in the future, as is functional richness and dispersion. In contrast, functional evenness peaks in northern regions and is predicted to decrease in the future. The different environmental drivers vary in degree of importance, effect sizes and -directions on the assemblage-averaged functional traits and -diversity. This underlines the importance of multiple drivers in determining plant assemblage functionality. In the face of climate- and land-use change, Norway is expected to become warmer, wetter and experience a substantial increase in anthropogenic land-uses, such as increased urbanisation. In turn, the functional composition of the Norwegian flora is predicted to shift towards tall, woody, fast-growing species.

BACKGROUND: Fluid treatment in sepsis is a challenge and clinical equipoise exists regarding intravenous volumes. We aimed to determine if a 24-hour protocol restricting intravenous (IV) fluid was feasible in adult patients with sepsis without shock presenting to the emergency department (ED).METHODS: The REFACED Sepsis trial is an investigator-initiated, multicenter, randomized, open-label, feasibility trial, assigning sepsis patients without shock to 24 hours of restrictive IV fluid administration or standard care. In the IV fluid restriction group fluid boluses were only permitted if pre-defined criteria for hypoperfusion occurred. Standard care was at the discretion of the treating team. The primary outcome was total IV crystalloid fluid volumes at 24 hours after randomization. Secondary outcomes included total fluid volumes, feasibility measures, and patient-centered outcomes.RESULTS: We included 123 patients (restrictive: 61 patients and standard care: 62 patients) in the primary analysis. 32% (95% confidence interval (CI) 28% to 37%) of eligible patients meeting all inclusion criteria and no exclusion criteria were included. At 24-hours, the mean IV crystalloid fluid volumes were 562 ml (standard deviation (SD): 1076) vs. 1370 ml (SD: 1438) in the restrictive vs. standard care group (mean difference -801 ml (95% CI: -1257 to -345), p = 0.001). Protocol violations occurred in 21 (34%) patients in the fluid restrictive group. There were no differences between groups in adverse events, use of mechanical ventilation or vasopressors, acute kidney failure, length of stay, or mortality.CONCLUSIONS: A protocol restricting IV crystalloid fluids in emergency department patients with sepsis reduced 24-hour fluid volumes compared to standard care. A future trial powered towards patient-centered outcomes appears feasible.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Climate change has dramatic impacts on ecological systems, affecting a range of ecological factors including phenology, species abundance, diversity, and distribution. The breadth of climate change impacts on ecological systems leads to the occurrence of fingerprints of climate change. However, climate fingerprints are usually identified across broad geographical scales and are potentially influenced by publication biases. In this study, we used natural history collections spanning over 250 years, to quantify a range of ecological responses to climate change, including phenology, abundance, diversity, and distributions, across a range of taxa, including vertebrates, invertebrates, plants, and fungi, within a single region, Central Norway. We tested the hypotheses that ecological responses to climate change are apparent and coherent at a regional scale, that longer time series show stronger trends over time and in relation to temperature, and that ecological responses change in trajectory at the same time as shifts in temperature. We identified a clear regional coherence in climate signal, with decreasing abundances of limnic zooplankton (on average by 7691 individuals m−3 °C−1) and boreal forest breeding birds (on average by 1.94 territories km−2 °C−1), and earlier plant flowering phenology (on average 2 days °C−1) for every degree of temperature increase. In contrast, regional-scale species distributions and species diversity were largely stable. Surprisingly, the effect size of ecological response did not increase with study duration, and shifts in responses did not occur at the same time as shifts in temperature. This may be as the long-term studies include both periods of warming and temperature stability, and that ecological responses lag behind warming. Our findings demonstrate a regional climate fingerprint across a long timescale. We contend that natural history collections provide a unique window on a broad spectrum of ecological responses at timescales beyond most ecological monitoring programs. Natural history collections are thus an essential source for long-term ecological research.

STUDY QUESTION Are transfer day, developmental stage and morphology of the competent blastocyst in pregnancies leading to live birth associated with preterm birth, birthweight, length at birth and sex of the child? SUMMARY ANSWER A high score in blastocyst developmental stage and in trophectoderm (TE) showed a significant association with the sex of the child, while no other associations with obstetric outcomes were observed. WHAT IS KNOWN ALREADY The association between blastocyst assessment scores and obstetric outcomes have been reported in small single-center studies and the results are conflicting. STUDY DESIGN, SIZE, DURATION Multicenter historical cohort study based on exposure data (transfer day (blastocyst developmental stage reached by Day 5 or Day 6)) blastocyst developmental stage (1–6) and morphology (TE and inner cell mass (ICM): A, B, C)) and outcome data (preterm birth, birthweight, length at birth, and sex of the child) from women undergoing single blastocyst transfer resulting in a singleton pregnancy and live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS Data from 16 private and university-based facilities for clinical services and research were used. A total of 7246 women, who in 2014–2018 underwent fresh-embryo transfer with a single blastocyst or frozen-thawed embryo transfer (FET) with a single blastocyst resulting in a singleton pregnancy were identified. Linking to the Danish Medical Birth Registry resulted in a total of 4842 women with a live birth being included. Cycles with pre-implantation genetic testing and donated gametes were excluded. The analyses were adjusted for female age (n = 4842), female BMI (n = 4302), female smoking (n = 4290), parity (n = 4365), infertility diagnosis (n = 4765), type of treatment (n = 4842) and center (n = 4842); some analyses additionally included gestational age (n = 4368) and sex of the child (n = 4833). MAIN RESULTS AND THE ROLE OF CHANCE No statistically significant associations between blastocyst assessment scores (transfer day, developmental stage, TE, ICM) and preterm birth (8.3%) or birthweight (mean 3461.7 g) were found. The adjusted association between blastocysts with a TE score of C and a TE score of A and length at birth (mean 51.6 cm) were statistically significant (adjusted mean difference 0.4 cm (95% CI: 0.02; 0.77)). Blastocysts transferred with developmental stage score 5 compared to blastocysts transferred with score 3 had a 34% increased probability of being a boy (odds ratio (OR) 1.34 (95% CI: 1.09; 1.64). Further, TE score B blastocysts compared to TE score A blastocysts had a 31% reduced probability of being a boy (OR 0.69 (95% CI: 0.60; 0.80)). LIMITATIONS, REASONS FOR CAUTION It is possible that some residual confounding remains. WIDER IMPLICATIONS OF THE FINDINGS Blastocyst selection during ART does not appear to introduce any negative effects on obstetric outcome. Therefore, clinicians and patients can be reassured that the assessment scores of the selected blastocyst will not in themselves pose a risk of preterm birth or affect birthweight and the length at birth. STUDY FUNDING/COMPETING INTEREST(S) Unrestricted grant from Gedeon Richter Nordics AB, Sweden. None of the authors have any competing interest to declare. TRIAL REGISTRATION NUMBER N/A.

Central sensitisation is assumed to be one of the underlying mechanisms for chronic low back pain. Because central sensitisation is not directly assessable in humans, the term ‘human assumed central sensitisation’ (HACS) is suggested. The objectives were to investigate what definitions for HACS have been used, to evaluate the methods to assess HACS, to assess the validity of those methods, and to estimate the prevalence of HACS. Database search resulted in 34 included studies. Forty different definition references were used to define HACS. This review uncovered twenty quantitative methods to assess HACS, including four questionnaires and sixteen quantitative sensory testing measures. The prevalence of HACS in patients with chronic low back pain was estimated in three studies. The current systematic review highlights that multiple definitions, assessment methods, and prevalence estimates are stated in the literature regarding HACS in patients with chronic low back pain. Most of the assessment methods of HACS are not validated but have been tested for reliability and repeatability. Given the lack of a gold standard to assess HACS, an initial grading system is proposed to standardize clinical and research assessments of HACS in patients with a chronic low back.

We present a typology of ‘Stayers’ and ‘Leavers’ among rural island youth (aged 18-30) to illustrate their employment-education-location decision, based on semi-structured interviews with 30 young adults, and 81 older adults, in rural locations in Ireland, Newfoundland, Faroe Islands, and Shetland. Although there are exceptions, rural labour markets tend to be less diverse, and jobs in the primary sector, which have historically sustained these communities, face restructuring and decline in many places. Regardless of location, young people typically struggle to find good-quality work because of their relative lack of credentials and/or experience, and a shortage of local options can trap some, and force others to look ‘away’. Outmigration decisions are based on economics, but also social and emotional factors. Thus, even in places with low unemployment, young adults must consider where to live, and what to do next, and down the road. The reviewed literature suggests that there are commonalities among the choices typically facing those in rural and remote communities, whether on an island or on a mainland. We believe, though, that this dilemma can be exacerbated for those living on islands because of the logistical and psychological complexity of the ‘stay or leave’ decision. Rather than presenting detailed summaries from the young islanders whom we interviewed, our intended contribution is to present our typology as a way to spur on research towards specific policy remedies. The challenges facing any young rural islander can be complicated and individualized. Nonetheless, after conducting dozens of interviews in many island communities, some clear patterns of Stayers and Leavers emerged across the various jurisdictions. In turn, we argue for the development of social and economic policies tailored to suit each category of rural island youth.

The Agricultural Research Service (ARS) Beef Grand Challenge is a cooperative, multidisciplinary effort evaluating differences in performance of genetic lines across production environments representative of different geographical regions. Weaned spring-born calves (n = 120 per location), representing natural service matings to Angus, Hereford, Simmental, Charolais, or indicus-composite (Beefmaster or Brangus) bulls from the U.S. Meat Animal Research Center Germplasm Evaluation program in south central Nebraska, are sent to wheat pasture (central Oklahoma) and winter range (eastern Montana), and weaned fall-born calves (n=40 per location) are sent to summer grazing on shortgrass prairie (northeastern Colorado) and southern mixed-grass rangeland (western Oklahoma). All cattle are fed a finishing ration representative of the region that approximately matches energy content across locations. Each calving season has a matching counterpart of calves that remain in Nebraska on a calf-fed drylot program (receiving ration followed by longer finishing ration). Breeds and sires are represented equally, to the extent possible, at each location. To detect differences in breed effects at each location and average over yearly variation, the study is being replicated for 4 years. Weights, stress measures, carcass composition (marbling, yield grade, quality grade, etc.), steak tenderness and steak fatty acid composition are collected from each location. Additionally, rumen metagenomic composition, metagenomic samples, preharvest food safety samples, and feed intake measures are collected at some locations. Grazing impacts and supplemental range feeding are also being evaluated. One year of sampling has been completed, with numeric differences observed for marbling and tenderness as well as growth performance among locations. Statistical differences will be evaluated when replicate years are collected. The USDA is an equal opportunity provider and employer.

Introduction: Chronic inflammation plays a critical role in lymphomagenesis and several dietary factors seem to be involved its regulation. The aim of the current study was to assess the association between the inflammatory potential of the diet and the risk of lymphoma and its subtypes in the European Investigation into Cancer and Nutrition (EPIC) study. Methods: The analysis included 476,160 subjects with an average follow-up of 13.9 years, during which 3,136 lymphomas (135 Hodgkin lymphoma (HL), 2606 non-Hodgkin lymphoma (NHL) and 395 NOS) were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory weights. The association between the ISD and lymphoma risk was estimated by hazard ratios (HR) and 95% confidence intervals (CI) calculated by multivariable Cox regression models adjusted for potential confounders. Results: The ISD was not associated with overall lymphoma risk. Among lymphoma subtypes, a positive association between the ISD and mature B-cell NHL (HR for a 1-SD increase: 1.07 (95% CI 1.01; 1.14), p trend = 0.03) was observed. No statistically significant association was found among other subtypes. However, albeit with smaller number of cases, a suggestive association was observed for HL (HR for a 1-SD increase = 1.22 (95% CI 0.94; 1.57), p trend 0.13). Conclusions: Our findings suggested that a high ISD score, reflecting a pro-inflammatory diet, was modestly positively associated with the risk of B-cell lymphoma subtypes. Further large prospective studies on low-grade inflammation induced by diet are warranted to confirm these findings. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Development and long-term retention of replacement beef females in a semi-arid environment are of a major concern for extensive livestock producers. Furthermore, the demand of not only producing a thriving, healthy calf, but having sufficient milk to support that first calf is essential. To address this issue, we conducted a 3-year study measuring milk production and milk constituent yields in primiparous beef heifers (n=48; 16/year reared under two different feeding regimens) raising steer calves. Cows received 1.8 or 1.2 kg/day winter supplementation for ~80 day before parturition and their heifer calves were then randomly assigned to heifer development treatments that provided ad libitum (AL) or 80% (less than ad libitum (LAL)) of ad libitum feed post weaning. Heifers developed on the AL treatment also received 1.8 kg/day winter supplementation for life, whereas heifers developed on the LAL treatment received 1.2 kg/day winter supplementation for life. Milk production of primiparous cows was measured with a portable milking machine every other week from days 27 to 125 postpartum. Milk yield for the 125-day lactation period was calculated from area under the lactation curve approximated by trapezoidal summation. The ANOVA model included in utero winter nutrition, post-weaning heifer development treatment, year and their interaction. Heifers subjected to the AL treatment reached peak milk yield ~12.3 day later (P=0.02) than heifers receiving LAL treatment. In addition, an in utero nutrition×post-weaning heifer treatment×year interaction existed (P⩽0.04) for milk peak yield, average daily milk yield (kg/day) and nutrient composition (protein, lactose, fat, solids non-fat, g/day). These interactions manifest as changes in magnitude and rank across the 3 years of the study. Livestock production in extensive environments is subject to variations in seasonal precipitation patterns and quality and quantity of grazeable forage and these fluctuations have a large impact on milk yield. In summary, the gestational nutritional environment of a heifer's mother may interact with the heifer's nutrient consumption during post-weaning growth and the current year to trigger variation in year-to-year milk production.

Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.

Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia, sensed primarily in this context by the fat tissue through HIF-1a prolyl hydroxylase (Hph). The fat relays its hypoxic status through release of one or more HIF-1a-dependent humoral factors that inhibit insulin secretion from the brain, thereby restricting systemic growth. Independently of HIF-1a, Hph is also required for nutrient-dependent Target-of-rapamycin (Tor) activation. Our findings show that the fat tissue acts as the primary sensor of nutrient and oxygen levels, directing adaptation of organismal metabolism and growth to environmental conditions., The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.

Seed dispersal by mammals provides functional connectivity between isolated plant habitat patches. Across much of Europe, red deer (Cervus elaphus) populations are growing steadily, potentially leading to increasing importance of this large mammal species to plant dispersal. While deer endozoochory is relatively well studied, epizoochory via fur and hoof attachment is much less understood. Seed dispersal internally and externally on 57 red deer individuals was investigated by sampling the seed content of intestinal tracts, fur, and hooves of animals shot during annual hunts in four contrasted landscapes in Denmark. We assessed compositional differences between dispersal modes whether plant species' association to a dispersal mode could be predicted by seed traits, whole-plant traits, and species' local abundance. We found the largest difference in seed species composition to be between epizoochory (fur and hooves) and endozoochory (gut contents). Probability of plant dispersal through guts and fur was correctly predicted from traits more often than not. Hoof-epizoochory, however, could not be correctly predicted from plant traits. Most plant species encountered were picked up by all three dispersal modes, suggesting an overriding effect of plant abundance in the landscapes in which the deer roam, which was also indicated by the statistical analysis. Nonetheless, a significant proportion of species were associated with either gut, fur, or hoof-borne dispersal, reflecting the effect of plant traits and, potentially, animal behavior. Plant species being dispersed more often than expected through intestines were mainly associated with ruderal habitats, whereas species transported via fur tended toward association with wooded habitats. Considering the increasing red deer populations in Europe, and the differences between seed dispersal modes, all modes of animal seed dispersal should be taken into account in future studies. Open research badges This article has been awarded Open Data and Open Materials Badges. All materials and data are publicly accessible via the Open Science Framework at https://doi.org/10.6084/m9.figshare.7982483 and https://doi.org/10.6084/m9.figshare.7982483.

Maize (Zea mays L.) stover is used globally as winter feed for livestock but the nutritive value is low, requiring supplementation. A 2-year randomized complete block study with three replicates at New Mexico State University&rsquo, s Alcalde Sustainable Agriculture Science Center compared sweet maize (Zea mays var. rugosa, maize-alone) with sweet maize relay intercropped with oat (Avena sativa L., maize-oat) or turnip (Brassica rapa L., maize-turnip). Relay intercropping had no effect (p &gt, 0.05) on sweet maize stover dry matter (DM) yield and there was no difference in aboveground biomass DM yield of the intercropped species. Turnip aboveground biomass had greater crude protein concentration and 48-h in vitro dry matter disappearance (IVDMD) than oat aboveground biomass. Relay intercropping with turnip improved sweet maize stover IVDMD (443, 439, and 515 g IVDMD kg&minus, 1 for maize-alone, maize-oat, and maize-turnip, respectively, p &lt, 0.0001). Intercropping increased animal gains compared to maize-alone (0.36, 0.52, and 0.59 kg/day for maize-alone, maize-oat, and maize-turnip, respectively, p &lt, 0.02), likely due to provision of additional crude protein. Relay intercropping oat or turnip into sweet maize is viable for improving sweet maize stover for fall forage. In addition turnip, specifically, had a positive effect on stover nutritive value.

