Biology subjects

Lynch, B.

Publications and source records attributed to Lynch, B..

9 recordsLinked to original sources

bioRxiv2026

Dynamic Changes in Endometrial Folding and Secretory Activity Across the Menstrual Cycle

Embryo implantation remains a major limitation of assisted reproductive technology, with failure occurring in approximately 30% of euploid embryo transfers. Implantation requires a synchronized dialogue between the blastocyst and receptive endometrium during the window of implantation (WOI), yet minimally invasive approaches to characterize the structural and molecular features of receptivity remain limited. We analyzed paired sonohysterogram images and uterine lavage samples collected during the proliferative and mid-secretory phases from subjects with regular ovulatory cycles and proven fertility. Endometrial folds were quantified, and lavage samples were analyzed by Luminex multiplex immunoassay. Folds were present in both phases but were significantly more abundant during the mid-secretory WOI, independent of imaging view and endometrial thickness. Folding correlated strongly with circulating estradiol level during the proliferative phase but not the mid-secretory phase, and folding patterns between phases were not correlated, suggesting distinct regulatory mechanisms. Consistent with these structural patterns, uterine lavage demonstrated phase-specific differences in expression of factors associated with endometrial receptivity and implantation, with glandular epithelium, and myeloid-lineage cells emerging as major contributors. Together, these findings identify coordinated structural and secretory processes during the WOI and support further evaluation of endometrial folding and uterine lavage as complementary, minimally invasive markers of endometrial receptivity.

developmental biology↗

bioRxiv2026

Minimally invasive monitoring of clonal evolution through integrated single cell and ctDNA analysis

Circulating cell-free DNA (cfDNA) offers a minimally invasive lens into tumor evolution. However, the accurate quantification of clonal composition from cfDNA remains challenging. Existing methods for clone tracking using liquid biopsies are constrained by issues such as their reliance on bulk tissue references, incomplete representations of clonal architecture or limited breadth of mutation panels. To address these limitations, we developed cfClone, a Bayesian framework that integrates single-cell whole-genome sequencing (scWGS) derived clonal structures with cfDNA whole-genome sequencing (cfDNA-WGS) data to enable high-resolution tissue-informed clonal tracking. By jointly modeling local copy-number alterations and haplotype-specific signals via Bayesian model selection and Markov chain Monte Carlo (MCMC) sampling, the algorithm yields uncertainty-aware estimates of clonal prevalence and tumour fraction (TF). Applied to longitudinal clinical cohorts, cfClone can be used to reconstruct evolutionary trajectories and uncovers clonal selection driving therapeutic resistance, including the de novo detection of emergent clonal populations. We demonstrate that cfClone achieves accurate TF estimates and circulating tumor DNA (ctDNA) detection in malignancies with varying degrees of copy-number variant (CNV) burden using semi-synthetic data. We then compare to the state of the art scWGS informed panel based approach, and demonstrate cfClone provides comparable accuracy while allowing for the tracking of more clones and detection of novel clones. Finally, we show how cfClone can be used to quantitatively track clonal dynamics in response to treatment in high grade serous ovarian cancer. Github link: https://github.com/Roth-Lab/cfclone

cancer biology↗

bioRxiv2025

Detection of Feline Coronavirus RNA in Cats with Feline Infectious Peritonitis and their Housemates

Feline coronavirus (FCoV), the causative agent behind feline infectious peritonitis (FIP), is one of the biggest infectious threats to feline health. Despite this threat, the tissue distribution and viral RNA levels in cats infected with feline coronaviruses are poorly understood in the context of natural infection. Here, we used quantitative reverse-transcription PCR (qRT-PCR) to examine viral RNA levels from different sampling sites in both cats that have been clinically suspected of FIP and their feline housemates. We show that the distribution and amount of FCoV viral RNA does not differ between infected FIP cats and their feline housemates in blood, conjunctiva, or feces. Furthermore, in all FIP and non-FIP cases, viral RNA levels were higher in fecal samples than the blood. Taken together these results indicate a need for closer examination of FCoVs and how they cause FIP.

biochemistry↗

bioRxiv2021

Comparative genomics and pangenomics of vancomycin resistant and susceptible Enterococcus faecium from Irish hospitals across 20 years

Enterococcus faecium has emerged as an important nosocomial pathogen, which is increasingly difficult to treat due to the genetic acquisition of vancomycin resistance. Ireland exhibits a recalcitrant vancomycin resistant bloodstream infection rate compared to other developed countries. A set of 28 vancomycin resistant isolates was sequenced to construct a dataset alongside 61 other publicly available Irish genomes. This dataset was extensively analysed using in-silico methodologies and uncovered distinct evolutionary, coevolutionary, and clinically relevant population trends. These results suggest that a stable (in terms of genome size, GC%, and number of genes), yet genetically diverse population (in terms of gene content) of Enterococcus faecium persist in Ireland with acquired resistance arising via plasmid acquisition (vanA) or to a lesser extent, chromosomal recombination (vanB). Population analysis described five clusters with one cluster partitioned into four clades which transcend isolation dates. Pangenomic and recombination analyses revealed an open (whole genome and chromosomal specific) pangenome illustrating a rampant evolutionary pattern. Comparative resistomics and virulomics uncovered distinct chromosomal and mobilomal propensity for multidrug resistance, widespread chromosomal point-mutation mediated resistance, and chromosomal harboured arsenals of virulence factors. Comparative phagomics revealed a core prophagome of three prophages throughout the dataset. Interestingly, a potential difference in biofilm formation strategies was highlighted by coevolutionary analysis, suggesting differential biofilm genotypes between vanA and vanB isolates. These results highlight the evolutionary history of Irish Enterococcus faecium isolates and may provide an insight into underlying infection dynamics in a clinical setting.

