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BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohns disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVies safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Despite a significant accumulation of research, there has been little systemic implementation of evidence-based practices (EBP) in youth mental health care. The fragmentation of the evidence base complicates implementation efforts. In light of this challenge, we sought to pilot a system that consolidates and coordinates the entire evidence base in a single direct service model (i.e., Managing and Adapting Practice; MAP) in the context of a legal reform of psychotherapy training in Germany. This pilot study aimed to evaluate the feasibility of the implementation of MAP into the curriculum of the reformed German masters program. Eligible participants were students in the masters program at Philipps-University Marburg during the winter-term 2022/2023. Students first learned about MAP through introductions and role plays (seminar 1), followed by actively planning and conducting interventions using MAP resources for patients in a case seminar under supervision (seminar 2). A repeated-measures survey was conducted to investigate students knowledge gains, perception of MAP and changes in their self-rated confidence to use EBP. Results indicated that students perceive MAP to be manageable to learn. Positive progress was achieved with regard to their knowledge and self-reported confidence to use EBP, although interpretation and generalization of the results are limited by small and homogeneous samples, lack of statistical power and missing comparison groups. The feasibility of the implementation and suitability of measures are discussed. Important implications could be drawn with regard to future investigations.

Trichomonas vaginalis, a common sexually transmitted parasite that colonizes the human urogenital tract, secretes extracellular vesicles (TvEVs) that are taken up by human cells and are speculated to be taken up by parasites as well. While the crosstalk between TvEVs and human cells has led to insight into host:parasite interactions, roles for TvEVs in infection have largely been one-sided, with little known about the effect of TvEV uptake by T. vaginalis. Approximately 11% of infections are found to be coinfections of multiple T. vaginalis strains. Clinical isolates often differ in their adherence to and cytolysis of host cells, underscoring the importance of understanding the effects of TvEV uptake within the parasite population. To address this question, our lab tested the ability of a less adherent strain of T. vaginalis, G3, to take up fluorescently labeled TvEVs derived from both itself (G3-EVs) and TvEVs from a more adherent strain of the parasite (B7RC2-EVs). Here, we showed that TvEVs generated from the more adherent strain are internalized more efficiently compared to the less adherent strain. Additionally, preincubation of G3 parasites with B7RC2-EVs increases parasite aggregation and adherence to host cells. Transcriptomics revealed that TvEVs up-regulate expression of predicted parasite membrane proteins and identified an adherence factor, heteropolysaccharide binding protein (HPB2). Finally, using comparative proteomics and superresolution microscopy, we demonstrated direct transfer of an adherence factor, cadherin-like protein, from TvEVs to the recipient parasites surface. This work identifies TvEVs as a mediator of parasite:parasite communication that may impact pathogenesis during mixed infections.

AimsQuantile regression is an alternate type of regression analysis that has been shown to have numerous advantages over standard linear regression. Unlike linear regression, which uses the mean to fit a linear model, quantile regression uses a data set's quantiles (or percentiles), which leads to a more comprehensive analysis of the data. However, while relatively common in other scientific fields such as economic and environmental modeling, it is infrequently used to understand biological and microbiological systems.Methods and resultsWe analyzed a set of bacterial growth rates using quantile regression analysis to better understand the effects of antibiotics on bacterial fitness. Using a bacterial model system containing 16 variant genotypes of the TEM β-lactamase enzyme, we compared our quantile regression analysis to a previously published study that uses the Tukey's range test, or Tukey honestly significantly difference (HSD) test. We find that trends in the distribution of bacterial growth rate data, as viewed through the lens of quantile regression, can distinguish between novel genotypes and ones that have been clinically isolated from patients. Quantile regression also identified certain combinations of genotypes and antibiotics that resulted in bacterial populations growing faster as the antibiotic concentration increased-the opposite of what was expected. These analyses can provide new insights into the relationships between enzymatic efficacy and antibiotic concentration.ConclusionsQuantile regression analysis enhances our understanding of the impacts of sublethal antibiotic concentrations on enzymatic (TEM β-lactamase) efficacy and bacterial fitness. We illustrate that quantile regression analysis can link patterns in growth rates with clinically relevant mutations and provides an understanding of how increasing sub-lethal antibiotic concentrations, like those found in our modern environment, can affect bacterial growth rates, and provide insight into the genetic basis for varied resistance.

