Treatment-resistant depression (TRD) is a major challenge in clinical psychiatry, characterized by insufficient response to at least two different classes of antidepressants. Despite advances in treatment, many TRD patients continue to experience significant symptoms and reduced quality of life. The study aims to provide an exploratory assessment of toludesvenlafaxine hydrochloride sustained-release tablets for efficacy and safety in TRD. We conducted an open-label, single-arm, exploratory 8-week study in adults with TRD (n = 31) receiving Toludesvenlafaxine. The primary endpoint was the change in the Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to week 8. Secondary endpoints included changes in anxiety, quality of life, and functional status, as well as the assessment of safety. Within-group improvements were observed in MADRS scores at weeks 2, 4, and 8 compared with baseline (P < 0.0001), with an average reduction of -13.0 ± 9.6 at week 8. The MADRS response rate (≥ 50

Objective:Agitation represents a serious and prevalent symptomatology within acute schizophrenia. This study aims to conduct a nuanced comparison of the efficacy and safety profiles of intramuscular (IM) ziprasidone versus IM haloperidol in the management of agitation among patients with acute schizophrenia. Methods:This investigation was structured as a randomized, 3-day study, utilizing flexible dosing strategies. It included 69 patients diagnosed with schizophrenia, who were randomly allocated to receive either IM ziprasidone (n = 35, 20 to 40 mg/day) or IM haloperidol (n = 34, 5 to 10 mg/day). The primary endpoints included comparative analyses of the change in Positive and Negative Syndrome Scale (PANSS) total scores and Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores from baseline to study completion across the two groups. Results:At baseline, there were no significant differences between the IM ziprasidone and haloperidol groups. Both treatments led to significant reductions in PANSS-EC total scores (haloperidol, p = 0.001; ziprasidone, p = 0.001) and PANSS total scores (haloperidol, p = 0.001; ziprasidone, p = 0.001) from baseline to study endpoint. Nevertheless, no significant difference was observed between the two groups in terms of changes in PANSS-EC scores (p = 0.312) and PANSS total scores (p = 0.159) from baseline to endpoint. The haloperidol group exhibited a higher incidence of adverse events compared with the ziprasidone group, reaching statistical significance (p = 0.027). Conclusions:Our findings indicate that both medications are equally effective in controlling agitation symptoms. However, ziprasidone exhibited superior characteristics in safety and tolerability, particularly in reducing the incidence of extrapyramidal symptoms. Clinical Trial Registration:The study was registered at https://www.chictr.org.cn/showproj.html?proj=246996, registration number: ChiCTR2500100002, date of registration: 1 April 2025.

Background Recent studies have shown that the excitatory amino acid transporters (EAATs) are associated with schizophrenia. The aim of this study was to investigate the relationship between the polymorphism of EAAT1 and EAAT2 genes and schizophrenia in Chinese Han population. Methods A total of 233 patients with schizophrenia and 342 healthy controls were enrolled. Two SNPs in EAAT1 gene (rs2269272, rs2731880) and four SNPs in EAAT2 gene (rs12360706, rs3088168, rs12294045, rs10836387) were genotyped by SNaPshot. Clinical features were collected using a self-made questionnaire. Psychotic symptoms of patients were measured by the Positive and Negative Syndrome Scale (PANSS), and patients’ cognitive function was assessed by Matrics Consensus Cognitive Battery (MCCB). Results Significant difference in allelic distributions between cases and controls was confirmed at locus rs12294045 ( Ρ = 0.004) of EAAT2 gene. Different genotypes of rs12294045 were associated with family history ( P = 0.046), in which patients with CT genotype had higher proportion of family history of psychosis. The polymorphism of rs12294045 was related to working operational memory (LNS: P = 0.016) and verbal learning function (HVLT-R: P = 0.042) in patients in which CT genotype had lower scores. However, these differences were no longer significant after Bonferroni correction. Conclusions Our study showed that the polymorphism of rs12294045 in EAAT2 gene may be associated with schizophrenia in Chinese Han population. CT genotype may be one of the risk factors for family history and cognitive deficits of patients.

