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BACKGROUND:CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells.METHODS:To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells.RESULTS:We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a

BackgroundEpidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.MethodsIn this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.Results[18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.ConclusionsThese findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA sequencing and protein expression by liquid chromatography-mass spectrometry directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.

BackgroundMaternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.MethodsA total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods.ResultsGestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.ConclusionsAlthough the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.

Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.

Alteration of benthic reef habitat after coral bleaching and mortality induces changes in fish assemblages, with implications for fisheries. Our understanding of climate impacts to coral reef fisheries is largely based on fish abundance and biomass. The rates at which biomass is produced and replenished (productivity and turnover) are also important to sustaining fisheries, yet the responses of these metrics following bleaching are largely unknown. Here, we examine changes in fish productivity and turnover after mass coral bleaching events in Seychelles, on reefs that were recovering to coral-dominated habitats and those that shifted to macroalgae-dominated regimes. Productivity of fish assemblages increased on all recovering reefs, particularly on fished reefs resulting in levels similar to protected reefs 19 years after bleaching. Herbivore-detritivores, such as scraping and excavating parrotfish, appeared to drive biomass production through increased abundance on recovering reefs. Productivity on regime-shifted reefs remained stable at 1994 levels in fished areas, with increases observed on protected reefs. Large increases in browser productivity (particularly on protected reefs), combined with increases for invertivores, maintained post-bleaching productivity on macroalgal reefs. For all diet groups, net turnover was generally higher on fished regime-shifted reefs than on recovering reefs, suggesting fish biomass is more readily replenished on macroalgal reefs. Reef structural complexity was a positive predictor of productivity for all diet groups. These findings indicate that post-bleaching reef fish productivity is strongly influenced by benthic recovery trajectories, and demonstrates the importance of herbivore and invertivore species in sustaining small-scale inshore fisheries following climatic disturbances.

Winter mixed-precipitation events across the mid-Atlantic region of the United States from 2013-2014 through 2018-2019 were used to analyze common short-term model forecasts of vertical atmospheric thermal structure. Using saturated forecast soundings of the North American Mesoscale (NAM), higher-resolution nested NAM (NAMnest), and the Rapid Refresh models-corresponding with observed warm-nose precipitation events (WNPEs)-several thermal metrics formed the basis of the analysis of observed and forecast soundings. including Bourgouin positive and negative areas. While the three models accurately forecast the general thermal structure well during WNPEs, a warm bias is evident within each. Well forecast are maximum and minimum temperatures within the warm nose and surface-based cold layer, respectively, but the cold layer is commonly too thin for each of the models, and the warm nose is regularly too thick, particularly within NAM and NAMnest forecasts. Forecasts of a cold layer that is too shallow tend to coincide with observations of stronger synoptic-scale upward motion, a deeper cold surface-based layer, and a higher isentropic surface. Forecasts of a warm nose that is too thick tend to coincide with observations of weaker upward motion, a shallower cold surface-based layer, and a lower isentropic surface across the region. Two-thirds of precipitation-type estimates from model soundings agreed with those derived from observed soundings, with the remaining third predominantly representing a warm bias in precipitation type.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.

Machine reading tools are able to quickly and automatically process vast amounts of information from relevant published literature, identifying and extracting the relevant information from a given paper or papers. This information can be used to build biological computational models or expand upon existing models. However, the information gleaned by machine readers is both vast and varied in quality. Machine readers must work to extract standardized biological interactions from inconsistent terminology and complex sentence structures, which sometimes leads to extraction errors. Here we present VIOLIN (Verifying Interactions of Likely Importance to the Network) a tool to automatically classify and judge biological interactions extracted from relevant literature. With VIOLIN, we are able to take these literature extracted events (LEEs) and compare them to an existing biological model, determining whether a given LEE agrees with the model (corroborates), introduces new information to the model (extends), disputes the model (contradicts), or requires manual review (flagged). Each LEE is assigned four numerical values to represent its relationship to the model system (Match Score), its classification category (Kind Score), its frequency (Evidence Score), and extraction confidence (Epistemic Value). These values are combined into a Total Score to allow for automatic filtering and classification of large sets of LEEs curated from multiple sources. We present VIOLIN in the context of five different models: melanoma, T-cell differentiation, the BDNF pathway as it relates to major depressive disorder, pancreatic cancer, and glioblastoma multiforme. These varied inputs show that VIOLIN has great utility across many biological systems, making it a powerful computational tool. We also show how VIOLIN integrates with other modeling tools as part of a larger model extensions framework. The goal of this work is to be able to automatically extend existing biological models using the

Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full-length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and heterosubtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. The adjuvanted vaccine was also associated with the elicitation of stalk-directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.

