The model student: GPT-4 performance on graduate biomedical science exams.

The GPT-4 large language model (LLM) and ChatGPT chatbot have emerged as accessible and capable tools for generating English-language text in a variety of formats. GPT-4 has previously performed well when applied to questions from multiple standardized examinations. However, further evaluation of trustworthiness and accuracy of GPT-4 responses across various knowledge domains is essential before its use as a reference resource. Here, we assess GPT-4 performance on nine graduate-level examinations in the biomedical sciences (seven blinded), finding that GPT-4 scores exceed the student average in seven of nine cases and exceed all student scores for four exams. GPT-4 performed very well on fill-in-the-blank, short-answer, and essay questions, and correctly answered several questions on figures sourced from published manuscripts. Conversely, GPT-4 performed poorly on questions with figures containing simulated data and those requiring a hand-drawn answer. Two GPT-4 answer-sets were flagged as plagiarism based on answer similarity and some model responses included detailed hallucinations. In addition to assessing GPT-4 performance, we discuss patterns and limitations in GPT-4 capabilities with the goal of informing design of future academic examinations in the chatbot era.

The intersection of social determinants of health, the microbiome, and health outcomes in immigrants: A scoping review.

In the present scoping review, we explore whether existing evidence supports the premise that social determinants of health (SDoH) affect immigrant health outcomes through their effects on the microbiome. We adapt the National Institute on Minority Health and Health Disparities' research framework to propose a conceptual model that considers the intersection of SDoH, the microbiome, and health outcomes in immigrants. We use this conceptual model as a lens through which to explore recent research about SDoH, biological factors associated with changes to immigrants' microbiomes, and long-term health outcomes. In the 17 articles reviewed, dietary acculturation, physical activity, ethnicity, birthplace, age at migration and length of time in the host country, socioeconomic status, and social/linguistic acculturation were important determinants of postmigration microbiome-related transformations. These factors are associated with progressive shifts in microbiome profile with time in host country, increasing the risks for cardiometabolic, mental, immune, and inflammatory disorders and antibiotic resistance. The evidence thus supports the premise that SDoH influence immigrants' health postmigration, at least in part, through their effects on the microbiome. Omission of important postmigration social-ecological variables (e.g., stress, racism, social/family relationships, and environment), limited research among minoritized subgroups of immigrants, complexity and inter- and intra-individual differences in the microbiome, and limited interdisciplinary and biosocial collaboration restrict our understanding of this area of study. To identify potential microbiome-based interventions and promote immigrants' well-being, more research is necessary to understand the intersections of immigrant health with factors from the biological, behavioral/psychosocial, physical/built environment, and sociocultural environment domains at all social-ecological levels.

An innovative transfer DNA experimental design and qPCR assay to identify primary, secondary, and tertiary DNA transfer.

"Touch DNA" is a form of trace DNA that is presumed to be deposited when an individual touches something and leaves behind DNA-containing skin cells, sweat, or other fluids. While touch DNA is often the result of direct contact (i.e., primary transfer), it can also be indirectly transferred between surfaces or individuals (e.g., secondary or tertiary transfer). Even experts cannot distinguish between different types of transfer and do not fully understand which variables affect direct versus indirect transfer or how often each type of transfer occurs. In this study, we utilize an innovative protocol that combines a paired male and female transfer DNA experimental design with an Amelogenin qPCR assay to generate data on primary, secondary, and tertiary DNA transfer. We report frequencies of indirect DNA transfer and also investigate the potential effects of participant age, self-identified ethnicity, and skin conditions on DNA transfer. Out of 22 experimental trials, we detected primary transfer (male + female) in 71% of trials, secondary DNA transfer in 50% of trials, and tertiary DNA transfer in 27% of trials. No significant associations were found between primary DNA transfer and age, self-identified ancestry, or skin conditions, however, all individuals with sloughing skin conditions demonstrated primary DNA transfer and we suggest this variable be explored in larger samples. These results contribute to a better understanding of the conditions under which secondary and tertiary DNA transfer occurs and can be used to propose realistic DNA transfer scenarios in court cases.

Low birthweight is associated with epigenetic age acceleration in the first 3 years of life.

Background and objectives: The Developmental Origins of Health and Disease hypothesis posits that early life adversity is associated with poor adult health outcomes. Epidemiological evidence has supported this framework by linking low birthweight with adult health and mortality, but the mechanisms remain unclear. Accelerated epigenetic aging may be a pathway to connect early life experiences with adult health outcomes, based on associations of accelerated epigenetic aging with increased morbidity and mortality. Methodology: Sixty-seven mother-infant dyads were recruited in the eastern Democratic Republic of Congo. Birthweight data were collected at birth, and blood samples were collected at birth and follow-up visits up to age 3. DNA methylation data were generated with the Illumina MethylationEPIC array and used to estimate epigenetic age. A multilevel model was used to test for associations between birthweight and epigenetic age acceleration. Results: Chronological age was highly correlated with epigenetic age from birth to age 3 (r = 0.95, p < 2.2 × 10-16). Variation in epigenetic age acceleration increased over time. Birthweight, dichotomized around 2500 g, predicted epigenetic age acceleration over the first 3 years of life (b = -0.39, p = 0.005). Conclusions and implications: Our longitudinal analysis provides the first evidence for accelerated epigenetic aging that emerges between birth and age 3 and associates with low birthweight. These results suggest that early life experiences, such as low birthweight, may shape the trajectory of epigenetic aging in early childhood. Furthermore, accelerated epigenetic aging may be a pathway that links low birthweight and poor adult health outcomes.

The social patterning of vicarious discrimination: Implications for health equity.

BACKGROUND: Most research on discrimination and health operationalizes discrimination as direct individual experiences. Here, we examine the social patterning of vicarious discrimination, an important but largely overlooked dimension of discrimination. METHODS: Drawing on community-based participatory research with a multi-stage probability sample (n = 178) of African Americans in Tallahassee, Florida, we measured vicarious discrimination, or exposure to discrimination through one's family and friends. We used chi-square tests to examine gender differences in the social domains and relational sources of vicarious discrimination. Negative binomial regression models were fit to identify predictors of exposure to vicarious discrimination. RESULTS: Vicarious discrimination is more prevalent than direct experiences of discrimination (73 versus 61%) and more than 20% of participants report vicarious discrimination in the absence of direct discrimination. For women, vicarious discrimination most often involved the workplace; for men, police. However, gender differences are smaller for vicarious versus direct discrimination. Close friends and children were top relational sources of vicarious discrimination for men and women, respectively. Middle-aged participants reported the most vicarious discrimination. CONCLUSIONS: Overall, our data show that vicarious discrimination is more common than widely understood and associated with individual-level sociodemographic characteristics that index one's position in broader social systems. The prevalence of vicarious discrimination in the absence of direct discrimination suggests that standard approaches, which measure individual exposures in isolation, are subject to misclassification bias. Our results imply that existing research on discrimination and health, which already demonstrates substantial harm, underestimates African Americans' true exposures to salient aspects of discrimination.

Prenatal maternal stress is associated with site-specific and age acceleration changes in maternal and newborn DNA methylation.

Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns.

Maternal Psychosocial Stress Is Associated with Reduced Diversity in the Early Infant Gut Microbiome.

The developing infant gut microbiome is highly sensitive to environmental exposures, enabling its evolution into an organ that supports the immune system, confers protection from infection, and facilitates optimal gut and central nervous system function. In this study, we focus on the impact of maternal psychosocial stress on the infant gut microbiome. Forty-seven mother-infant dyads were recruited at the HEAL Africa Hospital in Goma, Democratic Republic of Congo. Extensive medical, demographic, and psychosocial stress data were collected at birth, and infant stool samples were collected at six weeks, three months, and six months. A composite maternal psychosocial stress score was created, based on eight questionnaires to capture a diverse range of stress exposures. Full-length 16S rRNA gene sequences were generated. Infants of mothers with high composite stress scores showed lower levels of gut microbiome beta diversity at six weeks and three months, as well as higher levels of alpha diversity at six months compared to infants of low stress mothers. Longitudinal analyses showed that infants of high stress mothers had lower levels of health-promoting Lactobacillus gasseri and Bifidobacterium pseudocatenulatum at six weeks compared to infants of low stress mothers, but the differences largely disappeared by three to six months. Previous research has shown that L. gasseri can be used as a probiotic to reduce inflammation, stress, and fatigue, as well as to improve mental state, while B. pseudocatenulatum is important in modulating the gut-brain axis in early development and in preventing mood disorders. Our finding of reduced levels of these health-promoting bacteria in infants of high stress mothers suggests that the infant gut microbiome may help mediate the effect of maternal stress on infant health and development.

