Search

Porcine reproductive and respiratory syndrome virus (PRRSV) is a widely prevalent and endemic swine pathogen that causes significant economic losses for the global pig industry annually. Currently, the most prevalent strategy for PRRSV control remains the prevention of virus transmission, with highly effective therapeutic agents and vaccines still lacking. Proanthocyanidin A2 (PA2) belongs to the family of tea polyphenols, which have been reported to exhibit a range of biological activities including anti-oxidative, cardio-pro-tective, anti-tumoural, anti-bacterial, anti-viral, and anti-inflammatory effects in vitro as well as in vivo. Here, we demonstrate that PA2 exhibits potent anti-viral activity against PRRSV infection in Marc-145 cells. Similar inhibitory effects were also found in porcine alveolar macrophages, the primary target cell type of PRRSV infection in pigs in vivo. For traditional type II PRRSV CH-1a strain and high pathogenic GD-XH strain and GD-HD strain, PA2 exhibited broad-spectrum and comparable inhibitory activities in vitro with EC50 ranging from 2.2 to 3.2 μg/ml. Treatment of PRRSV-infected Marc-145 cells with PA2 significantly inhibited viral RNA synthesis, viral protein expression and progeny virus production in a dose-dependent manner. In addition, PA2 treatment reduced gene expressions of cytokines (TNF-α, IFN-α, IL-1β and IL-6) induced by PRRSV infection in PAMs. Mechanistically, PA2 inhibited PRRSV replication by targeting multiple pathways including blockade of viral entry and progeny virus release. Altogether, our findings suggest that PA2 has the potential to serve as a novel prophylactic and therapeutic strategies against PRRSV infection.

Purpose Low-velocity penetrating brain injury (LVPBI) caused by foreign bodies can pose life-threatening emergencies. Their complexity and lack of validated classification data have prevented standardization of clinical management. We aimed to compare the trans-base and trans-vault phenotypes of LVPBI to help provide guidance for clinical decision-making of such injury type. Methods A retrospective study on LVPBI patients managed at our institution from November 2013 to March 2020 was conducted. We included LVPBI patients admitted for the first time for surgery, and excluded those with multiple injuries, gunshot wounds, pregnancy, severe blunt head trauma, etc. Patients were categorized into trans-base and trans-vault LVPBI groups based on the penetration pathway. Discharged patients were followed up by outpatient visit or telephone. The data were entered into the Electronic Medical Record system by clinicians, and subsequently derived by researchers. The demography and injury characteristics, treatment protocols, complications, and outcomes were analyzed and compared between the two groups. A t-test was used for analysis of normally distributed data, and a Mann-Whitney U test for non-parametric data. A generalized linear model was further established to determine whether the factors length of stay and performance scale score were influenced by each factor. Results A total of 27 LVPBI patients were included in this analysis, comprised of 13 (48.1%) trans-base cases and 14 (51.9%) trans-vault cases. Statistical analyses suggested that trans-base LVPBI was correlated with deeper wounds; while the trans-vault phenotype was correlated with injury by metal foreign bodies. There was no difference in Glasgow Coma Scale score and the risk of intracranial hemorrhage between the two groups. Surgical approaches in the trans-base LVPBI group included subfrontal (n = 5, 38.5%), subtemporal (n = 5, 38.5%), lateral fissure (n = 2, 15.4%), and distal lateral (n = 1, 7.7%). All patients in the trans-vault group underwent a brain convex approach using the foreign body as reference (n = 14, 100%). Moreover, the two groups differed in application prerequisites for intracranial pressure monitoring and vessel-related treatment. Trans-base LVPBI was associated with higher rates of cranial nerve and major vessel injuries; in contrast, trans-vault LVPBI was associated with lower functional outcome scores. Conclusion Our findings suggest that trans-base and trans-vault LVPBIs differ in terms of characteristics, treatment, and outcomes. Further understanding of these differences may help guide clinical decisions and contribute to a better management of LVPBIs.

In recent years, circular RNA (circRNA) has been found to be involved in a variety of cancer processes. More and more attention has been paid to the research of circRNA in lung cancer. This study aims to investigate whether circ_0000517 affected the physiology of non‐small cell lung cancer (NSCLC) and the underlying mechanism. The results demonstrated that circ_0000517 was highly expressed in lung cancer tissues and cells, and overexpression of circ_0000517 was negatively correlated with the prognosis of NSCLC patients. Silencing of circ_0000517 significantly inhibited the proliferation, glycolysis, and glutamine decomposition of NSCLC cells in vitro and repressed the growth of xenografted tumors in vivo. Moreover, knockdown of circ_0000517 attenuated the expression of PCNA, HK2, LDHA, ASCT2, and GLS1. Further study found that circ_0000517 targeted miR‐330‐5p and miR‐330‐5p targeted YY1. In addition, miR‐330‐5p inhibitor reversed inhibition of cancer cell proliferation, glycolysis, and glutamine decomposition induced by si‐circ_0000517. In conclusion, our study revealed that silencing of circ_0000517 improved the progression of NSCLC through regulating miR‐330‐5p/YY1 axis.

Suicide is a major public health problem. The contribution of common genetic variants for major depressive disorder (MDD) independent of personal and parental history of MDD has not been established. Polygenic risk score (using PRS-CS) for MDD was calculated for US Army soldiers of European ancestry. Associations between polygenic risk for MDD and lifetime suicide attempt (SA) were tested in models that also included parental or personal history of MDD. Models were adjusted for age, sex, tranche (where applicable), and 10 principal components reflecting ancestry. In the first cohort, 417 (6.3%) of 6,573 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.83, 95% CI:3.09-4.75] and parental history of MDD [OR = 1.43, 95% CI:1.13-1.82 for one parent and OR = 1.64, 95% CI:1.20-2.26 for both parents), MDD PRS was significantly associated with SA (OR = 1.22 [95% CI:1.10-1.36]). In the second cohort, 204 (4.2%) of 4,900 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.82, 95% CI:2.77-5.26] and parental history of MDD [OR = 1.42, 95% CI:0.996-2.03 for one parent and OR = 2.21, 95% CI:1.33-3.69 for both parents) MDD PRS continued to be associated (at p = .0601) with SA (OR = 1.15 [95% CI:0.994-1.33]). A soldier's PRS for MDD conveys information about likelihood of a lifetime SA beyond that conveyed by two predictors readily obtainable by interview: personal or parental history of MDD. Results remain to be extended to prospective prediction of incident SA. These findings portend a role for PRS in risk stratification for suicide attempts.

