Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are ...rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted for population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The COVID-19 pandemic resulted in more than half the world's population being placed in lockdown to stem the spread of the virus. The severe restrictions imposed in many nations had the potential to ...significantly influence the physical and psychological well-being of those affected. The aim of the current study was to investigate mood responses during the period of restrictions from March to June, 2020. Mood responses of 1,062 participants (386 male, 676 female) were collected using the Brunel Mood Scale, hosted on the
website www.moodprofiling.com. The mean pattern of mood responses reflected an inverse iceberg profile, characterized by significantly elevated scores for tension, depression, anger, fatigue, and confusion, and below average scores for vigor; a profile associated with increased risk of mental health issues. Females reported more negative mood scores than males. Participants in the ≤25 age group reported the most negative profiles whereas those in the ≥56 age group reported the least negative profiles. Mood differences related to education status were also evident. Finally, mood scores fluctuated over time, with profiles being most negative during April and June. Overall, results confirmed significant mood disturbance during the period of COVID-19 restrictions, representing increased risk of psychopathology.
Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 ...glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.
PDXs were established from glioblastoma, IDH-wildtype (
= 93), glioblastoma, IDH-mutant (
= 2), diffuse midline glioma, H3 K27M-mutant (
= 1), and both primary (
= 60) and recurrent (
= 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES,
= 83), RNA-sequencing (
= 68), and genome-wide methylation profiling (
= 76). WES data from 24 patient tumors was compared with derivative models.
PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of
, and
, most at frequencies comparable with human glioblastoma. However,
amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes.
promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including
amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.
Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
Wildlife play a role in the acquisition, maintenance, and dissemination of antimicrobial resistance (AMR). This is especially true at the human-domestic animal-wildlife interface, like urbanized ...areas, where interactions occur that can promote the cross-over of AMR bacteria and genes. We conducted a 2-year fecal surveillance (
= 783) of a white-tailed deer (WTD) herd from an urban park system in Ohio to identify and characterize cephalosporin-resistant and carbapenemase-producing bacteria using selective enrichment. Using generalized linear mixed models we found that older (OR = 2.3,
< 0.001), male (OR = 1.8,
= 0.001) deer from urbanized habitats (OR = 1.4,
= 0.001) were more likely to harbor extended-spectrum cephalosporin-resistant Enterobacterales. In addition, we isolated two carbapenemase-producing Enterobacterales (CPE), a Klebsiella quasipneumoniae harboring
and an Escherichia coli harboring
, from two deer from urban habitats. The genetic landscape of the plasmid carrying
was unique, not clustering with other reported plasmids encoding KPC-2, and only sharing 78% of its sequence with its nearest match. While the plasmid carrying
shared sequence similarity with other reported plasmids encoding NDM-5, the intact IS26 mobile genetic elements surrounding multiple drug resistant regions, including the
, has been reported infrequently. Both carbapenemase genes were successfully conjugated to a J53 recipient conferring a carbapenem-resistant phenotype. Our findings highlight that urban environments play a significant role on the transmission of AMR bacteria and genes to wildlife and suggest WTD may play a role in the dissemination of clinically and epidemiologically relevant antimicrobial resistant bacteria.
The role of wildlife in the spread of antimicrobial resistance is not fully characterized. Some wildlife, including white-tailed deer (WTD), can thrive in suburban and urban environments. This may result in the exchange of antimicrobial resistant bacteria and resistance genes between humans and wildlife, and lead to their spread in the environment. We found that WTD living in an urban park system carried antimicrobial resistant bacteria that were important to human health and resistant to antibiotics used to treat serious bacterial infections. This included two deer that carried bacteria resistant to carbapenem antibiotics which are critically important for treatment of life-threatening infections. These two bacteria had the ability to transfer their AMR resistance genes to other bacteria, making them a threat to public health. Our results suggest that WTD may contribute to the spread of antimicrobial resistant bacteria in the environment.
Data on the safety of COVID-19 vaccines in early pregnancy are limited. We conducted a national, population-based, matched cohort study assessing associations between COVID-19 vaccination and ...miscarriage prior to 20 weeks gestation and, separately, ectopic pregnancy. We identified women in Scotland vaccinated between 6 weeks preconception and 19 weeks 6 days gestation (for miscarriage; n = 18,780) or 2 weeks 6 days gestation (for ectopic; n = 10,570). Matched, unvaccinated women from the pre-pandemic and, separately, pandemic periods were used as controls. Here we show no association between vaccination and miscarriage (adjusted Odds Ratio aOR, pre-pandemic controls = 1.02, 95% Confidence Interval CI = 0.96-1.09) or ectopic pregnancy (aOR = 1.13, 95% CI = 0.92-1.38). We undertook additional analyses examining confirmed SARS-CoV-2 infection as the exposure and similarly found no association with miscarriage or ectopic pregnancy. Our findings support current recommendations that vaccination remains the safest way for pregnant women to protect themselves and their babies from COVID-19.
