[Clinical and genetic analysis of five children with Catecholaminergic polymorphic ventricular tachycardia due to variants of RYR2 gene].

OBJECTIVE: To explore the clinical and genetic characteristics of five children with Catecholaminergic polymorphic ventricular tachycardia (CPVT). METHODS: Five children with clinical manifestations consistent with CPVT admitted to the Department of Cardiology of Children's Hospital Affiliated to Zhengzhou University from November 2019 to November 2021 were selected as the study subjects. Their clinical data were collected. Potential variants were detected by whole exome sequencing, and Sanger sequencing was used to verify the candidate variants. All patients were treated with ß-blocker propranolol and followed up. RESULTS: All patients had developed the disease during exercise and presented with syncope as the initial clinical manifestation. Electrocardiogram showed sinus bradycardia. The first onset age of the 5 patients were (10.4 ± 2.19) years, and the time of delayed diagnosis was (1.6 ± 2.19) years. All of the children were found to harbor de novo heterozygous missense variants of the RYR2 gene, including c.6916G>A (p.V2306I), c.527G>C (p.R176P), c.12271G>A (p.A4091T), c.506G>T (p.R169L) and c.6817G>A (p.G2273R). Among these, c.527G>C (p.R176P) and c.6817G>A (p.G2273R) were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.527G>C (p.R176P) was classified as a pathogenic variant (PS2+PM1+PM2_Supporting+PM5+PP3+PP4), and the c.6817G>A (p.G2273R) was classified as a likely pathogenic variant (PS2+PM2_Supporting+PP3+PP4). The symptoms of all children were significantly improved with the propranolol treatment, and none has developed syncope during the follow up. CONCLUSION: Discovery of the c.527G>C (p.R176P) and c.6817G>A (p.G2273R) variants has expanded the mutational spectrum of the RYR2 gene. Genetic testing of CPVT patients can clarify the cause of the disease and provide a reference for their genetic counseling.

[Genetic analysis of a child with restricted cardiomyopathy and phenylketonuria and a literature review].

OBJECTIVE: To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy (RCM) and phenylketonuria (PKU), and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review. METHODS: A child with RCM in conjunct with PKU who was admitted to the Children's Hospital Affiliated to Zhengzhou University in June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject. Relevant clinical data were collected. Peripheral blood samples of the child and his parents were collected for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatic analysis. Childhood, TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform, Chinese Journal Full-text database and PubMed database, and the search period was limited to from the time of establishment till August 2022. Clinical manifestations and characteristics of the TNNI3 gene variants were summarized. RESULTS: The child, a 2-year-old-and-4-month-old male, had normal intelligence, facial features and normal hair and skin color, but his motor and physical development was delayed, in addition with edema of bilateral eyelids and lower limbs. The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene, namely c.331C>T (p.R111X) and c.940C>A (p.P341T), which were inherited from his father and mother, respectively. In addition, he has also harbored a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the TNNI3: c.508C>T (p.R170W) was classified as a pathogenic variant (PS2+PS4+PM2_Supporting+PM5), PAH: c.331C>T (p.R111X) as a pathogenic variant (PVS1+PM2_Supporting+PM3+PP4), and c.940C>A (p.P341T) as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP4). In total 30 children with RCM caused by TNNI3 gene variants were retrieved, with a male-to-female ratio of 1 : 1.55 and manifestations including heart failure, sinus rhythm, bi-atrial enlargement, ST-T wave change, ventricular restricted filling, and decreased ventricular diastolic function. In total 16 variants of the TNNI3 gene were identified, among which c.575G>A was the most common, and all cases had conformed to an autosomal dominant inheritance. CONCLUSION: Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.

[Clinical and genetic analysis of eight children with Primary hypertrophic cardiomyopathy].

OBJECTIVE: To explore the clinical and genetic characteristics of eight children with Primary hypertrophic cardiomyopathy (HCM). METHODS: Eight children with HCM admitted to the Department of Cardiology of Henan Children's Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c.2155C>T (p.Arg719Trp), c.1208G>A (p.Arg403Gln), c.1358G>A (p.Arg453His), and c.1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c.1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+PM2_Supporting+PM6+PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, including MYL2: c.173G>A (p.Arg58Gln; classified as pathogenic), TPM1: c.574G>A (p.Glu192Lys) and ACTC1: c.301G>A (p.Glu101Lys)(both were classified as likely pathogenic), and MYBPC3: c.146T>G (p.Ile49Ser; classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event. CONCLUSION: Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c.1498G>A (p.Glu500Lys) variant has also expanded the spectrum of MYH7 gene mutations underlying HCM.

Somatic symptoms mediate the association between subclinical anxiety and depressive symptoms and its neuroimaging mechanisms.

BACKGROUND: Subclinical anxiety, depressive and somatic symptoms appear closely related. However, it remains unclear whether somatic symptoms mediate the association between subclinical anxiety and depressive symptoms and what the underlying neuroimaging mechanisms are for the mediating effect. METHODS: Data of healthy participants (n = 466) and participants in remission of major depressive disorder (n = 53) were obtained from the Human Connectome Project. The Achenbach Adult Self-Report was adopted to assess anxiety, depressive and somatic symptoms. All participants completed four runs of resting-state functional magnetic resonance imaging. Mediation analyses were utilized to explore the interactions among these symptoms and their neuroimaging mechanisms. RESULTS: Somatic symptoms partially mediated the association between subclinical anxiety and depressive symptoms in healthy participants (anxiety→somatic→depression: effect: 0.2785, Boot 95% CI: 0.0958-0.3729; depression→somatic→anxiety: effect: 0.0753, Boot 95% CI: 0.0232-0.1314) and participants in remission of MDD (anxiety→somatic→depression: effect: 0.2948, Boot 95% CI: 0.0357-0.7382; depression→somatic→anxiety: effect: 0.0984, Boot 95% CI: 0.0007-0.2438). Resting-state functional connectivity (FC) between the right medial superior frontal gyrus and the left thalamus and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in healthy participants (effect: 0.0020, Boot 95% CI: 0.0003-0.0043). The mean strength of common FCs of subclinical depressive and somatic symptoms, somatic symptoms, and the mean strength of common FCs of subclinical anxiety and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in remission of MDD (effect: 0.0437, Boot 95% CI: 0.0024-0.1190). These common FCs mainly involved the insula, precentral gyri, postcentral gyri and cingulate gyri. Furthermore, FC between the triangular part of the left inferior frontal gyrus and the left postcentral gyrus was positively associated with subclinical anxiety, depressive and somatic symptoms in remission of MDD (FDR-corrected p < 0.01). CONCLUSIONS: Somatic symptoms partially mediate the interaction between subclinical anxiety and depressive symptoms. FCs involving the right medial superior frontal gyrus, left thalamus, triangular part of left inferior frontal gyrus, bilateral insula, precentral gyri, postcentral gyri and cingulate gyri maybe underlie the mediating effect of somatic symptoms.

Prognostic and diagnostic significance of galectins in pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Galectins constitute a family of ß-galactoside-binding proteins, which influence various hallmarks of pancreatic cancer, including cell proliferation, invasion and migration; immune escape; and angiogenesis. Although many studies have concentrated on the role of galectins in pancreatic cancer, the results remain controversial. Hence, we performed a comprehensive meta-analysis to clarify the precise diagnostic and prognostic value of galectins in pancreatic cancer. METHODS: PubMed/MEDLINE, EMBASE and Web of Science were used to search related published literature up to July 2019. Pooled hazard ratios (HRs), diagnostic accuracy variables and related 95% confidence intervals (CIs) were calculated using STATA 14.0 software. RESULTS: Eleven studies including 1227 participants met our inclusion criteria. High expression of galectin family was not correlated with overall survival (OS) in pancreatic cancer (HR, 1.19; 95% CI 0.67-2.11). According to subgroup analysis, high levels of galectin-1 were significantly correlated with worse OS in pancreatic cancer (HR, 4.77; 95% CI 2.47-9.21), while high levels of tandem-repeat galectins (galectin-4 or galectin-9) predicted both better OS (HR, 0.63; 95% CI 0.46-0.86) and disease-free survival (DFS) (HR, 0.63; 95% CI 0.48-0.83). The expression levels of galectin-3 did not directly correlate with prognosis (HR, 0.99; 95% CI 0.40-2.46). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratios of galectin-3 were 0.64 (95% CI 0.41-0.82), 0.76 (95% CI 0.59-0.88), 2.70 (95% CI 1.21-6.1), and 0.47 (95% CI 0.23-0.98), respectively. The area under the curve (AUC) of galectin-3 was 0.77. CONCLUSION: Taken together, our results suggest that high expression of galectin-1 and low levels of galectin-4 or galectin-9 are predictors of worse prognosis in pancreatic cancer patients. The expression of galectin-3 was not directly related to OS and other clinical characteristics. Although galectin-3 exhibited some diagnostic value in patients with pancreatic cancer in this meta-analysis, clinical application prospects remain to be validated. Further studies are warranted to confirm and strengthen these findings.

Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma.

BACKGROUND: Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic ß cells. HNF4α has been reported to affect cell proliferation and chemoresistance in several cancers. However, the role of HNF4α in pancreatic adenocarcinoma (PDAC) has not been studied extensively and remains unclear. METHODS: By utilizing immunohistochemical (IHC) staining, we measured the expression of HNF4α in PDAC tissues. By silencing HNF4α in PDAC cell lines, we assessed the impact of HNF4α on pancreatic cancer cell proliferation and gemcitabine sensitivity. We used CCK8 and colony formation assays to examine the effect of HNF4α on cell proliferation. A flow cytometry assay was used to assess cell apoptosis. The expression of gemcitabine-related genes was detected by quantitative real­time PCR (qRT-PCR) and Western blotting. IHC was utilized to assess the correlation between HNF4α and human equilibrative nucleoside transporter 1 (hENT1) expression in PDAC patients. Chromatin immunoprecipitation (ChIP) and dual­luciferase reporter assays were used to confirm that hENT1 is a target gene of HNF4α. RESULTS: Increased HNF4α expression was detected in PDAC tissues; patients with higher HNF4α expression displayed worse prognosis. To elucidate the function of HNF4α, we examined its role in pancreatic cancer cell proliferation, apoptosis and gemcitabine resistance. In HNF4α-silenced Capan-1 and MiaPaCa-2 cells, we observed decreased cell proliferation and increased sensitivity to gemcitabine compared to those of controls. The mechanism of HNF4α in gemcitabine-related chemosensitivity was then explored. In response to HNF4α silencing, the expression levels of gemcitabine-related proteins, hENT1 and deoxycytidine kinase (dCK) were significantly increased. Additionally, hENT1 was negatively correlated with HNF4α in PDAC tissue samples. Moreover, we identified hENT1 as a downstream target of HNF4α. CONCLUSION: HNF4α is a prognostic marker for overall survival, is required for pancreatic cancer cell proliferation and promotes resistance to gemcitabine by downregulating hENT1. Therefore, targeting HNF4α might reverse gemcitabine resistance and provide novel treatment strategies for PDAC.

Management of solid pseudopapillary neoplasms of pancreas: A single center experience of 243 consecutive patients.

BACKGROUND: Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm, which mainly affects young women. The aim of this study was to investigate the clinicopathological features and surgical management of SPNs in our institution. METHODS: Patients who underwent surgery for a pathologically confirmed SPN in our institution between January 2008 and October 2018 were collected. Their clinical characteristics and survival associations were analyzed. RESULTS: In total, 243 pathologically confirmed patients were analyzed in this study, including 181(74.5%)females and 62(25.5%) males. The mean age was 35.3 years old (range: 12-64 years old) with average tumor size of 4.83 cm (range: 0.8-16 cm). 239 patients underwent complete surgical resection. After median follow-up of 46 months (range: 10-118 months), four patients died due to tumor progression. All the other people were absent of local recurrence or distant metastasis. CONCLUSIONS: SPN is a latent malignant tumor with excellent prognosis. Surgical resection is recommended even in the presence of liver metastasis. If possible, function-preserving surgery is advocated. High Ki67 index may predict the malignant potential and poor prognosis of SPNs.

PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis.

BACKGROUND: The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. METHODS: Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. RESULTS: PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. CONCLUSIONS: The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Laparoscopic pancreaticoduodenectomy: are the best times coming?

BACKGROUND: The introduction of laparoscopic technology has greatly promoted the development of surgery, and the trend of minimally invasive surgery is becoming more and more obvious. However, there is no consensus as to whether laparoscopic pancreaticoduodenectomy (LPD) should be performed routinely. MAIN BODY: We summarized the development of laparoscopic pancreaticoduodenectomy (LPD) in recent years by comparing with open pancreaticoduodenectomy (OPD) and robotic pancreaticoduodenectomy (RPD) and evaluated its feasibility, perioperative, and long-term outcomes including operation time, length of hospital stay, estimated blood loss, and overall survival. Then, several relevant issues and challenges were discussed in depth. CONCLUSION: The perioperative and long-term outcomes of LPD are no worse and even better in length of hospital stay and estimated blood loss than OPD and RPD except for a few reports. Though with strict control of indications, standardized training, and learning, ensuring safety and reducing cost are still and will always the keys to the healthy development of LPD; the best times for it are coming.