Background:. Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation (AF). Even though only 6% to 8% of AF patients die from stroke, about 90% are indicated for anticoagulants according to the current AF management guidelines. Therefore, we aimed to develop an accurate and easy-to-use new risk model for 1-year thromboembolic events (TEs) in Chinese AF patients. Methods:. From the prospective China Atrial Fibrillation Registry cohort study, we identified 6601 AF patients who were not treated with anticoagulation or ablation at baseline. We selected the most important variables by the extreme gradient boosting (XGBoost) algorithm and developed a simplified risk model for predicting 1-year TEs. The novel risk score was internally validated using bootstrapping with 1000 replicates and compared with the CHA2DS2-VA score (excluding female sex from the CHA2DS2-VASc score). Results:. Up to the follow-up of 1 year, 163 TEs (ischemic stroke or systemic embolism) occurred. Using the XGBoost algorithm, we selected the three most important variables (congestive heart failure or left ventricular dysfunction, age, and prior stroke, abbreviated as CAS model) to predict 1-year TE risk. We trained a multivariate Cox regression model and assigned point scores proportional to model coefficients. The CAS scheme classified 30.8% (2033/6601) of the patients as low risk for TE (CAS score = 0), with a corresponding 1-year TE risk of 0.81% (95% confidence interval [CI]: 0.41%–1.19%). In our cohort, the C-statistic of CAS model was 0.69 (95% CI: 0.65–0.73), higher than that of CHA2DS2-VA score (0.66, 95% CI: 0.62–0.70, Z = 2.01, P = 0.045). The overall net reclassification improvement from CHA2DS2-VA categories (low = 0/high ≥1) to CAS categories (low = 0/high ≥1) was 12.2% (95% CI: 8.7%–15.7%). Conclusion:. In Chinese AF patients, a novel and simple CAS risk model better predicted 1-year TEs than the widely-used CHA2DS2-VA risk score and identified a large proportion of patients with low risk of TEs, which could potentially improve anticoagulation decision-making. Trial Registration:. www.chictr.org.cn (Unique identifier No. ChiCTR-OCH-13003729).

Resting-state functional magnetic resonance imaging (rs-fMRI) allows estimation of individual-specific cortical parcellations. We have previously developed a multi-session hierarchical Bayesian model (MS-HBM) for estimating high-quality individual-specific network-level parcellations. Here, we extend the model to estimate individual-specific areal-level parcellations. While network-level parcellations comprise spatially distributed networks spanning the cortex, the consensus is that areal-level parcels should be spatially localized, that is, should not span multiple lobes. There is disagreement about whether areal-level parcels should be strictly contiguous or comprise multiple noncontiguous components; therefore, we considered three areal-level MS-HBM variants spanning these range of possibilities. Individual-specific MS-HBM parcellations estimated using 10 min of data generalized better than other approaches using 150 min of data to out-of-sample rs-fMRI and task-fMRI from the same individuals. Resting-state functional connectivity derived from MS-HBM parcellations also achieved the best behavioral prediction performance. Among the three MS-HBM variants, the strictly contiguous MS-HBM exhibited the best resting-state homogeneity and most uniform within-parcel task activation. In terms of behavioral prediction, the gradient-infused MS-HBM was numerically the best, but differences among MS-HBM variants were not statistically significant. Overall, these results suggest that areal-level MS-HBMs can capture behaviorally meaningful individual-specific parcellation features beyond group-level parcellations. Multi-resolution trained models and parcellations are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Kong2022_ArealMSHBM).

Background Vitamin D has been linked to a variety of diseases in observational studies. However, the causal role of vitamin D in human complex traits and diseases remains unclear and is under much debate. In this study, we conducted Mendelian randomization (MR) analyses using genetic variants associated with circulating 25-hydroxyvitamin D [25(OH)D] as instrumental variables to examine the causal role of vitamin D in human complex traits and diseases. Methods We performed MR analyses using genome-wide significant 25(OH)D-associated SNPs (N=58) from a vitamin D GWAS conducted in 329,247 unrelated UK Biobank (UKBB) participants of European ancestry, as well as 78 large-scale meta-GWASs of various outcomes to determine the causal role of 25(OH)D. In addition to inverse-variance weighted meta-analysis, we applied MR-Egger regression, MR-PRESSO and the weighted median approach to estimate the causal effect of 25(OH)D while examining and controlling for potential biases from horizontal pleiotropy. We conducted a sensitivity analysis by including additional genetic instruments (at a relaxed association threshold of P

Humans survive and thrive through social exchange. Yet, social dependency also comes at a cost. Perceived social isolation, or loneliness, affects physical and mental health, cognitive performance, overall life expectancy, and increases vulnerability to Alzheimer’s disease-related dementias. Despite severe consequences on behavior and health, the neural basis of loneliness remains elusive. Using the UK Biobank population imaging-genetics cohort (n = ~40,000, aged 40–69 years when recruited, mean age = 54.9), we test for signatures of loneliness in grey matter morphology, intrinsic functional coupling, and fiber tract microstructure. The loneliness-linked neurobiological profiles converge on a collection of brain regions known as the ‘default network’. This higher associative network shows more consistent loneliness associations in grey matter volume than other cortical brain networks. Lonely individuals display stronger functional communication in the default network, and greater microstructural integrity of its fornix pathway. The findings fit with the possibility that the up-regulation of these neural circuits supports mentalizing, reminiscence and imagination to fill the social void., Here, using pattern-learning analyses of structural, functional, and diffusion brain scans in ~40,000 UK Biobank participants, the authors provide population-scale evidence that the default network is associated with perceived social isolation.

Purpose Findings from a comparative qualitative study with parents in the USA and China increase the understanding of experiences of adults with autism in both countries. Design/methodology/approach Semi-Structured interviews were conducted with families in the USA and in China. In total, 18 families participated in the study – 7 in the USA, 11 in China. Findings Analysis of the comparative data led to the emergence of three overarching themes, expressing both similarities and differences in experiences: 1) transition to adult services plays out differently in the two nations, 2) parent advocacy and efforts in supporting and securing services for their children are strong in both countries but are also defined by the variability in access to services and 3) due to the scarcity of adult services in their country, Chinese parents express significantly more worries about their own aging and mortality as compared with USA parents. Research limitations/implications Practical implications and directions for future research are discussed. Originality/value By examining the experiences of families of adults with autism in the USA and China, the research reveals themes that would not be visible in a single-nation study.

Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

Large-scale datasets enable novel strategies to refine and discover relations among biomarkers of disease. Here 30,863 individuals ages 44-82 from the UK Biobank were analyzed to explore MRI biomarkers associated with Alzheimer’s disease (AD) genetic risk as contrast to general effects of aging. Individuals homozygotic for the E4 variant of apolipoprotein E (APOE4) overlapped non-carriers in their 50s but demonstrated neurodegenerative effects on the hippocampal system beginning in the seventh decade (reduced hippocampal volume, entorhinal thickness, and hippocampal cingulum integrity). Phenome-wide exploration further nominated the posterior thalamic radiation (PTR) as having a strong effect, as well as multiple diffusion MRI (dMRI) and white matter measures consistent with vascular dysfunction. Effects on the hippocampal system and white matter could be dissociated in the homozygotic APOE4 carriers supporting separation between AD and cerebral amyloid angiopathy (CAA) patterns. These results suggest new ways to combine and interrogate measures of neurodegeneration.

