Landscape of standing variation for tandem duplications in Drosophila yakuba and Drosophila simulans

We have used whole genome paired-end Illumina sequence data to identify tandem duplications in 20 isofemale lines of D. yakuba, and 20 isofemale lines of D. simulans and performed genome wide validation with PacBio long molecule sequencing. We identify 1,415 tandem duplications that are segregating in D. yakuba as well as 975 duplications in D. simulans, indicating greater variation in D. yakuba. Additionally, we observe high rates of secondary deletions at duplicated sites, with 8% of duplicated sites in D. simulans and 17% of sites in D. yakuba modified with deletions. These secondary deletions are consistent with the action of the large loop mismatch repair system acting to remove polymorphic tandem duplication, resulting in rapid dynamics of gain and loss in duplicated alleles and a richer substrate of genetic novelty than has been previously reported. Most duplications are present in only single strains, suggesting deleterious impacts are common. D. simulans shows larger numbers of whole gene duplications in comparison to larger proportions of gene fragments in D. yakuba. D. simulans displays an excess of high frequency variants on the X chromosome, consistent with adaptive evolution through duplications on the D. simulans X or demographic forces driving duplicates to high frequency. We identify 78 chimeric genes in D. yakuba and 38 chimeric genes in D. simulans, as well as 143 cases of recruited non-coding sequence in D. yakuba and 96 in D. simulans, in agreement with rates of chimeric gene origination in D. melanogaster. Together, these results suggest that tandem duplications often result in complex variation beyond whole gene duplications that offers a rich substrate of standing variation that is likely to contribute both to detrimental phenotypes and disease, as well as to adaptive evolutionary change.Comment: Revised Version- Accepted at Molecular Biology and Evolutio

A genomic map of the effects of linked selection in Drosophila

Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of 'linked selection' on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of linked selection from non-classic sweeps. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated

IMAGINE-ing interprofessional education: program evaluation of a novel inner city health educational experience

Background: Poverty is a key determinant of health that leads to poor health outcomes. Although most healthcare providers will work with patients experiencing poverty, surveys among healthcare students have reported a curriculum gap in this area. This study aims to introduce and evaluate a novel, student-run interprofessional inner city health educational program that combines both practical and didactic educational components.Methods: Students participating in the program answered pre- and post-program surveys. Wilcoxon signed-rank tests and descriptive thematic analysis were used for quantitative and qualitative data, respectively.Results: A total of 28 out of 35 participants responded (response rate: 80%). Student knowledge about issues facing underserved populations and resources for underserved populations significantly increased after program participation. Student comfort working with underserved populations also significantly increased after program participation. Valued program elements included workshops, shadowing, and a focus on marginalized populations.Conclusion: Interprofessional inner city health educational programs are beneficial for students to learn about poverty intervention and resources, and may represent a strategy to address a gap in the healthcare professional curriculum

Persistence by Undergraduates in an Urban Public University: Understanding the Effects of Financial Aid

The decline in federal grants over the past two decades could be problematic for urban higher education because of the concentration of poverty in urban settings. This case study examines the effects of student aid on within-year persistence at an urban public university in the 1990s. The analyses indicate that aid packages remained adequate at this urban university. It appears that state and institutional grants play an increasingly important role in maintaining affordability in this new context of higher tuition and higher loans

A Study of Wellness Education as a Burnout Coping Strategy

Introduction: The MedScape National Physician Burnout & Depression 2018 report states that over 40% of responding physicians reported burnout, with 12% reporting clinical depression. As such, there is a need to study burnout mitigation. Objective: This study seeks to validate the hypothesis that intervention will prevent burnout and promote physician well-being. Methods: 200 medical professionals attending the November 2018 NMPRA conference in Orlando were administered a survey to assess attitudes and prevalence of burnout. Education about burnout was provided through an information booth, handouts, and discussions. A monthly newsletter about wellness will seek to inspire participants. Another survey after 6 months will re-assess attitudes and burnout and the data will be analyzed. Results: Of 56 surveys returned, 66% were female respondents. 34% of responders have been practicing under 5 years, while 28% have over 20 years of practice. 63% of males and 86% of females reported burnout. While 72% reported participation in wellness activities, over 93% thought they worked too hard. At least 50% thought they were appreciated and supported at work by their colleagues, and 85-90% thought their work was meaningful. 73% of males and 62% of females blamed lack of sleep for burnout. Discussion: While physicians by and large are satisfied with their job and feel well supported, burnout is widespread, especially among females. Time pressure and wellness being lower priority may be issues, and this seems to indicate that the planned interventions should have a positive effect on wellness outcomes

Cosmological Magnetic Fields vs. CMB

I present a short review of the effects of a cosmological magnetic field on the CMB temperature and polarization anisotropies. Various possibilities for constraining the magnetic field amplitude are discussed.Comment: 6 pages, to appear in proc. of Dark Matter 200

Emergency Department Testing and Disposition of Deaf American Sign Language Users and Spanish-Speaking Patients