Introduction: Great investments are made in new hospital buildings all in favour of single bedrooms for patients. Conclusions regarding the impact of single bedrooms versus multi bedrooms vary. Method: We performed semi-structured interviews with patients undergoing surgery for rectal cancer about their preferences and experiences regarding hospitalization in a single bedroom or a multi bedroom. The data were collected during 2016. Results: The company of fellow patients seems to be of great importance. Patients find the company healing and it contributed to feeling safer. Disturbances like sound and too much activity in a four bedroom is a problem. Most patients preferred single bedrooms when talking to visitors and when they felt very sick. Conclusion: Many patients preferred four bedrooms over single bedrooms because of the company from fellow patients. This conflicts with the tendency in modern hospital design which favors all single bedrooms.

Psoriasis is a complex human-specific disease characterized by perturbed keratinocyte proliferation and a pro-inflammatory environment in the skin. Porcine skin architecture and immunity are very similar to that in humans, rendering the pig a suitable animal model for studying the biology and treatment of psoriasis. Expression of integrins, which is normally confined to the basal layer of the epidermis, is maintained in suprabasal keratinocytes in psoriatic skin, modulating proliferation and differentiation as well as leukocyte infiltration. Here, we generated minipigs co-expressing integrins α2 and β1 in suprabasal epidermal layers. Integrin-transgenic minipigs born into the project displayed skin phenotypes that correlated with the number of inserted transgenes. Molecular analyses were in good concordance with histological observations of psoriatic hallmarks, including hypogranulosis and T-lymphocyte infiltration. These findings mark the first creation of minipigs with a psoriasiform phenotype resembling human psoriasis and demonstrate that integrin signaling plays a key role in psoriasis pathology., Summary: A cloned porcine disease model to advance topical treatment in the debilitating skin disorder psoriasis.

Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule’s central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose., Author Summary Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. Challenging an explanatory mechanism in mice is problematic because variables determining causes and effects cannot be controlled adequately. We circumvent that impediment by performing virtual experiments that challenge the prevailing scientific explanation for the characteristic spatiotemporal pattern of early acetaminophen-induced hepatic necrosis. Virtual mice utilize a biomimetic software liver. Results of virtual experiments provide compelling evidence that the prevailing explanation is insufficient. Without further studies in mice, we discovered a new, marginally more complex explanatory mechanism that met stringent tests of sufficiency. We argue that this virtual causal mechanism and the actual mechanism in mice are strongly analogous within and across multiple biological levels. Variants of the virtual mechanism provide possible explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose.

Hepatic cytochrome P450 levels are down-regulated during inflammatory disease states, which can cause changes in downstream drug metabolism and hepatotoxicity. Long-term, we seek sufficient new insight into P450-regulating mechanisms to correctly anticipate how an individual’s P450 expressions will respond when health and/or therapeutic interventions change. To date, improving explanatory mechanistic insight relies on knowledge gleaned from in vitro, in vivo, and clinical experiments augmented by case reports. We are working to improve that reality by developing means to undertake scientifically useful virtual experiments. So doing requires translating an accepted theory of immune system influence on P450 regulation into a computational model, and then challenging the model via in silico experiments. We build upon two existing agent-based models—an in silico hepatocyte culture and an in silico liver—capable of exploring and challenging concrete mechanistic hypotheses. We instantiate an in silico version of this hypothesis: in response to lipopolysaccharide, Kupffer cells down-regulate hepatic P450 levels via inflammatory cytokines, thus leading to a reduction in metabolic capacity. We achieve multiple in vitro and in vivo validation targets gathered from five wet-lab experiments, including a lipopolysaccharide-cytokine dose-response curve, time-course P450 down-regulation, and changes in several different measures of drug clearance spanning three drugs: acetaminophen, antipyrine, and chlorzoxazone. Along the way to achieving validation targets, various aspects of each model are falsified and subsequently refined. This iterative process of falsification-refinement-validation leads to biomimetic yet parsimonious mechanisms, which can provide explanatory insight into how, where, and when various features are generated. We argue that as models such as these are incrementally improved through multiple rounds of mechanistic falsification and validation, we will generate virtual systems that embody deeper credible, actionable, explanatory insight into immune system-drug metabolism interactions within individuals.