Social relationships imbue life with meaning, whereas loneliness diminishes one's sense of meaning in life. Yet the extent of interdependence between these psychological constructs remains poorly understood. We took a multivariate network approach to examine resting-state fMRI functional connectivity’s association with loneliness and meaning in a large cohort of adults (N = 942). Loneliness and meaning in life were negatively correlated with one another. In their relationship with individually parcelled whole-brain measures of functional connectivity, a significant and reliable pattern was observed. Greater loneliness was associated with dense, and less modular, connections between default, frontoparietal, attention and perceptual networks. A greater sense of life meaning was associated with increased, and more modular, connectivity between default and limbic networks. Low loneliness was associated with more modular brain connectivity, and lower life meaning was associated with higher between-network connectivity. These findings advance our understanding of loneliness and life meaning as distinct, yet interdependent, features of sociality. The results highlight a potential role of the default network as a central hub, providing a putative neural mechanism for shifting between feelings of isolation and purpose.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS)1–4. However, the impact of rare coding variants on depression remains poorly understood. Here, we present the largest to date exome analysis of depression based on 320,356 UK Biobank participants. We show that the burden of rare disruptive coding variants in loss-of-function intolerant genes is significantly associated with depression risk. Among 30 genes with false discovery rate (FDR) SLC2A1, a blood-brain barrier glucose transporter underlying GLUT1 deficiency syndrome5–7, reached exome-wide significance (P=2.96e-7). Gene-set enrichment supports neuron projection development and muscle activities2, 3as implicated in depression. Integrating exomes with polygenic risk revealed additive contributions from common and rare variants to depression risk. The burden of rare disruptive coding variants for depression overlapped with that of developmental disorder, autism and schizophrenia. Our study provides novel insight into the contribution of rare coding variants on depression and genetic relationships across developmental and psychiatric disorders.

Humans survive and thrive through social exchange. Yet, social dependency also comes at a cost. Perceived social isolation, or loneliness, affects physical and mental health, cognitive performance, overall life expectancy, and increases vulnerability to Alzheimer's disease-related dementias. Despite severe consequences on behavior and health, the neural basis of loneliness remains elusive. Using the UK Biobank population imaging-genetics cohort (n = ~40,000, aged 40-69 years when recruited, mean age = 54.9), we test for signatures of loneliness in grey matter morphology, intrinsic functional coupling, and fiber tract microstructure. The loneliness-linked neurobiological profiles converge on a collection of brain regions known as the 'default network'. This higher associative network shows more consistent loneliness associations in grey matter volume than other cortical brain networks. Lonely individuals display stronger functional communication in the default network, and greater microstructural integrity of its fornix pathway. The findings fit with the possibility that the up-regulation of these neural circuits supports mentalizing, reminiscence and imagination to fill the social void.

Behavioural sensitization (BS) is characterized by enhanced psychomotor responses to a dose of substance of abuse after prior repeated exposure. We previously reported that BS can be induced by a single injection of morphine in rats, whereas septal nuclei are specifically involved in the development phase of BS. Here, we demonstrated that intra-LS or intra-MS microinjections also incubated BS to a systemic morphine injection in a cross-sensitization fashion, whereas inactivation of either subdivision of septal nuclei (LS: lateral septum; MS: medial septum) can negate this ability of morphine. Then, non-selective (naloxone) and selective (μ-, δ- and κ-)opioid receptor antagonists were directly delivered into LS or MS, respectively, ahead of a morphine microinjection, whereas only μ-opioid receptors in both LS and MS play indispensable roles in mediating the BS development. Finally, there was a pronounced elevation in the levels of the monoamines (i.e. dopamine, homovanillic acid, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid) in the septum, 8 h after a morphine injection detected with a HPLC-ECD method, suggesting that dopaminergi and serotoninergic systems are implicated in the BS formation. Our studies demonstrated that septal nuclei critically participate in the BS development. Essentially, μ- instead of δ- or κ-opioid receptors in LS and MS mediate sensitization to opiates.

The paracaval portion of the caudate lobe is located in the core of the liver. Lesions originating in the paracaval portion often cling to or even invade major hepatic vascular structures. The traditional open anterior hepatic transection approach has been adopted to treat paracaval-originating lesions. With the development of laparoscopic surgery, paracaval-originating lesions are no longer an absolute contraindication for laparoscopic liver resection. This study aimed to evaluate the safety and feasibility of laparoscopic anterior hepatic transection for resecting paracaval-originating lesions. This study included 15 patients who underwent laparoscopic anterior hepatic transection for paracaval-originating lesion resection between August 2017 and April 2020. The perioperative indicators, follow-up results, operative techniques and surgical indications were retrospectively evaluated. All patients underwent laparoscopic anterior hepatic transection for paracaval-originating lesion resection. The median operation time was 305 min (220–740 min), the median intraoperative blood loss was 400 ml (250–3600 ml), and the median length of postoperative hospital stay was 9 days (5–20 days). No conversion to laparotomy or perioperative deaths occurred. Six patients had Clavien grade III–IV complications (III/IV, 5/1). Two patients developed tumor recurrence after 13 months and 8 months. Although technically challenging, laparoscopic anterior hepatic transection is still a safe and feasible procedure for resecting paracaval-originating lesions in select patients.

This study aimed to summarize the effectiveness and safety of acupuncture in the treatment of autism spectrum disorder (ASD) through literature analysis and evaluation. All studies were retrieved from various databases as follows: English databases, such as PubMed, Cochrane Library, Ovid, and Web of Science, and Chinese databases, such as China National Knowledge Infrastructure (CNKI), WanFang Data (WF), and Technology Periodical Database (VIP). The Cochrane Collaboration’s Bias Risk Assessment Scale was used to assess the studies’ risk of bias. The effects of acupuncture treatment for ASD were determined using the following indicators: childhood autism rating scale (CARS), autism behavior check list (ABC), Reynell developmental language scale (RDLS), and functional independence measure of children (WeeFIM). The risk map of bias of these studies’ quality and the meta-analysis results of the indicators was prepared with RevMan 5.2 software. Finally, 16 studies were included, five of which were in English and 11 were in Chinese. The 16 studies included 1332 patients. The CARS results for subgroup analysis were as follows: acupuncture subgroup (MD = −2.65, 95% CI (−3.22, −2.07)) and acupuncture plus massage subgroup (MD = −10.35, 95% CI (−11.34, −9.36)). The ABC results were as follows: (MD = −6.70, 95% CI (−9.10, −4.29)). The analysis results of sensory, relating, language, body and object use, and social/self-help in the subitems of ABC were as follows: sensory (MD = −2.67, 95% CI (−2.90, −2.44)), relating (MD = −3.28, 95% CI (−3.55, −3.02)), language (MD = −2.45, 95% CI (−2.73, −2.16)), body and object use (MD = −1.19, 95% CI (−1.38, −1.00)), and social/self-help (MD = −2.09, 95% CI (−2.30, −1.89)). For the analysis results of comprehension and expression ages in the subitems of RDLS, the comprehension age results were as follows: (MD = 0.08, 95% CI (−0.06, 0.22), P = 0.27). Those of expression age were as follows: (MD = 0.15, 95% CI (0.04, 0.26), P = 0.009 ). The WeeFIM results were as follows: (MD = 3.70, 95% CI (2.38, 5.02)). This study suggested that acupuncture could effectively treat ASD. However, acupuncture methods and prescriptions at this stage remain heterogeneous, and acupuncture treatment operations require standardization. Studies using rigorous and standard research designs are needed to draw stronger conclusions about the advantages of using acupuncture to treat children and adolescents with ASD.

