Loss of the chromatin regulator MRG15 limits neural stem/progenitor cell proliferation via increased expression of the p21 Cdk inhibitor

AbstractChromatin regulation is crucial for many biological processes such as transcriptional regulation, DNA replication, and DNA damage repair. We have found that it is also important for neural stem/progenitor cell (NSC) function and neurogenesis. Here, we demonstrate that expression of the cyclin-dependent kinase inhibitor p21 is specifically up-regulated in Mrg15 deficient NSCs. Knockdown of p21 expression by p21 shRNA results in restoration of cell proliferation. This indicates that p21 is directly involved in the growth defects observed in Mrg15 deficient NSCs. Activated p53 accumulates in Mrg15 deficient NSCs and this most likely accounts for the up-regulation of p21 expression in the cells. We observed decreased p53 and p21 levels and a concomitant increase in the percentage of BrdU positive cells in Mrg15 null cultures following expression of p53 shRNA. DNA damage foci, as indicated by immunostaining for γH2AX and 53BP1, are detectable in a sub-population of Mrg15 deficient NSC cultures under normal growing conditions and the majority of p21-positive cells are also positive for 53BP1 foci. Furthermore, Mrg15 deficient NSCs exhibit severe defects in DNA damage response following ionizing radiation. Our observations highlight the importance of chromatin regulation and DNA damage response in NSC function and maintenance

Benefactors, Bonds, and Beholders: The Beliefs and Reality Behind Beethoven’s Behavior

This paper will explore the relationships which Beethoven had during the years he composed and premiered his Eroica Symphony. Some of the individuals who will be discussed in this paper include Prince Lobkowitz, Ferdinand Ries, and Franz Wegeler. After learning about the nature of these relationships, the reader should begin to realize that Beethoven’s notoriously irrational or ill-tempered behavior was only one facet of his life

Acceleration of Enterococcus faecalis Biofilm Formation by Aggregation Substance Expression in an Ex Vivo Model of Cardiac Valve Colonization

Infectious endocarditis involves formation of a microbial biofilm in vivo. Enterococcus faecalis Aggregation Substance (Asc10) protein enhances the severity of experimental endocarditis, where it has been implicated in formation of large vegetations and in microbial persistence during infection. In the current study, we developed an ex vivo porcine heart valve adherence model to study the initial interactions between Asc10+ and Asc10− E. faecalis and valve tissue, and to examine formation of E. faecalis biofilms on a relevant tissue surface. Scanning electron microscopy of the infected valve tissue provided evidence for biofilm formation, including growing masses of bacterial cells and the increasing presence of exopolymeric matrix over time; accumulation of adherent biofilm populations on the cardiac valve surfaces during the first 2–4 h of incubation was over 10-fold higher than was observed on abiotic membranes incubated in the same culture medium. Asc10 expression accelerated biofilm formation via aggregation between E. faecalis cells; the results also suggested that in vivo adherence to host tissue and biofilm development by E. faecalis can proceed by Asc10-dependent or Asc10-independent pathways. Mutations in either of two Asc10 subdomains previously implicated in endocarditis virulence reduced levels of adherent bacterial populations in the ex vivo system. Interference with the molecular interactions involved in adherence and initiation of biofilm development in vivo with specific inhibitory compounds could lead to more effective treatment of infectious endocarditis

The Stellar Content of Obscured Galactic Giant H II Regions III.: W31

We present near infrared (J, H, and K) photometry and moderate resolution (lambda/Deltalambda = 3000) K-band spectroscopy of the embedded stellar cluster in the giant H II region W31. Four of the brightest five cluster members are early O--type stars based on their spectra. We derive a spectro--photometric distance for W31 of 3.4 +/- 0.3 kpc using these new spectral types and infrared photometry. The brightest cluster source at K is a red object which lies in the region of the J - H vs. H - K color--color plot inhabited by stars with excess emission in the K-band. This point source has an H plus K-band spectrum which shows no photospheric features, which we interpret as being the result of veiling by local dust emission. Strong Brackett series emission and permitted FeII emission are detected in this source; the latter feature is suggestive of a dense inflow or outflow. The near infrared position of this red source is consistent with the position of a 5 GHz thermal radio source seen in previous high angular resolution VLA images. We also identify several other K-band sources containing excess emission with compact radio sources. These objects may represent stars in the W31 cluster still embedded in their birth cocoons.Comment: LaTeX2e/aastex, 29 pages including 9 figures, 3 table

Addressing Health Literacy in Patient Decision Aids:An Update from the International Patient Decision Aid Standards

