Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome.

Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.

Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations.

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction.

Frequent low-impact exposure to THC during adolescence causes persistent sexually dimorphic alterations in the response to viral infection in mice.

Adolescent exposure to Δ9-tetrahydrocannabinol (THC) has enduring effects on energy metabolism and immune function. Prior work showed that daily administration of a low-impact dose of THC (5 mg/kg, intraperitoneal) during adolescence alters transcription in adult microglia and disrupts their response to bacterial endotoxin or social stress. To explore the lasting impact of adolescent THC exposure on the brain's reaction to viral infection, we administered THC (5 mg/kg, intraperitoneal) in male and female mice once daily on postnatal day (PND) 30-43. When the mice reached adulthood (PND 70), we challenged them with the viral mimic, polyinosinic acid:polycytidylic acid [Poly(I:C)], and assessed sickness behavior (motor activity, body temperature) and whole brain gene transcription. Poly(I:C) caused an elevation in body temperature which was lessened by prior THC exposure in female but not male mice. Adolescent THC exposure did not affect the locomotor response to Poly(I:C) in either sex. Transcriptomic analyses showed that Poly(I:C) produced a substantial upregulation of immune-related genes in the brain, which was decreased by THC in females. Additionally, the viral mimic caused a male-selective downregulation in transcription of genes involved in neurodevelopment and synaptic transmission, which was abrogated by adolescent THC treatment. The results indicate that Poly(I:C) produces complex transcriptional alterations in the mouse brain, which are sexually dimorphic and differentially affected by early-life THC exposure. In particular, adolescent THC dampens the brain's antiviral response to Poly(I:C) in female mice and prevents the transcriptional downregulation of neuron-related genes caused by the viral mimic in male mice.

High-throughput analysis of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing.

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson's disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.

Practical wisdom in medicine through the eyes of medical students and physicians.

BACKGROUND: Practical wisdom is considered a multidimensional virtue of enduring relevance to medicine. Though it has received increasing attention in recent years, proposed frameworks for practical wisdom can differ, and little is known about how medical students and physicians describe its dimensions and relevance. METHODS: We used structured interviews, employing open-ended and closed-ended questions, to describe how medical students and physicians understand practical wisdom and identify the kinds of clinical situations they believe require practical wisdom. We interviewed 102 participants at two US medical schools in 2021, comprising a voluntary response sample of 40 pre-clinical medical students and 40 clinical medical students and a purposive sample of 22 nominated physicians. Interviews were conducted by videoconference using a structured interview guide. Open-ended responses were coded using qualitative content analysis (directed and conventional) and tabulated; closed-ended responses were tabulated. Quotations provided qualitative illustrations, and frequencies were used for summative results. RESULTS: Participants considered practical wisdom clinically meaningful, broadly relevant and multidimensional. Most described it as deliberative, goal-directed, context-sensitive, integrated with ethics and marked by integrity and motivation to act. Many described it as experience-based, person-centred or problem-solving. Participants also selected an average of 15.6 (SD = 4.9) additional virtues as being essential for practical wisdom in medicine and described a broad range of clinical situations that require practical wisdom in medicine. CONCLUSIONS: Participants described practical wisdom as a multidimensional capacity that entails deliberation, depends on a constellation of other virtues and is broadly applicable to medicine. Most agreed it is goal-directed and context-sensitive and involves ethics, integrity and motivation. Efforts to teach practical wisdom in medical education should clarify its dimensions and highlight its relationship to virtue ethics, professionalism, clinical judgement and the individualised care of patients as persons.

HIV proviral DNA integration can drive T cell growth ex vivo.

In vivo clonal expansion of HIV-infected T cells is an important mechanism of viral persistence. In some cases, clonal expansion is driven by HIV proviral DNA integrated into one of a handful of genes. To investigate this phenomenon in vitro, we infected primary CD4+ T cells with an HIV construct expressing GFP and, after nearly 2 mo of culture and multiple rounds of activation, analyzed the resulting integration site distribution. In each of three replicates from each of two donors, we detected large clusters of integration sites with multiple breakpoints, implying clonal selection. These clusters all mapped to a narrow region within the STAT3 gene. The presence of hybrid transcripts splicing HIV to STAT3 sequences supports a model of LTR-driven STAT3 overexpression as a driver of preferential growth. Thus, HIV integration patterns linked to selective T cell outgrowth can be reproduced in cell culture. The single report of an HIV provirus in a case of AIDS-associated B-cell lymphoma with an HIV provirus in the same part of STAT3 also has implications for HIV-induced malignancy.

The Emmaus Project: Aging, Illness, and Dying Among Older Christians-A Qualitative Study.

Older patients have an increased risk of depression, neglect, and abuse. Studies demonstrate that spiritual and religious coping is important at times of personal crisis, but few studies explore the impact of religion on older persons' experiences of aging, illness, and impending death. This study set out to identify recurring spiritual and clinical themes shared by retirement home residents in the context of a Christian faith-based processing group. A qualitative cohort study of residents over the age of 65 was conducted at a retirement home in Chicago, Illinois. The study consisted of 8 hour-long Scripture-based processing group sessions co-led by a study researcher and the onsite chaplain. Questionnaires were administered to each group and handwritten responses were collected and analyzed to identify recurring clinical and spiritual themes. Ten participants enrolled in the group study. The questionnaire completion rate was 35% (49/140). The most recurring clinical themes included 1) events of death or terminal illness and 2) physical limitations. The most recurring spiritual themes included 1) God's presence and 2) prayer and worship. The most recurring coded theme overall was family. This study provided insight into the spiritual experiences of older Christians in one retirement home community. Increased awareness of the spiritual perspectives of the geriatric population may strengthen the doctor-patient relationship and lead to improvements in clinical care.

Moral Elevation, Physician Role Models, and Selected Markers of Professional Identity Formation and Well-Being: A Secondary Analysis from Two National Surveys.

OBJECTIVES: Moral elevation is the underlying emotion that arises when witnessing admirable acts, and it is theorized to be the psychological mechanism driving the impact that positive clinical role models have on medical students' professional identity formation (eg, growth in professional virtues, higher sense of meaning, and well-being). This proof-of-concept study explores the development of the Moral Elevation Scale in Medicine by testing the association of moral elevation with various markers of professional identity formation. METHODS: A secondary data analysis of two nationally representative samples of 960 medical students and 2000 physicians was performed. Respondents completed validated measures of moral elevation as well as markers of professional identity formation, including patient-centered virtues (empathic compassion, interpersonal generosity, mindfulness) and measures of well-being (life meaning, life satisfaction, spirituality, burnout). RESULTS: The study obtained adjusted response rates of 56.2% (1047/1863, physician survey) and 48.7% (448/919, student survey). The national estimates for mean moral elevation in medical students and physicians are 4.34/5.00 and 4.22/5.00, respectively. In medical students and physicians, high moral elevation was associated with higher empathic compassion (student odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02-1.67; physician OR 1.22, 95% CI 1.23-1.65) and, similarly, generosity. In addition, higher moral elevation in the physician cohort was associated with greater life meaning (OR 2.03, 95% CI 1.25-3.32) and similarly spirituality. CONCLUSIONS: In medical students and practicing physicians, self-reported experiences of high moral elevation with physician role models were associated with higher self-reported measures of patient-centered virtues, spirituality, and life meaning. Our Moral Elevation Scale in Medicine demonstrates preliminary promise as a measure to assess environmental precursors needed for virtue development in professional identity formation, but further reliability and validity testing of this measure is needed.

Sustaining the Intrinsic Motivations of the "Good Physician": A Content Analysis of Medical Students' and Physicians' Responses from Two National Surveys.