Paracaval-originating cancers have been considered a contraindication for laparoscopic liver resection (LLR). This study aimed to explore the safety and feasibility of LLR in the treatment of paracaval-originating cancers. This study included 11 patients who underwent LLR and 20 who underwent open liver resection (OLR) for paracaval-originating cancers between May 2010 and November 2020. The outcomes of the procedures were retrospectively analyzed. There were no cases of perioperative death or conversion to laparotomy. The LLR group had an earlier postoperative feeding time, shorter postoperative hospital stay, and lower total bilirubin levels on the first day after surgery. No significant differences in the incidence of overall postoperative complications were noted between the LLR and OLR groups, but the incidence of grade IIIa complications was significantly higher in the LLR group than in the OLR group. Tumor recurrence occurred in 4 of 11 patients in the LLR group and in 11 of 20 patients in the OLR group. LLR for the treatment of paracaval-originating cancers is safe and feasible in selected patients.

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

Background Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between genetic risk for complex disease and quantitative physiological measurements collected on large populations. Methods A total of 3075 quantitative lab tests were extracted from Vanderbilt University Medical Center’s (VUMC) EHR system and cleaned for population-level analysis according to our QualityLab protocol. Lab values extracted from BioVU were compared with previous population studies using heritability and genetic correlation analyses. We then tested the hypothesis that polygenic risk scores for biomarkers and complex disease are associated with biomarkers of disease extracted from the EHR. In a proof of concept analyses, we focused on lipids and coronary artery disease (CAD). We cleaned lab traits extracted from the EHR performed lab-wide association scans (LabWAS) of the lipids and CAD polygenic risk scores across 315 heritable lab tests then replicated the pipeline and analyses in the Massachusetts General Brigham Biobank. Results Heritability estimates of lipid values (after cleaning with QualityLab) were comparable to previous reports and polygenic scores for lipids were strongly associated with their referent lipid in a LabWAS. LabWAS of the polygenic score for CAD recapitulated canonical heart disease biomarker profiles including decreased HDL, increased pre-medication LDL, triglycerides, blood glucose, and glycated hemoglobin (HgbA1C) in European and African descent populations. Notably, many of these associations remained even after adjusting for the presence of cardiovascular disease and were replicated in the MGBB. Conclusions Polygenic risk scores can be used to identify biomarkers of complex disease in large-scale EHR-based genomic analyses, providing new avenues for discovery of novel biomarkers and deeper understanding of disease trajectories in pre-symptomatic individuals. We present two methods and associated software, QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a Lab-Wide Association Scan.

