Biology subjects

Smith, A.

Publications and source records attributed to Smith, A..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

Model-based evaluation of critical nursery habitats for juvenile blue crabs through ontogeny: abundance and survival in seagrass, salt marsh, and unstructured bottom

Nursery habitats confer higher food availability and reduced predation risk, thereby contributing disproportionately more individuals per unit area to the population compared with other habitats. Nursery status is inferred through evaluation of four metrics: density, growth, survival, and linkage between juveniles and adults. Moreover, organisms commonly use multiple habitats as nurseries throughout ontogeny to satisfy shifting resource requirements. To this end, we conducted manipulative and mensurative field experiments to evaluate two nursery metrics, abundance and survival, for juvenile blue crabs across multiple size classes and habitats, including structurally complex habitats -- seagrass meadows and salt marshes -- and unstructured habitat (sand flats) in the York River, Chesapeake Bay. We also considered effects of site-specific spatial orientation within the York River, seasonality, physicochemical variables, and postlarval influx. Our results showed that abundance was higher in both seagrass meadows and salt marshes relative to unstructured sand, and positively associated with turbidity and post-larval abundance. Notably, seagrass habitats harbored the highest abundances of small ([≤] 15 mm carapace width) juveniles, whereas salt marsh edge harbored the highest abundance of medium (16-30 mm carapace width) and large (31- 60 mm carapace width) juveniles. Moreover, survival was positively associated with juvenile size and structurally complex habitats relative to unvegetated controls. Seasonally, survival peaked in April, reached a seasonal minimum in August, and increased throughout fall. Finally, habitat-specific survival was dependent on spatial position: survival was elevated at upriver salt marsh and unstructured sand habitats compared to downriver counterparts. In nursery habitats of marine species, evaluation of survival, growth, abundance and ontogenetic habitat shifts has typically focused on relatively broad size ranges through the juvenile phase. Yet, ontogenetic shifts in habitat use may occur within much narrower size ranges, which has not been well studied and which is critical to the conservation and restoration of nursery habitats. We found that habitat-specific utilization rates differed by juvenile size class over a surprisingly narrow range of size, and were related to (1) the structural and biological characteristics of the nominal nursery habitats, (2) spatial gradients of environmental variables within the tributary, and (3) the likely trade-offs between growth and survival through ontogeny. Taken together, abundance and survival results indicate that seagrass meadows are key nurseries primarily for early-stage juveniles, whereas salt marshes are an intermediate nursery habitat for larger individuals to maximize growth-to-mortality ratios. Our results underscore the need to consider both habitats as critical nurseries for juvenile blue crabs throughout ontogeny.

ecology↗

bioRxiv2023

Individuals lack the capacity to accurately detect emotional piloerection

Piloerection (e.g., goosebumps) is an essential thermoregulatory and social signalling mechanism in non-human animals. While humans also experience piloerection--often being perceived as an indicator of profound emotional experiences--its comparatively less effective role in thermoregulation and communication might influence our capacity to monitor its occurrence. We present three studies (total N = 617) demonstrating participants general inability to detect their own piloerection events and their lack of awareness that piloerection occurs with a similar frequency on multiple anatomical locations. Participants over-reported piloerection events with only 31.8% coinciding with observable piloerection, a bias unrelated to piloerection intensity, anatomical location, heart rate variability, or interoceptive awareness. We also discovered a self-report bias for the forearm, contradicting the observation that piloerection occurs with equal frequency on multiple anatomical locations. Finally, there was low correspondence between self-reports of being "emotionally moved" and observed piloerection. These counterintuitive findings not only highlight a disconnect between an obvious physiological response and our capacity for self-monitoring, but they underscore a fascinating divergence between human and non-human species. While piloerection is vital in non-human organisms, the connection between piloerection and psychological experience in humans may be less significant than previously assumed, possibly due to its diminished evolutionary relevance. Statement of ImpactThis research reveals a striking dissociation between an obvious physiological response-- piloerection--and human capacity for self-perception. While this highlights the limitations of relying on self-report measures, it also underscores an important divergence between humans and non-human species. We propose that the relation between piloerection and psychological experience in humans is less pronounced than in other species, potentially due to its diminished role in human evolution.

animal behavior and cognition↗

bioRxiv2023

ERK signalling orchestrates metachronous transition from naive to formative pluripotency