BACKGROUND: There is increasing recognition of the importance of addressing health literacy in patient decision aid (PtDA) development. PURPOSE: An updated review as part of IPDAS 2.0 examined the extent to which PtDAs are designed to meet the needs of low health literacy/disadvantaged populations. DATA SOURCES: Reference list of Cochrane review of randomised controlled trials (RCTs) of PtDAs (2014, 2017 and upcoming 2021 versions). STUDY SELECTION: RCTs that assessed the impact of PtDAs on low health literacy or other disadvantaged groups (i.e. ≥50% participants from disadvantaged groups and/or subgroup analysis in disadvantaged group/s). DATA EXTRACTION: Two researchers independently extracted data into a standardized form including PtDA development and evaluation details. We searched online repositories and emailed authors to access PtDAs to verify reading level, understandability and actionability. DATA SYNTHESIS: Twenty-five out of 213 RCTs met inclusion criteria illustrating that only 12% of studies addressed the needs of low health literacy or other disadvantaged groups. Reading age was calculated in 8/25 studies (33%), which is recommended in previous IPDAS guidelines. We accessed and independently assessed 11 PtDAs. None were written at 6(th) grade level or below. Ten PtDAs met the recommended threshold for understandability, but only 5 met the recommended threshold for actionability. We also conducted a post-hoc subgroup meta-analysis and found that knowledge improvements after receiving a PtDA were greater in studies that reported using strategies to reduce cognitive demand in PtDA development compared to studies that did not (Chi(2)=14.11, p=0.0002, I(2)=92.9%). LIMITATIONS: We were unable to access 13 out of 24 PtDAs. CONCLUSIONS: Greater attention to health literacy and disadvantaged populations is needed in the field of PtDAs to ensure equity in decision support

NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis

Funding Pathological Society of Great Britain and Ireland. Grant Number: Jean Shanks Foundation Clinical Lecturer Support G OR is funded by a Wellcome Trust PhD fellowship (108890/Z/15/Z). JMG is funded by a starter grant for clinical lecturers from the AMS (210JMG 3102 R45620) and a Clinical Lecturer Support Grant from The Pathological Society/Jean Shanks Foundation, and brain bank funding from the MRC (MR/L016400/1). EE is funded by a PhD fellowship from the CSO and MND Scotland: 217ARF R45951.Peer reviewedPublisher PD

om92, a glp-1 enhancer mutation, is an allele of ekl-1

Germline stem cell proliferation in C. elegans requires activation of the GLP-1/Notch receptor, which is located on the germline plasma membrane and encoded by the glp-1 gene. We previously identified several genes whose products directly or indirectly promote activity of the GLP-1 signaling pathway by finding mutations that enhance the germline phenotype of a glp-1(ts) allele, glp-1(bn18) . Here, we report phenotypic and molecular analysis of a new ekl-1 allele, ekl-1(om92) , that enhances the glp-1(bn18) phenotype. ekl-1(om92) is a 244 bp deletion predicted to generate a frameshift and premature termination codon, yielding a severely truncated protein, suggesting it is a null allele

Attitudes and Opinions About Direct-to-Consumer Genetic Testing in Undergraduate Science Students

Background: There has been exponential growth in the number of direct-to-consumer genetic testing kits sold in the past decade. Consumers utilize direct-to-consumer genetic tests for a number of reasons which include learning about one’s ancestry and potential ways to manage health. Emerging adults tend to be early adopters of new technologies; however, there has been little research regarding the opinions about direct-to-consumer genetic testing in emerging adults. Methods: Data came from a study conducted in an upper-level biology course focusing on understanding undergraduate science students’ overall experiences with receiving personalized genetic testing results from 23andMe. The present study used data collected at the baseline assessment which assessed their opinions and attitudes about direct-to-consumer genetic testing (N=133). Results: Over 80% of participants would recommend direct-to-consumer genetic testing options including carrier status reports, DNA ancestry reports, wellness reports, and trait reports to others. However, participants were not as confident that others would be able to accurately interpret their test results. Additionally, more than two-thirds of the participants stated that they would ask a healthcare provider to help interpret their personalized genetic test results. Conclusions: Participants lack confidence in both their ability to interpret their own results and others to interpret their results. It is important for direct-to-consumer genetic testing companies to educate consumers before providing results in order to minimize potential harms due to misinterpretation of results. Further research is needed to assess motivations to participate in direct-to-consumer genetic testing, impact of testing, and understanding of genetic testing results in emerging adults.https://scholarscompass.vcu.edu/gradposters/1124/thumbnail.jp

Genetic Variation in the ASTN2 Locus in Cardiovascular, Metabolic and Psychiatric Traits: Evidence for Pleiotropy Rather Than Shared Biology

Background: The link between cardiometabolic and psychiatric illness has long been attributed to human behaviour, however recent research highlights shared biological mechanisms. The ASTN2 locus has been previously implicated in psychiatric and cardiometabolic traits, therefore this study aimed to systematically investigate the genetic architecture of ASTN2 in relation to a wide range of relevant traits. Methods: Baseline questionnaire, assessment and genetic data of 402111 unrelated white British ancestry individuals from the UK Biobank was analysed. Genetic association analyses were conducted using PLINK 1.07, assuming an additive genetic model and adjusting for age, sex, genotyping chip, and population structure. Conditional analyses and linkage disequilibrium assessment were used to determine whether cardiometabolic and psychiatric signals were independent. Results: Associations between genetic variants in the ASTN2 locus and blood pressure, total and central obesity, neuroticism, anhedonia and mood instability were identified. All analyses support the independence of the cardiometabolic traits from the psychiatric traits. In silico analyses provide support for the central obesity signal acting through ASTN2, however most of the other signals are likely acting through other genes in the locus. Conclusions: Our systematic analysis demonstrates that ASTN2 has pleiotropic effects on cardiometabolic and psychiatric traits, rather than contributing to shared pathology