Biology subjects

McGowan, K.

Publications and source records attributed to McGowan, K..

6 recordsLinked to original sources

bioRxiv2026

Analysis of in vivo infection dynamics using bioluminescent Giardia duodenalis

Giardia duodenalis is an intestinal protozoan transmitted through contaminated food and water and is a major cause of diarrheal disease worldwide and has been linked to post-infectious sequelae and growth impairment in children. Quantifying parasite burden in vivo is essential for studying infection dynamics and host responses, yet commonly used methods (stool PCR, antigen detection, and terminal trophozoite counts from segments of the intestine) are limited by intermittent stool shedding, uneven parasite distribution, sampling error, and lack of longitudinal data. We developed a bioluminescent reporter system for the assemblage B strain GS to enable noninvasive tracking of infection in mice without antibiotic pretreatment. Using in vivo bioluminescent imaging (BLI), we observed peak signal in immunocompetent C57BL/6J and BALB/c mice at days 6-8 post-infection, followed by return to baseline by ~day 10, consistent with the self-limiting nature of giardiasis. In immunodeficient mice, radiance increased and persisted over time, demonstrating stable luciferase expression during chronic infection in vivo without continuous antibiotic selection. Whole-animal radiance strongly correlated with direct trophozoite counts from excised intestinal segments (r = 0.915, p < 0.001), validating BLI as a useful alternative for determining parasite burden. Together, these findings establish BLI as a robust platform for longitudinal studies of Giardia infection dynamics and for future applications that may examine host immunity, the microbiota, nutrient-dependent effects, and drug testing.

microbiology↗

bioRxiv2024

Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics

Molecular glue degraders (MGDs) are small molecules that harness the ubiquitin-proteasome system to induce degradation of target proteins, including those lacking conventional druggable pockets. Given the challenges in their rational design, MGD discovery predominantly relies on screening-based approaches, such as cell viability assays. However, one potential limitation of such screening methods is the risk of overlooking non-essential neosubstrates of potential therapeutic value. To address this concern, we present a high-throughput proteome-wide MGD screening platform utilizing label-free, data-independent acquisition mass spectrometry (DIA-MS) for integrated proteomics and ubiquitinomics analysis. Processing a diverse set of 100 CRBN-ligands across two cancer cell lines reveals a broad array of neosubstrates, including 50 novel candidates validated by MS-based ubiquitinomics. These findings considerably expand the current landscape of CRBN-mediated neosubstrates. Comprehensive hit validation and structure-degradation relationship analyses guided by global proteomics, identifies highly selective and potent phenyl glutarimide-based degraders of novel neosubstrates, including KDM4B, G3BP2 and VCL, none of which contain the classical CRBN degron motif. This study demonstrates that comprehensive, high-throughput proteomic screening offers new opportunities in MGD drug discovery.

biochemistry↗

bioRxiv2022

Genetic architecture and evolution of color variation in American black bears

Color variation is a frequent evolutionary substrate for camouflage in small mammals but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus, exhibits a range of colors including the cinnamon morph which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (P < 10-13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that impaired protein localization and decreased pigment production. Population genetic analyses and demographic modeling indicated that the R153C variant arose 9.36kya in a southwestern population where it likely provided a selective advantage, spreading both northwards and eastwards by gene flow. A different TYRP1 allele, R114C, contributes to the characteristic brown color of U. arctos, but is not fixed across the range. HIGHLIGHTSO_LIThe cinnamon morph of American black bears and brown bears have different missense mutations in TYRP1 that account for their similar coloration C_LIO_LITYRP1 variants in American black bears and brown bears are loss-of-function alleles associated with impaired protein localization to melanosomes C_LIO_LIIn American black bears, the variant causing the cinnamon morph arose 9,360 years ago in the western lineage where it provides an adaptive advantage, and has spread northwards and eastwards by migration C_LI

evolutionary biology↗

bioRxiv2022

Steering clear of the confusion effect: aerial predators target fixed points in dense prey aggregations