Alteration of benthic reef habitat after coral bleaching and mortality induces changes in fish assemblages, with implications for fisheries. Our understanding of climate impacts to coral reef fisheries is largely based on fish abundance and biomass. The rates at which biomass is produced and replenished (productivity and turnover) are also important to sustaining fisheries, yet the responses of these metrics following bleaching are largely unknown. Here, we examine changes in fish productivity and turnover after mass coral bleaching events in Seychelles, on reefs that were recovering to coral-dominated habitats and those that shifted to macroalgae-dominated regimes. Productivity of fish assemblages increased on all recovering reefs, particularly on fished reefs resulting in levels similar to protected reefs 19 years after bleaching. Herbivore-detritivores, such as scraping and excavating parrotfish, appeared to drive biomass production through increased abundance on recovering reefs. Productivity on regime-shifted reefs remained stable at 1994 levels in fished areas, with increases observed on protected reefs. Large increases in browser productivity (particularly on protected reefs), combined with increases for invertivores, maintained post-bleaching productivity on macroalgal reefs. For all diet groups, net turnover was generally higher on fished regime-shifted reefs than on recovering reefs, suggesting fish biomass is more readily replenished on macroalgal reefs. Reef structural complexity was a positive predictor of productivity for all diet groups. These findings indicate that post-bleaching reef fish productivity is strongly influenced by benthic recovery trajectories, and demonstrates the importance of herbivore and invertivore species in sustaining small-scale inshore fisheries following climatic disturbances.

Machine reading tools are able to quickly and automatically process vast amounts of information from relevant published literature, identifying and extracting the relevant information from a given paper or papers. This information can be used to build biological computational models or expand upon existing models. However, the information gleaned by machine readers is both vast and varied in quality. Machine readers must work to extract standardized biological interactions from inconsistent terminology and complex sentence structures, which sometimes leads to extraction errors. Here we present VIOLIN (Verifying Interactions of Likely Importance to the Network) a tool to automatically classify and judge biological interactions extracted from relevant literature. With VIOLIN, we are able to take these literature extracted events (LEEs) and compare them to an existing biological model, determining whether a given LEE agrees with the model (corroborates), introduces new information to the model (extends), disputes the model (contradicts), or requires manual review (flagged). Each LEE is assigned four numerical values to represent its relationship to the model system (Match Score), its classification category (Kind Score), its frequency (Evidence Score), and extraction confidence (Epistemic Value). These values are combined into a Total Score to allow for automatic filtering and classification of large sets of LEEs curated from multiple sources. We present VIOLIN in the context of five different models: melanoma, T-cell differentiation, the BDNF pathway as it relates to major depressive disorder, pancreatic cancer, and glioblastoma multiforme. These varied inputs show that VIOLIN has great utility across many biological systems, making it a powerful computational tool. We also show how VIOLIN integrates with other modeling tools as part of a larger model extensions framework. The goal of this work is to be able to automatically extend existing biological models using the

Winter mixed-precipitation events across the mid-Atlantic region of the United States from 2013-2014 through 2018-2019 were used to analyze common short-term model forecasts of vertical atmospheric thermal structure. Using saturated forecast soundings of the North American Mesoscale (NAM), higher-resolution nested NAM (NAMnest), and the Rapid Refresh models-corresponding with observed warm-nose precipitation events (WNPEs)-several thermal metrics formed the basis of the analysis of observed and forecast soundings. including Bourgouin positive and negative areas. While the three models accurately forecast the general thermal structure well during WNPEs, a warm bias is evident within each. Well forecast are maximum and minimum temperatures within the warm nose and surface-based cold layer, respectively, but the cold layer is commonly too thin for each of the models, and the warm nose is regularly too thick, particularly within NAM and NAMnest forecasts. Forecasts of a cold layer that is too shallow tend to coincide with observations of stronger synoptic-scale upward motion, a deeper cold surface-based layer, and a higher isentropic surface. Forecasts of a warm nose that is too thick tend to coincide with observations of weaker upward motion, a shallower cold surface-based layer, and a lower isentropic surface across the region. Two-thirds of precipitation-type estimates from model soundings agreed with those derived from observed soundings, with the remaining third predominantly representing a warm bias in precipitation type.