Naive epiblast cells in the embryo and pluripotent stem cells in vitro undergo developmental progression to a formative state competent for lineage specification. During this transition, transcription factors and chromatin are rewired to encode new functional features. Here, we examine the role of mitogen-activated protein kinase (ERK1/2) signalling in pluripotent state transition. We show that a primary consequence of ERK activation in mouse embryonic stem cells is elimination of Nanog, precipitating breakdown of the naive state gene regulatory network. Cell variability in pERK dynamics results in metachronous down-regulation of Nanog and naive state exit. Knockdown of Nanog allows exit without ERK activation. However, transition to formative pluripotency does not proceed and cells collapse to an indeterminate identity. This failure is attributable to loss of expression of the central pluripotency factor Oct4. Thus, during formative transition ERK signalling both dismantles the naive state and preserves pluripotency. These results illustrate that a single signalling pathway can both drive exit from a developmental state and safeguard progression to the successor state.

developmental biology↗

bioRxiv2023

Ontogenetic Patterns in Juvenile Blue Crab density: Effects of Habitat and Turbidity in a Chesapeake Bay Tributary

Nursery habitats are characterized by favorable conditions for juveniles, such as higher food availability and lower predation risk, and dispropor-tionately contribute more individuals per unit area to adult segments of the population compared to other habitats. However, nursery habitat inference is complicated by changes in habitat preferences with ontogeny; individuals in early-life stages frequently inhabit different habitats than older juveniles or adults. In this mensurative field experiment, we modeled the density of two juvenile blue crab, Callinectes sapidus, size classes based on carapace width (CW) across multiple habitats at various locations within an estuarine seascape during the blue crab recruitment season. We examined four habi-tat types--unstructured sand, seagrass meadows, salt marsh edge (SME), and shallow detrital habitat (SDH). Results indicated that densities of small ju-venile blue crabs ([≤]15 mm CW) were highest in seagrass, whereas densities of larger juveniles (16-30 mm CW) were highest in SME. Densities of large juveniles in SME were also greater than those of small juveniles, suggest-ing possible secondary dispersal to SME by small juveniles after settlement and recruitment in seagrass. Turbidity was positively correlated with densi-ties of both size classes, although our model did not address whether this was due to top-down (refuge) or bottom-up (food availability) mechanisms. Ob-served patterns in size-specific habitat utilization may result from changing requirements of juvenile blue crabs with size, as animals minimize mortality-to-growth ratios. Taken together with previous work and patterns observed in SME, these findings emphasize the role of salt marsh habitat within juve-nile blue crab ontogeny and underscore the need to quantify and preserve the complete chain of habitats used by juveniles.

ecology↗

bioRxiv2023

Efficient genetic editing of human intestinal organoids using ribonucleoprotein-based CRISPR

Organoids are currently one of the most widely used ex vivo models in epithelial biology. Combined with genetic editing strategies, organoids offer a promise of rapid and efficient investigation of gene function in many models of human disease. However, to date, the editing efficiency of organoids with the use of non-viral electroporation methods has been only up to 30%, with implications for the subsequent need for selection including including turnaround time and exhaustion or adaptation of the organoid population. Here, we describe an efficient method of intestinal organoid editing using a Ribonucleoprotein CRISPR-based approach. Editing efficiencies of up to 98% in target genes were robustly achieved across different anatomical gut locations and developmental timepoints from multiple patient samples with no off-target editing. The method allowed us to study the effect of the loss of the tumour suppressor gene, PTEN, in normal human intestinal cells. Analysis of PTEN deficient organoids defined phenotypes that likely relate to its tumour suppressive function in vivo, such as a proliferative advantage and increased organoid budding. Transcriptional profiling revealed differential expression of genes in pathways commonly known to be associated with PTEN loss including mTORC1 activation.

cell biology↗

bioRxiv2023

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacity in vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

cell biology↗

bioRxiv2022

Long-term ecological responses of a Dipterocarp forest to climate changes and nutrient availability

