Whole exome sequencing analysis identifies genes for alcohol consumption.

Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes.

Integration of pharmacodynamics and metabolomics to reveal rhubarb anthraquinone protection against nonalcoholic fatty liver disease rat model.

OBJECTIVES: The objective of the present study was to investigate the effect of Rhubarb anthraquinone (RA) on a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rat model, and explore potential biomarker and metabolic pathways by using the metabolomics method. MATERIALS AND METHODS: We established HFD rats as the NAFLD model. Forty Sprague-Dawley rats were randomly divided into a control group, model group, RA low-dose group, RA medium-dose group, and RA high-dose group, and evaluated the protective effect of RA on NAFLD by detecting biochemical indicators of serum and pathological changes of liver tissue. Investigating potential biomarkers and metabolic pathways connected with RA's protective effects against NAFLD by UHPLC-Q-TOF-MS untargeted metabolomics. RESULTS: The results showed that RA significantly reversed the increase of TG, TC, ALT, AST, and ALP (P < .05), the decrease of HDL-C (P < .05), and alleviated pathological conditions in NAFLD rats. Based on potential biomarker analysis, RA affected metabolic pathways such as fatty acids biosynthesis, bile acids biosynthesis, and pentose phosphate pathway, delaying the progression of NAFLD. CONCLUSION: RA improved blood lipid levels, liver function, and pathological conditions of NAFLD rats. Meanwhile, affected the metabolic pathways and regulated the synthesis of fatty acids and bile acids in NAFLD rats.

Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and Nonalcoholic Fatty Liver Disease Rats.

BACKGROUND AND OBJECTIVES: Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats. METHODS: This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography-ultraviolet. RESULTS: The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0 → ∞) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (Tmax), terminal elimination half-life (t1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05). CONCLUSIONS: This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.

Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders.

Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments. This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs. Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs. First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs. The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures. Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy. Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism. Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients. Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation. These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs.

Downregulation of mGluR1-mediated signaling underlying autistic-like core symptoms in Shank1 P1812L-knock-in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms that consist of social deficits and repetitive behaviors. Unfortunately, no effective medication is available thus far to target the core symptoms of ASD, since the pathogenesis remains largely unknown. To investigate the pathogenesis of the core symptoms in ASD, we constructed Shank1 P1812L-knock-in (KI) mice corresponding to a recurrent ASD-related mutation, SHANK1 P1806L, to achieve construct validity and face validity. Shank1 P1812L-KI heterozygous (HET) mice presented with social deficits and repetitive behaviors without the presence of confounding comorbidities. HET mice also exhibited downregulation of metabotropic glutamate receptor (mGluR1) and associated signals, along with structural abnormalities in the dendritic spines and postsynaptic densities. Combined with findings from Shank1 R882H-KI mice, our study confirms that mGluR1-mediated signaling dysfunction is a pivotal mechanism underlying the core symptoms of ASD. Interestingly, Shank1 P1812L-KI homozygous (HOM) mice manifested behavioral signs of impaired long-term memory rather than autistic-like core traits; thus, their phenotype was markedly different from that of Shank1 P1812L-KI HET mice. Correspondingly, at the molecular level, Shank1 P1812L-KI HOM displayed upregulation of AMPA receptor (GluA2)-related signals. The different patterns of protein changes in HOM and HET mice may explain the differences in behaviors. Our study emphasizes the universality of mGluR1-signaling hypofunction in the pathogenesis of the core symptoms in ASD, providing a potential target for therapeutic drugs. The precise correspondence between genotype and phenotype, as shown in HOM and HET mice, indicates the importance of reproducing disease-related genotypes in mouse models.

Wellens syndrome during chemotherapy for cholangiocarcinoma: A case report of cardiovascular toxicity associated with gemcitabine-containing regimen.