An innovative transfer DNA experimental design and qPCR assay: Protocol and pilot study.

Forensic "touch" DNA samples are low-quantity samples that are recovered from surfaces that have been touched by single or multiple individuals. These samples can include DNA from primary contributors who directly touched the surface, as well as secondary contributors whose DNA was transferred to the surface through an intermediary. It is difficult to determine the type of transfer, or how often and under what conditions DNA transfer occurs. In this paper, we present an innovative protocol that combines (1) a paired male and female transfer DNA experimental design in which the presence of male DNA indicates secondary transfer and (2) a cost-effective quantitative PCR (qPCR) assay of a sex-specific region in the Amelogenin gene to detect male and female DNA. We evaluate the ability of the Amelogenin qPCR assay to detect low concentrations of male and female DNA in mixed samples. We also test experimental DNA samples using our transfer DNA protocol to differentiate primary and secondary DNA transfer. Male DNA was detected in the majority of known mixed samples, even in samples with 4× more female DNA-this result demonstrates the ability to detect low concentrations of male DNA and the presence of secondary transfer DNA in our experimental design. Primary DNA transfer was detected in 100% of our experimental trials and secondary DNA transfer was detected in 37.5% of trials. Our innovative protocol mimics realistic case scenarios to establish rates of primary and secondary DNA transfer in an inexpensive and simplified manner.

Identification of a SGCD × Discrimination Interaction Effect on Systolic Blood Pressure in African American Adults in the Jackson Heart Study.

BACKGROUND: In the United States, hypertension disproportionately afflicts over half of African American adults, many of whom also experience racial discrimination. Understanding gene × discrimination effects may help explain racial disparities in hypertension. METHODS: We tested for the main effects and interactive effects of 5 candidate single nucleotide polymorphisms (SNPs: rs2116737, rs11190458, rs2445762, rs2597955, and rs2416545) and experiences of discrimination on blood pressure (BP) in African Americans not taking antihypertensive medications in the Jackson Heart Study from Mississippi (n = 2,933). Multiple linear regression models assumed an additive genetic model and adjusted for ancestry, age, sex, body mass index, education, and relatedness. We additionally tested recessive and dominant genetic models. RESULTS: Discrimination was significantly associated with higher diastolic BP (P = 0.003). In contrast, there were no main effects of any SNP on BP. When analyzing SNPs and discrimination together, SGCD (Sarcoglycan Delta; rs2116737) demonstrated a gene × environment interaction. Specifically, an SGCD × Discrimination interaction was associated with systolic BP (ß =1.95, P = 0.00028) in a recessive model. Participants carrying a T allele, regardless of discrimination experiences, and participants with a GG genotype and high experiences of discrimination had higher systolic BP than participants with a GG genotype and low experiences of discrimination. This finding suggests the SGCD GG genotype may have a protective effect on systolic BP, but only in a setting of low discrimination. CONCLUSIONS: The inclusion of culturally relevant stressors, like discrimination, may be important to understand the gene-environment interplay likely underlying complex diseases with racial health inequities.

Novel GxE effects and resilience: A case:control longitudinal study of psychosocial stress with war-affected youth.

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT, and catechol-O-methyltransferase, COMT) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents.

Ancestry of cells must be considered in bioengineering.

Bioengineered platforms, intended to be used in the investigation of human health and disease, often incorporate cells of unknown ancestry or that lack diversity. To develop tools and platforms that benefit the entire human population, we must consider the ancestry of cells and intentionally diversify the cells we use in our designs.

Stressful social environment and financial strain drive depressive symptoms, and reveal the effects of a FKBP5 variant and male sex, in African Americans living in Tallahassee.

OBJECTIVES: The World Health Organization estimates that almost 300 million people suffer from depression worldwide. African Americans are understudied for depression-related phenotypes despite widespread racial disparities. In our study of African Americans, we integrated information on psychosocial stressors with genetic variation in order to better understand how these factors associated with depressive symptoms. METHODS: Our research strategy combined information on financial strain and social networks with genetic data to investigate variation in symptoms of depression (CES-D scores). We collected self-report data on depressive symptoms, financial strain (difficulty paying bills) and personal social networks (a model of an individual's social environment), and we genotyped genetic variants in five genes previously implicated in depressive disorders (HTR1a, BDNF, GNB3, SLC6A4, and FKBP5) in 128 African Americans residing in Tallahassee, Florida. We tested for direct and gene-environment interactive effects of the psychosocial stressors and genetic variants on depressive symptoms. RESULTS: Significant associations were identified between high CES-D scores and a stressful social environment (i.e., a high percentage of people in participants' social network who were a source of stress) and high financial strain. Only one genetic variant (rs1360780 in FKBP5) was significantly associated with CES-D scores and only when psychosocial stressors were included in the model; the T allele had an additive effect on depressive symptoms. Sex was also significantly associated with CES-D score in the model with psychosocial stressors and genetic variants; males had higher CES-D scores. No significant interactive effects were detected. CONCLUSIONS: A stressful social environment and material disadvantage increase depressive symptoms in the study population. Additional associations with FKBP5 and male sex were revealed in models that included both psychosocial and genetic data. Our results suggest that incorporating psychosocial stressors may empower future genetic association studies and help clarify the biological consequences of social and financial stress.

Systemic racism can get under our skin and into our genes.

Special Issue - Race reconciled II: Interpreting and communicating biological variation and race in 2021 Many sociocultural factors, like poverty and trauma, or homelessness versus a safe neighborhood, can get "under our skin" and affect our lives. These factors may also get "into our genes" through epigenetic changes that influence how genes are expressed. Changes in gene expression can further influence how we respond to sociocultural factors and how those factors impact our physical and mental health, creating a feedback loop between our sociocultural environment and our genome.

Dehydroepiandrosterone at birth: Response to stress and relation to demographic, pregnancy and delivery factors.

Enhanced production of dehydroepiandrosterone (DHEA) by the foetal hypothalamic-pituitary-adrenal (HPA) axis enables maturational events critical for labour induction and neonatal adaptation. Despite knowledge of the interconnected nature of maternal and foetal physiology and dramatic changes in DHEA production after birth, few studies have examined DHEA levels in newborns and none have examined DHEA's response to acute stress. Understanding normative patterns of early DHEA activity is needed to accurately assess functioning of the biological stress system with relevance for health and development. The present study analysed DHEA concentrations and change after stress among 93 newborns and associations with pregnancy, delivery and demographic risk factors. Three saliva samples, collected prior to and following a blood draw stressor, were used to determine baseline and stress reactive DHEA levels. Mothers self-reported on health behaviours during pregnancy. Data on obstetric factors were obtained from medical records. DHEA levels declined from pre- to post-stressor assessments. Results also showed that post-stressor DHEA change was significantly associated with administration of medications used to treat pain and accelerate labour. However, there was no significant variation in DHEA pre-stress levels or change after stress as a function of time after birth. By capturing DHEA levels after birth, the present study provides a window into prenatal health of the HPA system. The study also advances knowledge of DHEA in newborns by providing data on reference levels and important covariates. This information on basic adrenal physiology provides a foundation that can be expanded on to enhance understanding of early hypothalamic-pituitary-adrenal axis activity.

Shortened telomere length is associated with unfair treatment attributed to race in African Americans living in Tallahassee, Florida.

