Altered extracellular vesicle microrna expression in ischemic stroke and small vessel disease

Active transport of microRNAs (miRNA) in extracellular vesicles (EV) occurs in disease. Circulating EV-packaged miRNAs in the serum of stroke patients were compared to stroke mimics with matched cardio- and cerebrovascular risk factors, with corroboration of results in a pre-clinical model. An unbiased miRNA microarray was performed in stroke vs stroke mimic patients (n=39). Results were validated (n=173 patients) by real-time quantitative polymerase chain reaction. miRNA expression was quantified in total serum/EV (n=5-7) of naïve adult spontaneously hypertensive stroke-prone rats (SHRSP), their normotensive reference strain (Wistar Kyoto, WKY) and in circulating EV (n=3), peri-infarct brain (n=6) or EV derived from this region (n=3) in SHRSP following transient middle cerebral artery occlusion (tMCAO). Circulating EV concentration did not differ between stroke and stroke mimic patients. The microarray identified many altered EV-packaged miRNAs: levels of miRNA-17-5p, -20b-5p and -93-5p (miRNA-17 family members) and miRNA-27b-3p were significantly (p≤0.05) increased in stroke vs stroke mimic patients. Patients with small vessel disease (SVD) consistently had the highest miRNA levels. Circulating EV concentration was unaltered between naïve SHRSP and WKY but levels of miRNA-17-5p and -93-5p were significantly increased in SHRSP. tMCAO in SHRSP did not further alter circulating EV miRNA-17 family member expression and nor did it change total miRNA-17 family levels in peri-infarct brain tissue or in EV isolated from this region at 24hrs post-tMCAO. Changes in EV packaged miRNA expression was validated in patients with stroke, particularly those with SVD, and corroborated pre-clinically. Together, altered circulating EV levels of miRNA-17 family members may reflect the chronic sequelae underlying cerebrovascular SVD rather than the acute ischemic stroke itself

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Integrating data types to estimate spatial patterns of avian migration across the Western Hemisphere

For many avian species, spatial migration patterns remain largely undescribed, especially across hemispheric extents. Recent advancements in tracking technologies and high-resolution species distribution models (i.e., eBird Status and Trends products) provide new insights into migratory bird movements and offer a promising opportunity for integrating independent data sources to describe avian migration. Here, we present a three-stage modeling framework for estimating spatial patterns of avian migration. First, we integrate tracking and band re-encounter data to quantify migratory connectivity, defined as the relative proportions of individuals migrating between breeding and nonbreeding regions. Next, we use estimated connectivity proportions along with eBird occurrence probabilities to produce probabilistic least-cost path (LCP) indices. In a final step, we use generalized additive mixed models (GAMMs) both to evaluate the ability of LCP indices to accurately predict (i.e., as a covariate) observed locations derived from tracking and band re-encounter data sets versus pseudo-absence locations during migratory periods and to create a fully integrated (i.e., eBird occurrence, LCP, and tracking/band re-encounter data) spatial prediction index for mapping species-specific seasonal migrations. To illustrate this approach, we apply this framework to describe seasonal migrations of 12 bird species across the Western Hemisphere during pre- and postbreeding migratory periods (i.e., spring and fall, respectively). We found that including LCP indices with eBird occurrence in GAMMs generally improved the ability to accurately predict observed migratory locations compared to models with eBird occurrence alone. Using three performance metrics, the eBird + LCP model demonstrated equivalent or superior fit relative to the eBird-only model for 22 of 24 species–season GAMMs. In particular, the integrated index filled in spatial gaps for species with over-water movements and those that migrated over land where there were few eBird sightings and, thus, low predictive ability of eBird occurrence probabilities (e.g., Amazonian rainforest in South America). This methodology of combining individual-based seasonal movement data with temporally dynamic species distribution models provides a comprehensive approach to integrating multiple data types to describe broad-scale spatial patterns of animal movement. Further development and customization of this approach will continue to advance knowledge about the full annual cycle and conservation of migratory birds

Microstructural Abnormalities in Subcortical Reward Circuitry of Subjects with Major Depressive Disorder

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression

Decision 2020 Electing Indiana's Future: Addressing 21st Century Environmental Challenges

Indiana University Center for Civic Literacy faculty and staff identified key policy areas facing Indiana in 2020, and enlisted experts in each of those areas. The resulting issue briefs provide policymakers and citizens with important context, background, and identify critical policy issues. Each brief is based upon research and analysis of available data about the state of Indiana, and includes comparisons with other states as well as national trends. Each guide also points readers to local and state level resources offering additional information on the topic

The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

<div><p>Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. <i>Chop</i>-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. <i>Chop</i>-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.</p></div

CHOP is induced by fibrotic insult and promotes fibrosis.

