Biology subjects

Marshall, B.

Publications and source records attributed to Marshall, B..

5 recordsLinked to original sources

bioRxiv2023

CZ CELLxGENE Discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data

Hundreds of millions of single cells have been analyzed to date using high throughput transcriptomic methods, thanks to technological advances driving the increasingly rapid generation of single-cell data. This provides an exciting opportunity for unlocking new insights into health and disease, made possible by meta-analysis that span diverse datasets building on recent advances in large language models and other machine learning approaches. Despite the promise of these and emerging analytical tools for analyzing large amounts of data, a major challenge remains the sheer number of datasets and inconsistent format, data models and accessibility. Many datasets are available via unique portals platforms that often lack interoperability. Here, we present CZ CellxGene Discover (cellxgene.cziscience.com), a data platform that provides curated and interoperable data. This single-cell data resource, available via a free-to-use online data portal, hosts a growing corpus of community contributed data that spans more than 50 million unique cells. Curated, standardized, and associated with consistent cell-level metadata, this collection of interoperable single-cell transcriptomic data is the largest of its kind. A suite of tools and features enables accessibility and reusability of the data via both computational and visual interfaces to allow researchers to rapidly explore individual datasets and perform cross-corpus analysis. This functionality is enabling meta-analyses of tens of millions of cells across studies and tissues and providing global views of human cells at the resolution of single cells.

cell biology↗

bioRxiv2023

Roles of Lipopolysaccharide Glycosyltransferases in Maintenance of Helicobacter pylori Morphology, Cell Wall Permeability, and Antimicobial Susceptibilities

Helicobacter pylori unique lipopolysaccharide structure is essential in maintaining the cell envelop integrity and renders the bacterium natural resistance to cationic antimicrobial peptides (CAMPs). Our group has recently elucidated the complete set of LPS glycosyltransferase genes in H. pylori reference strain G27. Here, with a series of 8 systematically constructed LPS glycosyltransferase gene mutants (G27{Delta}HP1578, G27{Delta}HP1283, G27{Delta}HP0159, G27{Delta}HP0479, G27{Delta}HP0102, G27{Delta}wecA, G27{Delta}HP1284 and G27{Delta}HP1191), we investigated the roles of H. pylori LPS glycosyltransferases in maintenance of cell morphology, cell wall permeability, and antimicrobial susceptibilities. We demonstrated that deletion of these LPS glycosyltransferase genes did not interfere with bacterial cell wall permeability, but resulted in significant morphological changes (coccoid, coiled "c"-shape, and irregular shapes) after 48 h growth as compared to the rod-like cell shape of the wild-type strain. Moreover, as compared with the wild-type, none of the LPS mutants had altered susceptibility against clarithromycin, levofloxacin, amoxicillin, tetracycline, and metronidazole. However, the deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, our findings suggest that the LPS glycosyltransferases play critical roles in the maintenance of the typical spiral morphology of H. pylori, as well as resistance to CAMPs and rifampicin. The LPS glycosyltransferases could be promising targets for developing novel anti-H. pylori drugs. ImportanceH. pylori typical helical morphology, cell wall integrity, as well as resistance to cationic CAMPs and antimicrobials are significant factors for its long-term colonization and persistent infection in human gastric mucosa. Our results show that each of the 8 LPS glycosyltransferase genes (HP1578, HP1283, HP0159, HP0479, HP0102, wecA, HP1284 and HP1191) deletion did not interfere with bacterial cell wall permeability, but resulted in significant loss of H. pylori typical helical shape. Furthermore, deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, we believe that the LPS glycosyltransferases are good targets for developing novel anti-H. pylori drugs.

microbiology↗

bioRxiv2022

Mass red blood cell extravasation and tubular uptake results in toxic injury to the tubules during kidney ischemia from venous clamping

Vascular congestion is common in ischemic acute kidney injury (AKI) and represents densely packed red blood cells (RBC) in the kidney circulation. In this study we tested the hypothesis that vascular congestion directly promotes tubular injury. Studies were performed in male and female Wistar-Kyoto rats. Vascular congestion and tubular injury were examined between renal venous clamping, arterial clamping and venous clamping of blood perfused and blood free kidneys. Vessels were occluded for either 15 or 45 minutes without reperfusion. We found that venous clamping resulted in greater vascular congestion than arterial clamping, particularly in the outer-medullary region (P<0.001). Venous clamping resulted in significant tubular injury, including cell swelling, tubular degeneration and luminal cast formation following as little as 15 minutes of occlusion. Tubular injury was significantly less following arterial clamping (P<0.001). Numerous red droplets were observed within tubular cells which were most prominent following venous clamping. Electron microscopy and immunohistochemistry identified these as derived from RBCs and indicated that RBCs from congested renal capillaries were extravasated and phagocytosed by tubular cells. CD235a staining confirmed tubular uptake and secretion of RBCs. Cast formation and tubular swelling were absent from blood free kidneys following venous clamping (P<0.001). Our data demonstrate that congestion of the kidney results in the rapid, mass extravasation and uptake of RBCs by tubular cells causing toxic injury to the tubules. Tubular toxicity from extravasation of RBCs appears to be a major component of tubular injury in ischemic AKI which has not previously been recognized.

physiology↗

bioRxiv2021

Gaps in global wildlife trade monitoring leave amphibians vulnerable

As the biodiversity crisis continues, we must redouble efforts to understand and curb pressures pushing species closer to extinction. One major driver is the unsustainable trade of wildlife. Trade in internationally regulated species gains the most research attention, but this only accounts for a minority of traded species and we risk failing to appreciate the scale and impacts of unregulated legal trade. Despite being legal, trade puts pressure on wild species via: direct collection, introduced pathogens, and invasive species. Smaller species-rich vertebrates, such reptiles, fish, and amphibians, may be particularly vulnerable to trading because of gaps in regulations, small distributions, and demand of novel species. Here we combine data from five sources: online web searches in six languages, CITES trade database, LEMIS trade database, IUCN assessments, and a recent literature review, to characterise the global trade in amphibians, and also map use by purpose including meat, pets, medicinal and for research. We show that 1,215 species are being traded (17% of amphibian species), almost three times previous recorded numbers, 345 are threatened, and 100 data deficient or unassessed. Traded species origin hotspots include South American, China, and Central Africa; sources indicate 42% of amphibians are taken from the wild. Newly described species can be rapidly traded (mean time lag of 6.5 years), including threatened and unassessed species. The scale and limited regulation of the amphibian trade, paired with the triptych of connected pressures (collection, pathogens, invasive species), warrants a re-examination of the wildlife trade status-quo, application of the precautionary principle in regards to wildlife trade, and a renewed push to achieve global biodiversity goals.

ecology↗

bioRxiv2020

Senotherapeutic peptide reduces skin biological age and improves skin health

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity. In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways. We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in "anti-aging" skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan of C. elegans worms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.

bioengineering↗