O_LIUnderstanding the long-term impact of projected climate change on tropical rainforests is critical given their central role in the Earths system. Palaeoecological records can provide a valuable perspective on this problem. Here we examine for the first time the effects of past climatic changes on the dominant forest type of Southeast Asia - Dipterocarp forest. C_LIO_LIWe use a range of proxies extracted from a 1,400-year-old lacustrine sedimentary sequence from north-eastern Philippines to model long-term vegetation responses of Dipterocarp forest, including its dominant tree group Dipterocarps, to changes in precipitation, fire and nutrient availability over time. C_LIO_LIOur results show a positive relationship between Dipterocarps pollen accumulation rates (PARs) and leaf wax hydrogen isotope values, which suggests a negative effect of drier conditions on Dipterocarp tree abundance. Furthermore, we find a positive relationship between Dipterocarp PARs and the proxy for phosphorus availability, which suggests phosphorus controls the productivity of these keystone trees on longer time scales. Other plant taxa show widely varying relationships with the abiotic factors, demonstrating a high diversity of functional responses. C_LIO_LIOur findings provide novel insights into Dipterocarp forest responses to changing climatic conditions in the past, and highlight potential impacts of future climate change on this globally important ecosystem. C_LI

ecology↗

bioRxiv2022

A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication and ciliogenesis in Caenorhabditis elegans

The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in C. elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined sas-6(L69T) effect on centrosome duplication, ciliogenesis and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.

genetics↗

bioRxiv2022

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated with Clostridioides difficile infection.

Background & AimClostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Two protein toxins, TcdA and TcdB, produced by C. difficile are the major determinants of disease. However, the physiological cause of diarrhea associated with CDI is not well understood. We investigated the effects of CDI on paracellular permeability and apical ion transporters. MethodsWe studied intestinal permeability and apical membrane transporters in female C57BL/6J mice. Ussing chambers were used to measure regional differences in paracellular permeability and ion transporter function in intestinal mucosa. Intestinal tissues were collected from mice and analyzed by immunofluorescence microscopy and RNA-sequencing. ResultsCDI increased intestinal permeability through the size-selective leak pathway in vivo, but permeability was not increased at the sites of pathological damage. Chloride secretion was reduced in the cecum during infection by decreased CaCC function. Infected mice had decreased SGLT1 (also called SLC5A1) activity in the cecum and colon along with diminished apical abundance and an increase in luminal glucose. SGLT1 and DRA (also called SLC26A3) expression was ablated by either TcdA or TcdB, but NHE3 (also called SLC9A3) was decreased in a TcdB-dependent manner. Finally, expression of these three ion transporters was drastically reduced at the transcriptional level. ConclusionsCDI increases intestinal permeability and decreases apical abundance of NHE3, SGLT1, and DRA. This combination may cause a dysfunction in water and solute absorption in the lower gastrointestinal tract, leading to osmotic diarrhea. These findings may open novel pathways for attenuating CDI-associated diarrhea. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/516162v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@e6e23corg.highwire.dtl.DTLVardef@ed6bborg.highwire.dtl.DTLVardef@33adcaorg.highwire.dtl.DTLVardef@d6e359_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Territorial aggression in male bower-building cichlids Nyassachromis cf. microcephalus is disrupted by exposure to environmental concentrations of fluoxetine

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed drugs for treating human depression, but the role of serotonin--often called the happy chemical--is complex, associated with the regulation of appetite, anxiety, aggression, and more. With such psychoactive pharmaceuticals being increasingly detected in aquatic environments and their effects on non-target species an uncertainty, this study seeks to investigate how inhibiting the serotonin pathway with the SSRI fluoxetine affects territorial aggression, using the cichlid fish Nyassachromis cf. microcephalus as a model. Males of this sand-dwelling Lake Malawi species build bowers to attract females within a lekking system, where male-male competition is intense. Being aggressive in defending against intruders would serve to maximise mating opportunities and reproductive success for the territory holding male. However, after a one-week exposure to fluoxetine at environmentally relevant concentrations, a decline in aggression was observed in the male cichlids. This implies the serotonergic system plays an important role in modulating aggression and therefore sexual selection in cichlid fishes, and that environmental pollution has the potential to disrupt these behaviours.

animal behavior and cognition↗

bioRxiv2022

Cardiac muscle-restricted partial loss of Nos1ap expression has limited impact on electro- and echo-cardiographic features

