Biology subjects

Moore, M. P.

Publications and source records attributed to Moore, M. P..

7 recordsLinked to original sources

bioRxiv2026

Hypoxia can set the elevational limits of dragonflies

Oxygen declines by ~10% for each 1000m gained above sea level. Although the impact of low oxygen on endotherms has received considerable attention, we know far less about whether or not hypoxia can set the elevational limits of terrestrial ectotherms. Here, we addressed this question using Nearctic dragonflies. First, we experimentally tested if dragonflies are vulnerable to the low oxygen found at high elevations. Our results show that even resting adults struggle with the PO2 that occurs at the highest elevations where dragonflies are found in Colorado, USA. Second, we used a comparative approach to test if the dragonfly species that can inhabit higher elevations are also more tolerant of low oxygen. Our analysis shows that a species upper elevational limit is precisely predicted by its vulnerability to low oxygen. Collectively, these results provide some of the first evidence that low oxygen can be an important constraint on the elevational maxima of terrestrial ectotherms.

ecology↗

bioRxiv2025

A hormetic model of rapid cold hardening in Drosophila melanogaster reveals threshold effects on survival and low fertility resilience

Variable thermal environments may have both detrimental and beneficial effects. For example, extreme temperatures may challenge homeostasis and inflict tissue damage but may also induce acclimation that improves stress resilience. Hormetic models provide a framework to understand dosage-dependent, contrasting beneficial and detrimental effects from physiological and ecological perspectives. We used a hormetic framework and associated quantitative models to investigate how a range of relatively cold, pre-exposure temperatures influence survival and fertility following cold shock at a more extreme cold temperature in the fruit fly Drosophila melanogaster. Cold pre-exposure can induce a protective rapid cold hardening (RCH) response, fail to stimulate a response, or cause direct cold injury. We found a plateau-shaped relationship between pre-exposure temperature and female survival resilience, where survival following a cold shock remains high across a range of temperatures, with sharp transitions at higher and lower temperatures. Bayesian fitting of a bi-logistic model highlights these transitions at temperature thresholds that govern processes mediating both acclimation and cold injury. In contrast to survival, female fertility resilience exhibited a muted response to pre-exposure temperature in the presence and absence of post-stress mating opportunities. Overall, a range of pre-exposure temperatures allowed low but successful reproduction following cold shock. High survival but low fertility resilience is consistent with a) differential impacts of cold on somatic and reproductive tissues and b) a growing body of literature suggesting that the thermal sensitivity of fertility may be more limiting than survival for population persistence in variable and changing climates. Summary statementA hormetic model shows how sharp temperature thresholds govern beneficial rapid cold hardening and detrimental cold injury that have well-defined effects on survival, but only weakly affect fertility.

physiology↗

bioRxiv2023

Genotypic and Phenotypic Analyses of Two Distinct Sets of Pseudomonas aeruginosa Urinary Tract Isolates

Urinary tract infections (UTIs) are associated with a high burden of morbidity, mortality, and cost. Pseudomonas aeruginosa employs a myriad of virulence factors, including biofilm formation and motility mechanisms, to cause infections including persistent UTIs. P. aeruginosa is highly resistant to antibiotics and the World Health Organization has identified it as a pathogen for which novel antimicrobials are urgently required. Genotypic and phenotypic characterization of P. aeruginosa from UTIs are underreported. In addition, the rise of antimicrobial resistance (AMR) is a cause for concern, particularly in many countries where surveillance is severely lacking. 22 P. aeruginosa UTI isolates were sourced from the United Kingdom (UK) and Kuwait. To establish the phenotypes of UK isolates, growth analysis, biofilm formation assays, motility assays, and antibiotic disc diffusion assays were performed. Whole genome sequencing, antimicrobial susceptibility assays, and in silico detection of AMR-associated genes were conducted on both sets of isolates. In terms of their phenotypic characteristics and genomic composition, the UTI isolates varied. Multiple resistance genes associated with resistance to various classes of antibiotics, such as aminoglycosides, fluoroquinolones, and {beta}-lactams, particularly in isolates from Kuwait. Extreme antibiotic resistance was detected in the isolates obtained from Kuwait, indicating that the country may be an antibiotic resistance hotspot. This study highlights that isolates from UTIs are diverse and can display extremely high resistance. Surveillance in countries such as Kuwait are currently limited and this study suggest the need for greater surveillance.

