Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages.

Progranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps in the understanding of the function(s) of progranulin in immune cells, and recent work has identified a novel target candidate called GPNMB. We addressed this gap by investigating the peritoneal macrophages of 5-6-month-old Grn KO mice, and we discovered that GPNMB is actively increased as a result of insufficient progranulin and that MITF, a transcription factor, is also dysregulated in progranulin-deficient macrophages. These findings highlight the importance of early-stage disease mechanism(s) in peripheral cell populations that may lead to viable treatment strategies to delay disease progression at an early, prodromal timepoint and extend therapeutic windows.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis.

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis.

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.

A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis.

The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis.

The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

Consequences of seafood mislabeling for marine populations and fisheries management.

Over the past decade, seafood mislabeling has been increasingly documented, raising public concern over the identity, safety, and sustainability of seafood. Negative outcomes from seafood mislabeling are suspected to be substantial and pervasive as seafood is the world's most highly traded food commodity. Here we provide empirical systems-level evidence that enabling conditions exist for seafood mislabeling in the United States (US) to lead to negative impacts on marine populations and support consumption of products from poorly managed fisheries. Using trade, production, and mislabeling data, we determine that substituted products are more likely to be imported than the product listed on the label. We also estimate that about 60% of US mislabeled apparent consumption associated with the established pairs involves products that are exclusively wild caught. We use these wild-caught pairs to explore population and management consequences of mislabeling. We find that, compared to the product on the label, substituted products come from fisheries with less healthy stocks and greater impacts of fishing on other species. Additionally, substituted products are from fisheries with less effective management and with management policies less likely to mitigate impacts of fishing on habitats and ecosystems compared with the label product. While we provide systematic evidence of environmental impacts from food fraud, our results also highlight the current challenges with production, trade, and mislabeling data, which increase the uncertainty surrounding seafood mislabeling consequences. More integrated, holistic, and collaborative approaches are needed to understand mislabeling impacts and design interventions to minimize mislabeling.

Academic progress of students across inclusive and traditional settings.

Effects of inclusive school settings for students in six Indiana school corporations were investigated. Results reveal that students without disabilities educated in inclusive settings made significantly greater academic progress in mathematics and reading. For students with disabilities, there were no significant differences in reading and math achievement across the comparison groups. However, a review of group means and the percentage of students making comparable or greater than average academic progress when compared to students without disabilities indicates a pattern in favor of inclusive settings. The academic progress of students with specific disability labels, namely, learning disabilities and mild mental handicaps, also supported inclusive education.