<p>(A) CCl₄ injection promotes collagen deposition. Masson's trichrome staining was used to assess collagen deposition (blue) in formalin-fixed paraffin-embedded liver sections of mice injected i.p. with 10% CCl₄ twice a week for 12 weeks, or with mineral oil as a control. (B–C) CHOP expression is associated with CCl₄-challenged livers. (B) CHOP was detected by IHC in mouse livers from (A) and samples were counterstained with hematoxylin as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#pgen-1003937-g001" target="_blank">Figure 1C</a>. Representative data are shown. (C) The number of CHOP-positive nuclei per microscopic field from (B) was quantitated in multiple fields from 3 mice per group, and is expressed here as mean +/− S.E.M. per field. (D–E) <i>Chop</i> deletion attenuates DEN-induced fibrosis. Mild-to-moderate fibrosis is seen in wild-type but not <i>Chop</i>−/− livers by trichrome staining after DEN treatment as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#pgen-1003937-g002" target="_blank">Figure 2</a>. Sections from two separate DEN-treated animals of each genotype are shown. (E) A METAVIR score was blindly determined from trichrome stains as described in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#s4" target="_blank">Materials and Methods</a>, and the p-value was calculated by Asymptotic Wilcoxon Rank Sum Test. 0 = no fibrosis; 1 = portal fibrosis lacking septa; 2 = portal fibrosis with some septa; 3 = abundant septa; 4 = cirrhosis.</p

CHOP promotes hepatocellular apoptosis and proliferation.

<p>(A) <i>Chop</i>−/− mice show reduced cell death upon DEN challenge. Apoptosis in vehicle- or DEN-treated livers of wild-type or <i>Chop</i>−/− mice was detected by IHC staining for the cleaved form of Caspase-3. Liver nodule borders are indicated by a dashed outline. Hematoxylin counterstain is not shown because it interfered with Caspase-3 staining. In (A–C), representative images are shown. (B–D) Reduced proliferation in <i>Chop</i>−/− DEN-challenged animals. Hepatocellular proliferation was detected by IHC staining for PCNA (B) or Ki-67 (C). (D) The extent of PCNA and Ki-67 staining was quantitated blindly as described in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003937#s4" target="_blank">Materials and Methods</a>. P-values were determined by Asymptotic Wilcoxon Rank Sum Test.</p

CHOP is expressed in human HCC tumors.

<p>(A) Histology of tumor-proximal liver (uninvolved HCC) and tumor (two regions) tissue from the same patient. H&E images are representative of 28 tumor samples and 5 uninvolved matched controls. For (A) only, scale bar = 100 µm (B–C) CHOP immunostaining is associated with human HCC but not uninvolved regions. (B) Samples from uninvolved tumor-proximal tissue and HCC tumors were probed for CHOP expression by immunohistochemistry. CHOP-positive nuclei are indicated by arrowheads. Cellular and nuclear architecture in some HCC samples was distorted as seen in the non-counterstained image, accounting for the large nuclei. Scale bar = 50 µm. (C) The average number of CHOP-positive nuclei per microscopic field per patient was quantitated blindly from 5 HCC tumors and their uninvolved matched controls, as well as from 4 non-HCC specimens, and these were aggregated by Boxplot. P-values were calculated by Asymptotic Wilcoxon Rank Sum Test. (D) HCC-associated CHOP is expressed in hepatocytes. Expression of CHOP (brown) and cell type-specific markers (blue) for hepatocytes (cytokeratin-18), macrophages (CD68), bile ducts (cytokeratin-7), or activated stellate cells (smooth muscle actin) is shown by immunohistochemistry, with a hematoxylin counterstain applied. Representative data are shown. Note that only hepatocytes show CHOP-positive nuclei; arrowheads are used to show CHOP-positive cells in other samples. Scale bar = 50 µm. Insets show 25 µm×25 µm regions with distinct CHOP-positive nuclei.</p