microbiology↗

bioRxiv2023

Hepatocyte-Targeted siTAZ Therapy Lowers Liver Fibrosis in NASH Diet-Fed Chimeric Mice with Hepatocyte-Humanized Livers

Nonalcoholic steatohepatitis (NASH) is emerging as the most common cause of liver disease. Although many studies in mouse NASH models have suggested therapies, translation to humans is poor, with no approved drugs for NASH. One explanation may lie in inherent differences between mouse and human hepatocytes. We used NASH diet-fed chimeric mice reconstituted with human hepatocytes (hu-liver mice) to test a mechanism-based hepatocyte-targeted siRNA, GalNAc-siTaz, shown previously to block the progression to fibrotic NASH in mice. Mice were reconstituted with human hepatocytes following ablation of endogenous hepatocytes, resulting in ~95% human hepatocyte reconstitution. The mice were then fed a high-fat choline-deficient Lamino acid-defined diet for 6 weeks to induce NASH, followed by six weekly injections of GalNAc-siTAZ to silence hepatocyte-TAZ or control GalNAc-siRNA (GalNAc-control) while still on the NASH diet. The results revealed that GalNAc-siTAZ lowered human hepatic TAZ and IHH, the major TAZ target that promotes liver fibrosis in NASH. Most importantly, GalNAc-siTAZ decreased liver inflammation, hepatocellular injury, hepatic fibrosis, and profibrogenic mediator expression, and profibrotic NOTCH vs. GalNAc-control, indicating that GalNAc-siTAZ decreased the progression of NASH in mice reconstituted with human hepatocytes. In conclusion, silencing TAZ in human hepatocytes suppresses liver fibrosis in a hu-liver model of NASH. Impact and ImplicationsNo drugs have yet been approved for NASH, which is a leading cause of liver disease worldwide. The findings here provide support for this therapeutic strategy of using hepatocyte-targeted siTAZ to decrease NASH progression. More generally, the study illustrates how hu-liver NASH mice can be used to evaluate therapeutic hepatocyte-targeted siRNAs to help prioritize future testing in human NASH.

pharmacology and toxicology↗

bioRxiv2022

KmerAperture: Retaining k-mer synteny for alignment-free estimation of within-lineage core and accessory differences

By decomposing genome sequences into k-mers, it is possible to estimate genome differences without alignment. Techniques such as k-mer minimisers (MinHash), have been developed and are often accurate approximations of distances based on full k-mer sets. These and other alignment-free methods avoid the large temporal and computational expense of alignment or mapping. However, these k-mer set comparisons are not entirely accurate within-species and can be completely inaccurate within-lineage. This is due, in part, to their inability to distinguish core polymorphism from accessory differences. Here we present a new approach, KmerAperture, which uses information on the k-mer relative genomic positions to determine the type of polymorphism causing differences in k-mer presence and absence between pairs of genomes. Single SNPs are expected to result in contiguous series of relative unique k-mers of length L= k. On the other hand, series of length L > k may be caused by accessory differences of length L-k+1; when the start and end of the sequence are contiguous with homologous sequence. Alternatively, they may be caused by multiple SNPs within k bp from each other and KmerAperture can determine whether that is the case. To demonstrate use cases KmerAperture was benchmarked using datasets including a very low diversity simulated population with accessory content independent from the number of SNPs, a simulated population were SNPs are spatially dense, a moderately diverse real cluster of genomes (Escherichia coli ST1193) with a large accessory genome and a low diversity real genome cluster (Salmonella Typhimurium ST34). We show that KmerAperture can accurately distinguish both core and accessory sequence diversity without alignment, outperforming other k-mer based tools.