Psoriasis is a chronic immune-mediated disorder that commonly affects adults and children. In recent years, pediatric psoriasis has increased in prevalence and the disease is often associated with various comorbidities and psychological distress. The conventional topical treatments for psoriasis, such as corticosteroids, calcineurin inhibitors, vitamin D analogs, anthralin, and coal tar, are often limited by their side effects, tolerability, and/or efficacy, particularly for use in children and on sensitive and intertriginous areas. Recently, the US Food and Drug Administration approved two new topical non-steroidal agents for treating psoriasis that target different pathogenic pathways than the conventional treatments. Roflumilast is a phosphodiesterase type 4 inhibitor approved for the treatment of plaque psoriasis in patients aged 12 years and older. Tapinarof is a novel aryl hydrocarbon receptor modulator approved for adult psoriasis and currently undergoing studies for pediatric psoriasis. Ongoing efforts are also being made to optimize conventional treatments, for instance, a new foam formulation of halobetasol propionate was recently approved for pediatric psoriasis. Clinical trials of various new drugs targeting one or multiple pathogenic pathways of psoriasis, such as Janus kinase inhibitors, different formulations of phosphodiesterase type 4 inhibitors, and aryl hydrocarbon receptor modulators have also been explored. The recent emergence of novel topical agents provides promising new options for managing pediatric psoriasis with the potential to improve clinical outcomes and quality of life. In this article, we review the mechanism of action, efficacy, and safety profile of novel topical agents and discuss their potential roles in the management of pediatric psoriasis.

Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias. Using a single PromethION flow cell, we can detect single nucleotide polymorphisms with F1-score comparable to Illumina short-read sequencing. Small indel calling remains difficult within homopolymers and tandem repeats, but achieves good concordance to Illumina indel calls elsewhere. Further, we can discover structural variants with F1-score on par with state-of-the-art de novo assembly methods. Our protocol phases small and structural variants at megabase scales and produces highly accurate, haplotype-specific methylation calls.

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

Factors such as subsistence turnover, warfare, or interaction between different groups can be major sources of cultural change in human populations. Global demographic shifts such as the transition to agriculture during the Neolithic and more recently the urbanization and globalization of the twentieth century have been major catalysts for cultural change. Here, we test whether cultural traits such as patri/matrilocality and postmarital migration persist in the face of social upheaval and gene flow during the past 150 years in postcolonial South Africa. The recent history of South Africa has seen major demographic shifts that resulted in the displacement and forced sedentism of indigenous Khoekhoe and San populations. During the expansion of the colonial frontier, the Khoe-San admixed with European colonists and enslaved individuals from West/Central Africa, Indonesia, and South Asia, introducing novel cultural norms. We conducted demographic interviews among Nama and Cederberg communities representing nearly 3,000 individuals across three generations. Despite the history of colonial expansion, and the subsequent incorporation of Khoe-San and Khoe-San-descendant communities into a colonial society with strong patrilocal norms, patrilocality is the least common postmarital residence pattern in our study populations today. Our results suggest that more recent forces of integration into the market economy are likely the primary drivers of change in the cultural traits examined in our study. Birthplace had a strong effect on an individual's odds of migration, distance moved, and postmarital residence form. These effects are at least partially explained by the population size of the birthplace. Our results suggest that market factors local to birthplaces are important drivers of residence decisions, although the frequency of matrilocal residence and a geographic and temporal cline in migration and residence patterns also indicate the persistence of some historic Khoe-San cultural traits in contemporary groups.

