Biology subjects

Carter, Z.

Publications and source records attributed to Carter, Z..

5 recordsLinked to original sources

bioRxiv2026

Comparison of localGEBV and Optimal Haplotype Stacking Fitness Functions using a Novel R Package: HapSelect

Haplotype-based breeding strategies have emerged as promising approaches to maximize long-term genetic gain by identifying complementary parental combinations while maintaining genetic diversity. However, these methods typically require phased genotypes and more intensive workflow pipelines and skillsets. We developed a novel local genomic estimated breeding value (localGEBV) fitness function with similar intent to the optimal haplotype stacking (OHS) framework fitness function and implemented both in the novel R package, HapSelect. Our aim was to evaluate whether phased haplotypes provide additional benefit over the more easily available dosage-based unphased genotypes in highly inbred crops. A subset of bread wheat nested association mapping (NAM) population comprising 444 lines genotyped with 6,054 DArT-Seq markers was analysed. Marker effects were estimated using rrBLUP, localGEBV and haplotype effects were calculated across linkage disequilibrium-defined haploblocks, and genetic algorithms (GA) were used to identify optimal sets of 30 founders using either a localGEBV derived fitness function with unphased, dosage inputs or the OHS fitness function with phased inputs. Selected parental sets were compared with conventional truncation selection (TS) through 150 generations of forward simulation. The OHS fitness function achieved a marginally greater optimized ultimate GEBV than the localGEBV fitness function during GA optimization, with only 18 of the 30 selected founders overlapped between the two methods. Despite these differences, forward simulations demonstrated nearly identical long-term genetic gain for localGEBV and OHS-selected founders, with both approaches outperforming conventional truncation selection by maintaining greater genetic diversity and delaying the genetic plateau. The minimal difference between localGEBV and OHS is likely attributable to the high homozygosity of the population, where localGEBV and haplotype effects are nearly confounded. These results demonstrate that dosage-based localGEBV provides a practical alternative to phased haplotype approaches for parent selection in inbred crops, substantially simplifying genomic workflows while maintaining long-term breeding performance. Future work should evaluate these methods in more diverse inbred populations and outbred species, where great haplotypic diversity may increase the advantage of true haplotype-based optimizations.

genetics↗

bioRxiv2026

Distinct fibrotic, epithelial and immune transcriptomic programs in phenotypes of chronic lung allograft dysfunction

BackgroundChronic lung allograft dysfunction (CLAD) is the major cause of late mortality after lung transplantation and includes two principal phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS and other phenotypes with RAS-like opacities (RLO) on chest imaging have a poorer prognosis. Despite clear clinical and pathological differences, molecular distinctions between phenotypes remain poorly defined. We aimed to explore gene transcriptional profiles across CLAD phenotypes and relevant controls. MethodsWe performed bulk RNA sequencing on explanted lung tissue from 45 lung transplant recipients with end-stage CLAD (20 with RLO and 25 without RLO). Samples from twenty-seven control donor and lobectomy lungs and sixteen idiopathic pulmonary fibrosis (IPF) lungs served as comparators. Non-negative matrix factorization (NMF) was used to identify latent transcriptomic signatures, which were correlated with clinical, radiologic, and histopathologic features. ResultsNMF identified seven distinct gene signatures that segregated CLAD phenotypes. RLO-CLAD lungs were enriched for extracellular matrix remodeling and B-cell/plasma cell-associated signatures, overlapping partly with IPF, whereas non-RLO-CLAD showed relative enrichment of epithelial injury and surfactant-response pathways. Signatures related to epithelial homeostasis and ciliary/microtubule function were progressively reduced from control lungs to non-RLO-CLAD and were most suppressed in RLO-CLAD. ConclusionsRLO-CLAD and non-RLO-CLAD, aligning with RAS and BOS phenotypes, show distinct transcriptomic signatures. RLO-CLAD is characterized by profibrotic and humoral immune signatures with profound epithelial dysfunction, whereas non-RLO-CLAD shows relative enrichment of epithelial injury responses. These data provide molecular stratification of CLAD and support the development of phenotype-specific biomarkers and targeted therapies.

bioinformatics↗

bioRxiv2023

Sequestrase chaperones protect against oxidative stress-induced protein aggregation and prion formation

