Florida State University

Merkel cell carcinoma (MCC) is a dermal neuroendocrine malignancy driven by inactivation of the tumor suppressors Rb and p53 either through Merkel cell polyomavirus (MCPyV) infection or ultraviolet (UV)-induced mutations. Virus-positive MCC exhibits pure neuroendocrine morphology, low UV-induced mutational burden, retained Rb protein, and low p53 expression. Viral-negative MCC includes pure neuroendocrine carcinomas and combined tumors with squamous and neuroendocrine components. These tumors typically exhibit loss of Rb expression and either overexpression of mutated p53 or a complete absence of p53. Intraepidermal, insitu MCC (MCCis) is a rare, primarily viral-negative variant that often coexists with actinic keratosis (AK) and squamous cell carcinoma insitu (SCCis), supporting a UV-driven pathogenesis. While MCCis is hypothesized as a potential precursor to select cases of combined MCC, its p53 and Rb expression remain largely uncharacterized. We report a CM2B4-negative MCCis in an 87-year-old man associated with AK and SCCis. Compared to normal epidermis, AK and SCCis exhibited increased Rb and p53 expression, whereas MCCis demonstrated loss of expression of both tumor suppressors. These findings suggest that dual downregulation of Rb and p53 may drive select cases of MCCis in sun-damaged skin.

Understanding the mechanisms driving behavioral evolution enhances our knowledge of speciation and how behavioral potentials are encoded. Drosophila male courtship behaviors, which evolve rapidly, are directed by fruitless-expressing neurons. Here, we investigate how species differences arise from shared molecular-genetic and circuit architecture. We examined courtship in pure species Drosophila melanogaster, Drosophila simulans, and hybrids. This design allowed us to assess how hybrid males integrate behavioral repertoires from both parental species. To identify the neural correlates for hybrid courtship behaviors, we examined fruitless-expressing neurons in hybrids. Their projection patterns resembled those in D. melanogaster, indicating largely conserved circuit architecture. To identify molecular differences that drive behavioral differences between species, we identified male-specific fruitless target genes in both species, revealing conserved core and species-specific targets. Focusing on chemosensory receptors with D. melanogaster-specific fruitless binding, we conducted a genetic screen in D. melanogaster, silencing neurons co-expressing fruitless and specific receptor genes. Courtship preference assays identified 3 additional olfactory receptor neuron subtypes that modulate behavior. Using a transsynaptic mapping approach, we mapped second-order projection neurons of these subtypes, revealing their targets in higher-order brain centers. This study uncovers new molecular and neural mechanisms underlying the specification and evolution of courtship behavior, highlighting how genetic and sensory inputs shape species-specific behavioral outcomes.

There has been considerable interest in understanding the causes, behavioral patterns, and consequences associated with career criminals. Much of the early research on career criminals was atheoretical, but with the advancement of life-course and developmental research more and more research on career criminals was guided by theoretical explanations. Even so, there remains much that is unknown about whether criminological theories are useful in explaining career criminals. The current study partially addressed this gap in the literature by examining whether concepts drawn from Gottfredson and Hirschi’s (1990) theory and Moffitt’s (1993) taxonomy were able to explain age of criminal onset and the duration of the criminal career and whether career criminal measures were associated with the odds of being convicted and incarcerated when accounting for measures from these criminological theories. Arrestees drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health) were analyzed. The results of some of the models revealed that low self-control and neuropsychological functioning were related to age of criminal onset, but not the duration of the criminal career. Moreover, measures of self-control, neuropsychological functioning, and age of criminal onset were unrelated to the odds of being convicted and incarcerated.

We introduce a novel variable selection method for high-dimensional generalized linear models, called Randomized Smart Subset Selection (RS3). RS3 combines randomized block-wise model fitting with importance-weighted stochastic subset sampling to efficiently identify active predictors. Two extensions are proposed: (i) RS3+SCAD, which applies penalized regression with the SCAD penalty to a reduced set of candidate variables, improving computational efficiency while adaptively determining model size; and (ii) RS3+FPCS, a subsampling-based procedure for false positive control based on coefficient sign stability. Simulation studies demonstrate that RS3 and its variants achieve high true positive rates with low false discovery, even under moderate predictor correlation. Applications to gene expression data show that RS3+SCAD consistently identifies sparse, biologically interpretable gene sets, outperforming existing methods in terms of prediction accuracy and stability. MSC Codes: 62F40, 62J12, 62H30

Living Biotherapeutic Products (LBPs) offer a promising therapeutic strategy for metabolic disorders rooted in gut microbiome dysfunction, yet quantitative frameworks for predicting their efficacy remain underdeveloped. We introduce the Bacterial Compartment Absorption and Transit (BCAT) model, a pharmacokinetic-pharmacodynamic framework that couples probiotic transit, endogenous microbiome metabolism, and enzymatic transformation within a unified dose-optimization setting. Building on the classical CAT model, BCAT incorporates mechanistically-derived colon compartments and treats dosing time as a control variable. We validate BCAT against clinical data for native choline metabolism and SYNB1618 probiotic trials, achieving 5% mean prediction error compared to ~30% for prior two-compartment models. Applying BCAT to trimethylaminuria (TMAU), we predict that ~109 CFU of engineered probiotic, administered 3-4 h before meals, achieves 95% reduction in systemic trimethylamine, matching healthy hepatic clearance. Global sensitivity analysis identifies enzyme expression level as the dominant design parameter, enforcing the broad applicability of this model. The BCAT framework generalizes to any gut microbiome-mediated metabolic disorder and provides quantitative dosing targets to guide live biotherapeutic development.