OBJECTIVE: Physician motivation has been described as the reason, purpose, and force that drives people to pursue their work, and motivating factors include those that are intrinsic or extrinsic to the work. Social forces may contribute to motivational disparities between medical school and actual practice. METHODS: A secondary data analysis of two national surveys (medical students and practicing physicians from various specialties) was conducted. Content analysis was performed on open-ended survey items that elicited students' and physicians' responses to meaningful experiences in medicine. RESULTS: In the medical student sample, four themes were identified as factors intrinsic to medicine: role models, clinical experiences, patient interactions, and peer interactions. In total, intrinsic factors comprised 86.5% (193/208) of coded responses. In the practicing physician sample, five themes were identified as factors intrinsic to medicine: difficult patient interactions, conflict with colleagues or staff, meaningful patient interactions, involvement in medical education-research-academia, and medicine as a calling/mission. In total, intrinsic factors comprised 24.0% (140/582) of coded responses. CONCLUSIONS: Our findings suggest that the reality of social forces in medicine threatens the ability of practicing physicians to derive meaning from their work, although students and physicians still report intrinsic motivation from establishing meaningful relationships. Further research is needed to explore what strategies enable physicians to wisely navigate the dynamic interactions of intrinsic and extrinsic motivators over various stages of their careers. These strategies could include encouraging reflective spaces in physicians' workplaces that have a specific focus on sustaining intrinsic motivation in medicine.

Association of Intrinsic Motivating Factors and Joy in Practice: A National Physician Survey.

OBJECTIVES: In response to the need to identify positive measures that more accurately describe physician wellness, this study seeks to assess the validity of a novel joy in practice measure using validated physician well-being measures and test its association with certain intrinsic and extrinsic motivators. METHODS: Secondary data analysis using a nationally representative dataset of 2000 US physicians, fielded October-December 2011. Multivariable logistic models with survey design provided nationally representative individual-level estimates. Primary outcome variables included joy in practice (enthusiasm, fulfillment, and clinical stamina in an after-hours setting). Secondary outcomes were validated measures of physician well-being such as job and life satisfaction and life meaning. Primary explanatory variables were sense of calling, number of personally rewarding hours per day, long-term relationships with patients, and burnout. RESULTS: The survey response rate was 64.5% (1289/2000). Physicians who demonstrated joy in practice were most likely to report high life satisfaction (odds ratio [OR] 2.75, 95% confidence interval [CI] 1.52-4.98) and high life meaning (OR 2.62, 95% CI 1.41-4.85). Joy in practice was strongly associated with having a sense of calling (OR 10.8, 95% CI 2.21-52.8) and ≥ 7.5 personally rewarding hours per day (OR 3.75, 95% CI 1.51-9.36); meanwhile, it was negatively associated with burnout (OR 0.26, 95% CI 0.14-0.51). Extrinsic factors such as specialty, practice setting, and annual income were not significantly associated with joy in practice in most regressions. CONCLUSIONS: The joy in practice measure shows preliminary promise as a positive marker of well-being, highlighting the need for future interventions that support physicians' intrinsic motivators and foster joy in one's practice.

Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress.

Completion of DNA replication after replication stress depends on PCNA, which undergoes monoubiquitination to stimulate direct bypass of DNA lesions by specialized DNA polymerases or is polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Here we report that the ZRANB3 translocase, a SNF2 family member related to the SIOD disorder SMARCAL1 protein, is recruited by polyubiquitinated PCNA to promote fork restart following replication arrest. ZRANB3 depletion in mammalian cells results in an increased frequency of sister chromatid exchange and DNA damage sensitivity after treatment with agents that cause replication stress. Using in vitro biochemical assays, we show that recombinant ZRANB3 remodels DNA structures mimicking stalled replication forks and disassembles recombination intermediates. We therefore propose that ZRANB3 maintains genomic stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events.

"Can virtue be taught?": a content analysis of medical students' opinions of the professional and ethical challenges to their professional identity formation.