Tool-selective lateral occipitotemporal cortex (LOTC) responds preferentially to images of tools (hammers, brushes) relative to non-tool objects (clocks, shoes). What drives these responses? Unlike other objects, tools exert effects on their surroundings. We tested whether LOTC responses are influenced by event schemas that denote different temporal relations. Participants learned about novel objects embedded in different event sequences. Causer objects moved prior to the appearance of an environmental event (e.g. stars), while Reactor objects moved after an event. Visual features and motor association were controlled. During functional magnetic resonance imaging, participants viewed still images of the objects. We localized tool-selective LOTC and non-tool-selective parahippocampal cortex (PHC) by contrasting neural responses to images of familiar tools and non-tools. We found that LOTC responded more to Causers than Reactors, while PHC did not. We also measured responses to images of hands, which elicit overlapping responses with tools. Across inferior temporal cortex, voxels tool and hand selectivity positively predicted a preferential response to Causers. We conclude that an event schema typical of tools is sufficient to drive LOTC and that category-preferential responses across the temporal lobe may reflect relational event structures typical of those domains.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Septins are cytoskeletal proteins conserved from algae and protists to mammals. A unique feature of septins is their presence as heteromeric complexes that polymerize into filaments in solution and on lipid membranes. Although animal septins associate extensively with actin-based structures in cells, whether septins organize as filaments in cells and if septin organization impacts septin function is not known. Customizing a tripartite split-GFP complementation assay, we show that all septins decorating actin stress fibers are octamer-containing filaments. Depleting octamers or preventing septins from polymerizing leads to a loss of stress fibers and reduced cell stiffness. Super-resolution microscopy revealed septin fibers with widths compatible with their organization as paired septin filaments. Nanometer-resolved distance measurements and single-protein tracking further showed that septin filaments are membrane bound and largely immobilized. Finally, reconstitution assays showed that septin filaments mediate actin-membrane anchoring. We propose that septin organization as octamer-based filaments is essential for septin function in anchoring and stabilizing actin filaments at the plasma membrane.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

OBJECTIVE: Posttraumatic growth (PTG) has been documented in the aftermath of a range of traumatic events, including bereavement, physical assault, and rape. However, only a handful of studies have examined whether levels of total PTG, as well as the 5 domains of PTG (Appreciation of Life, New Possibilities, Relating to Others, Personal Strength, and Spiritual Change), vary by the type of potentially traumatic event. The current study examined variation in total PTG and PTG domains, as well as posttraumatic stress (PTS), by event type using data from a large epidemiological study. METHOD: Participants were from a substudy of the Nurses Health Study 2, an epidemiologic study of female nurses in the United States (N = 1,574). RESULTS: Controlling for demographic covariates, we found that rape was consistently associated with lower PTG, both total PTG and all five PTG domains, relative to other event types. Other findings were limited to specific PTG domains; for example, intimate partner violence (IPV) was associated with higher Personal Strength and New Possibilities. In contrast, rape and IPV were associated with higher PTS, and the serious illness or injury of someone close with lower PTS, relative to other event types. CONCLUSION: These results add to the growing literature exploring variation in PTG by event type and suggest that different events could yield markedly different patterns of PTG domains and PTS. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Social monogamy is a reproductive strategy characterized by pair living and defense of a common territory. Pair bonding, sometimes displayed by monogamous species, is an affective construct that includes preference for a specific partner, distress upon separation, and the ability of the partner to buffer against stress. Many seahorse species show a monogamous social structure in the wild, but their pair bond has not been well studied. We examined the gene expression of lined seahorses (Hippocampus erectus) during and after the process of pairing in the laboratory as well as color change (luminance), a potential form of social communication and behavioral synchrony between pair mates. When a seahorse of either sex was interacting with its pair mate, their changes in luminance ("brightness") were correlated and larger than when interacting with an opposite-sex stranger. At the conclusion of testing, subjects were euthanized, RNA was extracted from whole brains and analyzed via RNA sequencing. Changes in gene expression in paired males versus those that were unpaired included processes governing metabolic activity, hormones and cilia. Perhaps most interesting is the overlap in gene expression change induced by pairing in both male seahorses and male prairie voles, including components of hormone systems regulating reproduction. Because of our limited sample size, we consider our results and interpretations to be preliminary, and prompts for further exploration. Future studies will expand upon these findings and investigate the neuroendocrine and genetic basis of these behaviors.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