We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development

Ehlers-Danlos Syndrome (EDS) describes a group of 14 heritable connective tissue disorders that have in common joint hypermobility. The most prevalent of the subtypes is the recently reclassified hypermobile EDS (hEDS) characterized by generalized joint hypermobility, skin features such as velvety texture and/or skin hyperextensibility, and musculoskeletal pain. Secondary features include autonomic dysfunction, gastrointestinal dysfunction, and fatigue. While the most prevalent EDS subtype, hEDS is the least understood without any consensus on associated causal genes or variants. Due to its complex and heterogeneous symptomatology, we hypothesize that hEDS is a genetically heterogenous disorder but with primary causal variants and/or genes. The focus of this dissertation, as part of the hEDS GENE study led by Dr. Christina Laukaitis, is to define the updated hEDS phenotype and identify both structural and rare single nucleotide variants that contribute to the hEDS phenotype. To explore the 2017 hEDS reclassification, 148 people were enrolled in the hEDS GENE study with 98 meeting the 2017 hEDS criteria, 27 having a hypermobility spectrum disorder (HSD) and 23 being asymptomatic family members. More than 80% of the participants were female. Each participant completed seven clinal questionnaires to thoroughly describe and quantify hEDS symptomatology including the 36-Item Short Form Health Survey, a subscale of the full Patient Health Questionnaire, the Tampa Scale for Kinesiophobia, the Fatigue Severity Scale, the Epworth Sleepiness Scale, the Gastro-Questionnaire, and a short form version of the Composite Autonomic Symptom Score. We concluded that symptom frequency and severity were generally indistinguishable between participants with hEDS and HSDs with both experiencing significant decrease in health-related quality of life, however, we also observed subtle differences in autonomic symptoms between the two hypermobile groups. In participants with a clearly-defined

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.

Background: The Gymnastics Functional Measurement Tool (GFMT) is a series of 10 sport-specific tests that evaluates the physical fitness of female gymnasts. The standardized scoring system has been validated in a wide range of competitive levels. To date, there is no screening tool to identify risk factors for injury in female gymnasts. Objective(s): To determine if the total score on the GFMT or the individual test components can identify female collegiate gymnasts who are at risk of developing an injury. Design(s): Prospective cohort study. Setting(s): Collegiate gymnastics training and competition facilities. Participant(s): One hundred female gymnasts from seven National Collegiate Athletic Association, Division I teams. Intervention(s): Gymnasts were tested with the GFMT (vertical jump, hanging leg lifts, agility sprint, 20-meter sprint, pull-ups, push-ups, rope climb, handstand hold, lower extremity flexibility, and shoulder flexibility). Each team's certified athletic trainer recorded injuries over the course of one season. Logistic regression modeling was used to assess the relationship between each individual test and the development of upper extremity, lower extremity, or trunk injuries. Main Outcome Measurements: Gymnastics-related injuries. Result(s): A total of 160 injuries from 100 gymnasts were included in the analysis. No tests were significantly associated with developing of upper or lower extremity injuries. A higher score on the vertical jump test was associated with fewer trunk injuries (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.52-0.91; P =.01). This relationship existed even after adjusting for gymnast characteristics in a multivariable analysis. Conclusion(s): A one-unit increase in vertical jump score was associated with a 30% decrease in trunk injuries in collegiate-level female gymnasts. Future research to identify risk factors for gymnastics-related injury and methods for prevention are needed. Level of Evidence: II.Copyright ©

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.