BACKGROUND: Efforts have begun to characterize the ethical and professional issues encountered by medical students in their clinical years. By applying previously identified taxonomies to a national sample of medical students, this study seeks to develop generalizable insights that can inform professional identity formation across various clerkships and medical institutions. METHODS: In a national survey of medical students, participants answered an open-ended survey item that asked them to describe a clinical experience involving an ethical or professional issue. We conducted a content analysis with these responses using the Kaldjian taxonomy of ethical and professionalism themes in medical education through an iterative, consensus-building process. Noting the emerging virtues-based approach to ethics and professionalism, we also reexamined the data using a taxonomy of virtues. RESULTS: The response rate to this survey item was 144 out of 499 eligible respondents (28.9%). All 144 responses were successfully coded under one or more themes in the original taxonomy of ethical and professional issues, resulting in a total of 173 coded responses. Professional duties was the most frequently coded theme (29.2%), followed by Communication (26.4%), Quality of care (18.8%), Student-specific issues of moral distress (16.7%), Decisions regarding treatment (16.0%), and Justice (13.2%). In the virtues taxonomy, 180 total responses were coded from the 144 original responses, and the most frequent virtue coded was Wisdom (23.6%), followed by Respectfulness (20.1%) and Compassion or Empathy (13.9%). CONCLUSIONS: Originally developed from students' clinical experiences in one institution, the Kaldjian taxonomy appears to serve as a useful analytical framework for categorizing a variety of clinical experiences faced by a national sample of medical students. This study also supports the development of virtue-based programs that focus on cultivating the virtue of wisdom in the practice of medicine.

Predictors of Empathic Compassion: Do Spirituality, Religion, and Calling Matter?

OBJECTIVE: To determine whether physician spirituality, religion, and sense of calling toward medicine are predictors of self-reported empathic compassion. METHODS: We sampled 2000 practicing US physicians from all specialties and used self-reported measures of general and clinical empathic compassion taken from previous studies. Independent variables were single-item measures of calling, spirituality, and religiosity (importance of religion). RESULTS: The survey response rate was 64.5% (1289/2000). Physicians with a strong sense of calling were more likely to report higher general empathic compassion (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.26-3.15) and higher clinical empathic compassion (OR 3.33, 95% CI 2.07-5.36). Similarly, physicians who considered themselves spiritual were more likely to report higher general empathic compassion (OR 2.76, 95% CI 1.69-4.50) and higher clinical empathic compassion (OR 2.32, 95% CI 1.38-3.90). We did not find an association between religiosity and measures of physicians' empathic compassion. CONCLUSIONS: This national study of practicing US physicians from various specialties found that spirituality (not religiousness) and the identification of medicine as a calling are associated with physicians' empathic compassion. Further study is needed to understand how spirituality and calling are linked to prosocial behaviors among physicians that may be enhancing their clinical empathy and promoting compassionate patient care.

Moral Controversy and Working with Colleagues with a Shared Ethical/Moral Outlook: A National Survey of US Primary Care Physicians.

OBJECTIVES: This study assesses physicians' attitudes on the importance of working with colleagues who share the same ethical or moral outlook regarding morally controversial healthcare practices and examines the association of physicians' religious and spiritual characteristics with these attitudes. METHODS: We conducted a secondary data analysis of a 2009 national survey that was administered to a stratified random sample of 1504 US primary care physicians (PCPs). In that dataset, physicians were asked: "For you personally, how important is it to work with colleagues who share your ethical/moral outlook regarding morally controversial health care practices?" We examined associations between physicians' religious/spiritual characteristics and their attitudes toward having a shared ethical/moral outlook with colleagues. RESULTS: Among eligible respondents, the response rate was 63% (896/1427). Overall, 69% of PCPs indicated that working with colleagues who share their ethical/moral outlook regarding morally controversial healthcare practices was either very important (23%) or somewhat important (46%). Physicians who were more religious were more likely than nonreligious physicians to report that a shared ethical/moral outlook was somewhat/very important to them (P < 0.001 for all measures of religiosity, including religious affiliation, attendance at religious services, intrinsic religiosity, and importance of religion as well as spirituality). Physicians with a high sense of calling were more likely than those with a low sense of calling to report a high importance of having a shared ethical/moral outlook with colleagues regarding morally controversial healthcare practices (multivariate odds ratio 2.5, 95% confidence interval 1.5-4.1). CONCLUSIONS: In this national study of PCPs, physicians who identified as religious, spiritual, or having a high sense of calling were found to place a stronger emphasis on the importance of shared ethical/moral outlook with work colleagues regarding morally controversial healthcare practices. Moral controversy in health care may pose a particular challenge for physicians with lower commitments to theological pluralism.