The fate of hunting and gathering populations following the rise of agriculture and pastoralism remains a topic of debate in the study of human prehistory. Studies of ancient and modern genomes have found that autochthonous groups were largely replaced by expanding farmer populations with varying levels of gene flow, a characterization that is influenced by the almost universal focus on the European Neolithic.1-5 We sought to understand the demographic impact of an ongoing cultural transition to farming in Southwest Ethiopia, one of the last regions in Africa to experience such shifts.6 Importantly, Southwest Ethiopia is home to several of the world's remaining hunter-gatherer groups, including the Chabu people, who are currently transitioning away from their traditional mode of subsistence.7 We generated genome-wide data from the Chabu and four neighboring populations, the Majang, Shekkacho, Bench, and Sheko, to characterize their genetic ancestry and estimate their effective population sizes over the last 60 generations. We show that the Chabu are a distinct population closely related to ancient people who occupied Southwest Ethiopia >4,500 years ago. Furthermore, the Chabu are undergoing a severe population bottleneck, which began approximately 1,400 years ago. By analyzing eleven Eastern African populations, we find evidence for divergent demographic trajectories among hunter-gatherer-descendant groups. Our results illustrate that although foragers respond to encroaching agriculture and pastoralism with multiple strategies, including cultural adoption of agropastoralism, gene flow, and economic specialization, they often face population decline.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

BackgroundRecombination maps are  important resources for epidemiological and evolutionary analyses; however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We infer the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derive a novel, population-specific recombination map from the whole genome sequencing of 54 Nama individuals. We hypothesise that there are no publicly available recombination maps representative of the Nama, considering the deep population divergence and subsequent isolation of the Khoe-San from other African groups.ResultsWe show that the recombination landscape of the Nama does not cluster with any continental groups with publicly available representative recombination maps. Finally, we use selection scans as an example of how fine-scale differences between the Nama recombination map and the combined Phase II HapMap recombination map can impact the outcome of selection scans.ConclusionsFine-scale differences in recombination can meaningfully alter the results of a selection scan. The recombination map we infer likely represents an upper bound on the extent of divergence we expect to see for a recombination map in humans and would be of interest to any researcher that wants to test the sensitivity of population genetic or GWAS analysis to recombination map input.

Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Emerging evidence links genes within human-specific segmental duplications (HSDs) to traits and diseases unique to our species. Strikingly, despite being nearly identical by sequence (>98.5%), paralogous HSD genes are differentially expressed across human cell and tissue types, though the underlying mechanisms have not been examined. We compared cross-tissue mRNA levels of 75 HSD genes from 30 families between humans and chimpanzees and found expression patterns consistent with relaxed selection on or neofunctionalization of derived paralogs. In general, ancestral paralogs exhibited greatest expression conservation with chimpanzee orthologs, though exceptions suggest certain derived paralogs may retain or supplant ancestral functions. Concordantly, analysis of long-read isoform sequencing data sets from diverse human tissues and cell lines found that about half of derived paralogs exhibited globally lower expression. To understand mechanisms underlying these differences, we leveraged data from human lymphoblastoid cell lines (LCLs) and found no relationship between paralogous expression divergence and post-transcriptional regulation, sequence divergence, or copy-number variation. Considering cis-regulation, we reanalyzed ENCODE data and recovered hundreds of previously unidentified candidate CREs in HSDs. We also generated large-insert ChIP-sequencing data for active chromatin features in an LCL to better distinguish paralogous regions. Some duplicated CREs were sufficient to drive differential reporter activity, suggesting they may contribute to divergent cis-regulation of paralogous genes. This work provides evidence that cis-regulatory divergence contributes to novel expression patterns of recent gene duplicates in humans.