A case of polyglucosan body myopathy caused by an RBCK1 gene variant and literature review.

OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the RBCK1 gene. METHODS: The clinical data of the patient were collected, next-generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. RESULTS: Through whole-exome sequencing, we found that there were c.919G>T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the RBCK1 gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with RBCK1 gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases. CONCLUSIONS: The patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the RBCK1 gene were discovered through whole-exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole-exome sequencing technology in disease diagnosis and genetic counseling was emphasized.

Case report of a child with long QT syndrome type 14 caused by CALM1 gene mutation and literature review.

OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with long QT syndrome type 14 (long QT syndrome-14, LQT14, OMIM # 616247) caused by a de novo CALM1 mutation. METHODS: The clinical data of the patient were collected, next-generation sequencing technology was used to determine the exome gene sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. RESULTS: A 5-year and 9-month-old girl was admitted to the hospital due to a syncopal episode. During the attack, the main symptoms were loss of consciousness, cyanosis of the face and lips, and weakness of limbs. The child had multiple seizures in the past, all of which occurred after emotional excitement and activity. She was diagnosed with epilepsy for more than 3 years, but the effect of antiepileptic treatment was not satisfactory. The electrocardiogram was normal in the past. A month ago, convulsions occurred again after exercise, and the electrocardiogram showed QTc 496 ms. The treadmill test showed a significant prolongation of QTc after exercise, and the genetic results suggested a new heterozygous variant of CALM1, c.395A>G; p. (Asp132Gly). Consequently, she was diagnosed with LQT14 and treated with propranolol. During a follow-up of 15 months, there were no seizures or syncope. CONCLUSIONS: This patient had multiple episodes of convulsions or syncope after emotional stimulation or activity, with intermittent prolongation of the QTc on routine ECG, marked prolongation of the QTc after exercise, and T-wave alternans, which differed from the LQT14 phenotype caused by the previous CALM1 mutation.

Shared and distinct aberrations in frontal-striatal system functional patterns among patients with irritable bowel syndrome and major depressive disorder.

BACKGROUND: Considering the high comorbidity, shared risk factors, and genetic pathways between irritable bowel syndrome (IBS) and major depressive disorder (MDD), we hypothesized that there would be both shared and disorder-specific alterations in brain function. METHODS: A total of 39 IBS patients, 39 MDD patients, and 40 healthy controls (HCs) were enrolled and matched for sex, age, and educational level. All subjects underwent resting-state functional MRI. The clinical variables of anxiety, depression, gastrointestinal symptoms and alexithymia were recorded. The 12 subregions of the striatum were employed as seeds to assess their functional connectivity (FC) with every voxel throughout the whole brain. RESULTS: Compared to HC, IBS and MDD patients exhibited aberrant frontal-striatal circuitry. We observed a common decrease in FC between the dorsal striatum and regions of the hippocampus, sensorimotor cortex, and prefrontal cortex (PFC) in both IBS and MDD patients. Patients with IBS exhibited disorder-specific decreases in FC within the striatum, along with reduced connectivity between the ventral striatum and sensorimotor cortex. In contrast, MDD patients showed disorder-specific hyperconnectivity in the medial PFC-limbic system. Receiver operating characteristic curve analysis showed that frontal-striatal FC values could serve as transdiagnostic markers of IBS and MDD. Within the IBS group, striatal connectivity was not only negatively associated with weekly abdominal pain days but also negatively correlated with the levels of anxiety and alexithymia. CONCLUSIONS: This exploratory analysis indicated that patients with IBS and MDD exhibited both shared and disorder-specific frontal-striatal circuit impairments, potentially explaining both comorbidity and distinct phenotypes.

Cardiomyopathy in children: a single-centre, retrospective study of genetic and clinical characteristics.

