Biology subjects

Morris, A.

Publications and source records attributed to Morris, A..

40 records · Page 3Linked to original sources

bioRxiv2019

Rectal swabs in critically-ill patients provide discordant representations of the gut microbiome compared to stool samples: a brief methodologic report.

The role of the gut microbiome in critical illness is being actively investigated, but the optimal sampling methods for sequencing studies of gut microbiota remain unknown. Stool samples are generally considered gold-standard but are not practical to obtain in the intensive care unit (ICU), and thus, rectal swabs are often used. However, the reliability of rectal swabs for gut microbiome profiling has not been established in this clinical setting. In this study, we compared 16S rRNA gene sequencing results between rectal swab and stool samples collected at three timepoints in mechanically-ventilated critically-ill adults. Rectal swabs comprised 89% of samples collected at the baseline timepoint, but stool samples became more available at later time-points. Significant differences in alpha and beta-diversity between rectal swabs and stool samples were observed (p<0.003), but these differences were primarily due to baseline samples. Higher relative abundance of Actinobacteria phyla (typically skin microbes) was present in rectal swabs compared to stool samples (p<0.02), a difference that was attenuated overtime. The progressive similarity of rectal swabs and stool samples likely results from increasing stool coating of the rectal vault and direct soiling of the rectal swabs taken at later time points. Therefore, inferences about the role of the gut microbiome in critical illness should be drawn cautiously and take into account the actual type and timing of samples analyzed. Statement of ImportanceRectal swabs are considered reliable alternatives to stool samples for gut microbiome profiling in outpatients or healthy adults, but their reliability in critically-ill patients has not been defined. Because stool sampling is not practical or often feasible in the intensive care unit, we performed a detailed comparison of gut microbial sequencing profiles between rectal swabs vs. stool samples in a longitudinal cohort of critically-ill patients. We identified systematic differences in gut microbial profiles between rectal swabs and stool samples, and highlighted that timing of rectal swabbing had a significant impact on sequencing results. Our methodological findings should inform future investigations of the role of the gut microbiome in critical illness.

microbiology↗

bioRxiv2018

Megakaryocyte emperipolesis mediates membrane transfer from intracytoplasmic neutrophils to platelets

Bone marrow megakaryocytes engulf neutrophils in a phenomenon termed emperipolesis. We show here that emperipolesis is a dynamic process mediated actively by both lineages, in part through the {beta}2-integrin/ICAM-1/ezrin pathway. Tethered neutrophils enter in membrane-bound vesicles before penetrating into the megakaryocyte cytoplasm. Intracytoplasmic neutrophils develop membrane contiguity with the demarcation membrane system, thereby transferring membrane to the megakaryocyte and to daughter platelets. This phenomenon occurs in otherwise unmanipulated marrow in vivo, resulting in circulating platelets that bear membrane from non-megakaryocytic hematopoietic donors. Transit through megakaryocytes can be completed as rapidly as minutes, after which neutrophils egress intact. Emperipolesis is amplified in models of inflammation associated with platelet overproduction, contributing to platelet production in vitro and in vivo. These findings identify emperipolesis as a new cell-in-cell interaction that enables neutrophils and potentially other cells passing through the megakaryocyte cytoplasm to modulate the production and membrane content of platelets.

cell biology↗

bioRxiv2018

Reproduction has different costs for immunity and parasitism in a wild mammal

1. Life history theory predicts that reproductive investment draws resources away from immunity, resulting in increased parasitism. However, studies of reproductive tradeoffs rarely examine multiple measures of reproduction, immunity, and parasitism. It is therefore unclear whether the immune costs of reproductive traits correlate with their resource costs, and whether increased parasitism emerges from weaker immunity.\n\n2. We examined these relationships in wild female red deer (Cervus elaphus) with variable reproductive investment and longitudinal data on mucosal antibody levels and helminth parasitism. We noninvasively collected faecal samples, counting propagules of strongyle nematodes (order: Strongylida), the common liver fluke Fasciola hepatica and the red deer tissue nematode Elaphostrongylus cervi. We also quantified both total and anti-strongyle mucosal IgA to measure general and specific immune investment.\n\n3. Contrary to our predictions, we found that gestation was associated with decreased total IgA but with no increase in parasitism. Meanwhile, the considerable resource demand of lactation had no further immune cost but was associated with higher counts of strongyle nematodes and Elaphostrongylus cervi. These contrasting costs arose despite a negative correlation between antibodies and strongyle count, which implied that IgA was indicative of protective immunity.\n\n4. Our findings suggest that processes other than classical resource allocation tradeoffs are involved in mediating observed relationships between reproduction, immunity, and parasitism in wild mammals. In particular, reproduction-immunity tradeoffs may result from hormonal regulation or maternal antibody transfer, with parasitism increasing as a result of increased exposure arising from resource acquisition constraints. We advocate careful consideration of resource-independent mechanistic links and measurement of both immunity and parasitism when investigating reproductive costs.

ecology↗

bioRxiv2018

Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

Protein-coding genetic variants that strongly affect disease risk can provide important clues into disease pathogenesis. Here we report an exome sequence analysis of 20,791 type 2 diabetes (T2D) cases and 24,440 controls from five ancestries. We identify rare (minor allele frequency<0.5%) variant gene-level associations in (a) three genes at exome-wide significance, including a T2D-protective series of >30 SLC30A8 alleles, and (b) within 12 gene sets, including those corresponding to T2D drug targets (p=6.1x10-3) and candidate genes from knockout mice (p=5.2x10-3). Within our study, the strongest T2D rare variant gene-level signals explain at most 25% of the heritability of the strongest common single-variant signals, and the rare variant gene-level effect sizes we observe in established T2D drug targets will require 110K-180K sequenced cases to exceed exome-wide significance. To help prioritize genes using associations from current smaller sample sizes, we present a Bayesian framework to recalibrate association p-values as posterior probabilities of association, estimating that reaching p<0.05 (p<0.005) in our study increases the odds of causal T2D association for a nonsynonymous variant by a factor of 1.8 (5.3). To help guide target or gene prioritization efforts, our data are freely available for analysis at www.type2diabetesgenetics.org.

genetics↗