RATIONALE: Wellens syndrome is a comprehensive electrocardiographic (ECG) diagnosis that combines medical history with characteristic ECG changes. These changes, characterized by biphasic T-wave inversions or symmetric and deep T-wave inversions in the anterior precordial leads, often indicate that the left anterior descending coronary artery is at a high risk of severe stenosis. Chemotherapy-related cardiovascular toxicity refers to damage to the cardiovascular system caused by chemotherapeutic drugs, which is unpredictable and may occur during or after chemotherapy. PATIENT CONCERNS: In this case report, a 41-year-old male patient with cholangiocarcinoma received sequential adjuvant chemotherapy with gemcitabine/nanoparticle albumin-bound paclitaxel and gemcitabine/cisplatin. This patient presented with recurrent brief chest pain episodes after the third dose of gemcitabine/cisplatin, and the characteristic T-wave morphological changes were captured in routine ECG monitoring prior to the 6th dose. DIAGNOSES: Acute coronary syndrome due to chemotherapy-related cardiovascular toxicity was diagnosed on the basis of characteristic ECG changes. INTERVENTIONS: The patient underwent coronary angiography, which revealed diffuse stenosis of up to 95% in the middle segment of the left anterior descending coronary artery. Stents were implanted in the stenotic segment for vascular reconstruction. OUTCOMES: The patient's chest pain was completely resolved, and electrocardiography returned to normal. LESSONS: Cardiovascular toxicity during chemotherapy in patients with cancer may be life threatening. This rare case highlights the importance of identifying the characteristic ECG pattern of the Wellens syndrome by monitoring electrocardiography during chemotherapy. Immediate and accurate identification of the morphological ECG features of Wellens syndrome with a slight elevation of the ST-segment is related to patient prognosis.

Neurodevelopmental trajectories, polygenic risk, and lipometabolism in vulnerability and resilience to schizophrenia.

BACKGROUND: Schizophrenia (SZ) arises from a complex interplay involving genetic and molecular factors. Early intervention of SZ hinges upon understanding its vulnerability and resiliency factors in study of SZ and genetic high risk for SZ (GHR). METHODS: Herein, using integrative and multimodal strategies, we first performed a longitudinal study of neural function as measured by amplitude of low frequency function (ALFF) in 21 SZ, 26 GHR, and 39 healthy controls to characterize neurodevelopmental trajectories of SZ and GHR. Then, we examined the relationship between polygenic risk score for SZ (SZ-PRS), lipid metabolism, and ALFF in 78 SZ, and 75 GHR in cross-sectional design to understand its genetic and molecular substrates. RESULTS: Across time, SZ and GHR diverge in ALFF alterations of the left medial orbital frontal cortex (MOF). At baseline, both SZ and GHR had increased left MOF ALFF compared to HC (P < 0.05). At follow-up, increased ALFF persisted in SZ, yet normalized in GHR. Further, membrane genes and lipid species for cell membranes predicted left MOF ALFF in SZ; whereas in GHR, fatty acids best predicted and were negatively correlated (r = -0.302, P < 0.05) with left MOF. CONCLUSIONS: Our findings implicate divergence in ALFF alteration in left MOF between SZ and GHR with disease progression, reflecting vulnerability and resiliency to SZ. They also indicate different influences of membrane genes and lipid metabolism on left MOF ALFF in SZ and GHR, which have important implications for understanding mechanisms underlying vulnerability and resiliency in SZ and contribute to translational efforts for early intervention.

Study on the mechanism of acute liver injury protection in Rhubarb anthraquinone by metabolomics based on UPLC-Q-TOF-MS.

As a traditional Chinese medicine, rhubarb has been used in a variety of liver diseases and it is widely used in clinic to prevent and treat acute liver injury. Anthraquinone, as the main medicinal component of rhubarb, can reverse the further development of liver fibrosis caused by acute liver injury. In this study, metabonomics was used to explore the mechanism of different doses of rhubarb anthraquinone on acute liver injury in rats. Rhubarb anthraquinone was administered intragastric to rats at doses of 3.9, 7.8 and 15.6 mg/kg, respectively, for 7 days, and then 30% CCl4 was injected intraperitoneally at the dose of 1 ml/kg to replicate the acute liver injury model. The biochemical indicators content of ALT, AST, ALP, γ-GT, TG, TC, LDL, HDL in serum and GSH, Hyp, SOD, TNF-α, IL-6 and IL-8 in liver tissue extract were tested respectively, and liver tissue was histopathologically analysis. At the same time, UPLC-Q-TOF-MS combined with non-targeted metabolomics were used to study the metabolites and metabolic pathways of rhubarb anthraquinone in treating acute liver injury. Compared with normal rats, the contents of ALT, AST, ALP, TG, TC, LDL, γ-GT in serum and Hyp, MDA, IL-6, IL-8, TNF-α in the liver tissue extract were significantly increased in model rats (p < 0.05, p < 0.01), and the content of HDL in the serum was significantly decreased (p < 0.05); the activities of GSH and SOD in liver tissue extract were also significantly decreased (p < 0.05). After administration of rhubarb anthraquinone, compared with the model group, with the increase of dosage, some biochemical indexes showed opposite changes, and gradually approached to normal rats. 12 different metabolites were identified by metabonomics, and the biosynthesis and metabolism of phenylalanine, tyrosine and tryptophan, the metabolism of amino sugars, nucleotide sugars and pyrimidines metabolism, and the biosynthesis of steroid hormone were identified based on the biomarker analysis. Based on the biochemical analysis and metabonomics analysis of rats with acute liver injury treated with different doses of rhubarb anthraquinone, combined with histopathological observation, the results show that the protective effect of rhubarb anthraquinone on acute liver injury is related to the dosage; Meanwhile, the metabolic pathway analysis suggested that rhubarb anthraquinone alleviate acute liver injury by regulating inflammation, oxidative stress and fibrosis disorders. This study explained the therapeutic effect of rhubarb anthraquinone on acute liver injury from both material basis and action pathway, and provided safe and effective research ideas for clinical application of rhubarb.