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

α Oscillations in sensory cortex, under frontal control, desynchronize during attentive preparation. Here, in a selective attention study with simultaneous EEG in humans of either sex, we first demonstrate that diminished anticipatory α synchrony between the mid-frontal region of the dorsal attention network and ventral visual sensory cortex [frontal-sensory synchrony (FSS)] significantly correlates with greater task performance. Then, in a double-blind, randomized controlled study in healthy adults, we implement closed-loop neurofeedback (NF) of the anticipatory α FSS signal over 10 d of training. We refer to this closed-loop experimental approach of rapid NF integrated within a cognitive task as cognitive NF (cNF). We show that cNF results in significant trial-by-trial modulation of the anticipatory α FSS measure during training, concomitant plasticity of stimulus-evoked α/θ responses, as well as transfer of benefits to response time (RT) improvements on a standard test of sustained attention. In a third study, we implement cNF training in children with attention deficit hyperactivity disorder (ADHD), replicating trial-by-trial modulation of the anticipatory α FSS signal as well as significant improvement of sustained attention RTs. These first findings demonstrate the basic mechanisms and translational utility of rapid cognitive-task-integrated NF.SIGNIFICANCE STATEMENT When humans prepare to attend to incoming sensory information, neural oscillations in the α band (8-14 Hz) undergo desynchronization under the control of prefrontal cortex. Here, in an attention study with electroencephalography, we first show that frontal-sensory synchrony (FSS) of α oscillations during attentive preparation significantly correlates with task performance. Then, in a randomized controlled study in healthy adults, we show that neurofeedback (NF) training of this α FSS signal within the attention task is feasible. We show that this rapid cognitive NF (cNF) approach engenders plasticity of stimulus-evoked neural responses, and improves performance on a standard test of sustained attention. In a final study, we implement cNF in children with attention deficit hyperactivity disorder (ADHD), replicating the improvement of sustained attention found in adults.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Food insecurity (FI), low social support, and low health-related quality of life (HRQoL) are associated with self-reported nonadherence to antiretroviral therapy (ART) among postpartum women, but these relationships have not been evaluated using objective adherence indicators. Hair samples were therefore analyzed among 83 postpartum Kenyan women living with HIV on efavirenz and nevirapine ART drug regimens in an observational cohort (NCT02974972). FI (0-27), social support (0-40), and HRQoL (8-40) in the prior month were also assessed. In multivariable models, each point increase in FI and decrease in HRQoL were associated with a 45.1% (95% CI: -64.3%, -15.6%) and 10.5% decrease (95% CI: 1.0%, 22.1%) in hair ART drug concentrations respectively, when social support was held constant. A significant interaction between social support and FI (β = 0.02, p = 0.017) indicated that greater social support was predicted to mitigate the negative impacts of FI on ART adherence. Addressing these modifiable barriers could improve ART adherence during this critical period.

Knowledge of predictive relations is a core aspect of learning. Beyond individual relations, we also represent intuitive theories of the world, which include interrelated sets of relations. We asked whether individual predictive relations learned incidentally in the same context become associatively bound and whether they spontaneously influence later learning. Participants performed a cover task while watching three sequences of events. Each sequence contained the same set of events, but differed in how the events related to each other. The first two sequences each had two strong predictive relations (R1 & R2, and R3 & R4). The third contained either a consistent pairing of relations (R1 & R2) or an inconsistent pairing (R1 & R3). We found that participants learning of the individual relations in the third sequence was affected by pairing consistency, suggesting the mind associates relations to each other as part of the intrinsic way it learns about the world. This was despite participants minimal ability to verbally describe most of the relations they had learned. Thus, participants spontaneously developed the expectation that pairs of relations should cohere, and this affected their ability to learn new evidence. Such associative binding of relational information may help us build intuitive theories.