OBJECTIVES: This study aimed to describe the genetic and clinical characteristics of paediatric cardiomyopathy in a cohort of Chinese patients. METHODS: We retrospectively reviewed the clinical history and mutation spectrum of 75 unrelated Chinese paediatric patients who were diagnosed with cardiomyopathy and referred to our hospital between January 2016 and December 2022. RESULTS: Seventy-five children with cardiomyopathy were enrolled, including 32 (42.7%) boys and 43 (57.3%) girls. Dilated cardiomyopathy was the most prevalent cardiomyopathy (61.3%) in the patients, followed by hypertrophic cardiomyopathy (17.3%), ventricular non-compaction (14.7%), restrictive cardiomyopathy (5.3%) and arrhythmogenic right ventricular cardiomyopathy (1.3%). Whole-exome sequencing and targeted next-generation sequencing identified 34 pathogenic/likely pathogenic variants and 1 copy number variant in 14 genes related to cardiomyopathy in 30 children, accounting for 40% of all patients. TNNC1 p.Asp65Asn and MYH7 p.Glu500Lys have not been reported previously. The follow-up time ranged from 2 months to 6 years. Twenty-two children died (mortality rate 29%). CONCLUSIONS: Comprehensive genetic testing was associated with a 40% yield of causal genetic mutations in Chinese cardiomyopathy cases. We found diversity in the mutation profile in different patients, which suggests that the mutational background of cardiomyopathy in China is heterogeneous, and the findings may be helpful to those counselling patients and families.

Bisphenol B induces developmental toxicity in zebrafish via oxidative stress.

Bisphenol A (BPA) is a typical endocrine disruptor, and the use of bisphenol B (BPB) as a substitute is gradually increasing. Some studies have shown that BPB also has endocrine disrupting effects, but its effects on the early stages of fish growth and development have not been reported. In this paper, zebrafish embryos were exposed to different concentrations of BPB until the 6th day post fertilization (dpf), and the toxic effects of BPB on the early development of zebrafish and the possible molecular mechanisms were investigated. The results showed that BPB exposure at 10, 100, and 1000 µg/L induced developmental toxic effects such as early neurotoxicity and cardiovascular toxicity in zebrafish, and the toxic effects were positively correlated with the degree of oxidative damage. These adverse results were ameliorated by the classical antioxidant N-acetyl-L-cysteine (NAC), suggesting the involvement of oxidative stress in BPB-induced early developmental toxicity. The above data suggest that BPB exposure increases oxidative damage and suppresses the expression of genes critical for early neurological and cardiovascular development, ultimately leading to early developmental toxicity in juvenile zebrafish. This study contributes to broadening our understanding of the toxic effects of BPB and provides a basic theoretical basis for the next management support of bisphenol analogs.

Disrupted diurnal oscillations of the gut microbiota in patients with alcohol dependence.

Background: Patients with alcohol dependence (AD) can exhibit gut dysbacteria. Dysbacteria may co-occur with disruptions of circadian rhythmicity of the gut flora, which can aggravate AD. Herein, this study aimed to investigate diurnal oscillations of the gut microbiota in AD patients. Methods: Thirty-two patients with AD, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 20 healthy subjects were enrolled in this study. Demographic and clinical data were collected by self-report questionnaires. Fecal samples at 7:00 AM, 11:00 AM, 3:00 PM, and 7:00 PM were collected from each subject. 16S rDNA sequencing was conducted. Wilcoxon and Kruskal-Wallis tests were performed to characterize alterations and oscillations of the gut microbiota. Results: We found that ß-diversity of the gut microbiota in AD patients oscillated diurnally compared with healthy subjects (p = 0.01). Additionally, 0.66% of operational taxonomic units oscillated diurnally in AD patients versus 1.68% in healthy subjects. At different taxonomic levels, bacterial abundance oscillated diurnally in both groups, such as Pseudomonas and Prevotella pallens (all p < 0.05). ß-diversity of the gut microbiota in AD patients with high daily alcohol consumption, high-level cravings, short AD durations, and mild withdrawal symptoms oscillated diurnally compared with other AD patients (all p < 0.05). Conclusion: The gut microbiota in AD patients exhibits disruptions of diurnal oscillation, which may provide novel insights into mechanisms of AD and the development of therapeutic strategies.

The association between the romantic relationships of parents and offspring depressive symptoms: Mediating effects of offspring communication patterns and romantic relationships.

This study investigated a conceptual model by testing how parental romantic relationships influenced the depressive symptoms of grown-up children and whether the constructive communication patterns of grown-up children and romantic relationships played mediation effects within it. A total of 421 Chinese participants were enrolled in the study. The level of depressive symptoms, romantic relationship satisfaction and closeness, couple communication patterns, and parental romantic relationships were measured via self-report questionnaires. According to the results, the structural equation modeling analysis verified that the severity of participants' depressive symptoms was negatively associated with the parental romantic relationship and that the association was mediated by participants' constructive communication patterns and their own romantic relationships. Furthermore, compared with nondepressed participants, depressed participants were less satisfied with their parental romantic relationships, exhibited fewer constructive communication patterns, and were more distant and unsatisfied with current romantic relationships.

