Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

“I attend at Vanguard and I attend here as well”: barriers to accessing healthcare services among older South Africans with HIV and non-communicable diseases

Background: HIV and non-communicable disease (NCD) are syndemic within sub-Saharan Africa especially among older persons. The two epidemics interact with one another within a context of poverty, inequality and inequitable access to healthcare resulting in an increase in those aged 50 and older living with HIV and experiencing an NCD comorbidity. We explore the challenges of navigating healthcare for older persons living with HIV and NCD co-morbidity. Methods: In-depth semi-structured interviews were conducted with a small sample of older persons living with HIV (OPLWH). The perspectives of key informants were also sought to triangulate the evidence of OPLWH. The research took place in two communities on the outskirts of Cape Town, South Africa. All interviews were conducted by a trained interviewer and transcribed and translated for analysis. Thematic content analysis guided data analysis. Results: OPLWH experienced an HIV-NCD syndemic. Our respondents sought care and accessed treatment for both HIV and other chronic (and acute) conditions, though these services were provided at different health facilities or by different health providers. Through the syndemic theory, it is possible to observe that OPLWH and NCDs face a number of physical and structural barriers to accessing the healthcare system. These barriers are compounded by separate appointments and spaces for each condition. These difficulties can exacerbate the impact of their ill-health and perpetuate structural vulnerabilities. Despite policy changes towards integrated care, this is not the experience of OPLWH in these communities. Conclusions: The population living with HIV is aging increasing the likelihood that those living with HIV will also be living with other chronic conditions including NCDs. Thus, it is essential that health policy address this basic need to integrate HIV and NCD care

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Narrative suspense. "When Slim turned sideways ..."

http://babel.hathitrust.org/cgi/pt?id=mdp.39015066080709;view=2up;ui=fullscreen#page/n0/mode/2u

The Romance of Space Travel: On the Sexual Iconography of Spacecraft

EDITOR'S INTRODUCTION | Eric Rabkin, professor of English at the University of Michigan, turns an eye to popular culture to look at America's romance with space exploration over the course of the past century. Providing a close reading of science fiction literature and movies, Rabkin examines the familiar images of spacecraft — probing rockets, invading saucers, and contemporary space stations — and their psychosexual dimension in the American cultural imagination.http://deepblue.lib.umich.edu/bitstream/2027.42/55287/11/3175_5vanguard_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/1/3175_1melies1_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/23/3175_9amazingstories.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/8/3175_3melies3_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/21/3175_9amazingstories_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/13/3175_5vanguard.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/5/3175_2melies2_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/16/3175_7columbia2_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/14/3175_6columbia.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/3/3175_1melies1.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/25/button_close.gifhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/19/3175_8dayearth_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/15/3175_7columbia2_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/29/rabkin.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/24/3175_10spacestation.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/20/3175_8dayearth.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/12/3175_5vanguard_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/9/3175_3melies3.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/7/3175_3melies3_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/4/3175_2melies2_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/27/main.csshttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/26/index.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/22/3175_9amazingstories_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/17/3175_7columbia2.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/6/3175_2melies2.htmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/2/3175_1melies1_sm.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/28/pop.csshttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/18/3175_8dayearth_lg.jpghttp://deepblue.lib.umich.edu/bitstream/2027.42/55287/10/3175_4germanv2.jp