Biology subjects

Carroll, C.

Publications and source records attributed to Carroll, C..

7 recordsLinked to original sources

bioRxiv2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma

PurposeSWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. Experimental DesignWe performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. ResultsApproximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A-mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. ConclusionsBAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

cancer biology↗

bioRxiv2024

An Open-Source Deep Learning-Based GUI Toolbox For Automated Auditory Brainstem Response Analyses (ABRA)

Hearing loss is a pervasive global health challenge with profound impacts on communication, cognitive function, and quality of life. Recent studies have established age-related hearing loss as a significant risk factor for dementia, highlighting the importance of hearing loss research. Auditory brainstem responses (ABRs), which are electrophysiological recordings of acoustically evoked synchronized neural activity from the auditory nerve and brainstem, serve as in vivo correlates for sensory hair cell and synaptic function, hearing sensitivity, and other critical readouts of auditory pathway physiology, making them highly valuable for both basic neuroscience and clinical research. Despite their utility, traditional ABR analyses rely heavily on subjective manual interpretation, which may introduce variability and pose challenges for reproducibility across studies. Here, we introduce Auditory Brainstem Response Analyzer (ABRA), a novel suite of open-source ABR analysis tools powered by deep learning, which automates and standardizes ABR waveform analysis. ABRA employs convolutional neural networks trained on diverse datasets collected from multiple experimental settings, achieving rapid and unbiased extraction of key ABR metrics, including peak amplitude, latency, and auditory threshold estimates. We demonstrate that ABRAs deep learning models provide performance comparable to expert human annotators while dramatically reducing analysis time and enhancing reproducibility across datasets from different laboratories. By bridging hearing research, sensory neuroscience, and advanced computational techniques, ABRA facilitates broader interdisciplinary insights into auditory function. An online version of the tool is available for use at no cost at https://abra.ucsd.edu.

neuroscience↗

bioRxiv2022

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload ([~]30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide array of biological processes and molecular functions in numerous cellular compartments differed in TGAC8 vs WT; and over 250 canonical signaling pathways characteristic of adaptive survival circuitry of cancers, including PI3K and growth factor signaling, cytokine and T cell receptor signaling, immune responses, ROS scavenging, proliferation, protection from apoptosis, and nutrient sensing, were activated in TGAC8; and compared to WT there was a shift from fatty acid oxidation to increased aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, the adaptive paradigm, that becomes activated in the LV of TGAC8 in response to severe chronic, intense AC/PKA/Ca2+ signaling embodies many hallmarks of cancer.

physiology↗

bioRxiv2020

Female excellence in rock climbing likely has an evolutionary origin

The human body is exceptional for many reasons, not the least of which is the wide variety of movements it is capable of executing. Because our species is able to execute so many discrete activities, researchers often disagree on which were the movements most essential to the evolution of our species. This paper continues a recently introduced analysis, that the performance gap between female and male athletes narrows in sports which most reflect movements humans evolved to do. Here, I examine the performance gap in rock climbing. Because rock climbing is so similar to tree climbing, which bountiful evidence suggests has been key to the origin and proliferation of our species, we would expect to see a narrow performance gap between men and women in the sport. Indeed, this is the case. Female climbers are some of the best in the world irrespective of gender, a trend that is not found in any other major sport. I conclude that exceptional ability of female climbers is further evidence of the existence of sex-blind musculoskeletal adaptations, which developed over the course of human evolution to facilitate essential movements. These adaptations abate the general physical sexual dimorphism which exists in humans. This paper provides more evidence that the performance gap in sport can be used as a measure of human evolution.

evolutionary biology↗

bioRxiv2020

Nectar-dwelling microbes of common tansy are attractive to its mosquito pollinator, Culex pipiens L.

BackgroundThere is widespread interkingdom signalling between insects and microbes. For example, microbes found in floral nectar may modify its nutritional composition and produce odorants that alter the floral odor bouquet which may attract insect pollinators. Mosquitoes consume nectar and can pollinate flowers. We identified microbes isolated from nectar of common tansy, Tanacetum vulgare, elucidated the microbial odorants, and tested their ability to attract the common house mosquito, Culex pipiens. ResultsWe collected 18 microbial isolates from T. vulgare nectar, representing at least 12 different taxa which we identified with 16S or 26S rDNA sequencing as well as by biochemical and physiological tests. Three microorganisms (Lachancea thermotolerans, Micrococcus lactis, Micrococcus luteus) were grown on culture medium and tested in bioassays. Only the yeast L. thermotolerans grown on nectar, malt extract agar, or in synthetic nectar broth significantly attracted C. pipiens females. The odorant profile produced by L. thermotolerans varied with the nutritional composition of the culture medium. Surprisingly, all three microbes grown separately, but presented concurrently, attracted fewer C. pipiens females than L. thermotolerans by itself. ConclusionsFloral nectar of T. vulgare contains various microbes whose odorants contribute to the odor profile of inflorescences. In addition, L. thermotolerans produced odorants that attract Cx. pipiens females. As the odor profile of L. thermotolerans varied with the composition of the culture medium, we hypothesize that microbe odorants inform nectar-foraging mosquitoes about the availability of certain macro-nutrients which, in turn, affect foraging decisions by mosquitoes.