The nonhuman primate provides a sophisticated animal model system both to explore neurobiological mechanisms underlying complex behaviors and to facilitate preclinical research for neurodevelopmental and neuropsychiatric disease. A better understanding of evolutionarily conserved behaviors and brain processes between humans and nonhuman primates will be needed to successfully apply recently released NIMH guidelines (NOT-MH-19-053) for conducting rigorous nonhuman primate neurobehavioral research. Here, we explore the relationship between two measures of social behavior that can be used in both humans and nonhuman primates-traditional observations of social interactions with conspecifics and eye gaze detection in response to social stimuli. Infant male rhesus macaques (Macaca mulatta) serving as controls (N = 14) for an ongoing study were observed in their social rearing groups and participated in a noninvasive, longitudinal eye-tracking study. We found significant positive relationships between time spent viewing eyes of faces in an eye tracker and number of initiations made for social interactions with peers that is consistent with similar observations in human populations. Although future studies are needed to determine if this relationship represents species-typical social developmental processes, these preliminary results provide a novel framework to explore the relationship between social interactions and social attention in nonhuman primate models for neurobehavioral development.

Eye-tracking methods measure what humans and other animals visually attend to in the environment. In nonhuman primates, eye tracking can be used to test hypotheses about how primates process social information. This information can further our understanding of primate behavior as well as offer unique translational potential to explore causes of or treatments for altered social processing as seen in people with neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. However, previous methods for collecting eye-tracking data in nonhuman primates required some form of head restraint, which limits the opportunities for research with respect to the number of or kinds of primates that can undergo an eye-tracking study. We developed a novel, noninvasive method for collecting eye tracking data that can be used both in animals that are difficult to restrain without sedation as well as animals that are of different ages and sizes as the box size can be adjusted. Using a transport box modified with a viewing window, we collected eye-tracking data in both New (Callicebus cupreus) and Old World monkeys (Macaca mulatta) across multiple developmental time points. These monkeys had the option to move around the box and avert their eyes from the screen, yet, they demonstrated a natural interest in viewing species-specific imagery with no previous habituation to the eye-tracking paradigm. Provided with opportunistic data from voluntary viewing of stimuli, we found that juveniles viewed stimuli more than other age groups, videos were viewed more than static photo imagery, and that monkeys increased their viewing time when presented with multiple eye tracking sessions. This noninvasive approach opens new opportunities to integrate eye-tracking studies into nonhuman primate research.

We review the theory and applications of complex stochastic quantization to the quantum many-body problem. Along the way, we present a brief overview of a number of ideas that either ameliorate or in some cases altogether solve the sign problem, including the classic reweighting method, alternative Hubbard-Stratonovich transformations, dual variables (for bosons and fermions), Majorana fermions, density-of-states methods, imaginary asymmetry approaches, and Lefschetz thimbles. We discuss some aspects of the mathematical underpinnings of conventional stochastic quantization, provide a few pedagogical examples, and summarize open challenges and practical solutions for the complex case. Finally, we review the recent applications of complex Langevin to quantum field theory in relativistic and nonrelativistic quantum matter, with an emphasis on the nonrelativistic case., Comment: 51 pages, 19 figures, review article

Eye-tracking methods measure what humans and other animals visually attend to in the environment. In nonhuman primates, eye tracking can be used to test hypotheses about how primates process social information. This information can further our understanding of primate behavior as well as offer unique translational potential to explore causes of or treatments for altered social processing as seen in people with neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. However, previous methods for collecting eye-tracking data in nonhuman primates required some form of head restraint, which limits the opportunities for research with respect to the number of or kinds of primates that can undergo an eye-tracking study. We developed a novel, noninvasive method for collecting eye tracking data that can be used both in animals that are difficult to restrain without sedation as well as animals that are of different ages and sizes as the box size can be adjusted. Using a transport box modified with a viewing window, we collected eye-tracking data in both New (Callicebus cupreus) and Old World monkeys (Macaca mulatta) across multiple developmental time points. These monkeys had the option to move around the box and avert their eyes from the screen, yet, they demonstrated a natural interest in viewing species-specific imagery with no previous habituation to the eye-tracking paradigm. Provided with opportunistic data from voluntary viewing of stimuli, we found that juveniles viewed stimuli more than other age groups, videos were viewed more than static photo imagery, and that monkeys increased their viewing time when presented with multiple eye tracking sessions. This noninvasive approach opens new opportunities to integrate eye-tracking studies into nonhuman primate research.