It is well established that hormones can cause cancer, much less known is how they induce this change in our somatic cells. This review highlights the recent finding that estrogen can exert its DNA-damaging potential by directly activating DNA deaminases. This recently discovered class of proteins deaminate cytosine to uracil in DNA, and are essential enzymes in the immune system. The enhanced production of a given DNA deaminase, induced by estrogen, can lead not only to a more active immune response, but also to an increase in mutations and oncogenic translocations. Identifying the direct molecular link between estrogen and a mutation event provides us with new targets for studying and possibly inhibiting the pathological side-effects of estrogen.

Lamenting the lack of public awareness of international events and U.S. foreign policy is not a particularly novel exercise; yet, explaining the process by which issues enter and exit the public realm remains a challenging endeavor. Despite contributions from researchers working in international relations and mass communication, explaining public inattentiveness continues to vex scholars. However, in his article, "Up and Down with Ecology: The 'Issue-Attention Cycle,'" Anthony Downs provides a parsimonious and tractable model of public opinion that can be applied to foreign policy issues.1 While Downs concerns himself exclusively with domestic issues, particularly environmental issues, his model has thepotential to contribute to our understanding of the relationship between the public and policymakers over critical issues such as international terrorism. With minor modifications, the model has the potential to explain public support for failed foreign policies as well. Downs' model, when applied to international terrorism, explains why policymakers seek simple solutions, why the public supports such solutions, and why the media fail to provide meaningful coverage of intractable issues such as international terrorism. Before discussing Downs' model, the basic tenets and shortcomings of some of the more prevalent theories of the relationship between public opinion and foreign policy are discussed below.

Ranching is a challenging and sometimes risky business, with cattle production (and associated enterprise income) largely being dependent on seasonal weather patterns and corresponding forage production. To help reduce this risk, the USDA–Agricultural Research Service performed a multistate study of seasonal weather effects on cattle production across the Northern Great Plains (Wyoming, North Dakota, and Montana). Cool, wet springs and longer, cooler growing seasons increased cattle production across the Northern Great Plains. Knowledge of these seasonal weather influences on cattle production is important for management decision making, but practical application of this knowledge remains problematic. Increased enterprise flexibility to deal with variable forage production can be achieved by using seasonal weather forecasts, as well as reducing base cow-calf herd numbers to less than 100% of typical ranch carrying capacity. Yearlings or seasonal contract grazing can then be used to increase grazing to use additional forage in good years. Recently launched USDA Regional Climate Hubs will deliver science-based knowledge, practical information, management and conservation strategies, and decision tools to ranchers that will help them adapt to weather variability and changing climatic conditions. Fil: Reeves,Justin L.. US Dept of Agriculture. Agricultural Research Service. Rangeland Resources Research Unit; Estados Unidos Fil: Derner, Justin D.. US Dept of Agriculture. Agricultural Research Service. Rangeland Resources Research Unit; Estados Unidos Fil: Sanderson, Matt A.. US Dept of Agriculture. Agricultural Research Service. Northern Great Plains Research Laboratory; Estados Unidos Fil: Kronberg, Scott L.. US Dept of Agriculture. Agricultural Research Service. Northern Great Plains Research Laboratory; Estados Unidos Fil: Hendrickson, John R.. US Dept of Agriculture. Agricultural Research Service. Northern Great Plains Research Laboratory; Estados Unidos Fil: Vermeire, Lance T.. US Dept of Agriculture. Agricultural Research Service. Ft Keogh Livestock and Range Research Laboratory; Estados Unidos Fil: Petersen, Mark K.. US Dept of Agriculture. Agricultural Research Service. Ft Keogh Livestock and Range Research Laboratory; Estados Unidos Fil: Irisarri, Jorge Gonzalo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. University of Wyoming. Department of Agricultural and Applied Economics; Estados Unidos