Recent efforts to comprehensively characterize great ape genetic diversity using short-read sequencing and single-nucleotide variants have led to important discoveries related to selection within species, demographic history, and lineage-specific traits. Structural variants (SVs), including deletions and inversions, comprise a larger proportion of genetic differences between and within species, making them an important yet understudied source of trait divergence. Here, we used a combination of long-read and -range sequencing approaches to characterize the structural variant landscape of two additional Pan troglodytes verus individuals, one of whom carries 13% admixture from Pan troglodytes troglodytes. We performed optical mapping of both individuals followed by nanopore sequencing of one individual. Filtering for larger variants (>10 kbp) and combined with genotyping of SVs using short-read data from the Great Ape Genome Project, we identified 425 deletions and 59 inversions, of which 88 and 36, respectively, were novel. Compared with gene expression in humans, we found a significant enrichment of chimpanzee genes with differential expression in lymphoblastoid cell lines and induced pluripotent stem cells, both within deletions and near inversion breakpoints. We examined chromatin-conformation maps from human and chimpanzee using these same cell types and observed alterations in genomic interactions at SV breakpoints. Finally, we focused on 56 genes impacted by SVs in >90% of chimpanzees and absent in humans and gorillas, which may contribute to chimpanzee-specific features. Sequencing a greater set of individuals from diverse subspecies will be critical to establish the complete landscape of genetic variation in chimpanzees.

PurposeAccess to genetics health-care services is often complicated by the distance to hospitals, workforce shortages, and insurance coverage. Despite technological advances and decreasing costs of genetic sequencing, the benefits of personalized medicine may be inaccessible to many patients. To assess potential disparities in care, we examined the genetics workforce in California and geographical issues that people encounter in seeking care.MethodsData on all board-certified genetics providers were analyzed including medical geneticists (MGs) and genetic counselors (GCs) in California. To assess distance traveled for care, we computed the distance patients traveled for n = 288 visits to University of California-San Francisco (UCSF) Medical Genetics. We performed geographic optimization to minimize the distance to genetics providers.ResultsThe provider-to-patient ratio in California is 1:330,000 for MGs, 1:100,000 for GCs, and 1:1,520,000 for biochemical MGs. Genetics providers are concentrated in major metropolitan areas in California. People travel up to 386 miles for genetics care within the state (mean = 76.6 miles).ConclusionThere are substantial geographic barriers to genetics care that could increase disparities. Our findings highlight a challenging genetics workforce shortage. The shortage may be even greater due to care subspecialization or lack of full-time equivalency and staffing. We are currently promoting efforts to increase remote health-care options, training, and modified models of care.

A comprehensive literature review revealed cultural beliefs, societal obligations, and gender roles within the South Asian community to be indirect contributors to the health of South Asian immigrants (SAIs). Health professionals need to increase their work with SAI communities to change less beneficial cultural elements such as misconceptions about health and exercise, and lack of communication when using alternative medicines. Community engaged efforts and continuing medical education are both needed to improve the health of the South Asian immigrant population in a culturally appropriate manner.

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Adenosine 5' triphosphate (ATP) is a universal intracellular energy source and an evolutionarily ancient, ubiquitous extracellular signal in diverse species. Here, we report the generation and characterization of single-wavelength genetically encoded fluorescent sensors (iATPSnFRs) for imaging extracellular and cytosolic ATP from insertion of circularly permuted superfolder GFP into the epsilon subunit of F0F1-ATPase from Bacillus PS3. On the cell surface and within the cytosol, iATPSnFR1.0 responds to relevant ATP concentrations (30 μM to 3 mM) with fast increases in fluorescence. iATPSnFRs can be genetically targeted to specific cell types and sub-cellular compartments, imaged with standard light microscopes, do not respond to other nucleotides and nucleosides, and when fused with a red fluorescent protein function as ratiometric indicators. After careful consideration of their modest pH sensitivity, iATPSnFRs represent promising reagents for imaging ATP in the extracellular space and within cells during a variety of settings, and for further application-specific refinements.