ENIGMA-CNV working group., Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function., 1000BRAINS: The 1000BRAINS study was funded by the Institute of Neuroscience and Medicine, Research Center Juelich, Germany. We thank the Heinz Nixdorf Foundation (Germany) for the generous support of the Heinz Nixdorf Recall Study on which 1000BRAINS is based. We also thank the scientists and the study staff of the Heinz Nixdorf Recall Study and 1000BRAINS. Funding was also granted by the Initiative and Networking Fund of the Helmholtz Association (Caspers) and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 945539 (Human Brain Project SGA3; Amunts, Caspers, Cichon). Brainscale: The Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Dorret I. Boomsma), 51.02.060 (Hilleke E. Hulshoff Pol), 668.772 (Dorret I. Boomsma and Hilleke E. Hulshoff Pol); NWO/SPI 56-464-14192 (Dorret I. Boomsma), the European Research Council (ERC-230374) (Dorret I. Boomsma), High Potential Grant Utrecht University (Hilleke E.Hulshoff Pol) and NWO Brain and Cognition 433-09-220 (Hilleke E.Hulshoff Pol). Betula: The Betula study was funded by the Knut and Alice Wallenberg (KAW) foundation (Nyberg). The Freesurfer segmentations on the Betula sample were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at HPC2N (in Umeå, Sweden), partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative has received support from the participating departments and centres and from external grants, that is, the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland and the Netherlands Organization for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant ‘Language in Interaction’, the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement nos. 602450 (IMAGEMEND), 278948 (TACTICS) and 602805 (Aggressotype), as well as from the European Community’s Horizon 2020 programme under grant agreement no. 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. deCODE genetics: deCODE genetics acknowledges support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nos. 115008 (NEWMEDS) and 115300 (EUAIMS), of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7-funded grant agreement no. 602450 (IMAGEMEND) and EU-funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC). Dublin: This work was supported by Science Foundation Ireland (SFI grant 12/IP/1359 to Gary Donohoe and grant SFI08/IN.1/B1916-Corvin to Aidan C. Corvin). ECHO-DEFINE: The ECHO study acknowledges funding from a Medical Research Council (MRC) Centre Grant to Michael J. Owen (G0801418), the Wellcome Trust (Institutional Strategic Support Fund (ISSF) to van den Bree and Clinical Research Training Fellowship to Joanne L. Doherty), the Waterloo Foundation (WF 918-1234 to van den Bree), the Baily Thomas Charitable Fund (2315/1 to van den Bree), National Institute of Mental Health (NIMH 5UO1MH101724 to van den Bree and Michael J. Owen), the IMAGINE-2 study (funded by the MRC (MR/T033045/1) to van den Bree, Jeremy Hall and Michael J. Owen), the IMAGINE-ID study (funded by MRC (MR/N022572/1) to Jeremy Hall, van den Bree and Owen). The DEFINE study was supported by a Wellcome Trust Strategic Award (100202/Z/12/Z) to Michael J. Owen. ENIGMA: ENIGMA is supported in part by NIH grants U54 EB20403, R01MH116147 and R56AG058854. NIA T32AG058507; NIH/NIMH 5T32MH073526. EPIGEN-Dublin: The EPIGEN-Dublin cohort was supported by a Science Foundation Ireland Research Frontiers Programme award (08/RFP/GEN1538). EPIGEN-UK (Sisodiya): The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner. GAP: This work was supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, Psychology and Neuroscience, King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. GOBS: The GOBS study data collection was supported in part by the National Institutes of Health (NIH) grants: R01 MH078143, R01 MH078111 and R01 MH083824, with work conducted in part in facilities constructed under the support of NIH grant C06 RR020547. GSP: Data were in part provided by the Brain Genomics Superstruct Project (GSP) of Harvard University and Massachusetts General Hospital (MGH) (Principal Investigators: Randy Buckner, Jordan Smoller and Joshua Roffman), with support from the Center for Brain Science Neuroinformatics Research Group, Athinoula A. Martinos Center for Biomedical Imaging, Center for Genomic Medicine and Stanley Center for Psychiatric Research. Twenty individual investigators at Harvard and MGH generously contributed data to the overall project. We would like to thank Randy Buckner for insightful comments and feedback on this work. HUBIN: The HUBIN study was financed by the Swedish Research Council (K2010-62X-15078-07-2, K2012-61X-15078-09-3, 521-2014-3487 K2015-62X-15077-12-3, 2017-00949), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet. HUNT: The HUNT study is a collaboration between HUNT Research Centre (Faculty of Medicine and Movement Sciences, NTNU—Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. IMAGEN: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907),the FP7 projects IMAGEMEND(602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EUAIMS (115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152, 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants, SM 80/7-2, SFB 940/2), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1). Further support was provided by grants from: ANR (project AF12-NEUR0008-01—WM2NA, ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. Lifespan: The study is funded by the Research Council of Norway (230345, 288083 and 223273). NCNG: NCNG sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the Research Council of Norway, to le Hellard, Steen and Espeseth. The Bergen group was supported by grants from the Western Norway Regional Health Authority (Grant 911593 to Arvid Lundervold, Grant 911397 and 911687 to Astri Johansen Lundervold). NTR: The NTR cohort was supported by the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192), KNAW Academy Professor Award (PAH/6635) and University Research Fellow grant (URF) to Dorret I. Boomsma; Amsterdam Public Health research institute (former EMGO+), Neuroscience Amsterdam research institute (former NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community’s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, grant 01413: ENGAGE and grant 602768: ACTION); the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the National Institutes of Health (NIH, R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/00408559, BiG Grid, the Dutch e-Science Grid and SURFSARA. OATS: The OATS study has been funded by a National Health & Medical Research Council (NHMRC) and Australian Research Council (ARC) Strategic Award Grant of the Ageing Well, Ageing Productively Programme (ID No. 401162) and NHMRC Project Grants (ID Nos. 1045325 and 1085606). This research was facilitated through Twins Research Australia, a national resource in part supported by an NHMRC Centre for Research Excellence Grant (ID No.: 1079102). We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/project/older-australian-twins-study) to this study. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organization Flagship Collaboration Fund Grant. Osaka: Osaka study was supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS: Grant Number JP18dm0207006), Brain/MINDS& beyond studies (Grant Number JP20dm0307002) and Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities (Grant Number JP20dk0307081) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (KAKENHI; Grant Numbers JP25293250 and JP16H05375). Some computations were performed at the Research Center for Computational Science, Okazaki, Japan. PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS 00/3095, 01/3129, PI020499, PI060507, PI10/00183, the SENY Fundació Research Grant CI2005-0308007 and the FundaciónMarqués de Valdecilla API07/011. Biological samples from our cohort were stored at the Valdecilla Biobank and genotyping services were conducted at the Spanish ‘Centro Nacional de Genotipado’ (CEGEN-ISCIII). MCIC/COBRE: The study is funded by the National Institutes of Health studies R01EB006841, P20GM103472 and P30GM122734 and Department of Energy DE-FG02-99ER62764. PING: Data collection and sharing for the Paediatric Imaging, Neurocognition and Genetics (PING) Study (National Institutes of Health Grant RC2DA029475) were funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. A full list of PING investigators is at http://pingstudy.ucsd.edu/investigators.html. QTIM: The QTIM study was supported by the National Institute of Child Health and Human Development (R01 HD050735) and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. Genotyping was supported by NHMRC (389875). Medland is supported in part by an NHMRC fellowship (APP1103623). SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide single-nucleotide polymorphism typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. StrokeMRI: StrokeMRI was supported by the Norwegian ExtraFoundation for Health and Rehabilitation(2015/FO5146), the Research Council of Norway (249795, 262372), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073) and the Department of Psychology, University of Oslo. Sydney MAS: The Sydney Memory and Aging Study (Sydney MAS) is funded by National and HealthMedical Research Council (NHMRC) Programme and Project Grants (ID350833, ID568969 and ID109308). We also thank the Sydney MAS participants and the Research Team. SYS: The SYS Study is supported by Canadian Institutes of Health Research. TOP: Centre of Excellence: RCN #23273 and RCN #226971. Part of this work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) (tsd-drift@usit.uio.no). The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement no. 609020—Scientia Fellows; the Research Council of Norway (RCN) #276082—A lifespan perspective on mental illness: toward precision medicine using multimodal brain imaging and genetics. Ida E. Sønderby and Rune Bøen are supported by South-Eastern Norway Regional Health Authority (#2020060). Ida E. Sønderby and Ole A. Andreassen have received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement no. 847776 (CoMorMent project) and the KG Jebsen Foundation (SKGJ-MED-021). UCLA_UMCU: The UCLA_UMCU cohort comprises of six studies which were supported by National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) (20244 to Prof. Hillegers), The Netherlands Organisation for Health Research and Development (ZonMw) (908-02-123 to Prof. Hulshoff Pol), and Netherlands Organisation for Scientific Research (NWO 9120818 and NWO-VIDI 917-46-370 to Prof. Hulshoff Pol). The GROUP study was funded through the Geestkracht programme of the Dutch Health Research Council (ZonMw, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly and Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ inGeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord-Holland-Noord. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia Psycho-medical Center, The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh, voor Geestelijke Gezondheid, Mondriaan, Virenzeriagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-JozefKortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions: Altrecht, GGZ Centraal and Delta.). UK Biobank: This work made use of data sharing from UK Biobank (under project code 27412). Others: Work by Pierre Vanderhaeghen was funded by Grants of the European Research Council (ERC Adv Grant GENDEVOCORTEX), the EOS Programme, the Belgian FWO, the AXA Research Fund and the Belgian Queen Elizabeth Foundation. Ikuo K. Suzuki was supported by a postdoctoral fellowship of the FRS/FNRS.

Orbitocranial penetrating injury (OPI) with multiple vascular invasions is a rare occurrence. To our knowledge, experience with its clinical treatment is rather limited, especially for infants. This case report describes an infant who fell from a 0.5 m high bed and landed on a toy with a keen-edged plastic rod. The fractured end of the rod was noted at the medial aspect of the left eyelid, and she was experiencing impaired consciousness. Computed tomography showed that the foreign body penetrated the cavernous sinus with internal carotid artery involvement, and compressed the transverse sinus through the cerebellum. Emergency surgery was performed with temporal occlusion of the left common carotid artery. The rod was removed from the orbital side, and bleeding from cavernous sinus region was effectively controlled under direct inspection via a sub-temporal approach. The patient was successfully treated and recovered consciousness after 17 days. This is the first report of successful management of OPI combined with multiple vascular injury in an infant. Herein, we highlight the anatomical imaging features of the injuries and also the individualized strategy concerning vascular invasion.

