Biology subjects

McLaughlin, T.

Publications and source records attributed to McLaughlin, T..

5 recordsLinked to original sources

bioRxiv2025

COVID-19 induces persistent transcriptional changes in adipose tissue that are not associated with Long COVID

Long COVID is a heterogeneous condition characterized by a wide range of symptoms that persist for 90 days or more following SARS-CoV-2 infection. Now more than five years out from the onset of the SARS-CoV-2 pandemic, the mechanisms driving Long COVID are just beginning to be elucidated. Adipose tissue has been proposed as a potential reservoir for viral persistence and tissue dysfunction contributing to symptomology seen in Long COVID. To test this hypothesis, we analyzed subcutaneous adipose tissue (SAT) from two cohorts: participants with subacute COVID-19 (28-89 days post-infection) compared to pre-pandemic controls, and participants with Long COVID compared to those with those classified as "indeterminate" based on the RECOVER-Adult Long COVID Research Index (12-47 months post-infection). We found no evidence of persistent SARS-CoV-2 RNA in adipose tissue in any participant. SAT from participants with subacute COVID-19 displayed significant transcriptional remodeling, including depleted immune activation pathways and upregulated Hox genes and integrin interactions, suggesting resident immune cell exhaustion and perturbations in tissue function. However, no consistent changes in gene expression were observed between Long COVID samples and samples from indeterminant participants. Thus, SAT may contribute to inflammatory dysregulation following COVID-19, but does not appear to play a clear role in Long COVID pathophysiology. Further research is needed to clarify the role of adipose tissue in COVID-19 recovery.

immunology↗

bioRxiv2024

A toxic environment selects for specialist microbiome in poison frogs

Shifts in microbiome community composition can have large effects on host health. It is therefore important to understand how perturbations, like those caused by the introduction of exogenous chemicals, modulate microbiome community composition. In poison frogs within the family Dendrobatidae, the skin microbiome is exposed to the alkaloids that the frogs sequester from their diet and use for defense. Given the demonstrated antimicrobial effects of these poison frog alkaloids, these compounds may be structuring the skin microbial community. To test this, we first characterized microbial communities from chemically defended and closely related non-defended frogs from Ecuador. Then we conducted a laboratory experiment to monitor the effect of the alkaloid decahydroquinoline (DHQ) on the microbiome of a single frog species. In both the field and lab experiments, we found that alkaloid-exposed microbiomes are more species rich and phylogenetically diverse, with an increase in rare taxa. To better understand the strain-specific behavior in response to alkaloids, we cultured microbial strains from poison frog skin and found the majority of strains exhibited either enhanced growth or were not impacted by the addition of DHQ. Additionally, stable isotope tracing coupled to nanoSIMS suggests that some of these strains are able to metabolize DHQ. Taken together, these data suggest that poison frog chemical defenses open new niches for skin-associated microbes with specific adaptations, including the likely metabolism of alkaloids, that enable their survival in this toxic environment. This work helps expand our understanding of how exposure to exogenous compounds like alkaloids can impact host microbiomes.

microbiology↗

bioRxiv2023

Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes

Pancreatic {beta}-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We have identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low levels of HA are present in healthy pancreatic islets. However, HA substantially accumulates in cadaveric islets of human T2D and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the major HA receptor CD44, preserve glycemic control and insulin levels in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserve glycemic control in other settings of {beta}-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we find that 4-MU increases the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on {beta}-cells such that caspase 3 activation does not result in {beta}-cell apoptosis. These data indicate a role for HA accumulation in diabetes pathogenesis and suggest that it may be a viable target to ameliorate {beta}-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.

immunology↗

bioRxiv2021

Engineering genetically-encoded synthetic biomarkers for breath-based cancer detection

Breath analysis holds great promise for rapid, noninvasive early cancer detection; however, clinical implementation is impeded by limited signal from nascent tumors and high background expression by non-malignant tissues. To address this issue, we developed a novel breath-based reporter system for early cancer detection using D-limonene, a volatile organic compound (VOC) from citrus fruit that is not produced in humans, in order to minimize background signal and maximize sensitivity and specificity for cancer detection. We metabolically engineered HeLa human cervical cancer cells to express limonene at levels detectable by mass spectrometry by introducing a single plant gene encoding limonene synthase. To improve limonene production and detection sensitivity twofold, we genetically co-expressed a modified form of a key enzyme in the cholesterol biosynthesis pathway. In a HeLa xenograft tumor mouse model, limonene is a sensitive and specific volatile reporter of tumor presence and growth, permitting detection of tumors as small as 5 mm. Moreover, tumor detection in mice improves proportionally with breath sampling time. By continuously collecting VOCs for 10 hours, we improve sensitivity for cancer detection 100-fold over static headspace sampling methods. Whole-body physiologically-based pharmacokinetic (PBPK) modeling and simulation of tumor-derived limonene predicts detection of tumors as small as 7 mm in humans, equivalent to the detection limit of clinical imaging modalities, such as PET, yet far more economical. Significance StatementWe developed a breath-based reporter system using the plant terpene, D-limonene - a volatile secondary metabolite that gives citrus fruit its characteristic scent but is not produced in human tissues - as a biomarker for early cancer detection. Results from this study could pave the way for in vivo gene delivery and tumor-specific expression of exogenous volatile cancer reporters with broad applicability to the early diagnosis of a wide variety of cancers.

bioengineering↗

bioRxiv2017

High Frequency Actionable Pathogenic Exome Mutations in an Average-Risk Cohort

Whole exome sequencing (WES) is increasingly utilized in both clinical and non-clinical settings, but little is known about the utility of WES in healthy individuals. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study at Stanford University. We assessed exomes for rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We used American College of Medical Genetics (ACMG) guidelines were used for the classification of rare sequence variants, and additionally we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes, including 6 (9%) with mutations in genes not currently included in the ACMGs list of 59 actionable genes. This number is higher than that reported in previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 60 participants (89%) had non-actionable findings identified including 57 who were found to be mutation carriers for recessive diseases and 21 who have increased Alzheimers disease risk due to heterozyg ous or homozygous APOE e4 alleles (18 participants had both). These results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.

genomics↗