Science relies on increasingly complex data sets for progress, but common data management methods such as spreadsheet programs are inadequate for the growing scale and complexity of this information. While database management systems have the potential to rectify these issues, they are not commonly utilized outside of business and informatics fields. Yet, many research labs already generate "medium sized", low velocity, multi-dimensional data that could greatly benefit from implementing similar systems. In this article, we provide a conceptual overview explaining how databases function and the advantages they provide in tissue engineering applications. Structural fibroblast data from individuals with a lamin A/C mutation was used to illustrate examples within a specific experimental context. Examples include visualizing multidimensional data, linking tables in a relational database structure, mapping a semi-automated data pipeline to convert raw data into structured formats, and explaining the underlying syntax of a query. Outcomes from analyzing the data were used to create plots of various arrangements and significance was demonstrated in cell organization in aligned environments between the positive control of Hutchinson-Gilford progeria, a well-known laminopathy, and all other experimental groups. In comparison to spreadsheets, database methods were enormously time efficient, simple to use once set up, allowed for immediate access of original file locations, and increased data rigor. In response to the National Institutes of Health (NIH) emphasis on experimental rigor, it is likely that many scientific fields will eventually adopt databases as common practice due to their strong capability to effectively organize complex data.

Soluble epoxide hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH inhibitors for treatment of neurological diseases.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083-90. ©2018 AACR.

Background & aimsGenetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants.MethodsWe studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations.ResultsWe identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.ConclusionsIn a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cell transplantation, may hold promise as a stroke therapy, because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria-one that is potentially transferrable into ischemic cells-may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells to critically evaluate the potential of mitochondria-based stem cell therapy for stroke patients.

BackgroundWidespread increases in caesarean section (CS) rates have sparked concerns about risks to mothers and infants and rising healthcare costs. A multicentre, two-arm, cluster-randomized trial in Quebec, Canada assessed whether an audit and feedback intervention targeting health professionals would reduce CS rates for pregnant women compared to usual care, and concluded that it reduced CS rates without adverse effects on maternal or neonatal health. The effect was statistically significant but clinically small. We assessed cost-effectiveness to inform scale-up decisions.MethodsA prospective economic evaluation was undertaken using individual patient data from the Quality of Care, Obstetrics Risk Management, and Mode of Delivery (QUARISMA) trial (April 2008 to October 2011). Analyses took a healthcare payer perspective. The time horizon captured hospital-based costs and clinical events for mothers and neonates from labour onset to 3 months postpartum. Resource use was identified and measured from patient charts and valued using standardized government sources. We estimated the changes in CS rates and costs for the intervention group (versus controls) between the baseline and post-intervention periods. We examined heterogeneity between clinical subgroups of high-risk versus low-risk pregnancies and estimated the joint uncertainty in cost-effectiveness over 20,000 trial simulations. We decomposed costs to identify drivers of change.ResultsThe intervention group experienced per-patient reductions of 0.005 CS (95% confidence interval (CI): -0.015 to 0.004, P = 0.09) and $180 (95% CI: -$277 to - $83, P

Background and purposeChronic infections and cardiac dysfunction are risk factors for stroke. We hypothesized that blood biomarkers of infection (procalcitonin) and cardiac dysfunction (midregional proatrial natriuretic peptide [MR-proANP]), previously associated with small vessel stroke and cardioembolic stroke are also associated with subclinical cerebrovascular damage, including silent brain infarcts and white matter hyperintensity volume.MethodsThe NOMAS (Northern Manhattan Study) was designed to assess risk factors for incident vascular disease in a multiethnic cohort. A subsample underwent brain magnetic resonance imaging and had blood samples available for biomarker measurement (n=1178). We used logistic regression models to estimate the odds ratios and 95% confidence intervals (95% CIs) for the association of these biomarkers with silent brain infarcts after adjusting for demographic, behavioral, and medical risk factors. We used linear regression to assess associations with log-white matter hyperintensity volume.ResultsMean age was 70±9 years; 60% were women, 66% Hispanic, 17% black, and 15% were white. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile, compared with the lowest quartile were more likely to have silent brain infarcts (adjusted odds ratio for procalcitonin, 2.2; 95% CI, 1.3-3.7 and for MR-proANP, 3.3; 95% CI, 1.7-6.3) and increased white matter hyperintensity volume (adjusted mean change in log-white matter hyperintensity volume for procalcitonin, 0.29; 95% CI, 0.13-0.44 and for MR-proANP, 0.18; 95% CI, 0.004-0.36).ConclusionsHigher concentrations of procalcitonin, a marker of infection, and MR-proANP, a marker of cardiac dysfunction, are independently associated with subclinical cerebrovascular damage. If further studies demonstrate an incremental value for risk stratification, biomarker-guided primary prevention studies may lead to new approaches to prevent cerebrovascular disease.

