Biology subjects

McCabe, M.

Publications and source records attributed to McCabe, M..

6 recordsLinked to original sources

bioRxiv2026

Fibroblast-specific Deletion of Yap/Taz Impairs Mouse Postnatal Dermal Development by Suppressing Collagen Production and Deposition

The Hippo pathway effectors YAP and TAZ are key regulators of cell proliferation, apoptosis, and differentiation, thereby maintaining tissue homeostasis and controlling organ size. While their roles in epithelial tissues and cancer are well established, their role in dermal fibroblast extracellular matrix (ECM) regulation is less understood. Here, we investigated the role of Yap/Taz during postnatal skin dermis development. During postnatal growth, mouse skin steadily grows and undergoes significant surface expansion. Postnatal deletion of Yap/Taz in dermal fibroblasts, the primary cells responsible for dermal ECM homeostasis, significantly impaired dermal maturation, as evidenced by marked deficiencies in collagen synthesis and deposition. Isolated fibroblasts from Yap/Taz knockout mice showed reduced proliferation and diminished expression of Yap/Taz target genes (Ccn2, Col1a1), which were rescued by reintroduction of active Yap/Taz. RNA-seq, and spatial transcriptomics and proteomics of Yap/Taz knockout skin revealed substantial downregulation of matrisome genes, including type I (Col1a1, Col1a2) and type III (Col1a3) collagens, which together constitute more than 90% of the skins collagen content. These findings demonstrate that Yap/Taz are essential for dermal ECM homeostasis, highlighting their therapeutic potential in skin regeneration, fibrosis, and aging-related ECM decline.

cell biology↗

bioRxiv2025

The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells

High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients is hypomethylating agents; however, the response rate is poor. There is thus a need to explore vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that HR-MDS HSPCs have significant upregulation of metabolic proteins required for glycolysis, citric acid cycle, and oxidative phosphorylation. Consistently, we see increased oxygen consumption rate in HR-MDS HSPCs compared to healthy, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of mitochondrial complex I proteins, which are NADH dehydrogenases, and crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition significantly decreased NAD(H) in HR-MDS HSPCs. Consequently, NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired the self-renewal and colony-forming potential, increased cell death and reduced disease burden specifically of HR-MDS HSPCs, compared to healthy controls. Collectively, our data suggest that NAMPT is selectively required for the function and survival of HR-MDS HSPCs representing a promising therapeutic target.

cancer biology↗

bioRxiv2025

Hot and Bothered, Bees Gut Microbiome Shifts Under Thermal Stress and Pathogen Infection.

Understanding bumble bee gut health is imperative as these vital pollinators are subjected to pathogenic infections and thermal stress from climate change. The gut microbiome serves as an indicator for health and fitness and indicates the types of stress. To investigate the combined effects of thermal stress and pathogenic infection on bee guts, we performed a two-by-two crossed design where Bombus impatiens workers were subjected to hot conditions, pathogenic infection, or both. Incubation groups were given 2-weeks of stress conditions, with infected bees initially inoculated with Crithidia bombi, a common bee gut parasite. We measured body size, quantified the infection intensity of C. bombi using qPCR, and defined the composition of the gut microbiome using full-length 16S rRNA gene amplicon sequencing on an Oxford Nanopore Technologies Mk1D. While the core gut microbiome thrived with genera such as Bombilactobacillus and Snodgrassila which were not impacted by treatment; there were notable changes in other key organisms. Asaia bogorensis spiked in control temperature infected organisms, while species of Lactobacillus were overtaken in hot temperatures by significant increases in Apilactobacillus kunkeei. Species such as Citrobacter freundii dominated in hot infected bees suggesting an increased immunocompromised state from the combined stressors impacts on bee gut health. Our novel combined effects from thermal stress and pathogenic infection strengthen existing literature and provide new directions on how to quantify the health-state of wild bees based on their gut microbiome composition. These insights enable us to better understand how bees will be further impacted in changing landscapes. ImportanceWe find significant changes in bees gut microbiome especially with an increased abundance of lactic acid bacteria. These lactic acid bacteria are often specialized: based on infection status, temperature, and the combined effects. These insights are vital to researchers, especially those studying wild bee gut health where they have an uncontrolled system and need to make assumptions about bee stress based on fitness and microbiome. Our detailed outline of relevant species will provide wild bee researchers with a baseline to determine thermal stress and recent infection status based on microbiome communities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/687019v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1528ae6org.highwire.dtl.DTLVardef@1d100dorg.highwire.dtl.DTLVardef@8ea77org.highwire.dtl.DTLVardef@159620a_HPS_FORMAT_FIGEXP M_FIG C_FIG Overview of the experimental design where bees were either given control temperatures or thermal stress and/or an infection by Crithidia bombi. The bees microcolonies were incubated for 2-weeks before sacrificing the bees, extracting DNA, and performing downstream analysis. Full length 16S rRNA gene amplicon sequencing was performed on an Oxford Nanopore MK1D sequencer while Crithidia bombi infections were quantified using quantitative polymerase chain reaction.