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since no stress sensitivity has been reported in deletion mutants. We show here that Btn2 and Hsp42 are required for oxidant tolerance and act to sequestering misfolded proteins into defined PQC sites following ROS exposure. We have used the Sup35 translation termination factor as a model oxidized protein to show that protein aggregation is elevated and widespread in mutants lacking Btn2 and Hsp42. Oxidant-induced prion formation is also elevated in sequestrase mutants consistent with the idea that Btn2 and Hsp42 function to sequester oxidatively damaged Sup35, thus preventing templating to form its heritable prion form. Taken together, our data identify protein sequestration as key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.

biochemistry↗

bioRxiv2023

Glycine fermentation by C. difficile promotes virulence, spore formation, and is induced by host cathelicidin

The amino acid glycine is enriched in the dysbiotic gut and is suspected to contribute to Clostridioides difficile infection. We hypothesized that the use of glycine as an energy source contributes to colonization of the intestine and pathogenesis of C. difficile. To test this hypothesis, we deleted the glycine reductase genes grdAB, rendering C. difficile unable to ferment glycine, and investigated the impact on growth and pathogenesis. We found that the grd pathway promoted growth, toxin production, sporulation, and pathogenesis of C. difficile in the hamster model of disease. Further, we determined that the grd locus is regulated by host cathelicidin (LL-37) and the cathelicidin-responsive regulator, ClnR, indicating that the host peptide signals to control glycine catabolism. The induction of glycine fermentation by LL-37 demonstrates a direct link between the host immune response and the bacterial reactions of toxin production and spore formation.

microbiology↗

bioRxiv2022

Distinct cohorts of Aspergillus fumigatus transcription factors are required for epithelial damage occurring via contact- or soluble effector-mediated mechanisms

Damage to the lung epithelium is a unifying feature of disease caused by the saprophytic fungus Aspergillus fumigatus. However, the mechanistic basis and the regulatory control of such damage is poorly characterized. Previous studies have identified A. fumigatus mediated pathogenesis as occurring at early ([≤] 16 hours) or late (>16 hours) phases of the fungal interaction with epithelial cells, and respectively involve direct contact with the host cell or the action of soluble factors produced by mature fungal hyphae. Both early and late phases of epithelial damage have been shown to be subject to genetic regulation by the pH-responsive transcription factor PacC. This study sought to determine whether other transcriptional regulators play a role in modulating epithelial damage. In particular, whether the early and late phases of epithelial damage are governed by same or distinct regulators. Furthermore, whether processes such as spore uptake and hyphal adhesion, that have previously been documented to promote epithelial damage, are governed by the same cohorts of epithelial regulators. Using 479 strains from the recently constructed library of A. fumigatus transcription factor null mutants, two high-throughput screens assessing epithelial cell detachment and epithelial cell lysis were conducted. A total of 17 transcription factor mutants were found to exhibit reproducible deficits in epithelial damage causation. Of these, 10 mutants were defective in causing early phase damage via epithelial detachment and 8 mutants were defective in causing late phase damage via epithelial lysis. Remarkably only one transcription factor, PacC, was required for causation of both phases of epithelial damage. The 17 mutants exhibited varied and often unique phenotypic profiles with respect to fitness, epithelial adhesion, cell wall defects, and rates of spore uptake by epithelial cells. Strikingly, 9 out of 10 mutants deficient in causing early phase damage also exhibited reduced rates of hyphal extension, and culture supernatants of 7 out of 8 mutants deficient in late phase damage were significantly less cytotoxic. Our study delivers the first high-level overview of A. fumigatus regulatory genes governing lung epithelial damage, suggesting highly coordinated genetic orchestration of host-damaging activities that govern epithelial damage in both space and time. Contribution to the Field StatementAspergillus fumigatus is a soil dwelling fungus that can cause lethal lung infections in individuals with a compromised immune system. Disease initiates with inhalation of the fungal spores, followed by growth of the fungus leading to destruction of the lung. Our understanding of the A. fumigatus genes and mechanisms driving lung damage leading to establishment of disease is limited. This study has identified the genes moderating lung damage by assessing 479 regulatory mutants of A. fumigatus for their ability to cause epithelial damage using a lung cell line model. We observed that distinct cohorts of transcriptional regulators are required for driving early, and late phases of epithelial damage and that early- and late-occurring damage are associated respectively with hyphal growth rates and secreted fungal products. This study is the first to reveal that mechanistically distinct programs of host damage elicited during early and late stage of fungal interaction with epithelial cells are genetically regulated via distinct cohorts of A. fumigatus transcription factors.

microbiology↗