Evidence on associations between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies is limited. Here we report a national, population-based, matched cohort study using ...linked electronic health records from Scotland (May 2020-April 2022) to estimate the association between COVID-19 vaccination and, separately, SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days gestation and the risk of 1 any major congenital anomaly and 2 any non-genetic major congenital anomaly. Mothers vaccinated in this pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273). Of the 6731 babies whose mothers were vaccinated in the pregnancy exposure period, 153 had any anomaly and 120 had a non-genetic anomaly. Primary analyses find no association between any vaccination and any anomaly (adjusted Odds Ratio aOR = 1.01, 95% Confidence Interval CI = 0.83-1.24) or non-genetic anomalies (aOR = 1.00, 95% CI = 0.81-1.22). Primary analyses also find no association between SARS-CoV-2 infection and any anomaly (aOR = 1.02, 95% CI = 0.66-1.60) or non-genetic anomalies (aOR = 0.94, 95% CI = 0.57-1.54). Findings are robust to sensitivity analyses. These data provide reassurance on the safety of vaccination, in particular mRNA vaccines, just before or in early pregnancy.
Coral reefs are under increasing threat from increasing warm temperature stress. Coral bleaching is caused by a combination of heat and light anomalies and therefore fewer corals should bleach in ...areas where either heat or light anomalies are ameliorated, such as in turbid waters or at depth. Here, we explore the overall response of the coral assemblage and of 16 individual taxa to a thermal anomaly along a depth gradient during the 2016 mass bleaching event at sites on the outer shelf of the northern Great Barrier Reef. Across all taxa, there was a curvilinear decline in the percentage of colonies bleached with depth that was consistent among sites and reflected the attenuation of light in the ocean. The percentage of colonies bleached was also higher on reefs with higher levels of temperature stress. In 10 taxa, including the abundant and ecologically significant Acropora, Pocillopora and Porites, the percentage of colonies bleached declined with depth. In 4 taxa, the percentage of colonies bleached peaked at intermediate depth. In 2 taxa, there was no effect of depth because bleaching was uniformly low. These data suggest that deeper areas of reef can provide a refuge from mass bleaching for many colonies of most taxa.
Abstract
Depending on seasonal availability and quality of range forage, extensively managed ewes can experience nutrient restriction during any point of gestation. Neonatal lamb performance after ...severe experimental nutrient restriction during gestation has been well studied; however, there is a gap in understanding of how practical nutrient restriction experienced over the course of a production cycle impacts lamb success. Therefore, the objective of this study was to investigate the first week fetal growth and development, and thermoregulation biomarkers in neonatal lambs from ewes fed a diet that simulates winter forage. Time-mated and confirmed pregnant Rambouillet x Merino ewes were blocked by body weight and allocated to one of two dietary treatments. Treatments consisted of 1) Control diet (CONT) formulated to meet or exceed the National Research Council (NRC) nutrient requirements for gestating ewes fed throughout gestation; 2) Nutrient restricted diet (NR) formulated to meet 70% of total digestible nutrient (TDN) and 50% of protein requirements from 30 to 125 d of gestation (dGA) and then re-alimented with the CONT diet for the remainder of gestation. Ewes were individually fed from 25 dGA to 137 dGA, then group fed through lambing. From 30 dGA to lambing, weekly body weights, bimonthly body condition scores (BCS), and monthly blood glucose concentrations were recorded for all ewes. A treatment by time interaction was observed where NR ewes weighed less (P < 0.05) starting at week 8 of the treatment period through lambing. There were effects of treatment and time on BCS, as ewes receiving the NR diet had lesser (P < 0.05) BCS compared with CONT ewes regardless of time in gestation. There were no observed differences in blood glucose concentrations between groups. At lambing, rectal temperature, birth weight and morphometrics (crown-rump length, abdominal circumference, head circumference, and cannon bone length) were collected on all lambs. Collection of rectal temperature and bodyweight continued daily for the first week of life. There were no differences in birthweight or birth morphometrics; however, growth by body weight in the first week of life was greater (P < 0.05) in NR (n = 10) compared with CONT lambs (n = 12), with an effect of progeny number. Additionally, treatment by day interactions were observed with NR lambs having lower (P < 0.05) body temperatures on days one, four, and five compared with CONT lambs. These data suggest that sustained nutrient challenge during gestation, even when re-alimented in late gestation, may produce lambs that are at increased risk of hypothermia. While maternal nutrient supplementation in late gestation is a common practice, it is crucial for producers to consider nutritional supplementation strategies throughout gestation to limit the number of lambs that require increased intervention after birth.
IFN regulatory factor (IRF) 8 is a transcription factor that has a key role in the cellular response to IFN-γ and is pivotal in myeloid cell differentiation. Whether IRF8 plays a role in the ...development and function of microglia, the tissue-resident myeloid cells of the brain, is unknown. Here, we show IRF8 is a constitutively produced nuclear factor in microglia, which suggested that IRF8 might also be a key homeostatic transcriptional determinant of the microglial cell phenotype. In support of this, in mice with a targeted disruption of the IRF8 gene, microglia were increased in number and showed gross alterations in morphology and surface area. In situ analysis of some key myeloid markers revealed that IRF8-deficient microglia had significantly reduced levels of Iba1, but increased levels of CD206 (mannose receptor) and F4/80 as well as increased tomato lectin binding. Analysis of microglia ex vivo revealed IRF8-deficient microglia had significantly increased levels of CD45, CD11b and F4/80, but significantly decreased levels of the chemokine receptors CCR2, CCR5 and CX3CR1. The known involvement of some of these molecular markers in membrane dynamics and phagocytosis led us to examine the phagocytic capacity of cultured IRF8-deficient microglia, however, this was found to be similar to wild type microglia. We conclude IRF8 is a constitutively produced nuclear factor in resident microglia of the CNS being a crucial transcriptional determinant of the phenotype of these cells in the healthy brain.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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