👤 Brian T Palmisano

Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Former American football players ( Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration. Show less

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only Show less

Chronic alcohol drinking increases susceptibility to cognitive impairment; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of chronic alcohol drinking on working and recognition memory in a Marchigian Sardinian alcohol-preferring (msP) rat line. Due to interest in insulin-based medications for alcohol use disorder, we examined insulin/insulin-like growth factor 1 (IGF-1) genes in the prelimbic (PL) and infralimbic (IL) medial prefrontal cortex, a region linked to alcohol dependence and cognition. Male and female msPs received access to alcohol (20% v/v) and water (H Show less

Elevated triglycerides (TGs) and impaired TG clearance increase the risk of cardiovascular disease in both men and women, but molecular mechanisms remain poorly understood. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein cholesterol. Although mice lack CETP, transgenic expression of CETP in mice alters TG metabolism in males and females by sex-specific mechanisms. A unifying mechanism explaining how CETP alters TG metabolism in both males and females remains unknown. Since low-density lipoprotein receptor (LDLR) regulates both TG clearance and very low density lipoprotein (VLDL) production, LDLR may be involved in CETP-mediated alterations in TG metabolism in both males and females. We hypothesize that LDLR is required for CETP to alter TG metabolism in both males and females. We used LDLR null mice with and without CETP to demonstrate that LDLR is required for CETP to raise plasma TGs and to impair TG clearance in males. We also demonstrate that LDLR is required for CETP to increase TG production and to increase the expression and activity of VLDL synthesis targets in response to estrogen. Additionally, we show that LDLR is required for CETP to enhance β-oxidation. These studies support that LDLR is required for CETP to regulate TG metabolism in both males and females. Show less

Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease. Show less

The histology-based Gleason score (GS) of prostate cancer (PCa) tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide treatment strategies and patient management. The variability associated with PCa tumor sampling and the subjective determination of the GS are challenges that limit accurate diagnostication and prognostication. Thus, novel molecular signatures are needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, label-free LC-MS/MS proteomics is used to profile the proteome of 50 PCa tissues spanning five grade groups (n = 10 per group) relative to tissues from individuals with benign prostatic hyperplasia (BPH). Over 2000 proteins are identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. A panel of 11 prostate-derived proteins including IGKV3D-20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, and CTSZ display the potential to stratify patients from low and high PCa grade groups. Parallel reaction monitoring of the same sample cohort validate the differential expression of LMOD1, GYG1, IGKV3D-20, and RNASET2. The four proteins associated with low and high PCa grades reported here warrant further exploration as candidate biomarkers for PCa aggressiveness. Show less

In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast. Show less