We review the theory and applications of complex stochastic quantization to the quantum many-body problem. Along the way, we present a brief overview of a number of ideas that either ameliorate or in some cases altogether solve the sign problem, including the classic reweighting method, alternative Hubbard-Stratonovich transformations, dual variables (for bosons and fermions), Majorana fermions, density-of-states methods, imaginary asymmetry approaches, and Lefschetz thimbles. We discuss some aspects of the mathematical underpinnings of conventional stochastic quantization, provide a few pedagogical examples, and summarize open challenges and practical solutions for the complex case. Finally, we review the recent applications of complex Langevin to quantum field theory in relativistic and nonrelativistic quantum matter, with an emphasis on the nonrelativistic case., Comment: 68 pages, 19 figures, review article, version submitted to Physics Reports

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), the protein that shuttles LPL to the capillary lumen, is essential for plasma triglyceride metabolism. When GPIHBP1 is absent, LPL remains stranded within the interstitial spaces and plasma triglyceride hydrolysis is impaired, resulting in severe hypertriglyceridemia. While the functions of GPIHBP1 in intravascular lipolysis are reasonably well understood, no one has yet identified DNA sequences regulating GPIHBP1 expression. In the current studies, we identified an enhancer element located ∼3.6 kb upstream from exon 1 of mouse Gpihbp1. To examine the importance of the enhancer, we used CRISPR/Cas9 genome editing to create mice lacking the enhancer (Gpihbp1Enh/Enh). Removing the enhancer reduced Gpihbp1 expression by >90% in the liver and by ∼50% in heart and brown adipose tissue. The reduced expression of GPIHBP1 was insufficient to prevent LPL from reaching the capillary lumen, and it did not lead to hypertriglyceridemia-even when mice were fed a high-fat diet. Compound heterozygotes (Gpihbp1Enh/- mice) displayed further reductions in Gpihbp1 expression and exhibited partial mislocalization of LPL (increased amounts of LPL within the interstitial spaces of the heart), but the plasma triglyceride levels were not perturbed. The enhancer element that we identified represents the first insight into DNA sequences controlling Gpihbp1 expression.

© 2018 American Academy of Forensic Sciences Forensic science laboratories are being challenged by the expanding decentralization of forensic capabilities, particularly for digital traces. This study recommends laboratories undertake digital transformations to capitalize on the decentralization movement, develop a more comprehensive understanding of crime and security-relevant problems, and play a more central role in problem-solving collaboratively with law enforcement organizations and other stakeholders. A framework for the bilateral transfer of information and knowledge is proposed to magnify the impact of forensic science laboratories on abating crime, strengthening security, and reinforcing the criminal justice system. To accomplish digital transformations, laboratories require personnel with different expertise, including investigative reasoning, knowledge codification, data analytics, and forensic intelligence. Ultimately, this study encourages managers, educators, researchers, and policymakers to look beyond the usefulness of forensic results for solving individual investigations, and to realize the value of combined forensic knowledge and intelligence for developing broader strategies to deal with crime in digitalized society.

We review the theory and applications of complex stochastic quantization to the quantum many-body problem. Along the way, we present a brief overview of a number of ideas that either ameliorate or in some cases altogether solve the sign problem, including the classic reweighting method, alternative Hubbard-Stratonovich transformations, dual variables (for bosons and fermions), Majorana fermions, density-of-states methods, imaginary asymmetry approaches, and Lefschetz thimbles. We discuss some aspects of the mathematical underpinnings of conventional stochastic quantization, provide a few pedagogical examples, and summarize open challenges and practical solutions for the complex case. Finally, we review the recent applications of complex Langevin to quantum field theory in relativistic and nonrelativistic quantum matter, with an emphasis on the nonrelativistic case., Comment: 68 pages, 19 figures, review article, version submitted to Physics Reports

© 2018 American Academy of Forensic Sciences Forensic science laboratories are being challenged by the expanding decentralization of forensic capabilities, particularly for digital traces. This study recommends laboratories undertake digital transformations to capitalize on the decentralization movement, develop a more comprehensive understanding of crime and security-relevant problems, and play a more central role in problem-solving collaboratively with law enforcement organizations and other stakeholders. A framework for the bilateral transfer of information and knowledge is proposed to magnify the impact of forensic science laboratories on abating crime, strengthening security, and reinforcing the criminal justice system. To accomplish digital transformations, laboratories require personnel with different expertise, including investigative reasoning, knowledge codification, data analytics, and forensic intelligence. Ultimately, this study encourages managers, educators, researchers, and policymakers to look beyond the usefulness of forensic results for solving individual investigations, and to realize the value of combined forensic knowledge and intelligence for developing broader strategies to deal with crime in digitalized society.