Nephroprotective and nephrotoxic effects of Rhubarb and their molecular mechanisms.

Rhubarb, in the form of a traditional Chinese medicine, is used in the treatment of chronic kidney disease (CKD). Previous studies have demonstrated that Rhubarb possesses a good nephroprotective effect, which primarily protects the kidneys from fibrosis, oxidation, inflammation, autophagy, and apoptosis. However, studies have shown that the long-term inappropriate use of Rhubarb may cause damage to renal function. Therefore, how to correctly understand and scientifically evaluate the pharmacodynamics and toxicity of Rhubarb with regard to CKD is a scientific question that urgently needs to be answered. In this review, we explain and illustrate how Rhubarb exerts its nephroprotective effect against CKD. We also describe the mechanisms of action that may cause its nephrotoxicity. Valuable and practical clinical guidance is proposed with regard to methods for mitigating the nephrotoxicity of Rhubarb.

Efficacy and safety of total glucosides of paeony in the treatment of systemic lupus erythematosus: A systematic review and meta-analysis.

Background: Total glucosides of paeony (TGP), extracted from the Chinese medicine Paeonia lactiflora Pall., have been proven to be effective in various autoimmune diseases. We aim to systematically evaluate the efficacy and safety of TGP combined with different conventional therapeutic agents in the treatment of systemic lupus erythematosus (SLE). Methods: Eight databases were searched for randomized controlled studies of TGP for SLE. The search time was set from the establishment of the databases to March 2022. The risk of bias was assessed by the Cochrane Evaluation Manual (5.1.0), RevMan 5.3 software was used for meta-analysis, and the certainty of the evidence was assessed by the GRADE methodology. Results: A total of 23 articles were included, including 792 patients overall in the treatment group and 781 patients overall in the control group. The meta-analysis results showed that TGP combined with conventional treatments was superior to the conventional treatments in reducing the SLE disease activity and the incidence of adverse reactions (SMDTGP+GC+CTX = -1.98, 95% Cl = [-2.50, -1.46], p < 0.001; SMDTGP+GC+HCQ = -0.65, 95% Cl = [-1.04, -0.26], p <0.001; SMDTGP+GC+TAC = -0.94, 95% Cl = [-1.53, -0.34], p < 0.05; SMDTGP+GC = -1.00, 95% Cl = [-1.64, -0.36], p < 0.05; and RRTGP+GC+CTX = 0.37, 95% Cl = [0.21, 0.64], p < 0.001). The results also showed that TGP helped improve other outcomes related to SLE disease activity, such as complement proteins (C3 and C4), immunoglobulins (IgA, IgM and, IgG), ESR, CRP, 24 h urine protein, and recurrence rate. In addition, TGP may also be effective in reducing the average daily dosage of glucocorticoids (GCs) and the cumulative dosage of cyclophosphamide (CTX). The certainty of the evidence was assessed as moderate to low. Conclusion: TGP is more effective and safer when used in combination with different conventional therapeutic agents. It helped reduce the disease activity of SLE and the incidence of adverse reactions. However, we should be cautious about these conclusions as the quality of the evidence is poor. Future studies should focus on improving the methodology. High-quality randomized controlled trials (RCTs) will be necessary to provide strong evidence for the efficacy of TGP for SLE. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42021272481.

A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.

The genetic etiology and underlying mechanism of autism spectrum disorder (ASD) remain elusive. SHANK family genes (SHANK1/2/3) are well known ASD-related genes. However, little is known about how SHANK missense mutations contribute to ASD. Here, we aimed to clarify the molecular mechanism of and the multilevel neuropathological features induced by Shank1 mutations in knock-in (KI) mice. In this study, by sequencing the SHANK1 gene in a cohort of 615 ASD patients and 503 controls, we identified an ASD-specific recurrent missense mutation, c.2621 G > A (p.R874H). This mutation demonstrated strong pathogenic potential in in vitro experiments, and we generated the corresponding Shank1 R882H-KI mice. Shank1 R882H-KI mice displayed core symptoms of ASD, namely, social disability and repetitive behaviors, without confounding comorbidities of abnormal motor function and heightened anxiety. Brain structural changes in the frontal cortex, hippocampus and cerebellar cortex were observed in Shank1 R882H-KI mice via structural magnetic resonance imaging. These key brain regions also showed severe and consistent downregulation of mGluR1-IP3R1-calcium signaling, which subsequently affected the release of intracellular calcium. Corresponding cellular structural and functional changes were present in Shank1 R882H-KI mice, including decreased spine size, reduced spine density, abnormal morphology of postsynaptic densities, and impaired hippocampal long-term potentiation and basal excitatory transmission. These findings demonstrate the causative role of SHANK1 in ASD and elucidate the underlying biological mechanism of core symptoms of ASD. We also provide a reliable model of ASD with core symptoms for future studies, such as biomarker identification and therapeutic intervention studies.

Associations between polygenic risk scores and amplitude of low-frequency fluctuation of inferior frontal gyrus in schizophrenia.

Schizophrenia (SCZ) is a serious and complex mental disorder with high heritability. Polygenic risk score (PRS) is a useful tool calculating the accumulating effects of multiple common genetic variants of schizophrenia. The amplitude of low-frequency fluctuation (ALFF) is an efficient index to reflect spontaneous, intrinsic neuronal activity. Aberrant ALFF of brain regions were reported in schizophrenia frequently, but the relationship between PRS and ALFF has not been studied. In the present study, we compared PRS and ALFF in 101 schizophrenia patients and 106 age-matched healthy controls to test their associations with schizophrenia. Then, the correlation of PRS with ALFF was measured to reveal the effect of polygenic risk on brain activity in schizophrenia. We found that schizophrenia patients showed significant differences in PRS and ALFF compared with controls. Twenty-six brain regions showed significant difference of ALFF between schizophrenia cases and controls, of which left inferior frontal gyrus, triangular part (IFGtriang.L) showed increased activity in schizophrenia. PRS-SCZ was positively correlated with ALFF in IFGtriang.L in 57 non-chronic patients. Genes involved in synaptic organization and transmission, especially in glutamatergic synapse, were highly enriched in PRS-SCZ genes, suggesting the dysfunction of synapses in schizophrenia. These results help to understand the molecular mechanism underlying schizophrenia and related brain dysfunction.

ANK3 Gene Polymorphism Rs10994336 Influences Executive Functions by Modulating Methylation in Patients With Bipolar Disorder.

Background: A large body of evidence suggests that epigenetic modification including DNA methylation plays a critical role in BD's pathogenesis while the identification of methylation quantitative trait loci (meQTLs) shed light on the interpretation of the function of genetic variants in non-coding regions. The intronic single nucleotide polymorphism (SNP) rs10994336 within the ANK3 has emerged as one of the most replicated risk variants for bipolar disorder (BD) in genome-wide association studies. Whether rs10994336 functions as a meQTL to mediate the association between genotype and phenotype remains unclear. Method: A total of 154 patients with BD and 181 healthy controls (HC) were recruited. The genotypes of rs10994336 and methylation levels of CpG sites within ANK3 were tested. Executive functions were assessed using a computerized version of the Wisconsin Card Sorting Test (WCST). Results: Bipolar disorder patients with the risk-T allele of rs10994336 scored lower on tests of executive function compared to homozygous CC carriers, after controlling for age, gender, and education level. No significant difference was found in HC individuals. The risk-T allele is associated with a lower methylation level of CpG site cg02172182 in HC after multiple corrections and replicated in the BD group in the same direction. Further mediation analysis revealed that the cg02172182 methylation significantly mediated the association between the polymorphism rs10994336 and PE index of WCST in patients with BD. Conclusion: Our study suggests that BD-related genetic variant rs10994336 in ANK3 impacts executive functions by modulating ANK3 methylation, supporting the theory that methylation acts as a mediator between genotype and phenotype.

Identifying and validating subtypes within major psychiatric disorders based on frontal-posterior functional imbalance via deep learning.

Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 with MDD) and 363 healthy controls (HC). We identified two subtypes with differentiating patterns of functional imbalance between frontal and posterior brain regions, as compared to HC: (1) Archetypal MPDs (60% of MPDs) had increased frontal and decreased posterior ALFF, and decreased cortical thickness and white matter integrity in multiple brain regions that were associated with increased polygenic risk scores and enriched risk gene expression in brain tissues; (2) Atypical MPDs (40% of MPDs) had decreased frontal and increased posterior ALFF with no associated alterations in validity measures. Medicated Archetypal MPDs had lower symptom severity than their unmedicated counterparts; whereas medicated and unmedicated Atypical MPDs had no differences in symptom scores. Our findings suggest that frontal versus posterior functional imbalance as measured by ALFF is a novel putative trans-diagnostic biomarker differentiating subtypes of MPDs that could have implications for precision medicine.

Associations between hemispheric asymmetry and schizophrenia-related risk genes in people with schizophrenia and people at a genetic high risk of schizophrenia.

BACKGROUND: Schizophrenia is considered a polygenic disorder. People with schizophrenia and those with genetic high risk of schizophrenia (GHR) have presented with similar neurodevelopmental deficits in hemispheric asymmetry. The potential associations between neurodevelopmental abnormalities and schizophrenia-related risk genes in both schizophrenia and those with GHR remains unclear. AIMS: To investigate the shared and specific alternations to the structural network in people with schizophrenia and those with GHR. And to identify an association between vulnerable structural network alternation and schizophrenia-related risk genes. METHOD: A total of 97 participants with schizophrenia, 79 participants with GHR and 192 healthy controls, underwent diffusion tensor imaging (DTI) scans at a single site. We used graph theory to characterise hemispheric and whole-brain structural network topological metrics. For 26 people in the schizophrenia group and 48 in the GHR group with DTI scans we also calculated their schizophrenia-related polygenic risk scores (SZ-PRSs). The correlations between alterations to the structural network and SZ-PRSs were calculated. Based on the identified genetic-neural association, bioinformatics enrichment was explored. RESULTS: There were significant hemispheric asymmetric deficits of nodal efficiency, global and local efficiency in the schizophrenia and GHR groups. Hemispheric asymmetric deficit of local efficiency was significantly positively correlated with SZ-PRSs in the schizophrenia and GHR groups. Bioinformatics enrichment analysis showed that these risk genes may be linked to signal transduction, neural development and neuron structure. The schizophrenia group showed a significant decrease in the whole-brain structural network. CONCLUSIONS: The shared asymmetric deficits in people with schizophrenia and those with GHR, and the association between anomalous asymmetry and SZ-PRSs suggested a vulnerability imaging marker regulated by schizophrenia-related risk genes. Our findings provide new insights into asymmetry regulated by risk genes and provides a better understanding of the genetic-neural pathological underpinnings of schizophrenia.

Electrocardiographic Characteristics of Breast Cancer Patients Treated with Chemotherapy.