This retrospective 10-year case study evaluated the perioperative results and long-term efficacy of laparoscopic middle-hepatic-vein-guided hemihepatectomy (L-MHV-H) and traditional anatomical hemihepatectomy (TAH) in the treatment of hepatolithiasis (HL). From January 2010 to December 2019, 99 patients with regional HL underwent laparoscopic anatomical hemihepatectomy (LAH) at our centre, including 43 patients in the L-MHV-H group and 56 patients in the TAH group. All patients in both groups were Child–Pugh grade A before operation. No significant between-group differences in general information, stone distribution, comorbidities, history of previous abdominal surgery or co-occurrence of gallstones and common bile duct stones were observed. The L-MHV-H group exhibited a higher intraoperative stone clearance rate (95.3% vs. 75.0%, p = 0.014) and a lower postoperative complication rate (10.1% vs. 48.2%, p = 0.005) compared with the TAH group. In the median follow-up time of 60 months (range 6–125 months), the L-MHV-H group had lower stone recurrence (2.3% vs. 19.6%, p = 0.013) and cholangitis recurrence (2.3% vs. 17.9%, p = 0.034) rates. No significant between-group differences in the other results were observed. L-MHV-H is safe and feasible for HL with certain advantages over TAH in improving the intraoperative stone clearance rate, reducing postoperative complication incidence and reducing stone and cholangitis recurrence rates.

IntroductionRecent advances in psychiatric genomics have enabled large-scale genome-wide scans that elucidated genetic architecture both in mood disorder and schizophrenia across individuals of East Asian and European descent. Investigating joint genetic architecture of these psychiatric traits enables the identification of common and diverging etiological mechanisms underlying these psychiatric illnesses. Here, we leverage on the largest GWAS of schizophrenia and mood disorder conducted to date in East Asian and European descent samples to elucidate the joint genetic architecture that underlie these psychiatric disorders.MethodologyWe carried out GWAS meta-analysis on both European (EUR) and East Asian (EAS) Ancestry summary statistics for Major Depressive Disorder (MDD) and Schizophrenia via Multi-Trait Analysis of GWAS. Downstream pathway, eQTL, chromatin interaction analysis were carried out to characterize genome-wide results. In addition we carried out genetic correlations and polygenic risk prediction analysis to further study the joint genetic architectures of mood disorder and schizophrenia.ResultsThere were 308 loci that was significantly associated with at least one trait. Specifically, there were 98 independent loci in EUR-MDD, 5 loci for MTAGx-EAS-MDD, 121 loci for MTAGx-EUR-MDD, 8 independent loci for EAS-SZ, 171 independent loci for EUR-SZ, 124 independent loci for MTAGx-EAS-SZ, and 159 independent loci for MTAGx-EUR-SZ. In all, 61 loci were novel across traits. SOAT1 and FOXO3 genes were implicated based on genome-wide associations. 114 gene(s) were implicated in eQTL analysis of gene expression in brain tissue. Gene-set analysis show support for GABA-egic pathways implicated in MDD, driven by several GABA-alpha receptor genes as well as more peripheral PLCL1 and NISCH genes that are responsible for endocytosis and neuronal trafficking. Cross-Ancestry genetic correlations ascertained that the CONVERGE MDD phenotype generally holds higher SNP based heritability and is likely driven by case-ascertainment procedures. Finally, polygenic risk score modelling indicates that MTAGx procedures were effective in enriching GWAS signals in the EAS-MDD for prediction in an independent case-control sample.DiscussionHere we are able to demonstrate that cross-trait cross-ancestry approaches in schizophrenia and MDD not only yields new discoveries to the genetic architecture of these illnesses; we were able to identify new biological underpinnings within the GABA pathways for depressive disorders. The evidence in the current report underscores the importance of taking into consideration both phenotype and ancestry complexities in genome-wide studies.

OBJECTIVE: Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression.METHODS: Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression.RESULTS: Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53).CONCLUSIONS: Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry.

Significance The widespread use of population-average cortical parcellations has provided important insights into broad properties of human brain organization. However, the size, location, and spatial arrangement of regions comprising functional brain networks can vary substantially across individuals. Here, we demonstrate considerable heritability in both the size and spatial organization of individual-specific network topography across cortex. Genetic factors had a regionally variable influence on brain organization, such that heritability in network size, but not topography, was greater in unimodal relative to heteromodal cortices. These data suggest individual-specific network parcellations may provide an avenue to understand the genetic basis of variation in human cognition and behavior., Human cortex is patterned by a complex and interdigitated web of large-scale functional networks. Recent methodological breakthroughs reveal variation in the size, shape, and spatial topography of cortical networks across individuals. While spatial network organization emerges across development, is stable over time, and is predictive of behavior, it is not yet clear to what extent genetic factors underlie interindividual differences in network topography. Here, leveraging a nonlinear multidimensional estimation of heritability, we provide evidence that individual variability in the size and topographic organization of cortical networks are under genetic control. Using twin and family data from the Human Connectome Project (n = 1,023), we find increased variability and reduced heritability in the size of heteromodal association networks (h2: M = 0.34, SD = 0.070), relative to unimodal sensory/motor cortex (h2: M = 0.40, SD = 0.097). We then demonstrate that the spatial layout of cortical networks is influenced by genetics, using our multidimensional estimation of heritability (h2-multi; M = 0.14, SD = 0.015). However, topographic heritability did not differ between heteromodal and unimodal networks. Genetic factors had a regionally variable influence on brain organization, such that the heritability of network topography was greatest in prefrontal, precuneus, and posterior parietal cortex. Taken together, these data are consistent with relaxed genetic control of association cortices relative to primary sensory/motor regions and have implications for understanding population-level variability in brain functioning, guiding both individualized prediction and the interpretation of analyses that integrate genetics and neuroimaging.

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk., Interneuron subtypes have distinct properties and spatial distributions. Here, the authors show that the molecular-genetic basis of cortical resting-state brain function is shaped by distributions of interneuron-related transcripts and may capture individual differences in schizophrenia risk.