Social networks influence health behavior and health status. Within social networks, "key players" often influence those around them, particularly in traditionally underserved areas like the Appalachian region in the USA. From a total sample of 787 Appalachian residents, we identified and interviewed 10 key players in complex networks, asking them what comprises a key player, their role in their network and community, and ideas to overcome and increase colorectal cancer (CRC) screening. Key players emphasized their communication skills, resourcefulness, and special occupational and educational status in the community. Barriers to CRC screening included negative perceptions of the colonoscopy screening procedure, discomfort with the medical system, and misinformed perspectives on screening. Ideas to improve screening focused on increasing awareness of women's susceptibility to CRC, providing information on different screening tests, improving access, and the key role of health-care providers and key players themselves. We provide recommendations to leverage these vital community resources.

Social networks influence health behavior and health status. Within social networks, key players often influence those around them, particularly in traditionally underserved areas like the Appalachian region in the USA. From a total sample of 787 Appalachian residents, we identified and interviewed 10 key players in complex networks, asking them what comprises a key player, their role in their network and community, and ideas to overcome and increase colorectal cancer (CRC) screening. Key players emphasized their communication skills, resourcefulness, and special occupational and educational status in the community. Barriers to CRC screening included negative perceptions of the colonoscopy screening procedure, discomfort with the medical system, and misinformed perspectives on screening. Ideas to improve screening focused on increasing awareness of womens susceptibility to CRC, providing information on different screening tests, improving access, and the key role of health-care providers and key players themselves. We provide recommendations to leverage these vital community resources.

The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a "cargo" of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.

BackgroundThe optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences.MethodsWe identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment.ResultsBV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection.ConclusionsDeferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.

Given the association between mutational load and cancer, the observation that genetic aberrations are frequently found in human pluripotent stem cells (hPSCs) is of concern. Prior studies in human induced pluripotent stem cells (hiPSCs) have shown that deletions and regions of loss of heterozygosity (LOH) tend to arise during reprogramming and early culture, whereas duplications more frequently occur during long-term culture. For the corresponding experiments in human embryonic stem cells (hESCs), we studied two sets of hESC lines: one including the corresponding parental DNA and the other generated from single blastomeres from four sibling embryos. Here, we show that genetic aberrations observed in hESCs can originate during preimplantation embryo development and/or early derivation. These early aberrations are mainly deletions and LOH, whereas aberrations arising during long-term culture of hESCs are more frequently duplications. Our results highlight the importance of close monitoring of genomic integrity and the development of improved methods for derivation and culture of hPSCs.

Developmental dyslexia is a neurobiological deficit characterized by persistent difficulty in learning to read in children and adults who otherwise possess normal intelligence. Functional and structural connectivity data suggest that developmental dyslexia could be a disconnection syndrome. However, whether abnormalities in connectivity exist in beginning readers at-risk for reading difficulties is unknown. Using graph-theoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 42 beginning readers with (FH+) and without (FH-) familial risk for reading difficulties. We constructed separate structural correlation networks based on measures of surface area and cortical thickness. Results revealed changes in topological properties in brain regions known to be abnormal in dyslexia (left supramarginal gyrus, left inferior frontal gyrus) in the FH+ group mainly in the network constructed from measures of cortical surface area. We also found alterations in topological properties in regions that are not often advertised as dyslexia but nonetheless play important role in reading (left posterior cingulate, hippocampus, and left precentral gyrus). To our knowledge, this is the first report of altered topological properties of structural correlation networks in children at risk for reading difficulty, and motivates future studies that examine the mechanisms underlying how these brain networks may mediate the influences of family history on reading outcome.