Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.

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Microplastics are ubiquitous environmental pollutants that are a growing concern to many ecosystems, as well as human health. Many of the effects of microplastics on mammalian cells and tissues remain unknown. To address this, we treated L929 murine fibroblasts and Madin–Darby canine kidney (MDCK) epithelial cell lines with 1 μg/mL, 10 μg/mL, or 20 μg/mL of polyethylene (PE) or polystyrene (PS) microspheres in vitro for 6 and 24 h and measured the resulting changes in cell viability, metabolism, and transcriptional expression of inflammatory cytokines and antioxidant enzymes. We observed dose-dependent decreases in cell viability corresponding to increases in doses of both PE and PS. We conducted cell metabolism assays and observed dose-dependent increases in metabolism per cell with increasing doses of both PE and PS. Similarly, we also observed increased expression of the superoxide dismutase-3 gene ( SOD3 ), indicating oxidative stress caused by the microplastics treatments. We also observed increased expression of TNFα , but decreased expression of IFNβ , suggesting different mechanisms by which the microplastics regulate inflammatory responses in mammalian cells. Our results contribute new data to the growing understanding of the effects of microplastics on mammalian cells and indicate complex cellular stress responses to microplastics in the environment.

The commensal microbes inhabiting a host tissue can interact with invading pathogens and host physiology in ways that alter pathogen growth and disease manifestation. Prior work in house finches (Haemorhous mexicanus) found that resident ocular microbiomes were protective against conjunctival infection and disease caused by a relatively high dose of Mycoplasma gallisepticum (MG). Here, we used wild-caught house finches to experimentally examine whether protective effects of the resident ocular microbiome vary with the dose of invading pathogen. We hypothesized that commensal protection would be strongest at low MG inoculation doses because the resident microbiome would be less disrupted by invading pathogen. Our five MG dose treatments were fully factorial with an antibiotic treatment to perturb resident microbes just prior to MG inoculation. Unexpectedly, we found no indication of protective effects of the resident microbiome at any pathogen inoculation dose, which was inconsistent with prior work. The ocular bacterial communities at the beginning of our experiment differed significantly from those previously reported in local wild-caught house finches, likely causing this discrepancy. These variable results underscore that microbiome-based protection in natural systems can be context dependent, and natural variation in community composition may alter the function of resident microbiomes in free-living animals.

2 7 SARS-CoV-2, the causative agent of COVID-19, is widespread in several countries around the 2 8 world following its late-2019 emergence in the human population. Rapid development of 2 9 molecular diagnostic tests and subunit vaccines have been prioritized, and as such evaluating 3 0 the SARS-CoV-2 genomic plasticity and evolutionary dynamics is an urgent need. We 3 1 determined the SARS-CoV-2 selectome by calculating rates of pervasive and episodic 3 2 diversifying selection for every amino acid coding position in the SARS-CoV-2 genome. To 3 3 provide context for evolutionary dynamics of a highly pathogenic betacoronavirus following a 3 4 zoonotic spillover into human hosts, we also determined the selectomes of SARS-CoV and 3 5 MERS-CoV, and performed evolvability calculations for SARS-CoV-2 based on SARS-CoV. 6These analyses identify the amino acid sites within each coding sequence that have been 3 7 subjected to pervasive diversifying selection or episodic diversifying selection, and report 3 8 significantly evolvable sites in the ORF1a polyprotein, the spike protein, and the membrane 3 9 protein of SARS-CoV-2. These findings provide a comprehensive view of zoonotic, highly 4 0 pathogenic betacoronavirus evolutionary dynamics that can be directly applied to diagnostic 4 1 assay and vaccine design for SARS-CoV-2. 4 2 4 3 4 4 4 5