Objectives: Non-English speaking patients frequently present to the emergency department (ED) for acute care and may present a challenge to efficient clinical ED management and disposition. This study aimed to assess differences in the disposition and clinical management of Spanish-speaking patients and Deaf American Sign Language (ASL) users, who worked with a certified, in-person interpreter, compared with English proficient patients who did not utilize interpreter services. Methods: A retrospective study querying electronic medical records was performed at an academic medical center ED. Patients with a chief complaint of abdominal pain were chosen for this study, as this is a common chief complaint and these patients often require numerous tests. Variables obtained from the query included patient demographic information, number of tests and imaging studies ordered, and arrival and disposition times. Bivariate tests were used to assess differences in the management and disposition of patients who worked with an in-person, certified Spanish or ASL interpreter compared with those who did not utilize interpreter services. Results: The study sample was comprised of 310 patients, 155 of whom utilized interpreter services and 155 controls who did not. Of those who utilized interpreter services, 69% were Spanish speaking and 31% Deaf ASL users. For patients who worked with an interpreter, compared with those who did not, the median door-to-ED disposition time was significantly longer (398 minutes vs. 322 minutes; p=0.0049). There were also more imaging studies ordered (p=0.0135) in the non-English speaking group. For English proficient patients, there was a higher rate of leaving before complete evaluation (2.6% vs. 0.0%) or against medical advice (3.2% vs. 0.0%) [p\u3c0.0088]. Conclusions: In a sample of ED patients with a chief complaint of abdominal pain, there were statistically significant differences in the door-to-disposition time and number of imaging tests among those who were non-English speaking, utilizing in-person certified interpreter services, compared with those who were proficient in English. These results underscore the need for future research to further investigate the reasons for the differences in the evaluation and timely management of Deaf ASL users and Spanish-speaking ED patients

Glucocorticoids delivered by inorganic‐organic hybrid nanoparticles mitigate acute graft‐versus‐host disease and sustain graft‐versus‐leukemia activity

Glucocorticoids (GCs) are widely used to treat acute graft‐versus‐host disease (aGvHD) due to their immunosuppressive activity, but they also reduce the beneficial graft‐versus‐leukemia (GvL) effect of the allogeneic T cells contained in the graft. Here, we tested whether aGvHD therapy could be improved by delivering GCs with the help of inorganic–organic hybrid nanoparticles (IOH‐NPs) that preferentially target myeloid cells. IOH‐NPs containing the GC betamethasone (BMP‐NPs) efficiently reduced morbidity, mortality, and tissue damage in a totally MHC mismatched mouse model of aGvHD. Therapeutic activity was lost in mice lacking the GC receptor (GR) in myeloid cells, confirming the cell type specificity of our approach. BMP‐NPs had no relevant systemic activity but suppressed cytokine and chemokine gene expression locally in the small intestine, which presumably explains their mode of action. Most importantly, BMP‐NPs delayed the development of an adoptively transferred B cell lymphoma better than the free drug, although the overall incidence was unaffected. Our findings thus suggest that employing IOH‐NPs could diminish the risk of relapse associated with GC therapy of aGvHD patients while still allowing to efficiently ameliorate the disease

Investigation of Type 2 Diabetes Risk Alleles Support CDKN2A/B, CDKAL1, and TCF7L2 As Susceptibility Genes in a Han Chinese Cohort

Background: Recent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort. Methodology/Principal Findings: Selected type 2 diabetes-associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P <= 0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12-1.43) P = 1.8* 10(-4); CDKAL1 rs10946398, OR: 1.23 (1.09-1.39); P = 7.1* 10(-4), and TCF7L2 rs7903146, OR: 1.61 (1.19-2.18) P = 2.3* 10(-3). Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002), postprandial plasma glucose (P = 0.002), and fasting C-peptide levels (P = 0.006) in the diabetic patients, and with BMI in controls (P = 0.033). Conclusions/Significance: We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities

Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A

Ribosomal translation factors are fundamental for protein synthesis and highly conserved in all kingdoms of life. The essential eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl tRNAs to the A-site of the translating 80S ribosome. Several studies have revealed that eEF1A is posttranslationally modified. Using MS analysis, site-directed mutagenesis, and X-ray structural data analysis of Saccharomyces cerevisiae eEF1A, we identified a posttranslational modification in which the α amino group of mono-l-glutamine is covalently linked to the side chain of glutamate 45 in eEF1A. The MS analysis suggested that all eEF1A molecules are modified by this glutaminylation and that this posttranslational modification occurs at all stages of yeast growth. The mutational studies revealed that this glutaminylation is not essential for the normal functions of eEF1A in S. cerevisiae. However, eEF1A glutaminylation slightly reduced growth under antibiotic-induced translational stress conditions. Moreover, we identified the same posttranslational modification in eEF1A from Schizosaccharomyces pombe but not in various other eukaryotic organisms tested despite strict conservation of the Glu45 residue among these organisms. We therefore conclude that eEF1A glutaminylation is a yeast-specific posttranslational modification that appears to influence protein translation