ecology↗

bioRxiv2019

The impact of genistein supplementation on tendon functional properties and gene expression in estrogen deficient rats

PurposeTendinopathy risk increases with menopause. The phytoestrogen genistein prevents collagen loss during estrogen deficiency [ovariectomy (OVX)]. The influence of genistein on tendon function and extracellular matrix (ECM) regulation are not well known. We determined the impact of genistein on tendon function and examined potential mechanisms by which genistein alters tendon ECM.\n\nMaterials and MethodsEight-week-old rats (n=42) were divided into three groups: intact, OVX, or OVX-genistein (6mg/kg/day) for 6-weeks. Tail fascicles were assessed with a Deben tensile stage. Achilles tendon mRNA expression was determined with digital droplet PCR. Tendon-derived fibroblasts were also treated with genistein in the presence of estrogen receptor (ER) antagonists.\n\nResultsCompared to intact, stress tended to be lower in untreated OVX rats (p=0.022). Further, modulus and energy density were greater in genistein-treated rats (p<0.05) compared to intact. Neither OVX nor genistein altered expression of Col1a1, Col3a1, Casp3, Casp8, Mmp1a, Mmp2, or Mmp9 (p>0.05). Compared to intact, Tnmd and Esr1 expression was greater and Pcna and Timp1 expression lower in OVX rats (p<0.05). Genistein treatment returned Tnmd, Pcna, and Timp1 to levels of Intact-Vehicle (p<0.05), but did not alter Scx or Esr1 (p>0.05). Several {beta}-catenin/Wnt signaling related molecules were not altered by OVX or genistein (p>0.05). In vitro, genistein blunted cell proliferation but not via ERs.\n\nConclusionsOur findings demonstrate that genistein improves tendon function. Genistein inhibits cell proliferation in vitro but not via ER. The effect of genistein in vivo was predominately on genes related to cell proliferation rather than collagen remodeling.

physiology↗

bioRxiv2019

Effect of Antimicrobial Stewardship with Rapid MALDI-TOF Identification and Vitek 2 Antimicrobial Susceptibility Testing on Hospitalization Outcome

IntroductionRapid organism identification (ID) and antimicrobial susceptibility testing (AST) along with antibiotic stewardship (ASP) are critical to appropriate treatment. We sought to capture time for bacterial culture and initiation of appropriate therapy for patients, from 2017 (without MALDI-TOF/Vitek 2 and ASP) and 2018 (with MALDI-TOF/Vitek 2 and ASP).\n\nMethodsEligible patients admitted to our hospital with a positive sputum, blood, or urine culture. Sequential patients were retrospectively obtained from March 1 to May 31, 2017. Seventy-seven patients from 2017 were compared to 77 patients from 2018. A time-in-motion study was performed to compare time to identification (ID), AST results, and ASP team intervention for the two periods. Data were entered into SPSS (ver 25) for analysis. Results are reported as mean ({+/-} SD) or percentage.\n\nResultsTime to organism ID was significantly faster in 2018 (2018 24.9 {+/-} 14.4, 2017 33.8 {+/-} 17 h, p=0.001). Time to AST results was also significantly faster for patients in 2018 compared to 2017 (18.2 {+/-} 14 compared to 28.5 {+/-} 14.9 h, p<0.001). ASP team recommended significantly more adjustments to empiric antimicrobial therapy in 2018 (28% of 2018 vs. 2% in 2017, p< 0.001). Length of hospital stay was significantly shorter in 2018 compared to 2017 (2018 10.7 {+/-} 11.1 days and 2017 15.5 {+/-} 18.1 days, p=0.05).\n\nConclusionsUse of MALDI-TOF/Vitek 2 leads to an average 21.5 h faster ID and AST results that can be acted upon by ASP for appropriate antimicrobial recommendations.

microbiology↗