Collective behaviours are widely assumed to confuse predators, but empirical support for a confusion effect is often lacking, and its importance must depend on the predators targeting mechanism. Here we show that raptors steer attacks on swarming bats by turning towards a fixed point in the swarm, rather than by using closed-loop pursuit of an individual. Any prey that the predator is on a collision course with will appear on a constant bearing, so target selection emerges naturally from the geometry of a collision. Our results show how predators can simplify the demands on their sensory system by decoupling steering from targeting when grabbing prey from a dense swarm. We anticipate that the same tactic will be used against flocks and schools across a wide range of taxa, in which case a confusion effect is paradoxically more likely to occur in attacks on sparse groups, for which steering and targeting cannot be decoupled.

animal behavior and cognition↗

bioRxiv2020

PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta

The obstetrical conditions placenta accreta spectrum (PAS) and placenta previa are a significant source of pregnancy-associated morbidity and mortality, yet the specific molecular and cellular underpinnings of these conditions are not known. In this study, we identified misregulated gene expression patterns in tissues from placenta previa and percreta (the most extreme form of PAS) compared with control cases. By comparing this gene set with existing placental single-cell and bulk RNA-Seq datasets, we show that the upregulated genes predominantly mark extravillous trophoblasts. We performed immunofluorescence on several candidate molecules and found that PRG2 and AQPEP protein levels are upregulated in both the fetal membranes and the placental disk in both conditions. While this increased AQPEP expression remains restricted to trophoblasts, PRG2 is mislocalized and is found throughout the fetal membranes. Using a larger patient cohort with a diverse set of gestationally aged-matched controls, we validated PRG2 as a marker for both previa and PAS and AQPEP as a marker for only previa in the fetal membranes membranes. Our findings suggest that the extraembryonic tissues surrounding the conceptus, including both the fetal membranes membranes and the placental disk, harbor a signature of previa and PAS that reflects increased trophoblast invasiveness. Summary sentence3SEQ and immunofluorescence reveal that extravillous trophoblast factors, most notably PRG2 and AQPEP, define the diseases placenta previa and placenta accreta spectrum (PAS) in both the chorioamniotic membranes and the placental disk.

pathology↗

bioRxiv2020

Birds versus bats: attack strategies of bat-hunting hawks, and the dilution effect of swarming

Aggregation behaviors can often reduce predation risk, whether through dilution, confusion, or vigilance effects, but these effects are challenging to measure under natural conditions, involving strong interactions between the behaviors of predators and prey. Here we study aerial predation of massive swarms of Brazilian free-tailed bats Tadarida brasiliensis by Swainsons hawks Buteo swainsoni, testing how the behavioral strategies of predator and prey influence catch success and predation risk. The hawks achieved high overall catch success, but they were no more successful against lone bats than against bats flying in column formation. There was therefore no evidence of any net vigilance or confusion effect, and hawks attacking the column benefitted from the opportunity to make several attempted grabs. Even so, the bats overall risk of predation was an order of magnitude higher when flying alone. Attacks on lone bats ([~]10% of attacks) were greatly overrepresented relative to the proportion of bats classified as flying alone ([~]0.2%), so dilution is both necessary and sufficient to explain the higher survival rates of bats flying in the column. From the hawks perspective, their odds of catching a bat more than trebled if the attack involved a stoop rather than level flight, or a rolling rather than pitching grab maneuver. These behavioral tactics were independently deployed in nearly three-quarters of all attacks. Hence, whereas the survival rate of a bat depends principally on whether it flies alone or in a group, the catch success of a hawk depends principally on how it maneuvers to attack. Lay summaryBats emerging by daylight from a massive desert roost are able to minimise their predation risk by maintaining tight column formation, because the hawks that attack them target stragglers disproportionately often. Whereas the predation risk of a bat therefore depends on how it maintains its position within the swarm, the catch success of a hawk depends on how it maneuvers to attack. Catch success is maximised by executing a stooping dive or a rolling grab.

animal behavior and cognition↗