Modification of Proteins by Norepinephrine is Important for Vascular Contraction

Norepinephrine (NE) is thought to mediate its effects through G-protein coupled receptors. However, previous studies have shown that NE and another primary amine, serotonin, also have the ability to exert effects in a receptor-independent manner. We hypothesized that the enzyme transglutaminase II (TG II) has the ability to modify proteins with NE and that this modification is physiologically relevant. As our model we used rat aortic and vena cava tissues, two tissues that depend on NE to modulate vascular tone. Immunohistochemical and immunocytochemical staining showed that NE and TG II are present in smooth muscle cells of these tissues. Western analysis shows aorta and vena cava homogenate proteins are recognized by an antibody raised against NE conjugated to bovine serum albumin (NE-BSA). NE and α-actin colocalize in cultured aorta and vena cava smooth muscle cells. Freshly dissociated smooth muscle cells from these vessels were able to take up NE-biotin. In isolated tissue baths, inhibition of TG II with cystamine (0.5 mM) completely abolished NE-induced contraction in the aorta but only attenuated the receptor-independent contractant KCl (max contraction to 100 mM KCl in cystamine treated = 88.8 ± 7.0% of vehicle treated, p < 0.05). In the vena cava, contraction to NE was abolished with 0.1 mM cystamine and KCl contraction was attenuated (max contraction to 100 mM KCl in cystamine treated = 54.8 ± 7.0% of vehicle treated, p < 0.05). Taken together, these results show that vascular smooth muscle cells take up and utilize NE for the modification of proteins, and that this modification may play an important role in vascular contraction

Perspectives of healthcare workers on the integration of overdose detection technologies in acute care settings

Abstract Background People who use drugs (PWUD) face disproportionately high rates of hospitalizations and patient-initiated discharge (leaving against medical advice), explained by a combination of stigma, withdrawal, judgment, blame, and improper pain management. In addition, evidence has shown that despite abstinence-based policies within healthcare settings, PWUD continue to use their substances in healthcare environments often hidden away from hospital staff, resulting in fatalities. Various novel overdose detection technologies (ODTs) have been developed with early adoption in a few settings to reduce the morbidity and mortality from risky substance use patterns within healthcare environments. Our study aimed to gain the perspectives of healthcare workers across Canada on implementing ODTs within these settings. Method We used purposive and snowball sampling to recruit 16 healthcare professionals to participate in semi-structured interviews completed by two evaluators. Interview transcripts were analyzed using thematic analysis to identify key themes and subthemes. Results Participants recognized ODTs as a potentially feasible solution for increasing the safety of PWUD in healthcare settings. Our results suggest the mixed ability of these services to decrease stigma and build rapport with PWUD. Participants further highlighted barriers to implementing these services, including pre-established policies, legal recourse, and coordination of emergency responses to suspected overdoses. Lastly, participants highlight that ODTs should only be one part of a multifaceted approach to reducing harm in healthcare settings and could currently be integrated into discharge planning. Conclusion Healthcare professionals from across Canada found ODTs to be an acceptable intervention, but only as part of a larger suite of harm reduction interventions to reduce the harms associated with illicit drug use in healthcare settings. In contrast, participants noted institutional policies, stigma on behalf of healthcare workers and leadership would present significant challenges to their uptake and dissemination

Koinonia

Spotlight FeaturesSovereign Stumbling: My Life Journey to Date, Larry Crabb Conversations About Racism, Jessie Brown Anxiety: A Growing Problem in College Students, Steven M. Conn Thinking TheologicallyTeaching the Truth, Michael and Stephanie Santarosa Book ReviewsKingdom Triangle: Recover the Christian Mind, Renovate the Soul, Restore the Spirit\u27s Power (by J.P. Moreland), reviewed by Steve Ivester The Soul of a Christian University: A Field Guide for Educators (edited by Stephen T. Beers), reviewed by Kyle Lantz The Outrageous Idea of Academic Faithfullness (by Donald Opitz and Derek Melleby), reviewed by Nathan Geer I Once Was Lost: What Postmodern Skeptics Taught Us About Their Path to Jesus (by Don Everts and Doug Schaupp), reviewed by Andrew D. Rowell FeaturesThe President\u27s Corner Editor\u27s Deskhttps://pillars.taylor.edu/acsd_koinonia/1012/thumbnail.jp

A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Staphylococcus aureus bacteremia in pediatric patients: Uncovering a rural health challenge

BACKGROUND: METHODS: To investigate factors influencing RESULTS: Of 251 patients, 69 (27%) were from rural areas; 28 (11%) were initially admitted to an OSH. Treatment failure occurred in 39 (16%) patients. Patients from rural areas were more likely to be infected with methicillin-resistant CONCLUSIONS: Children from rural areas face barriers to specialized health care. These challenges may contribute to severe illness and worse outcomes among children wit

Galactic Globular and Open Clusters in the Sloan Digital Sky Survey. I. Crowded Field Photometry and Cluster Fiducial Sequences in ugriz

We present photometry for globular and open cluster stars observed with the Sloan Digital Sky Survey (SDSS). In order to exploit over 100 million stellar objects with r < 22.5 mag observed by SDSS, we need to understand the characteristics of stars in the SDSS ugriz filters. While star clusters provide important calibration samples for stellar colors, the regions close to globular clusters, where the fraction of field stars is smallest, are too crowded for the standard SDSS photometric pipeline to process. To complement the SDSS imaging survey, we reduce the SDSS imaging data for crowded cluster fields using the DAOPHOT/ALLFRAME suite of programs and present photometry for 17 globular clusters and 3 open clusters in a SDSS value-added catalog. Our photometry and cluster fiducial sequences are on the native SDSS 2.5-meter ugriz photometric system, and the fiducial sequences can be directly applied to the SDSS photometry without relying upon any transformations. Model photometry for red giant branch and main-sequence stars obtained by Girardi et al. cannot be matched simultaneously to fiducial sequences; their colors differ by ~0.02-0.05 mag. Good agreement (< ~0.02 mag in colors) is found with Clem et al. empirical fiducial sequences in u'g'r'i'z' when using the transformation equations in Tucker et al.Comment: 30 pages, 25 figures. Accepted for publication in ApJS. Version with high resolution figures available at http://www.astronomy.ohio-state.edu/~deokkeun/AnJohnson.pd

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity

Global Times Call for Global Measures: Investigating Automated Essay Scoring in Linguistically-Diverse MOOCs

This paper utilizes a case-study design to discuss global aspects of massive open online course (MOOC) assessment. Drawing from the literature on open-course models and linguistic gatekeeping in education, we position freeform assessment in MOOCs as both challenging and valuable, with an emphasis on current practices and student resources. We report on the findings from a linguistically-diverse pharmacy MOOC, taught by a native English speaker, which utilized an automated essay scoring (AES) assignment to engage students in the application of course content. Native English speakers performed better on the assignment overall, across both automated- and human-graders. Additionally, our results suggest that the use of an AES system may disadvantage non-native English speakers, with agreement between instructor and AES scoring being significantly lower for non-native English speakers. Survey responses also revealed that students often utilized online translators, though analyses showed that this did not detrimentally affect essay grades. Pedagogical and future assignment suggestions are then outlined, utilizing a multicultural-lens and acknowledging the possibility of certain assessments disadvantaging non-native English speakers within an English-based MOOC system

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease