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McMahan, C.

Publications and source records attributed to McMahan, C..

5 recordsLinked to original sources

Infectious Disease Forecasting via Physics-Informed Machine Learning

Infectious disease transmission evolves as a dynamic process shaped by biological mechanisms, population behavior, and intervention policies, yet public health responses are often driven by lagging indicators. Accurate short- and long-term disease forecasting is essential for the timely deployment of intervention strategies, healthcare capacity planning, and uncertainty-aware, risk-informed decision-making. To address this challenge, three broad classes of forecasting models have traditionally been used: statistical, machine learning, and mechanistic approaches. However, each of these modeling paradigms faces fundamental limitations. In particular, traditional statistical models often lack the flexibility needed to capture complex disease dynamics, machine learning approaches require large, high-quality data streams, and mechanistic models are notoriously difficult to calibrate. To overcome these challenges, we propose a novel physics-informed machine learning (PIML) framework for forecasting infectious disease dynamics. Our approach simultaneously forecasts new case and hospitalization counts, along with other key epidemiological quantities such as the time-varying reproduction number. This is achieved through the design of a machine learning model and estimation strategy regularized by a system of differential equations that encode disease dynamics of the SIHR model, thereby bridging the gap between purely data-driven and mechanistic models. We demonstrate the proposed methodology through in-depth numerical studies and an application to COVID-19 data collected in the state of South Carolina.

bioinformatics↗

Exosome-like biogenesis from the Golgi releases extracellular vesicles lacking conventional tetraspanins that mediate immune evasion in cancer

Immunotherapy has improved survival across multiple malignancies but remains largely ineffective in solid cancers such as lung, breast, and pancreatic cancer. A key driver of resistance is the immunosuppressive tumor microenvironment (TME). Although numerous mediators of TME immunosuppression have been identified, therapeutic targeting has provided limited clinical benefit. Tumor-derived extracellular vesicles (EVs) have recently emerged as contributors to resistance, yet their mechanisms remain unclear. We developed human non-small cell lung cancer models to investigate EV-mediated immunosuppression. We identified a distinct Golgi-derived EV subpopulation that potently suppress T cell function and tumor infiltration. These EVs express the trans-Golgi network marker TGOLN2, and exhibit minimal levels of canonical EV markers. TGOLN2 overexpression drives this suppressive phenotype. Clinically, elevated TGOLN2 associates with poor survival and correlate with an immunosuppressive TME signature across more than 20 cancer types, including NSCLC. Collectively, this work defines a previously unrecognized mechanism of TGOLN2-driven, EV-mediated immunosuppression. Statement of SignificanceWe revealed TGOLN2 overexpression as a new immune evasion mechanism that mediates T cell suppression through increased secretion of a Golgi-derived extracellular vesicle (EV) subpopulation. These findings redefine current paradigms of EV biology and nominate TGOLN2 as a potential biomarker and therapeutic target in immunosuppressive cancers.

cell biology↗

Real-time activity of dynorphin-expressing neurons in mouse central amygdala during alcohol drinking

Alcohol use disorder (AUD) is a chronic disease that poses significant economic burden and health risks. It is pivotal to better understand brain mechanisms engaged by alcohol that promote misuse. The central amygdala (CeA) has emerged as a key mediator of excessive preclinical alcohol consumption. A dynorphin-expressing subpopulation within the CeA (CeADyn) has been implicated in excessive alcohol drinking, yet how cellular activity of CeADyn neurons relates to ongoing alcohol drinking is not well-understood. The current study interrogated the engagement of CeADyn neurons in male and female mice during voluntary alcohol consumption using fiber photometry and compared this cellular response with that of other solutions having similar motivational and/or taste characteristics. Activity of a calcium sensor, GCaMP7f, expressed in mouse CeADyn neurons was recorded and time-locked to bouts of drinking. Multilevel linear mixed modeling was applied to better resolve focal effects from complex data. These analyses revealed a relatively large increase in CeADyn neuron calcium transients after bouts of alcohol drinking compared to water or sucrose drinking, indicating these neurons are uniquely engaged during alcohol consumption. Drinking behavior unique to alcohol (i.e., longer bout durations) did not fully explain signal differences between alcohol and other solutions nor did the relatively increased alcohol response diminish over time. No other conditions or solutions tested reproduced the pronounced change in CeADyn activity associated with alcohol drinking. These findings, collectively, support the presence of a unique functional signature for alcohol in a cell population known to control excessive alcohol drinking. HighlightsO_LICentral amygdala dynorphin cells (CeADyn) are firmly implicated in alcohol misuse. C_LIO_LICeADyn neuron activity was higher when mice drank alcohol versus other solutions. C_LIO_LINeither how mice drank alcohol nor motivational states could explain this activity. C_LIO_LICeADyn neurons having uniquely high alcohol responses may underlie AUD development. C_LI

neuroscience↗

Adaptor protein complex 2 in the orbitofrontal cortexpredicts alcohol use disorder

Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences. The inability of individuals with AUD to regulate drinking may involve functional deficits in cortical areas that normally balance actions that have aspects of both reward and risk. Among these, the orbitofrontal cortex (OFC) is critically involved in goal-directed behavior and is thought to maintain a representation of reward value that guides decision making. In the present study, we analyzed post-mortem OFC brain samples collected from age- and sex-matched control subjects and those with AUD using proteomics, bioinformatics, machine learning, and reverse genetics approaches. Of the 4,500+ total unique proteins identified in the proteomics screen, there were 47 proteins that differed significantly by sex that were enriched in processes regulating extracellular matrix and axonal structure. Gene ontology enrichment analysis revealed that proteins differentially expressed in AUD cases were involved in synaptic and mitochondrial function, as well as transmembrane transporter activity. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and social interactions. Machine learning analysis of the post-mortem OFC proteome revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Using a reverse genetics approach to validate a target protein, we found that prefrontal Ap2a1 expression significantly correlated with voluntary alcohol drinking in male and female genetically diverse mouse strains. Moreover, recombinant inbred strains that inherited the C57BL/6J allele at the Ap2a1 interval consumed higher amounts of alcohol than those that inherited the DBA/2J allele. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms and proteins that control drinking in individuals with AUD.

neuroscience↗

Genetic Risk Factors for Colorectal Cancer in Multiethnic Indonesians

PurposeColorectal cancer is a common cancer in Indonesia, yet it has been understudied. We conduct a genome-wide association study focused on evaluation and discovery of colorectal cancer risk factors in Indonesians.\n\nMethodsWe administered detailed questionnaires and collecting blood samples from 162 colorectal cancer cases throughout Makassar, Indonesia. We also established a control set of 193 healthy individuals frequency matched by age, sex, and ethnicity. A genome-wide association analysis was performed on 84 cases and 89 controls passing quality control. We evaluated known colorectal cancer genetic variants using logistic regression and established a genome-wide polygenic risk model using a Bayesian variable selection technique.\n\nResultsWe replicate associations for rs9497673, rs6936461 and rs7758229 on chromosome 6; rs11255841 on chromosome 10; and rs4779584, rs11632715, and rs73376930 on chromosome 15. Polygenic modeling identified 10 SNP associated with colorectal cancer risk.\n\nConclusionsThis work helps characterize the relationship between variants in the SCL22A3, SCG5, GREM1, and STXBP5-AS1 genes and colorectal cancer in a diverse Indonesian population. With further biobanking and international research collaborations, variants specific to colorectal cancer risk in Indonesians will be identified.

genomics↗