bioinformatics↗

bioRxiv2021

K-mer based prediction of Clostridioides difficile relatedness and ribotypes

Comparative analysis of Clostridioides difficile whole-genome sequencing (WGS) data enables fine scaled investigation of transmission and is increasingly becoming part of routine surveillance. However, these analyses are constrained by the computational requirements of the large volumes of data involved. By decomposing WGS reads or assemblies into k-mers and using the dimensionality reduction technique MinHash, it is possible to rapidly approximate genomic distances without alignment. Here we assessed the performance of MinHash, as implemented by sourmash, in predicting single nucleotide differences between genomes (SNPs) and C. difficile ribotypes (RTs). For a set of 1,905 diverse C. difficile genomes (differing by 0-168,519 SNPs), using sourmash to screen for closely related genomes, at a sensitivity of 100% for pairs [≤]10 SNPs, sourmash reduced the number of pairs from 1,813,560 overall to 161,934, i.e., by 91%, with a positive predictive value of 32% to correctly identify pairs [≤]10 SNPs (maximum SNP distance 4,144). At a sensitivity of 95%, pairs were reduced by 94% to 108,266 and PPV increased to 45% (maximum SNP distance 1,009). Increasing the MinHash sketch size above 2000 produced minimal performance improvement. We also explored a MinHash similarity-based ribotype prediction method. Genomes with known ribotypes (n=3,937) were split into a training set (2,937) and test set (1,000) randomly. The training set was used to construct a sourmash index against which genomes from the test set were compared. If the closest 5 genomes in the index had the same ribotype this was taken to predict the searched genomes ribotype. Using our MinHash ribotype index, predicted ribotypes were correct in 780/1000 (78%) genomes, incorrect in 20 (2%), and indeterminant in 200 (20%). Relaxing the classifier to 4/5 closest matches with the same RT improved the correct predictions to 87%. Using MinHash it is possible to subsample C. difficile genome k-mer hashes and use them to approximate small genomic differences within minutes, significantly reducing the search space for further analysis. Impact statementThe genetic code, or DNA, of bacteria is increasingly used to track how infection spreads and to guide infection control interventions, as similar or identical DNA sequences are expected in samples from pair of individuals related by transmission. While obtaining the DNA sequence for bacteria is increasingly straightforward, comparing thousands or even millions of sequences requires substantial computing power and time using current approaches. Here we describe how a method for summarising sequencing data, MinHash, can be used to rapidly reduce the number of possible close sequence matches in Clostridioides difficile, an important healthcare-associated pathogen. It can also be used to approximate traditional schemes used to classify C. difficile into smaller subgroups in transmission analyses, such as ribotyping. Data summaryThe authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.

genomics↗

bioRxiv2019

A megaplasmid family responsible for dissemination of multidrug resistance in Pseudomonas

Multidrug resistance (MDR) represents a global threat to health. Although plasmids can play an important role in the dissemination of MDR, they have not been commonly linked to the emergence of antimicrobial resistance in the pathogen Pseudomonas aeruginosa. We used whole genome sequencing to characterize a collection of P. aeruginosa clinical isolates from a hospital in Thailand. Using long-read sequence data we obtained complete sequences of two closely related megaplasmids (>420 kb) carrying large arrays of antibiotic resistance genes located in discrete, complex and dynamic resistance regions, and revealing evidence of extensive duplication and recombination events. A comprehensive pangenomic and phylogenomic analysis indicated that 1) these large plasmids comprise a family present in different members of the Pseudomonas genus and associated with multiple sources (geographical, clinical or environmental); 2) the megaplasmids encode diverse niche-adaptive accessory traits, including multidrug resistance; 3) the pangenome of the megaplasmid family is highly flexible and diverse, comprising a substantial core genome (average of 48% of plasmid genes), but with individual members carrying large numbers of unique genes. The history of the megaplasmid family, inferred from our analysis of the available database, suggests that members carrying multiple resistance genes date back to at least the 1970s.\n\nFundingThis work was supported by the International Pseudomonas Genomics Consortium, funded by Cystic Fibrosis Canada [RCL]; and the Secretaria de Educacion, Ciencia, Tecnologia e Innovacion (SECTEI), Mexico [AC].

microbiology↗