ObjectivesTo characterize the MDR genomic islands (GIs) in Proteus mirabilis isolates.MethodsTwo P. mirabilis strains (C55 and C74) of chicken origin were subjected to WGS (HiSeq and PacBio) and the MDR GIs were determined.ResultsP. mirabilis strains C55 and C74 are clonal strains and harbour different Proteus genomic island 2 (PGI2) variants (PGI2-C55 and PGI2-C74). The MDR region of PGI2-C55 is composed of two class 1 integrons, separated by a region containing seven copies of IS26 and eight resistance genes, including blaCTX-M-3 and fosA3. The region in PGI2-C74 is a complete In4-type class 1 integron, harbouring five gene cassettes (dfrA16, blaCARB-2, aadA2, cmlA1 and aadA1). In addition, C55 and C74 carry an SXT/R391 integrative and conjugative element (ICEPmiJpn1), harbouring blaCMY-2, and a novel 50.46 kb genomic resistance island named PmGRI1-C55. PmGRI1-C55 harbours a tyrosine-type recombinase/integrase that might be responsible for the integration of PmGRI1-C55 at the 3′ end of tRNA-Sec. It carries an MDR region derived from Tn2670 that harbours a Tn21 region and carries six resistance genes (catA1, blaTEM-1b, aphA1a, sul2, strA and strB). Blast analysis showed diverse PmGRI1 variants in P. mirabilis and Escherichia coli strains.ConclusionsThe finding of the two new PGI2 variants highlights that the homologous recombination between shared components of class 1 integrons and transposition by IS26 promote the diversity of MDR regions in PGI2. PmGRI1 is a new GI that carries various resistance genes identified in P. mirabilis and E. coli.

ObjectiveTo investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation.MethodsWe analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between APOE ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements.ResultsAPOE ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. APOE ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When APOE ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ− participants and weakly associated with baseline hippocampal volume in Aβ+ participants.ConclusionsGenetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.

Key Points Question Are genes that increase predisposition to depression associated with increased inflammatory biomarkers, specifically white blood cell count? Findings In this genetic association study of 382 485 participants, an association was noted between depression polygenic scores and white blood cell count across 4 independent biobanks. Mediation analyses suggest a bidirectional association between white blood cell count and depression diagnosis and implicate neutrophils as the main driver of the association. Meaning These findings suggest that genes associated with depression (rather than only the clinical presentation of depressive symptoms) may be implicated in the proinflammatory state observed in clinical depression; this outcome may motivate future development of targeted biomarker panels and treatments., This genetic association study uses data from Vanderbilt University Medical Center and the PsycheMERGE network to investigate the association between inflammatory biomarkers, such as white blood cell count, and the genes that predispose an individual to depression., Importance Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression. Objective To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count. Design, Setting, and Participants This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center’s biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent. Exposures Depression polygenic scores. Main Outcomes and Measures White blood cell count. Results Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 [range, birth-90.0 years]). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (β, 0.03; SE, 0.004; P = 1.07 × 10−17), which was replicated in a meta-analysis across the 4 health care systems (β, 0.03; SE, 0.002; P = 1.03 × 10−136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10−70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10−44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts. Conclusions and Relevance This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.

Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs.

Objective: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. Methods: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. Results: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. Conclusions: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.

Accumulating data indicates that brain inflammation plays an important role in the pathophysiology of chronic exercise-induced fatigue. Moxibustion in traditional Chinese medicine has been found to alleviate exercise-induced fatigue. However, it remains unclear whether the effect of moxibustion is related to its anti-inflammatory properties. In this study, rats were exposed to 3-week exhaustive swimming to induce chronic exercise-induced fatigue. The body weight, exhaustive swimming time, tail suspension test and open-field test were observed. Real-time polymerase chain reaction (RT-PCR) was used to determine the mRNA expression of proinflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6], and tumor necrosis factor-α[TNF-α]), and enzyme-linked immunosorbent assay (ELISA) was used to detect IL-1β, IL-6, and TNF-α concentrations. Chronic exhaustive exercise significantly reduced the body weight and exhaustive swimming time, and increased tail suspension immobility time, which were reversed by moxibustion treatment. Compared with control rats, the mRNA and protein expression of IL-1β, IL-6, and TNF-α in the hippocampus was significantly increased in exhaustive swimming trained rats. Moxibustion significantly decreased the level of IL-6 in the hippocampus, but not affected IL-1β and TNF-α level significantly. Our results suggested that a potential inflammatory damage in the brain may be involved during chronic exhaustive exercise-induced fatigue. Moxibustion could attenuate the inflammatory impairment in exercise-induced fatigue, which might be mediated by inhibition of the proinflammatory cytokine IL-6 levels in the brain region.

BackgroundAlthough depression is recognized as the leading cause of disability worldwide, decades of research have identified few actionable preventive factors. Using phenotypic and genomic data from the UK Biobank, we took advantage of a unique opportunity to screen a wide range of potentially modifiable factors that could offset known risk factors for depression.MethodsWe curated baseline data on more than 100 lifestyle and environmental factors in participants’ lives, including behavioral (e.g., exercise, sleep, media use, diet), social (e.g., support, activities), and environmental (e.g., greenspace, pollution) variables. In a follow-up survey, participants reported on their traumatic life experiences and mental health, including depression. Polygenic risk scores for depression were generated based on large-scale genome-wide association results. Excluding those meeting criteria for depression at baseline, we identified at-risk individuals at high predicted probability (> 90th percentile) for clinically significant depression at follow-up based on their (i) polygenic risk, or (ii) reported traumatic life events. Using a factors-wide design corrected for multiple testing and adjusted for potential confounders, we identified modifiable factors associated with follow-up depression in the full sample and among at-risk individuals. Using a two-sample Mendelian randomization (MR) design, we then examined which significant factors showed potential causal influences on depression risk, or vice versa.ResultsA range of baseline modifiable factors were prospectively associated with follow-up depression, including factors related to social engagement, physical activity, media use, and diet. MR follow-up analyses provided further support for the effects of social support-seeking, TV use, and other factors on depression risk.ConclusionAs the field increasingly quantifies the role of genetic factors in complex conditions such as depression, knowledge of modifiable factors that could offset one’s genetic risk has become highly relevant. Here, we present an approach to screening for potentially modifiable factors that may offset the risk of depression in general and among at-risk individuals. In light of the burden of disease associated with depression and the urgent need for actionable preventive strategies, this approach could help prioritize candidates for follow-up studies including clinical trials for depression prevention.

The aims of the present study were to investigate the effects of angiotensin receptor neprilysin inhibitors (ARNi) on the susceptibility of ventricular arrhythmias (VAs) in rats with myocardial infarction (MI) and to explore the related mechanisms.A total of 32 adult male Sprague-Dawley rats were divided into 3 groups: a control group, MI group, and MI+ARNi group. MI was generated by ligation of the left anterior descending coronary artery. ARNi was given at 68 mg/kg/day for 4 weeks after MI surgery. At 4 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for the evaluation of VAs, and echocardiography was used to evaluate cardiac function. Indicators of sympathetic neural remodeling and cardiac remodeling were detected to further explore the related mechanisms.Four weeks after MI, rats in the ARNi group exhibited low susceptibility of VAs in comparison with that in the MI group, which was coincident with the attenuation of sympathetic nerve remodeling, amelioration of cardiac fibrosis, and regulation of Cx43 expression.ARNi is effective in reducing VAs in rats with ischemic cardiomyopathy, which is associated with attenuating sympathetic nerve remodeling and myocardial fibrosis.