microbiology↗

bioRxiv2020

Elucidating the antiviral mechanism of different MARCH proteins

The Membrane Associated RING-CH (MARCH) proteins belong to a family of E3 ubiquitin ligases, whose main function is to remove transmembrane proteins from the plasma membrane. Recent work has shown that the human MARCH1, 2 and 8 are antiretroviral factors that target the Human Immunodeficiency virus-1 (HIV-1) envelope glycoproteins by reducing their incorporation in the budding virions. Nevertheless, the dearth of information regarding the antiviral mechanism of this family of proteins necessitates further examination. In this study, using both the human MARCH proteins and their mouse homologues, we provide a comprehensive analysis of the antiretroviral mechanism of this family of proteins. Moreover, we show that human MARCH proteins restrict to varying degrees the envelope glycoproteins of a diverse number of viruses. This report sheds light on the important antiviral function of MARCH proteins and their significance in cell intrinsic immunity.

microbiology↗

bioRxiv2020

SERINC5 potently restricts retrovirus infection in vivo

The Serine Incorporator (SERINC) proteins are multipass transmembrane proteins that affect sphingolipid and phosphatidylserine synthesis. Human SERINC5 and SERINC3 were recently shown to possess antiretroviral activity to a number of retroviruses including human immunodeficiency virus (HIV), murine leukemia virus (MLV) and equine infectious anemia virus (EIAV). In the case of MLV, the glycosylated Gag (glyco-Gag) protein was found to counteract SERINC5-mediated restriction in in vitro experiments and that the viral envelope determines virion sensitivity or resistance to SERINC5. However, nothing is known about the in vivo function of SERINC5. Antiretroviral function of a host factor in vitro is not always associated with antiretroviral function in vivo. Using SERINC5-/- mice we generated, we show that mouse SERINC5 (mSERINC5) restriction of MLV infection in vivo is dependent not only on glyco-Gag, but also on the retroviral envelope. Finally, we also examined the in vivo function of the other SERINC gene with known antiretroviral functions, SERINC3. By using SERINC3-/- mice, we found that the murine homologue, mSERINC3, had no antiretroviral role both in vivo and in vitro. This report provides the first data showing that SERINC5 restricts retrovirus infection in vivo and that restriction of retrovirus infectivity in vivo is dependent on both the presence of glyco-Gag and the viral envelope. IMPORTANCEThis study examines for the first time the in vivo function of the Serine Incorporator (SERINC) proteins during retrovirus infection. SERINC3/5 restrict a number of retroviruses including human immunodeficiency virus 1 (HIV-1) and murine leukemia virus (MLV) by blocking their entry into cells. Nevertheless, HIV-1 and MLV encode factors, Nef and glycosylated Gag respectively, that counteract SERINC3/5 in vitro. We recently developed SERINC3 and SERINC5 knockout mice to examine the in vivo function of these genes. We found that SERINC5 potently restricted retrovirus infection in a glycosylated Gag and envelope dependent manner. On the other hand, SERINC3 had no antiviral function. Our findings have implication in the development of therapeutics that target SERINC5 during retrovirus infection.

microbiology↗

bioRxiv2020

Isolation and characterization of SARS-CoV-2 from the first US COVID-19 patient

The etiologic agent of the outbreak of pneumonia in Wuhan China was identified as severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) in January, 2020. The first US patient was diagnosed by the State of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens, and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into two virus repositories, making it broadly available to the public health and research communities. We hope that open access to this important reagent will expedite development of medical countermeasures. Article SummaryScientists have isolated virus from the first US COVID-19 patient. The isolation and reagents described here will serve as the US reference strain used in research, drug discovery and vaccine testing.

microbiology↗

bioRxiv2019

High throughput Characterization of KCNB1 variants Associated with Developmental and Epileptic Encephalopathy

Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel Kv2.1, are associated with developmental and epileptic encephalopathies (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. We evaluated a series of 17 KCNB1 variants associated with DEE or neurodevelopmental disorder (NDD) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant Kv2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage-dependence of activation and/or inactivation, as homotetramers or when co-expressed with wild-type Kv2.1. Quantification of protein expression also identified variants with reduced total Kv2.1 expression or deficient cell-surface expression.\n\nOur study establishes a platform for rapid screening of functional defects of KCNB1 variants associated with DEE and other NDDs, which will aid in establishing KCNB1 variant pathogenicity and may enable discovery of targeted strategies for therapeutic intervention based on molecular phenotype.

genetics↗

bioRxiv2017

Abdominal adiposity negatively associates with the rate of long term sequential skill learning

Obesity is associated with functional and structural differences in the corticostriatal systems of the brain. These pathways are known to be critical for the acquisition of complex sensorimotor skills, such as the ability to learn a coordinated sequence of actions. Thus, individual differences in obesity should be associated with reduced efficiency of learning sequential skills. Here we measured long-term sequence learning across five days of training on the serial reaction time task in a cohort of neurologically healthy adults (N=30) with body types ranging from lean to obese. As expected, individuals with a greater degree of central adiposity, measured as central waist circumference, exhibited slower rates of learning, across all training days, than their leaner counterparts. This association between learning and central adiposity was restricted to response speeds, but not accuracy. These findings show that obesity is negatively associated with the efficiency of learning a long-term sequential skill, possibly due to previously observed associations between obesity and general basal ganglia function.

neuroscience↗