ecology↗

bioRxiv2025

Age-dependent expression and antiviral activity of interferon epsilon in respiratory epithelium

Respiratory syncytial virus (RSV) disease burden is greatest between six weeks and 6 months of life, with young age the most common risk factor among hospitalised children. A robust innate immune response in the airway epithelium is crucial for mitigating RSV-associated disease, but early-life immune responses to infection remain largely unexplored. RNA-seq analysis of RSV-infected primary nasal epithelial cell cultures from healthy infants at birth and one year revealed diminished expression of interferon epsilon (IFNE), a poorly characterised type I IFN, in newborns versus one-year. We hypothesised, therefore, that IFNE plays an important role during infant RSV infection. We found that IFNE is endogenously expressed in airway epithelial cell lines. Recombinant human IFN{varepsilon} (rhIFN{varepsilon}) induced an antiviral state against an RSV clinical isolate and related Sendai virus, but not SARS-CoV-2 under the conditions tested. The antiviral potency of rhIFN{varepsilon} was diminished relative to rhIFN beta (rhIFN{beta}1) or rhIFN lambda-1 (rhIFN{lambda}1), as evidenced by IC50 data. Importantly, rhIFN{varepsilon} induced similar ISGs as rhIFN{beta}1 but demonstrated a transient temporal expression profile that differed from both rhIFN{beta}1 and rhIFN{lambda}1. These results suggest that lower IFN{varepsilon} expression at birth may contribute to increased susceptibility to severe RSV-associated disease, offering insights into potential therapeutic interventions.

microbiology↗

bioRxiv2021

Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution

SARS-CoV-2 continues to evolve, resulting in several variants of concern with novel properties. The factors driving SARS-CoV-2 fitness and evolution in the human respiratory tract remain poorly defined. Here, we provide evidence that both viral and host factors co-operate to shape SARS-CoV-2 genotypic and phenotypic change. Through viral whole-genome sequencing, we explored the evolution of two clinical isolates of SARS-CoV-2 during passage in unmodified Vero-derived cell lines and in parallel, in well-differentiated primary nasal epithelial cell (WD-PNEC) cultures. We identify a consistent, rich genetic diversity arising in vitro, variants of which could rapidly rise to near-fixation with 2 passages. Within isolates, SARS-CoV-2 evolution was dependent on host cells, with Vero-derived cells facilitating more profound genetic changes. However, most mutations were not shared between strains. Furthermore, comparison of both Vero-grown isolates on WD-PNECs disclosed marked growth attenuation mapping to the loss of the polybasic cleavage site (PBCS) in Spike while the strain with mutations in NSP12 (T293I), Spike (P812R) and a truncation of ORF7a remained viable in WD-PNECs. Our work highlights the significant genetic plasticity of SARS-CoV-2 while uncovering an influential role for collaboration between viral and host cell factors in shaping viral evolution and fitness in human respiratory epithelium.

microbiology↗

bioRxiv2018

Simultaneous detection of DNA and RNA virus species involved in bovine respiratory disease by PCR-free rapid tagmentation-based library preparation and MinION nanopore sequencing

AbstactThe Oxford Nanopore MinION Mk1B is a portable 90 g device that sequences DNA directly at 450 bases/second generating sequence reads in excess of 400 kb. Recent improvements in error rate and speed of library preparation mean that this device has considerable potential for rapid molecular bovine pathogen diagnostics. We tested the MinION for rapid untargeted detection of viral pathogens associated with bovine respiratory disease (BRD), an economically important disease often involving primary infection of the lung by one or more of a number of DNA and/or RNA viruses. We combined three foetal lung cell cultures which were infected with either Bovine Respiratory Syncytial Virus (BRSV), Bovine Herpes Virus 1 (BoHV1) or Bovine Parainfluenza Virus 3 (BPI-3). BoHV1 is a DNA virus and BPI-3 and BRSV are RNA viruses. The cell cultures were treated with DNase and RNase to deplete bovine nucleic acid prior to viral nucleic acid extraction and double-stranded cDNA synthesis. Sequencing libraries were generated by PCR-free tagmentation in under 10 minutes and loaded onto a MinION sequencer. Approximately 7,000 sequencing reads were generated and analysed using high-throughput local BLAST against the NCBI nr/nt database. The top BLAST hit for 2,937 of these reads was identified as a virus. Of these, 2,926 (99.6%) were correctly identified either as BoHV1, BRSV or BPI-3.

molecular biology↗