Magnetically warped discs in close binaries

We demonstrate that measurable vertical structure can be excited in the accretion disc of a close binary system by a dipolar magnetic field centred on the secondary star. We present the first high resolution hydrodynamic simulations to show the initial development of a uniform warp in a tidally truncated accretion disc. The warp precesses retrogradely with respect to the inertial frame. The amplitude depends on the phase of the warp with respect to the binary frame. A warped disc is the best available explanation for negative superhumps.Comment: 11 pages, 10 figures, MNRAS accepte

LGBT Trainee and Health Professional Perspectives on Academic Careers—Facilitators and Challenges

Purpose: Diversity efforts in the academic medicine workforce have often neglected the identification and inclusion of lesbian, gay, bisexual, and transgender (LGBT) health professionals. Many of these professionals have served as educators, researchers, administrators, and leaders at their academic institutions, but their perspectives on the barriers to and facilitators of pursuing academic careers, as well as the perspectives of trainees, have not been explored. Methods: We applied a purposeful convenience sampling strategy to collect quantitative and qualitative data among LGBT health care professionals (HCP) and trainees. The authors identified trends in data using bivariate analyses and consensual qualitative research methods. Results: We analyzed data from 252 surveys completed by HCPs and trainees and a subset of 41 individuals participated in 8 focus groups. Among survey participants, 100% identified as lesbian, gay, and bisexual (LGB) or queer; 4.5% identified along the trans-spectrum; 31.2% identified as a racial or ethnic minority; 34.1% identified as faculty; and 27.4% as trainees. Eighty-one percent of trainees were interested in academia and 47% of HCPs held faculty appointments. Overall, 79.4% were involved in LGBT-related educational, research, service, or clinical activities. Facilitators of academic careers included engagement in scholarly activities, mentorship, LGBT-specific networking opportunities, personal desire to be visible, campus opportunities for involvement in LGBT activities, and campus climate inclusive of LGBT people. Barriers included poor recognition of LGBT scholarship, a paucity of concordant mentors or LGBT networking opportunities, and hostile or non-inclusive institutional climates. Conclusion: LGBT trainees and HCPs contribute significantly to services, programs, and scholarship focused on LGBT communities. LGBT individuals report a desire for a workplace environment that encourages and supports diversity across sexual orientation and gender identities. Institutional policies and programming that facilitate LGBT inclusion and visibility in academia may lead to greater faculty work satisfaction and productivity, higher retention and supportive role modeling and mentoring for the health professions pipeline.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140160/1/lgbt.2015.0024.pd

Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes.

From Europe PMC via Jisc Publications RouterHistory: epub 2021-09-01, ppub 2021-09-01Publication status: PublishedFunder: Cancer Research UK; Grant(s): C147/A25254, C1422/A19842Funder: Manchester Biomedical Research Centre; Grant(s): R120700/CAA070107BackgroundEpithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70-80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics.MethodsNon-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2-10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models.ResultsApplication of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features.ConclusionsThis robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes

Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes

AIM: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. METHODS: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. RESULTS: In the discovery sample, three independent regions containing variants associated with time to dependence at CONCLUSIONS: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs

Genome-wide association study of opioid cessation

The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for \u3e1 year or \u3c6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 i

The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders

Introduction: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. Methods: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. Results: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. Conclusions: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity. Confirmatory factor analysis was used to derive a higher order, childhood trauma factor representing a measure of the common variance across three forms of trauma: childhood physical abuse, childhood sexual abuse, and parental partner abuse. We replicated the model in a second sample. We then examined the association of childhood trauma score with risk for psychiatric and substance use disorders in these samples and a third sample in which the primary sample's factor loadings were applied finding factor scores to be strongly and consistently associated with liability for psychiatric and substance use disorders in all three samples

Human spermbots for patient-representative 3D ovarian cancer cell treatment

Cellular micromotors are attractive for locally delivering high concentrations of drug, and targeting hard-to-reach disease sites such as cervical cancer and early ovarian cancer lesions by non-invasive means. Spermatozoa are highly efficient micromotors perfectly adapted to traveling up the female reproductive system. Indeed, bovine sperm-based micromotors have shown potential to carry drugs toward gynecological cancers. However, due to major differences in the molecular make-up of bovine and human sperm, a key translational bottleneck for bringing this technology closer to the clinic is to transfer this concept to human material. Here, we successfully load human sperm with Doxorubicin (DOX) and perform treatment of 3D cervical cancer and patient-representative ovarian cancer cell cultures, resulting in strong anticancer cell effects. Additionally, we define the subcellular localization of the chemotherapeutic drug within human sperm, using high-resolution optical microscopy. We also assess drug effects on sperm motility and viability over time, employing sperm samples from healthy donors as well as assisted reproduction patients. Finally, we demonstrate guidance and release of human drug-loaded sperm onto cancer tissues using magnetic microcaps, and show the sperm microcap loaded with a second anticancer drug, camptothecin (CPT), which unlike DOX is not suitable for directly loading into sperm due to its hydrophobic nature. This co-drug delivery approach opens up novel targeted combinatorial drug therapies for future applications. © 2020 The Royal Society of Chemistry

ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure

Context: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. Objective: To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs)with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations. Design: Case-control genetic association study that included 2 control groups (lacking an established optimal control group). Setting: Semistructured psychiatric interviews. Participants: A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample. Main Outcome Measure: Lifetime heroin dependence. Results: Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P≥.01); a similar comparison with neighborhood controls revealed greater differences (P≥1.8×10-4). Comparing cases (n=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n=340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio=1.59; 95% CI, 1.32-1.92; P=9.7×10-7), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n=191) and nondependent (n=340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P=2.7×10-9 for the risk-associated linear trend). Conclusions: Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence