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Major depression is a common and severe psychiatric disorder with a highly polygenic genetic architecture. Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with major depression, but the exact causal genes and biological mechanisms are largely unknown. Tissue-specific network approaches may identify molecular mechanisms underlying major depression and provide a biological substrate for integrative analyses. We provide a framework for the identification of individual risk genes and gene co-expression networks using genome-wide association summary statistics and gene expression information across multiple human brain tissues and whole blood. We developed a novel gene-based method called eMAGMA that leverages tissue-specific eQTL information to identify 99 biologically plausible risk genes associated with major depression, of which 58 are novel. Among these novel associations is Complement Factor 4A (C4A), recently implicated in schizophrenia through its role in synaptic pruning during postnatal development. Major depression risk genes were enriched in gene co-expression modules in multiple brain tissues and the implicated gene modules contained genes involved in synaptic signalling, neuronal development, and cell transport pathways. Modules enriched with major depression signals were strongly preserved across brain tissues, but were weakly preserved in whole blood, highlighting the importance of using disease-relevant tissues in genetic studies of psychiatric traits. We identified tissue-specific genes and gene co-expression networks associated with major depression. Our novel analytical framework can be used to gain fundamental insights into the functioning of the nervous system in major depression and other brain-related traits.
BACKGROUND - Human papillomavirus (HPV) vaccine hesitancy among parents contributes to low vaccination coverage in adolescents. To improve health care provider communication and vaccine recommendation practices with hesitant parents, it is important to understand how providers perceive parental HPV vaccine hesitancy.
OBJECTIVE - This study aimed to characterize perceived reasons for parental HPV vaccine hesitancy and identify factors associated with perceived parental hesitancy among providers at community-based pediatric clinics.
METHODS - In 2018, providers in 23 community-based pediatric clinics in Tennessee were invited to complete a Web-based baseline survey as part of a larger quality improvement study focused on HPV vaccine uptake. These survey data were used for a cross-sectional, secondary data analysis. Scale scores ranging from 0 to 100 were calculated for provider self-efficacy (confidence in ability to recommend HPV vaccine), provider outcome expectations (expectations that recommendation will influence parents' decisions), and perceived parental HPV vaccine hesitancy. Provider confidence in HPV vaccine safety and effectiveness were categorized as high versus low. Clinic-level exposures examined were clinic size and rural-urban location. Descriptive analyses were used to characterize perceived parental barriers by provider type. Mixed-effects linear regression models were fit taking one exposure variable at a time, whereas controlling for provider type, age, gender, and race to identify provider- and clinic-level factors associated with perceived parental barriers to HPV vaccination.
RESULTS - Of the 187 providers located in the 23 clinics, 137 completed the survey. The majority of physician providers were white and female, with a higher percentage of females among nurse practitioners (NPs) and physician assistants (PAs). The most common parental barriers to HPV vaccination perceived by providers were concerns about HPV vaccine safety (88%), child being too young (78%), low risk of HPV infection for child through sexual activity (70%), and mistrust in vaccines (59%). In adjusted mixed models, perceived parental HPV vaccine hesitancy was significantly associated with several provider-level factors: self-efficacy (P=.001), outcome expectations (P<.001), and confidence in HPV vaccine safety (P=.009). No significant associations were observed between perceived parental HPV vaccine hesitancy and clinic-level factors clinic size nor location.
CONCLUSIONS - Researchers developing provider-focused interventions to reduce parental HPV vaccine hesitancy should consider addressing providers' self-efficacy, outcome expectations, and confidence in HPV vaccine safety to help providers communicate more effectively with HPV vaccine hesitant parents.
©Jennifer Cunningham-Erves, Tatsuki Koyama, Yi Huang, Jessica Jones, Consuelo H Wilkins, Lora Harnack, Caree McAfee, Pamela C Hull. Originally published in JMIR Cancer (http://cancer.jmir.org), 02.07.2019.
OBJECTIVES - Cardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.
DESIGN - Single-center prospective observational cohort pilot study.
SETTING - Pediatric cardiac ICU at a tertiary children's hospital.
PATIENTS - Children less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.
INTERVENTION - None.
MEASUREMENTS AND MAIN RESULTS - Laser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).
CONCLUSIONS - Cutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.
PURPOSE - Manually tracing regions of interest (ROIs) within the liver is the de facto standard method for measuring liver attenuation on computed tomography (CT) in diagnosing nonalcoholic fatty liver disease (NAFLD). However, manual tracing is resource intensive. To address these limitations and to expand the availability of a quantitative CT measure of hepatic steatosis, we propose the automatic liver attenuation ROI-based measurement (ALARM) method for automated liver attenuation estimation.
METHODS - The ALARM method consists of two major stages: (a) deep convolutional neural network (DCNN)-based liver segmentation and (b) automated ROI extraction. First, liver segmentation was achieved using our previously developed SS-Net. Then, a single central ROI (center-ROI) and three circles ROI (periphery-ROI) were computed based on liver segmentation and morphological operations. The ALARM method is available as an open source Docker container (https://github.com/MASILab/ALARM).
RESULTS - Two hundred and forty-six subjects with 738 abdomen CT scans from the African American-Diabetes Heart Study (AA-DHS) were used for external validation (testing), independent from the training and validation cohort (100 clinically acquired CT abdominal scans). From the correlation analyses, the proposed ALARM method achieved Pearson correlations = 0.94 with manual estimation on liver attenuation estimations. When evaluating the ALARM method for detection of nonalcoholic fatty liver disease (NAFLD) using the traditional cut point of < 40 HU, the center-ROI achieved substantial agreements (Kappa = 0.79) with manual estimation, while the periphery-ROI method achieved "excellent" agreement (Kappa = 0.88) with manual estimation. The automated ALARM method had reduced variability compared to manual measurements as indicated by a smaller standard deviation.
CONCLUSIONS - We propose a fully automated liver attenuation estimation method termed ALARM by combining DCNN and morphological operations, which achieved "excellent" agreement with manual estimation for fatty liver detection. The entire pipeline is implemented as a Docker container which enables users to achieve liver attenuation estimation in five minutes per CT exam.
© 2019 American Association of Physicists in Medicine.
Correlations between fluctuations in resting state BOLD fMRI signals are interpreted as measures of functional connectivity (FC), but the neural basis of their origins and their relationships to specific features of underlying electrophysiologic activity, have not been fully established. In particular, the dependence of FC metrics on different frequency bands of local field potentials (LFPs), and the relationship of dynamic changes in BOLD FC to underlying temporal variations of LFP correlations, are not known. We compared the spatial profiles of resting state coherences of different frequency bands of LFP signals, with high resolution resting state BOLD FC measurements. We also compared the probability distributions of temporal variations of connectivity in both modalities using a Markov chain model-based approach. We analyzed data obtained from the primary somatosensory (S1) cortex of monkeys. We found that in areas 3b and 1 of S1 cortex, low frequency LFP signal fluctuations were the main contributions to resting state LFP coherence. Additionally, the dynamic changes of BOLD FC behaved most similarly to the LFP low frequency signal coherence. These results indicate that, within the S1 cortex meso-scale circuit studied, resting state FC measures from BOLD fMRI mainly reflect contributions from low frequency LFP signals and their dynamic changes.
p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function.
Bacterial type IV secretion systems (T4SSs) are molecular machines that can mediate interbacterial DNA transfer through conjugation and delivery of effector molecules into host cells. The Cag T4SS translocates CagA, a bacterial oncoprotein, into gastric cells, contributing to gastric cancer pathogenesis. We report the structure of a membrane-spanning Cag T4SS assembly, which we describe as three sub-assemblies: a 14-fold symmetric outer membrane core complex (OMCC), 17-fold symmetric periplasmic ring complex (PRC), and central stalk. Features that differ markedly from those of prototypical T4SSs include an expanded OMCC and unexpected symmetry mismatch between the OMCC and PRC. This structure is one of the largest bacterial secretion system assemblies ever reported and illustrates the remarkable structural diversity that exists among bacterial T4SSs.
© 2019, Chung et al.
Pizzo F, Roehri N, Medina Villalon S, Trébuchon A, Chen S, Lagarde S, Carron R, Gavaret M, Giusiano B, McGonigal A, Bartolomei F, Badier JM, Bénar CG. . 2019;10(1):971. The hippocampus and amygdala are key brain structures of the medial temporal lobe, involved in cognitive and emotional processes as well as pathological states such as epilepsy. Despite their importance, it is still unclear whether their neural activity can be recorded noninvasively. Here, using simultaneous intracerebral and magnetoencephalography (MEG) recordings in patients with focal drug-resistant epilepsy, we demonstrate a direct contribution of amygdala and hippocampal activity to surface MEG recordings. In particular, a method of blind source separation, independent component analysis, enabled activity arising from large neocortical networks to be disentangled from that of deeper structures, whose amplitude at the surface was small but significant. This finding is highly relevant for our understanding of hippocampal and amygdala brain activity as it implies that their activity could potentially be measured noninvasively.
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.