While colorectal cancer (CRC) incidence has decreased over the past 20 years, the reduction in incidence has not been uniform across all stages of disease. The reduction in late stage (distant) CRC was significantly less than that of than earlier stage CRC, a trend enriched for early-onset CRCs. African Americans have the highest incidence and mortality rates of CRC of any ethnic group in the United States and are more likely to present before recommended guidelines for screening (i.e., age of 50 years). Despite this ongoing health disparity, relatively few studies have sought to address risk factors and etiological signatures unique to African American CRC. We hypothesized that molecular characteristics in the gut microenvironment and tumor mutation profiles of African American CRCs are unique. The studies presented here sought to address this hypothesis through molecular studies in a low-income cohort from urban Chicago, the Chicago Colorectal Cancer Consortium, as well as a publicly available cohort, The Cancer Genome Atlas. We found that African Americans have higher abundances of the sulfidogenic bacterium Bilophila wadsworthia, a trend that remained after adjusting for covariates including diet. African American cases had significantly higher abundances than African American controls, a trend that did not exist in non-Hispanic Whites. We found that African American CRCs had molecular features that were distinct from non-Hispanic Whites. CCCC African American CRCs had significantly fewer mutations than expected in APC, a gene typically mutated in 80% of CRCs, and that the lack of APC mutation was associated with younger age, chromosome stability, and a non-CIMP DNA methylation profile. Together, the findings presented here suggest that unknown risk factors and unique tumorigenic processes drive CRC in African Americans.

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency., National Institutes of Health (U.S.) (Grant EB000244), National Institutes of Health (U.S.) (Grant EB000351), National Institutes of Health (U.S.) (Grant DE013023), National Institutes of Health (U.S.) (Grant CA151884)

Cell-specific patterns of gene expression are determined by combinatorial actions of sequence-specific transcription factors at cis-regulatory elements. Studies indicate that relatively simple combinations of lineage-determining transcription factors (LDTFs) play dominant roles in the selection of enhancers that establish cell identities and functions. LDTFs require collaborative interactions with additional transcription factors to mediate enhancer function, but the identities of these factors are often unknown. We have shown that natural genetic variation between individuals has great utility for discovering collaborative transcription factors. Here, we introduce MMARGE (Motif Mutation Analysis of Regulatory Genomic Elements), the first publicly available suite of software tools that integrates genome-wide genetic variation with epigenetic data to identify collaborative transcription factor pairs. MMARGE is optimized to work with chromatin accessibility assays (such as ATAC-seq or DNase I hypersensitivity), as well as transcription factor binding data collected by ChIP-seq. Herein, we provide investigators with rationale for each step in the MMARGE pipeline and key differences for analysis of datasets with different experimental designs. We demonstrate the utility of MMARGE using mouse peritoneal macrophages, liver cells, and human lymphoblastoid cells. MMARGE provides a powerful tool to identify combinations of cell type-specific transcription factors while simultaneously interpreting functional effects of non-coding genetic variation.

BackgroundMutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction.MethodsHere we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples.ResultsComparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure.ConclusionsThis multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.

Common sports injuries include bone stress injuries (BSIs), anterior cruciate ligament (ACL) injuries, and concussions. Less commonly recognized are the specific sex differences in epidemiology, risk factors, and outcomes of these conditions by sex. An understanding of these factors can improve their clinical management, from prescribing appropriate prehabilitation to guiding postinjury rehabilitation and return to play. This narrative review summarizes the sex differences in the diagnosis and management of BSIs, ACL injuries, and concussions. Although BSIs are more common in female athletes, risk factors for both sexes include prior injury and relative energy deficiency in sport (RED-S). Risk factors in female athletes include smaller calf girth, femoral adduction, and higher rates of loading. Female athletes are also at greater risk for developing ACL injuries in high school and college, but their injury rate is similar in professional sports. Increased lateral tibial slope, smaller ACL size, and suboptimal landing mechanics are additional risk factors more often present in female athletes. Male athletes are more likely to have ACL surgery and have a higher rate of return to sport. Concussions occur more commonly in female athletes; however, female athletes are also more likely to report concussions. Male athletes more commonly sustain concussion through contact with another player. Female athletes more commonly sustain injury from contact with playing equipment. Managing post-concussion symptoms is important, and female athletes may have prolonged symptoms. An understanding of the sex-specific differences in these common sports injuries can help optimize their prehabilitation and rehabilitation. Level of Evidence: IVCopyright © 2018 American Academy of Physical Medicine and Rehabilitation