Stressing the journey: using life stories to study medical student wellbeing.

While previous studies have considered medical student burnout and resilience at discrete points in students' training, few studies examine how stressors and resilience-building factors can emerge before, and during, medical school. Our study focuses on students' life stories to comprehensively identify factors contributing to student wellbeing. We performed a secondary analysis of life-story interviews with graduating fourth year medical students. These interviews were originally conducted in 2012 as part of the Project on the Good Physician, and then re-analyzed, focusing on student wellbeing. Respondents were encouraged to identify turning points in their life stories. De-identified transcripts were then coded using a consensus-based iterative process. 17 of 21 respondents reported feeling burned out at least once during medical school. Students identified three major stressors: negative role models, difficult rotations, and the United States Medical Licensing Examination Step 1. Two "motivational stressors"-financial concerns and personal life events-emerged as sources of stress that also motivated students to persevere. Finally, students identified four factors-positive role models, support networks, faith and spirituality, and passion-that helped them reframe stressors, making the struggle seem more worthwhile. These findings suggest that a life-story approach can add granularity to current understandings of medical student wellbeing. Initiatives to reduce stress and burnout should extend beyond the immediate medical school context and consider how past challenges might become future sources of resilience. This study also provides an example of secondary analysis of qualitative data, an approach which could be useful to future research in medical education.

Religious Characteristics of Physicians Who Care for Underserved Populations or Work in Religiously Oriented Practices.

OBJECTIVES: This study examined the relation between physicians' religious characteristics and working for medically underserved populations or in religiously oriented practices. METHODS: Secondary data analysis of 2009-2010 national survey of 896 primary care physicians (PCPs) and 312 psychiatrists. Predictors included physicians' religious characteristics. RESULTS: Adjusted response rates among eligible physicians were 63% (896 of 1427) for PCPs and 64% (312 of 487) for psychiatrists. Overall, 41.3% of US PCPs and 53.2% of US psychiatrists reported working with medically underserved populations. A smaller percentage reported working in religiously oriented practices. Physicians who rated religion as most important in their lives were more likely to report working for medically underserved populations (52.5% most important vs 36.7% not important, P = 0.02) or report working in religiously oriented practices (23.9% most important vs 6.8% not important, P < 0.01). CONCLUSIONS: Religious physicians may be serving in medically underserved areas or religiously oriented practices as a way to integrate their professional and personal identities.

Demographic and Practice Characteristics of Physicians Who Care for Medically Underserved People: A National Survey.

OBJECTIVES: Few national studies have examined the influence of role models as a potential predictor for caring for medically underserved (MUS) patients. This study tested associations between previous physician role model exposure and caring for MUS populations, as well as examines the practice environments of these physicians. METHODS: Between October and December 2011, we mailed a confidential questionnaire to a representative sample of 2000 US physicians from various specialties. The primary criterion variable was "Is your patient population considered medically underserved?" We assessed demographic and other personal characteristics (calling, spirituality, and reporting a familial role model). We also asked about their practice characteristics, including a validated measure that assessed whether their work environment was considered chaotic/hectic or calm. RESULTS: The survey response rate was 64.5% (1289/2000). Female physicians and African American physicians were more likely to report working in MUS settings (multivariate odds ratio [OR] 1.32, confidence interval [CI] 1.00-1.76 and OR 2.65, CI 1.28-5.46, respectively). Physicians with high spirituality (OR 1.69, CI 1.02-2.79) and who reported familial role model exposure (OR 1.91, CI 1.11-3.30) also were associated with working with MUS populations. Physicians who worked in academic medical centers (OR 1.93, CI 1.45-2.56) and in chaotic work environments (OR 3.25, CI 1.64-6.44) also were more likely to report working with MUS patients. CONCLUSIONS: Familial role models may be influencing physicians to work with MUS patients, but the quality of their current work environments raises concerns about the long-term retention of physicians in MUS settings.

Project on the Good Physician: Further Evidence for the Validity of a Moral Intuitionist Model of Virtuous Caring.