OBJECTIVES: Experiences of interpersonal discrimination are pervasive stressors in the lives of African Americans. Increased discrimination stress may cause premature aging. Telomere length (TL) is a plastic genetic trait that is an emerging indicator of cellular health and aging. Short TL is a risk factor for the earlier onset of disease. TL shortens with age, a process that may be accelerated by psychosocial stress. Our study explores the relationship between TL and experiences of discrimination in the form of self-reported unfair treatment (UT). METHODS: Using a qPCR-based method, we measured TL in DNA from saliva samples provided by 135 African American adults from Tallahassee, FL. We developed discrimination measures using a modified survey that explores nine social domains of self-reported unfair treatment experienced both directly and indirectly. We used multiple regression to examine associations between UT and TL. RESULTS: We found that racial discrimination in the form of self-reported unfair treatment attributed to race (UT-Race-Self) is inversely associated with TL. CONCLUSIONS: The significant association between increased UT-Race-Self and shorter telomeres supports the hypothesis that psychosocial stress stemming from racial discrimination may affect TL. The potential impact of discrimination on TL may contribute to premature biological aging and racial health inequalities seen in African Americans.

Association of MAOA genetic variants and resilience with psychosocial stress: A longitudinal study of Syrian refugees.

Early childhood trauma can have profound and lifelong effects on adult mental health and psychosocial wellbeing. Nevertheless, responses to trauma are highly variable. Genetic variants may help explain variation in responses to trauma by identifying alleles that associate with changes in mental health measures. Protective factors, such as resilience, likely also play an important role in responses to trauma. The effects of genetic variants, in combination with protective factors, on psychosocial health are not well understood, particularly in non-Western contexts. In this study, we test the relative influence of genetic variants of monoamine oxidase A (MAOA, a gene proposed to influence the impact of childhood trauma on adult violence and antisocial behavior), levels of resilience, and exposure to traumatic events on psychosocial stress and mental health trajectories over time. We use data from a cohort of 12-18-year-old Syrian refugees who were forcibly displaced to neighboring Jordan (n = 399). DNA samples and survey data on trauma exposure, resilience (CYRM-12), and psychosocial stress were collected at three time points: baseline, ~13 weeks, and ~48 weeks. Using multilevel models, we identified an association of MAOA variant, in males only, with symptom scores of psychosocial stress on the Perceived Stress Scale (PSS) over time (p = 8.1 x 10-4). We also found that resilience is strongly associated with PSS (p = 7.9 x 10-9), underscoring the importance of protective factors in influencing levels of psychosocial stress. Furthermore, there was an additive effect wherein the sharpest reductions in perceived psychosocial stress are seen in low-activity MAOA males with low trauma exposure or high resilience levels. Our results highlight the value of studies that integrate genetic and psychosocial factors to better understand complex phenotypes, such as responses to trauma in contexts of high trauma exposure.

Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history.

OBJECTIVES: Modern humans are thought to have interbred with Neanderthals in the Near East soon after modern humans dispersed out of Africa. This introgression event likely took place in either the Levant or southern Arabia depending on the dispersal route out of Africa that was followed. In this study, we compare Neanderthal introgression in contemporary Levantine and southern Arabian populations to investigate Neanderthal introgression and to study Near Eastern population history. MATERIALS AND METHODS: We analyzed genotyping data on >400,000 autosomal SNPs from seven Levantine and five southern Arabian populations and compared these data to those from populations from around the world including Neanderthal and Denisovan genomes. We used f4 and D statistics to estimate and compare levels of Neanderthal introgression between Levantine, southern Arabian, and comparative global populations. We also identified 1,581 putative Neanderthal-introgressed SNPs within our dataset and analyzed their allele frequencies as a means to compare introgression patterns in Levantine and southern Arabian genomes. RESULTS: We find that Levantine and southern Arabian populations have similar levels of Neanderthal introgression to each other but lower levels than other non-Africans. Furthermore, we find that introgressed SNPs have very similar allele frequencies in the Levant and southern Arabia, which indicates that Neanderthal introgression is similarly distributed in Levantine and southern Arabian genomes. DISCUSSION: We infer that the ancestors of contemporary Levantine and southern Arabian populations received Neanderthal introgression prior to separating from each other and that there has been extensive gene flow between these populations.