Objectives: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. Design(s): Harmonized data from prospective multicenter international longitudinal cohort studies Setting: Diverse mix of ICUs. Patient(s): Critically ill patients expected to be ventilated for longer than 24 hours. Intervention(s): Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. Measurements and Main Results: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (sd) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47-8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15-1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10-1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73-0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04-1.49), p value equals to

Common sports injuries include bone stress injuries (BSIs), anterior cruciate ligament (ACL) injuries, and concussions. Less commonly recognized are the specific sex differences in epidemiology, risk factors, and outcomes of these conditions by sex. An understanding of these factors can improve their clinical management, from prescribing appropriate prehabilitation to guiding postinjury rehabilitation and return to play. This narrative review summarizes the sex differences in the diagnosis and management of BSIs, ACL injuries, and concussions. Although BSIs are more common in female athletes, risk factors for both sexes include prior injury and relative energy deficiency in sport (RED-S). Risk factors in female athletes include smaller calf girth, femoral adduction, and higher rates of loading. Female athletes are also at greater risk for developing ACL injuries in high school and college, but their injury rate is similar in professional sports. Increased lateral tibial slope, smaller ACL size, and suboptimal landing mechanics are additional risk factors more often present in female athletes. Male athletes are more likely to have ACL surgery and have a higher rate of return to sport. Concussions occur more commonly in female athletes; however, female athletes are also more likely to report concussions. Male athletes more commonly sustain concussion through contact with another player. Female athletes more commonly sustain injury from contact with playing equipment. Managing post-concussion symptoms is important, and female athletes may have prolonged symptoms. An understanding of the sex-specific differences in these common sports injuries can help optimize their prehabilitation and rehabilitation. Level of Evidence: IVCopyright © 2018 American Academy of Physical Medicine and Rehabilitation

BackgroundMutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction.MethodsHere we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples.ResultsComparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure.ConclusionsThis multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.

Cell-specific patterns of gene expression are determined by combinatorial actions of sequence-specific transcription factors at cis-regulatory elements. Studies indicate that relatively simple combinations of lineage-determining transcription factors (LDTFs) play dominant roles in the selection of enhancers that establish cell identities and functions. LDTFs require collaborative interactions with additional transcription factors to mediate enhancer function, but the identities of these factors are often unknown. We have shown that natural genetic variation between individuals has great utility for discovering collaborative transcription factors. Here, we introduce MMARGE (Motif Mutation Analysis of Regulatory Genomic Elements), the first publicly available suite of software tools that integrates genome-wide genetic variation with epigenetic data to identify collaborative transcription factor pairs. MMARGE is optimized to work with chromatin accessibility assays (such as ATAC-seq or DNase I hypersensitivity), as well as transcription factor binding data collected by ChIP-seq. Herein, we provide investigators with rationale for each step in the MMARGE pipeline and key differences for analysis of datasets with different experimental designs. We demonstrate the utility of MMARGE using mouse peritoneal macrophages, liver cells, and human lymphoblastoid cells. MMARGE provides a powerful tool to identify combinations of cell type-specific transcription factors while simultaneously interpreting functional effects of non-coding genetic variation.

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.

Nonhuman primates provide a human-relevant experimental model system to explore the mechanisms by which oxytocin (OT) regulates social processing and inform its clinical applications. Here, we highlight contributions of the nonhuman primate model to our understanding of OT treatment and address unique challenges in administering OT to awake behaving primates. Prior preclinical research utilizing macaque monkeys has demonstrated that OT can modulate perception of other individuals and their expressions, attention to others, imitation, vigilance to social threats, and prosocial decisions. We further describe ongoing efforts to develop an OT delivery system for use in experimentally naïve juvenile macaque monkeys compatible with naturalistic social behavior outcomes. Finally, we discuss future directions to further develop the rhesus monkey as a preclinical test bed to evaluate the effects of OT exposure and advance efforts to translate basic science OT research into safe and effective OT therapies.

Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years) prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.

Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.