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

Background The present study focused on understanding the prognostic value of the methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms rs1801133 (C667T) and rs1801131 (A1298C) in patients with colorectal cancer (CRC). Methods A systematic literature search was conducted in March 2016. Databases, including Medline, EMBASE, Cochrane and Chinese databases (including CNKI, Wanfang and VIP), were searched to identify the relevant articles describing MTHFR polymorphisms in patients with CRC. Data regarding overall survival (OS), progression‐free survival (PFS) and disease‐free survival (DFS) were collected and analysed. Results Twenty‐four studies with 5423 patients with CRC were included. Significant differences in OS, PFS and DFS were not observed among the different comparisons of patients carrying different alleles of the MTHFR rs1801133 polymorphism (including TT versus CC, TT versus CT + CC, CT + TT versus CC and CT versus CC). Compared with patients with the rs1801131 CA + AA genotypes, patients with the CC genotype had a shorter OS (hazard ratio = 1.85; 95% confidence interval = 1.30–2.65) and DFS (hazard ratio = 2.16; 95% confidence interval= 1.19–3.93). Significant differences in OS, PFS and DFS were not observed among the other patient groups (including CC versus AA, CC + CA versus AA and CA versus AA). Subgroup analysis of rs1801133 and rs1801131 showed that patients with CRC from Asian regions and Western regions demonstrated similar results. Conclusions The MTHFR rs1801133 polymorphism was not associated with the prognosis of patients with CRC; however, rs1801131 may be associated with the prognosis of patients with CRC. Well‐designed prospective studies are necessary to obtain a better understanding of the prognostic value of rs1801133 and rs1801131.

Objectives The aim of this study was to characterise the whole genome sequence of linezolid-intermediate Enterococcus hirae strain CQP3-9 isolated from a large-scale swine farm in Sichuan Province, China, in August 2018. Methods An Illumina MiSeq platform (400-bp paired-end reads with 230-fold average coverage) and PacBio RS II sequencing instrument (100-fold average read depth) were used for genome sequencing. The chromosome and two plasmids were assembled using the software SMRT portal v.3.2.0. Acquired antimicrobial resistance genes were identified using ResFinder 3.1. Results The genome of E. hirae strain CQP3-9 consists of one 2 695 881-bp chromosome, one 125 915-bp plasmid (pCQP3-9_1) and one 33 132-bp plasmid (pCQP3-9_2). The genome of CQP3-9 contains 2458 coding sequences and 89 RNA genes. The poxtA gene is the only linezolid resistance gene in CQP3-9, located on plasmid pCQP3-9_2 that co-harbours erm(B) (macrolide resistance), fexB (chloramphenicol and florfenicol resistance), and tet(M) and tet(L) (tetracycline resistance). Conclusion Here we report for the first time the phenicol–oxazolidinone–tetracycline resistance gene poxtA in E. hirae, located on a plasmid that co-harbours erm(B), fexB, tet(L) and tet(M). The genome sequence of E. hirae CQP3-9 provides valuable information for the dissemination of poxtA among enterococci.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Elatostema qinzhouense L.F. Fu, A.K. Monro & Y.G. Wei, a new species from Guangxi, China is described and illustrated. Morphologically, E. qinzhouense is most similar to E. hezhouense from which it differs by having smaller size of leaf laminae, fewer and smaller staminate peduncle bracts, longer pistillate peduncle bracts and a larger achene. This result is supported by the molecular evidence. The phylogenetic position of the new species within Elatostema is evaluated using three DNA regions, ITS, trnH-psbA and psbM-trnD, for 107 taxa of Elatostema s.l. (including E. qinzhouense). Bayesian inference (BI) and maximum likelihood (ML) analyses each recovered the same strongly supported tree topologies, indicating that E. qinzhouense is a member of the core Elatostema clade and sister to E. hezhouense. Along with the phylogenetic studies, plastid genome and ribosomal DNA (rDNA) sequences of the new species are assembled and annotated. The plastid genome is 150,398 bp in length and comprises two inverted repeats (IRs) of 24,688 bp separated by a large single-copy of 83,919 bp and a small single-copy of 17,103 bp. A total of 113 functional genes are recovered, comprising 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. The rDNA is 5,804 bp in length and comprised the 18S ribosomal RNA partial sequence (1,809 bp), internal transcribed spacer 1 (213 bp), 5.8S ribosomal RNA (164 bp), internal transcribed spacer 2 (248 bp) and 26S ribosomal RNA partial sequence (3,370 bp). In addition, the chromosome number of E. qinzhouense is observed to be 2n = 26, suggesting that the species is diploid. Given a consistent relationship between ploidy level and reproductive system in Elatostema, the new species is also considered to be sexually reproducing. Our assessment of the extinction threat for E. qinzhouense is that it is Endangered (EN) according to the criteria of the International Union for Conservation of Nature.

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Objective Aim to create a three-dimension (3D) reconstruction of acupuncture needling at Sidu ( TE 9). Methods First, the skin, subcutaneous tissue, muscles, the blood vessels and nerves near TE 9 were defined in anatomical terms. Second, the above anatomical structures including the dissected muscles associated with at TE 9, the underlying blood vessels and nerves were reconstructed in 3D. Third, the process of acupuncturing TE 9 on a virtual human body was simulated using the VOXEL-MAN technology. Results Both the local anatomy of the point and the process of acupuncture needling at TE 9 were reconstructed. Different layers of tissues were visualized during the process of needling, as the needle was inserted and manipulated at the point. Conclusions Virtual 3D reconstruction can contribute to research on the anatomical structure of acupoints and the visualization of the acupoints. We recommend that it be fully utilized in acupuncture research.

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions.

Inhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric illness. Although classes of interneurons have unique functional properties and spatial distributions throughout the brain, the relative influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational properties of somatostatin and parvalbumin related transcripts within human and non-human primates. Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI signal amplitude. This relationship is spatially dependent, following the topographic organization of parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular genetic basis of resting-state brain function across cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual differences in risk for schizophrenia.Key FindingsSpatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in mature human and non-human primate cortex, paralleling patterns observed in utero.SST and PVALB are differentially expressed within distinct limbic and somato/motor cortico-striato-thalamic networks, respectively.In-vivo resting-state signal amplitude is heritable in the general population and tracks relative SST/PVALB expression across cortex.Single-nucleotide polymorphisms tied to PVALB-related genes account for an enriched proportion of the heritable variance in resting-state signal amplitude.PVALB-mediated heritability of resting-state signal amplitude in the general population is spatially heterogeneous, mirroring the cortical expression of PVALB in independent post-mortem brain tissue.Polygenic risk for schizophrenia is enriched among interneuron-linked genes and predicts resting-state signal amplitude in a manner that also follows the cortical expression of PVALB.