INTRODUCTION: Patients receiving chemotherapy for breast cancer may be at risk of developing cardiac dysfunction and electrophysiological abnormalities. The aim of this study is to evaluate alterations in electrocardiographic (ECG) parameters in breast cancer patients receiving chemotherapy. MATERIALS AND METHODS: This was a prospective single-center cohort study conducted in the Fourth Hospital of Hebei Medical University, China. Participants with breast cancer referred for chemotherapy from May 1, 2019, to October 1, 2019, were invited to participate in the study. Standard 12-lead ECG and echocardiography were performed at baseline or before chemotherapy (prechemotherapy) (T0), after 1 cycle (T1), after 3 cycles (T2), and at the end of chemotherapy (T3). RESULTS: A total of 64 patients with diagnosed breast cancer undergoing chemotherapy were included. Echocardiographic parameters showed no significant variation during the entire procedure (all P > 0.05). The incidence of abnormal ECG increased from 43.75% at baseline to 65.63% at the end of chemotherapy, of which only the prevalence of fragmented QRS (fQRS) was significantly increased after the drug regimen (26.56% to 53.13%). At the end of the treatment, heart rate, P-wave dispersion, corrected QT interval, T-peak to T-end, RR, SV1, RV5, Sokolow-Lyon index (SLI), and index of cardioelectrophysiological balance deteriorated markedly (all P < 0.05). The area under the curve for SLI and QT dispersion (QTd) derived by ECG was 0.710 and 0.606, respectively. The cutoff value with 2.12 of SLI by ECG had a sensitivity of 67.2% and specificity of 71.9% for differentiating patients after therapy from baselines. The cutoff value with 0.55 of QTd had a sensitivity of 60.9% and specificity of 60.9%. CONCLUSIONS: The current study demonstrated that ECGs can be used to detect electrophysiological abnormalities in breast cancer patients receiving chemotherapy. ECG changes can reflect subclinical cardiac dysfunction before the echocardiographic abnormalities.

Polygenic risk for autism spectrum disorder affects left amygdala activity and negative emotion in schizophrenia.

Although the diagnoses based on phenomenology have many practical advantages, accumulating evidence shows that schizophrenia and autism spectrum disorder (ASD) share some overlap in genetics and clinical presentation. It remains largely unknown how ASD-associated polygenetic risk contributes to the pathogenesis of schizophrenia. In the present study, we calculated high-resolution ASD polygenic risk scores (ASD PRSs) and selected optimal ten ASD PRS with minimal P values in the association analysis of PRSs, with schizophrenia to assess the effect of ASD PRS on brain neural activity in schizophrenia cases and controls. We found that amplitude of low-frequency fluctuation in left amygdala was positively associated with ASD PRSs in our cohort. Correlation analysis of ASD PRSs with facial emotion recognition test identified the negative correlation of ASD PRSs with negative emotions in schizophrenia cases and controls. Finally, functional enrichment analysis of PRS genes revealed that neural system function and development, as well as signal transduction, were mainly enriched in PRS genes. Our results provide empirical evidence that polygenic risk for ASD contributes to schizophrenia by the intermediate phenotypes of left amygdala function and emotion recognition. It provides a promising strategy to understand the relationship between phenotypes and genotypes shared in mental disorders.

A review of the processed Polygonum multiflorum (Thunb.) for hepatoprotection: Clinical use, pharmacology and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum (Thunb.) (PMT) is a member of Polygonaceae. Traditional Chinese medicine considers that the processed PMT can tonify liver, nourish blood and blacken hair. In recent years, the processed PMT and its active ingredients have significant therapeutic effects on nonalcoholic fatty liver disease, alcoholic fatty liver disease, viral hepatitis, liver fibrosis and liver cancer. AIM OF THE STUDY: The main purpose of this review is to provide a critical appraisal of the existing knowledge on the clinical application, hepatoprotective pharmacology and hepatotoxicity, it provides a comprehensive evaluation of the liver function of the processed PMT. MATERIALS AND METHODS: A detailed literature search was conducted using various online search engines, such as Pubmed, Google Scholar, Mendeley, Web of Science and China National Knowledge Infrastructure (CNKI) database. The main active components of the processed PMT and the important factors in the occurrence and development of liver diseases are used as key words to carry out detailed literature retrieval. RESULTS: In animal and cell models, the processed PMT and active components can treat various liver diseases, such as fatty liver induced by high-fat diet, liver injury and fibrosis induced by drugs, viral transfected hepatitis, hepatocellular carcinoma, etc. They can protect liver by regulating lipid metabolism related enzymes, resisting insulin resistance, decreasing the expression of inflammatory cytokines, inhibiting the activation of hepatic stellate cells, reducing generation of extracellular matrix, promoting cancer cell apoptosis and controlling the growth of tumor cells, etc. However, improperly using of the processed PMT can cause liver injury, which is associated with the standardization of processing, the constitution of the patients, the characteristics of the disease, and the administration of dosage and time. CONCLUSION: The processed PMT can treat various liver diseases via reasonably using, and the active compounds (2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside, emodin, physcion, etc.) are promising candidate drugs for developing new liver protective agents. However, some components have a "toxic-effective" bidirectional effect, which should be used cautiously.