Adverse Childhood Experiences Are Associated With Adult Dream Content: A Cross-Sectional Survey.

Background: Dreams can be affected by recent life events and long-term life experiences. Previous evidence has shown that childhood adverse experiences are associated with sleep quality and dream experiences. Objective: The aim of this study was to explore the relationship between childhood adverse experiences and dream content in adults. Participants and Setting: A total of 163 participants without current or past physical or mental disorders aged between 18 and 35 were screened in the hospital. Among them, 120 subjects who completed a dream content record at home and whose anxiety and depression levels and sleep quality were within the normal range were included in the data analysis. Methods: A cross-sectional survey was conducted from June 2017 to December 2019. Dream content for 10 consecutive days was recorded by the participants and coded by the Hall and Van de Castle coding system. Childhood adversity was assessed by the Childhood Trauma Questionnaire (CTQ). In the end, 719 dreams out of 626 nights for 120 participants (44 female) were included in the data analysis, gender differences between groups were analyzed using t-tests or U tests, and Spearman's partial correlation and multiple linear regression were used to investigate the relationship between childhood trauma and dream content. Results: Childhood adversity was associated with characters, friendly interactions, and objects in dream content. Regression models of childhood adversity predicting characters and objects in dream content were constructed. There were no gender differences in general demographic data, sleep quality, emotional state, childhood adversity, dream recall frequency, or dream content. Conclusion: Childhood adversity is associated with adult dream content.

Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. CDH2 encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell-cell adhesion in a calcium-dependent manner. Deficiency of CDH2 is associated with arrhythmogenic right ventricular cardiomyopathy (OMIM: 618920) and agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (OMIM: 618929). However, there have been no reports of isolated DCM associated with CDH2 deficiency. Methods: We performed whole exome sequencing in a 12-year-old girl with non-syndromic DCM and her unaffected parents. Variants in both known DCM-related genes and novel candidate genes were analyzed and pathogenicity confirmation experiments were performed. Results: No pathogenic/likely pathogenic variant in known DCM-related genes was identified in the patient. We found a de novo variant in a candidate gene CDH2 in the patient, namely, c.474G>C/p.Lys158Asn (NM_001792.5). This variant has not been reported in the ClinVar or Human Gene Mutation Database (HGMD). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with the hydrolysis of the precursor segment and interference with adhesiveness. Furthermore, we tested the expression and efficiency of cell-cell adhesion while overexpressing the CDH2 Lys158Asn mutant and two previously reported variants in CDH2 as positive controls. The adhesion efficiency was considerably reduced in the presence of the mutated CDH2 protein compared with wild-type CDH2 protein, which suggested that the mutated CDH2 protein's adhesion capacity was impaired. The variant was probably pathogenic after integrating clinical manifestations, genetic analysis, and functional tests. Conclusion: We identified a CDH2 variant in DCM. We observed a new clinical symptom associated with N-cadherin deficiency and broadened the genetic spectra of DCM.

Spindle-related brain activation in patients with insomnia disorder: An EEG-fMRI study.

Sleep spindles have been implicated in sleep protection, depression and anxiety. However, spindle-related brain imaging mechanism underpinning the deficient sleep protection and emotional regulation in insomnia disorder (ID) remains elusive. The aim of the current study is to investigate the relationship between spindle-related brain activations and sleep quality, symptoms of depression and anxiety in patients with ID. Participants (n = 46, 28 females, 18-60 years) were recruited through advertisements including 16 with ID, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and 30 matched controls. Group differences in spindle-related brain activations were analyzed using multimodality data acquired with simultaneous electroencephalography and functional magnetic resonance imaging during sleep. Compared with controls, patients with ID showed significantly decreased bilateral spindle-related brain activations in the cingulate gyrus (familywise error corrected p ˂ 0.05, cluster size 4401 mm3). Activations in the cingulate gyrus were negatively correlated with Pittsburgh Sleep Quality Index scores (r = -0.404, p = 0.005) and Self-Rating Anxiety Scale scores (r = -0.364, p = 0.013), in the pooled sample. These findings underscore the key role of spindle-related brain activations in the cingulate gyrus in subjective sleep quality and emotional regulation in ID.