THEORY: In the Project on the Good Physician, the authors propose a moral intuitionist model of virtuous caring that places the virtues of Mindfulness, Empathic Compassion, and Generosity at the heart of medical character education. HYPOTHESES: Hypothesis 1a: The virtues of Mindfulness, Empathic Compassion, and Generosity will be positively associated with one another (convergent validity). Hypothesis 1b: The virtues of Mindfulness and Empathic Compassion will explain variance in the action-related virtue of Generosity beyond that predicted by Big Five personality traits alone (discriminant validity). Hypothesis 1c: Virtuous students will experience greater well-being ("flourishing"), as measured by four indices of well-being: life meaning, life satisfaction, vocational identity, and vocational calling (predictive validity). Hypothesis 1d: Students who self-report higher levels of the virtues will be nominated by their peers for the Gold Humanism Award (predictive validity). Hypothesis 2a-2c: Neuroticism and Burnout will be positively associated with each other and inversely associated with measures of virtue and well-being. METHOD: The authors used data from a 2011 nationally representative sample of U.S. medical students (n = 499) in which medical virtues (Mindfulness, Empathic Compassion, and Generosity) were measured using scales adapted from existing instruments with validity evidence. RESULTS: Supporting the predictive validity of the model, virtuous students were recognized by their peers to be exemplary doctors, and they were more likely to have higher ratings on measures of student well-being. Supporting the discriminant validity of the model, virtues predicted prosocial behavior (Generosity) more than personality traits alone, and students higher in the virtue of Mindfulness were less likely to be high in Neuroticism and Burnout. CONCLUSIONS: Data from this descriptive-correlational study offered additional support for the validity of the moral intuitionist model of virtuous caring. Applied to medical character education, medical school programs should consider designing educational experiences that intentionally emphasize the cultivation of virtue.

Wnt signaling regulates mitochondrial physiology and insulin sensitivity.

Mitochondria serve a critical role in physiology and disease. The genetic basis of mitochondrial regulation in mammalian cells has not yet been detailed. We performed a large-scale RNAi screen to systematically identify genes that affect mitochondrial abundance and function. This screen revealed previously unrecognized roles for >150 proteins in mitochondrial regulation. We report that increased Wnt signals are a potent activator of mitochondrial biogenesis and reactive oxygen species (ROS) generation, leading to DNA damage and acceleration of cellular senescence in primary cells. The signaling protein insulin receptor substrate-1 (IRS-1), shown here to be a transcriptional target of Wnt, is induced in this setting. The increased level of IRS-1 drives activation of mitochondrial biogenesis; furthermore, in insulin-responsive cell types, it enhances insulin signaling, raising the possibility that Wnt proteins may be used to modulate glucose homeostasis. Our results identify a key component of the mitochondrial regulatory apparatus with a potentially important link to metabolic and degenerative disorders.

Personality Traits Are Associated with Academic Achievement in Medical School: A Nationally Representative Study.

OBJECTIVE: This nationally representative study sought to identify personality traits that are associated with academic achievement in medical school. METHODS: Third-year medical students, who completed an initial questionnaire in January 2011, were mailed a second questionnaire several months later during their fourth year. Controlling for sociodemographic characteristics and burnout, the authors used multivariate logistic regressions to determine whether Big Five personality traits were associated with receiving honors/highest grade in clinical clerkships, failing a course or rotation, and being selected for the Alpha Omega Alpha or Gold Humanism Honor Society. RESULTS: The adjusted response rates for the two surveys were 61 (n = 564/919) and 84% (n = 474/564). The personality trait conscientiousness predicted obtaining honors/highest grade in all clinical clerkships. In contrast, students high in neuroticism were less likely to do well in most specialties. Students with higher conscientiousness were more likely to be inducted into the Alpha Omega Alpha Honor Society, while students high in openness or agreeableness traits were more likely to be inducted into the Gold Humanism Honor Society. Burnout was not associated with any clinical performance measures. CONCLUSIONS: This study suggests the importance of personality traits, particularly conscientiousness, in predicting success during the clinical years of medical school. Medical educators should consider a nuanced examination of personality traits and other non-cognitive factors, particularly for psychiatry.