Genome-wide association studies (GWAS) of QT interval variation have identified common noncoding variants at the NOS1AP gene as the most common genetic regulators of trait variation in the general population. Invoking a cis-regulatory mechanistic hypothesis, we have reported identification of a functional enhancer variant underlying the GWAS signal that influenced human cardiac NOS1AP expression. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT interval in vivo. Constitutive loss of Nos1ap led to genetic background-dependent variable lethality at or right before birth. Heart muscle-restricted Nos1ap knockouts generated using cardiac specific alpha-myosin heavy chain promoter-driven tamoxifen-inducible Cre resulted in tissue-level Nos1ap expression reduced by half. This partial loss of expression had no detectable effect on the QT interval, but led to a small yet significant reduction in the QRS interval. Given that challenges associated with defining the end of T wave on murine electrocardiogram can limit identification of subtle effects on QT interval, and that common noncoding NOS1AP variants are also associated with QRS interval, our findings support the role of NOS1AP in regulation of the cardiac electrical cycle.

genetics↗

bioRxiv2022

Immune-related molecular changes in the olfactory epithelium, structural alteration in the olfactory bulb, and psychosis

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.

molecular biology↗

bioRxiv2022

Development and application of a computable genotype model in the GA4GH Variation Representation Specification

As the diversity of genomic variation data increases with our growing understanding of the role of variation in health and disease, it is critical to develop standards for precise inter-system exchange of these data for research and clinical applications. The Global Alliance for Genomics and Health (GA4GH) Variation Representation Specification (VRS) meets this need through a technical terminology and information model for disambiguating and concisely representing variation concepts. Here we discuss the recent Genotype model in VRS, which may be used to represent the allelic composition of a genetic locus. We demonstrate the use of the Genotype model and the constituent Haplotype model for the precise and interoperable representation of pharmacogenomic diplotypes, HGVS variants, and VCF records using VRS and discuss how this can be leveraged to enable interoperable exchange and search operations between assayed variation and genomic knowledgebases.

bioinformatics↗

bioRxiv2022

UltraSEQ: a universal bioinformatic platform for information-based clinical metagenomics and beyond

Applied metagenomics is a powerful emerging capability enabling untargeted detection of pathogens, and its application in clinical diagnostics promises to alleviate the limitations of current targeted assays. While metagenomics offers a hypothesis-free approach to identify any pathogen, including unculturable and potentially novel pathogens, its application in clinical diagnostics has so far been limited by workflow-specific requirements, computational constraints, and lengthy expert review requirements. To address these challenges, we developed UltraSEQ, a first-of its kind metagenomics-based clinical diagnostics and biosurveillance tool that is accurate and scalable. Here we present results for evaluation of our novel UltraSEQ pipeline using an in silico synthesized metagenome, mock microbial community datasets, and publicly available clinical datasets from samples of different infection types, and both short-read and long-read sequencing data. Our results show that UltraSEQ successfully detected all expected species across the tree of life in the in silico sample and detected all 10 bacterial and fungal species in the mock microbial community dataset. For clinical datasets, even without requiring dataset-specific configuration settings changes, background sample subtraction, or prior sample information, UltraSEQ achieved an overall accuracy of 91%. Further, we demonstrated UltraSEQs ability to provide accurate antibiotic resistance and virulence factor genotypes that are consistent with phenotypic results. Taken together, the above results demonstrates that the UltraSEQ platform offers a transformative approach to microbial and metagenomic sample characterization, employing a biologically informed detection logic, deep metadata, and a flexible system architecture for classification and characterization of taxonomic origin, gene function, and user-defined functions, including disease-causing infection.

bioinformatics↗

bioRxiv2022

Helicobacter pylori vacuolating cytotoxin A exploits human endosomes for intracellular activation

Helicobacter pylori infection is the main cause of gastric cancer. Vacuolating cytotoxin A (VacA) is a H. pylori pore-forming toxin and a key determinant of gastric cancer risk. VacA is secreted as an 88-kDa polypeptide (p88) that upon interaction with host cells induces cytotoxic effects, including cell vacuolation and mitochondrial dysfunction. These effects are currently believed to be due to VacA p88 accumulating inside host cells and forming oligomeric anion-specific channels in membranes of intracellular compartments. However, the molecular nature of intracellular VacA channels in host cells remains undefined. Here we show that VacA p88 does not accumulate inside human epithelial cells, but instead is rapidly processed in endosomes into smaller p31/p28 and p37 products in a manner that precedes VacA-induced vacuolation. VacA processing requires endosomal acidification and concerted cleavage by multiple endo-lysosomal proteases including cathepsins. In situ structural mapping reveals that upon processing, the toxins central hydrophilic linker and globular C-terminus are excised, whereas oligomerization determinants are retained. Congruently, the processed products are constituents of a high-molecular-weight complex inside the host cell [boxh] which we propose is the intracellular, mature and active VacA pore. These findings suggest that VacA exploits human endosomes for proteolytic processing and intracellular activation. Significance StatementHelicobacter pylori is a cancer-causing bacterium that infects the stomach of billions of people worldwide. Vacuolating cytotoxin A (VacA) is an important H. pylori virulence factor and its activity directly correlates with gastric carcinogenesis. Yet despite decades of intense research, the mechanisms underlying VacA activity in human cells remain incompletely understood. Here, we present evidence suggesting that VacA is activated inside human cells by multi-step proteolytic processing involving endo-lysosomal proteases including cathepsins. We also track and identify the functional processed VacA isoforms in host cells. These results revolutionize our understanding of the mechanism of VacA activation in human cells, whilst expanding our knowledge of the diversity of microbial virulence factors that exploit human endo-lysosomes for pathogenesis.

molecular biology↗

bioRxiv2022

Internal calibration for opportunistic computed tomography muscle density analysis

IntroductionMuscle weakness can lead to reduced physical function and quality of life. Computed tomography (CT) can be used to assess muscle health through measures of muscle cross-sectional area and density loss associated with fat infiltration. However, there are limited opportunities to measure muscle density in clinically acquired CT scans because a density calibration phantom, allowing for the conversion of CT Hounsfield units into density, is typically not included within the field-of-view. For bone density analysis, internal density calibration methods use regions of interest within the scan field-of-view to derive the relationship between Hounsfield units and bone density, but these methods have yet to be adapted for muscle density analysis. The objective of this study was to design and validate a CT internal calibration method for muscle density analysis. MethodologyWe CT scanned 10 bovine muscle samples using two scan protocols and five scan positions within the scanner bore. The scans were calibrated using internal calibration and a reference phantom. We tested combinations of internal calibration regions of interest (e.g., air, blood, bone, muscle, adipose). ResultsWe found that the internal calibration method using two regions of interest, air and adipose or blood, yielded accurate muscle density values (< 1% error) when compared with the reference phantom. The muscle density values derived from the internal and reference phantom calibration methods were highly correlated (R2 > 0.99). The coefficient of variation for muscle density across two scan protocols and five scan positions was significantly lower for internal calibration (mean = 0.33%) than for Hounsfield units (mean = 6.52%). There was no difference between coefficient of variation for the internal calibration and reference phantom methods. ConclusionsWe have developed an internal calibration method to produce accurate and reliable muscle density measures from opportunistic computed tomography images without the need for calibration phantoms.

bioengineering↗

bioRxiv2022

Outbreak of Highly Pathogenic Avian Influenza H5N1 in New England Seals

The recent incursion of Highly Pathogenic Avian Influenza A (H5N1) virus into North America and subsequent dissemination of virus across the continent, has had significant adverse impacts on domestic poultry, and has led to widespread mortality in many wild bird species. Here we report the recent spillover of H5N1 into marine mammals in the northeastern United States, with associated mortality on a regional scale. This spillover is coincident with a second wave of H5N1 in sympatric wild birds also experiencing regional mortality events. Viral sequences derived from both seal and avian hosts reveal distinct viral genetic differences between the two waves of infection. Spillover into seals was closely related to virus from the second wave, and one of eight seal-derived sequences had the mammalian adaptation PB2 E627K. One-Sentence SummaryAn outbreak of H5N1 in New England seals is the first known population-scale mammalian mortality event associated with the emerging highly pathogenic avian influenza clade 2.3.4.4b.

molecular biology↗

bioRxiv2022

Epigenome-wide meta-analysis of BMI in nine population-based cohorts: examining the utility of methylation as a biomarker of BMI

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Womens Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p<1E-7), and 1238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European descent and individuals of African descent. We found five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log normalized BMI in the WHI (80% training/20% testing). This model found 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides, and lower HDL-cholesterol and LDL-cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL-cholesterol and lower glucose and triglycerides. This study identified 553 previously identified and 685 novel CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.

genetics↗