[Genetic analysis of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 due to variant of PIGN gene].

OBJECTIVE: To analyze the clinical phenotype and genetic etiology of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). METHODS: Clinical data of a 2-year-old boy who had presented at the Affiliated Hospital of Qingdao University in March 2023 for "intermittent limb twitching for 2 years" was collected. Peripheral blood samples were collected from the child and his parents for whole-exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The child had manifested with distinctive facial features, limb deformities, hypotonia, motor and intellectual delays, and epileptic seizures. WES revealed that he has harbored compound heterozygous variants of the PIGN gene, namely c.963G>A (p.Q321=) and c.994A>T (p.I332F), which were inherited from his phenotypically normal mother and father, respectively. Based on the ACMG guidelines, the c.963G>A was classified as a pathogenic variant (PVS1+PM2_Supporting+PM3), whilst the c.994A>T was classified as a variant of uncertain significance (PM2_Supporting+PP3). CONCLUSION: Above discovery has expanded the mutational spectrum of the PIGN gene variants associated with MCAHS1, which may facilitate delineation of its genotype-phenotype correlation.

Controlling Conjugated Antibodies at the Molecular Level for Active Targeting Nanoparticles toward HER2-Positive Cancer Cells.

For active targeting nanodrug delivery systems conjugated with antibodies, both lack of control of the antibody at the molecular level and protein corona formation remarkably decreases targeting efficacy. Herein, we designed a series of silica nanoparticles toward HER2-positive breast cancer cells, with an anti-HER2 Fab-6His density ranging from 50 to 180 molecules per nanoparticle. Through the site-directed immobilization method we developed, the antigen-binding domain of anti-HER2 Fab was mostly accessible to the HER2 receptor. Both polyethylene glycol (PEG) chains and a high density of Fab were shown to suppress protein corona formation and macrophage uptake. The dependency of targeting efficacy and cytotoxicity on Fab density was shown using a series of breast cancer cell lines with different levels of the HER2 expression. The high density of Fab stimulates quick responses from HER2-positive cells. Combined with PEG chains, conjugated antibodies with a well-controlled orientation and density significantly improves delivery performance and sheds light on the design and preparation of an improved active targeting nanodrug delivery system.

Efficacy and safety of escitalopram in treatment of severe depression in Chinese population.

Severe depression accounts for one-third of depressed patients. Increasing severity of depression usually hinders patients from achieving remission. This study evaluated the efficacy and safety of escitalopram in acute-phase treatment of severe major depressive disorder (MDD). A total of 225 participants with severe MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria), with a current depressive episode and Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥30 were enrolled. Participants received flexible dose escitalopram (10-20 mg/d) treatment for 8 weeks. Symptoms status was assessed by MADRS, Hamilton Depression Rating Scale (HAM-D-17), and Hamilton Anxiety Rating Scale (HAM-A). Quality of life was assessed by Short Form-12 (SF-12) and safety by adverse events, laboratory investigations, vital signs and physical findings. The remission (MADRS total score ≤ 10) rate in the intent-to-treat set (n = 207) was 72.9% at week 8. Significant improvement in symptoms compared to baseline, as evaluated by MADRS, HAMD-17 and HAMA scores at baseline, week 1, week 2, week 4, and week 8 (p < 0.0001 for all), was noted. Mean (SD) reduction from baseline in MADRS total score was 26.6 (11.38). Improvements in SF-12 score were significant (p = 0.000) and positively related to symptom improvement and negatively related to treatment-emergent adverse events (TEAEs). TEAEs were reported in 28.38% of participants. Most common TEAEs (>4%) were somnolence (9.0%), nausea (7.7%), hyperhidrosis (4.5%), dry mouth and dizziness (4.1% each). No serious TEAEs were reported. Escitalopram was effective and well-tolerated for acute-phase treatment of severe depression in Chinese population.

Relationship between intestinal flora, inflammation, BDNF gene polymorphism and generalized anxiety disorder: A clinical investigation.

INTRODUCTION: Understanding factors related to generalized anxiety disorder pathogenesis is critical for elucidating the mechanism and preventing its establishment. Intestinal flora and hereditary factors such as brain-derived neurotrophic factor (BDNF) gene polymorphism may have a role in the development of generalized anxiety disorder. This work explored the relationship between intestinal flora, inflammatory changes and BDNF gene polymorphisms and the occurrence of generalized anxiety disorder. METHODS: Forty-eight patients with generalized anxiety disorder and 57 healthy people were included in the study. As the disease group and control group, the polymorphisms of rs10767664 and rs7124442 of the BDNF gene, differences in the distribution of intestinal flora, and changes in inflammatory and immune indicators were analyzed. RESULTS: The distribution of BDNF gene alleles, genotypes and haplotypes in the disease group were different from those in the control group. The levels of TNF-α (P = .000), interleukin-4 (P = .000), interleukin-10 (P = .043) and IgG (P = .008) in patients with generalized anxiety disorder in the disease group were different from those in the control group. The distribution of gut microbes in patients with generalized anxiety disorder in the disease group was different from that in the control group. CONCLUSION: The onset of generalized anxiety disorder is related to BDNF gene polymorphism, and is accompanied by changes in intestinal flora and inflammatory immune status in the body.

ASH1L may contribute to the risk of Tourette syndrome: Combination of family-based analysis and case-control study.

OBJECTIVE: Tourette syndrome (TS) is a childhood neurodevelopmental disorder caused by various genetic and environmental factors and presents with apparent genetic heterogeneity. As ASH1L potentially contributes to neurodevelopmental diseases, especially in TS, we aim to investigate the susceptibility of ASH1L on TS in the Chinese Han population. METHODS: Three tag single nucleotide polymorphisms (SNPs) (rs5005770, rs12734374, and rs35615695) in ASH1L were screened in 271 TS nuclear family trios and 337 healthy subjects by the TaqMan assays real time. A case-control study combined with family-based analysis was applied to study the genetic susceptibility of common variants of ASH1L. RESULTS: The results revealed a significant over-transmission of rs35615695 and rs5005770 (for rs35615695, transmission disequilibrium test, χ2  = 57.375, p = .000, HHRR, χ2  = 4.807, p = .028; for rs5005770, HRR, χ2  = 4.116, p = .042, HHRR, χ2  = 8.223, p = .004) in family-based study. Furthermore, rs5005770 and rs35615695 still remained significant after Bonferroni correction (p < .017). However, the two SNPs (rs5005770 and rs35615695) were found not to be associated with TS in case-control study. CONCLUSIONS: Our study suggests that ASH1L may contribute to TS susceptibility in the Han Chinese population and involved in TS development as a risk factor.

MicroRNA-345-5p regulates depression by targeting suppressor of cytokine signaling 1.

BACKGROUND/AIMS: MicroRNA(miR)-345-5p plays a key role in various cellular functions. However, the function of miR-345-5p in resistant depression (TRD) is unclear. The aim of this study was to evaluate the role and mechanism of miR-345-5p in the treatment of resistance depression (TRD). METHODS: RT-qPCR was used to detect the expression of miR-345-5p in BV-2 microglia. CCK-8 method and flow cytometry were used for cell viability and apoptosis of microglia. Target gene prediction and screening, and luciferase reporter assays were used to verify the downstream target gene of miR-345-5p. Western blot was used to analyze the protein expression of related proteins. RESULTS: miR-345-5p increased the cell viability of BV-2 microglia and the expression level of pro-inflammatory cytokines. In addition, the conditioned medium of microglia treated with miR-345-5p reduced the cell viability of HT22 hippocampal cells and caused S-phase arrest. The miR-345-5p-treated microglia induced apoptosis by regulating the expression levels of Bax, Bcl-2, pro-caspase-3, and cleaved caspase-3. Furthermore, SOCS1 was a direct target of miR-345-5p, and overexpression of SOCS1 was able to reverse the proapoptotic effect of miR-345-5p on activation of microglia on hippocampal neurons. CONCLUSION: miR-345-5p induced inflammatory damage in hippocampal neurons by activating microglia. MiR-345-5p may be an effective target for TRD therapy.

Excitatory transmission from ventral pallidum to lateral habenula mediates depression.

Objectives: Lateral habenula (LHb) is a key brain structure for mediating behavioural responses to aversive stimuli. It receives presynaptic inputs from ventral pallidum (VP) which relates to reward, motivation and hedonics. This study investigated the role of glutamatergic VP-LH projection in negative emotions and depression-like behaviour.Methods: The glutamatergic VP-LHb circuits in Vglut2-Cre mice were activated or inhibited using optogenetic manipulation. Real time place aversion test was performed to access aversive behaviour. Mice underwent chronic social defeat stress or subthreshold social defeat stress paradigm. Then social interaction test and tail suspension test were carried out to evaluate the stress-induced depression-like behaviours.Results: Activation of VP-LHb glutamatergic projections induced aversive behaviour in the real time place aversion test. Activation of this circuit induced depressive-like phenotype after social stress, while optogenetic inhibition of this circuit exerted an antidepressant effect in social stress susceptible mice. Local LHb ketamine administration rescued the depression-like phenotype caused by activation of this circuit.Conclusions: Data from our study demonstrated an involvement of the glutamatergic VP-LHb circuit in the stress-induced depression-related behaviours.

RasGRF1 participates in the protective effect of tanshinone IIA on depressive like behaviors of a chronic unpredictable mild stress induced mouse model.

Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aß25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28 days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10 mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1ß and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1-/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1.

Family-Based Analysis Combined with Case-Controls Study Implicate Roles of PCNT in Tourette Syndrome.

OBJECTIVE: Tourette syndrome (TS) is a childhood-onset neuro-developmental disorder and the genetic factors play an important role in its etiology. As pericentrin (PCNT) binds to disruption-in-schizophrenia 1 (DISC1) and is a risk factor for many mental illnesses, we aimed to investigate the effect of PCNT on TS in the Chinese Han population. METHODS: Five tag single nucleotide polymorphisms (SNPs) (rs17371795, rs2839227, rs2839228, rs6518291 and rs9983522) in PCNT were screened in 407 TS nuclear family trios and 506 healthy persons by the TaqMan assays real-time. A common case-control study was designed to recognize differences in the genetic distributions. Additionally, we conducted a family based association study including transmission disequilibrium test, haplotype relative risk, and haplotype-based haplotype relative risk for these SNPs. RESULTS: The allele frequencies revealed a significant difference of rs17371795, rs2839227 and rs2839228 between TS patients and controls (for rs17371795: P=0.002, OR=0.691, 95% CI=0.547-0.874; for rs2839227: P=0.001, OR=0.682, 95% CI=0.540-0.860; for rs2839228: P=0.028, OR=0.775, 95% CI=0.618-0.973) and genotypic distributions showed a positive association only in rs17371795 and rs2839227 (for rs17371795: P=0.010; for rs2839227: P=0.008). Moreover, only rs2839227 remained significant after Bonferroni correction (P<0.01). CONCLUSION: Our study suggested genetic variability at the PCNT locus may be associated with TS risk in the Chinese Han population.

Smoking and major depressive disorder in Chinese women.

OBJECTIVE: To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers. METHODS: We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status. RESULTS: Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence. CONCLUSIONS: Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.

Suicidal risk factors of recurrent major depression in Han Chinese women.

The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.

S100B gene polymorphisms predict prefrontal spatial function in both schizophrenia patients and healthy individuals.

Animal studies have strongly implicated a role of S100B in spatial ability and our recent study of humans found that S100B gene polymorphisms (rs9722, rs1051169, and rs2839357) were associated with schizophrenia patients' spatial ability (as assessed by a block design task and a mental rotation task). In this study, we explored the associations between these and three additional SNPs in S100B and prefrontal functions (working memory and executive control) among 434 schizophrenia patients and 412 healthy controls. Results showed that, for both schizophrenia patients and healthy controls, two SNPs were significantly associated with prefrontal functions in the spatial domain (P value threshold was set at 0.014 after correcting for multiple comparisons), with the AA genotype of rs9722 and the GG genotype of rs2839357 linked to poorer performance. No SNP was associated with prefontal functions in the verbal domain (all Ps >0.05). These results extend our previous study and further confirm the important roles of the S100B gene in spatial abilities.