Schizophrenia is ranked among the top 25 leading causes of disability worldwide in 2013 which resulting in social and economic burden. By observing patients with schizophrenia one year before and after switching from oral antipsychotics (OAPs) to once-monthly paliperidone palmitate (PP1M), we can better understand the change of total costs in schizophrenic patients, including direct costs and indirect costs, after switching treatment patterns. A total of 100 schizophrenic (ICD-10) patients from Shandong Mental Health Center were collected from December 2016 to June 2019. Treatment modalities, health care resource utilization and costs were compared before and after switching directly from oral antipsychotics to PP1M. Of the 82 patients included in the main analyses, treatment with PP1M resulted in an increase in direct costs of 31.92% (P < 0.01), an increase in medicine costs of approximately 142% (P < 0.01), and a reduction in hospital costs of 68.15% (P > 0.05). There was no significant increase in total costs (P = 0.25), while 31.92% increase in direct costs (P < 0.01), and 35.62% decrease in indirect costs (P < 0.01) after conversion to PP1M. Compared with before administration of PP1M, patients with ≥ 1 inpatient stay in 1 year Pre-PP1M treatment with OAPs (n = 32) had a 20.16% decrease in direct costs (P < 0.01), a 144% increase in medicine costs (P < 0.01), and a significant 72.02% decrease in hospital costs (P < 0.01). The observed reduction in the number of hospitalizations (t = 2.56, P ≤ 0.01) and inpatient stays (t = 1.73, P < 0.05) and after transition to PP1M resulted in a reduction in hospitalization costs (P < 0.01). Switching from OAPs to PP1M decreased the household workforce burden without increasing clinical healthcare costs. Direct costs were significantly reduced in patients with ≥ 1 inpatient stay in 1 year pre-PP1M treatment with OAPs after the switch, which decreased by improving adherence to therapy and reducing the number and length of hospital stays, suggesting that those patients may benefit after switching to PP1M.

Abstract Background: Inflammatory cytokines are involved in the pathophysiological process of various mental disorders.CRP,Neutrophil/lymphocyte (NLR),monocyte/lymphocyte (MLR),platelet/lymphocyte (PLR) are commonly used and readily available inflammatory markers in clinic，However, their results in Anorexia Nervosa (AN) are few and inconsistent. Methods: We did an exploratory analysis, including (1) comparison of plasma CRP concentration and NLR, PLR, and MLR values in 53 AN patients and 55 healthy controls, and (2) correlation of age,body mass index (BMI),and disease course with CRP concentration and NLR,PLR,and MLR values (after logarithmic transformation).To explore the relationship between malnutrition and inflammatory indicators. Results: The plasma levels of CRP and MLR in AN Patients were significantly lower than those in the normal control group, while NLR and PLR were significantly increased. In all researchers. CRP and MLR were positively correlated with BMI, while NLR and PLR were negatively correlated with BMI. However, such correlation was only correlated with CRP in AN patient, positively correlated with age and BMI, and negatively correlated with the course of disease. Conclusions: The CRP level was negatively correlated with the course of disease in AN patient. The course of disease was independent risk factor for CRP level in AN patients.

Abstract Background: Schizophrenia is ranked among the top 25 leading causes of disability worldwide in 2013 which resulting in social and economic burden. By observing patients with schizophrenia one year before and after switching from oral antipsychotics (OAPs) to once-monthly paliperidone palmitate (PP1M), we can better understand the change of total costs in schizophrenic patients, including direct costs and indirect costs, after switching treatment patterns. Methods: A total of 100 schizophrenic (ICD-10) outpatient and inpatient patients from Shandong Mental Health Center were collected from December 2016 to June 2019. Treatment modalities, health care resource utilization and costs were compared before and after switching directly from oral antipsychotics to PP1M.Results: Of the 82 patients included in the main analyses, hospitalization costs decreased was partly offset by the increase of medical costs, which causing direct costs slightly increased (t=-1.81, P＞0.05). The reduction of productivity costs (t=2.06, P＜0.05) and caregiver care costs (t=1.99, P≤0.05) was seen at post-PP1M switch, therefore the indirect costs also obviously reduced (t=2.31, P＜0.05). Total costs slightly increased (t=-0.05, P＞0.05）compared to pre-PP1M period. For patients with ≥ 1 all-cause inpatient stay in the baseline period (n=32), compared with pre-PP1M, a fewer number of inpatient stays (t=1.73, P＜0.05) and hospitalizations (t=2.56, P≤0.01) were observed and a significant reduction in direct costs (t=2.20, P＜0.01) was observed post-transition to PP1M. Conclusions: Switching to PP1M from OAPs can improve adherence to therapy and not increase the costs of health care in the clinical. Patients with ≥1 recent all-cause inpatient stay had a significant reduction in direct costs after switching from oral antipsychotics to PP1M, suggesting that patients with ≥1 all-cause inpatient stay may benefit after switching to PP1M. Indirect costs decrease from OAPs to PP1M, suggesting that reduce the burden of the family labor after switch to PP1M.

Proteoliposomes mimic the cell membrane environment allowing for structural and functional membrane protein analyses as well as antigen presenting and drug delivery devices. To make proteoliposomes, purified functional membrane proteins are required. Detergents have traditionally been used for the first step in this process. However, they can irreversibly denature or render membrane proteins unstable, and the necessary removal of detergents after reconstitution can decrease proteoliposome yields. The recently developed native cell membrane nanoparticles (NCMN) system has provided a variety of detergent-free alternatives for membrane protein preparation for structural biology research. Here we attempt to employ the MCMN system for the functional reconstitution of channels into proteoliposomes. NCMN polymers NCMNP1-1 and NCMNP7-1, members of a NCMN polymer library that have been successful in extraction and affinity purification of a number of intrinsic membrane proteins, were selected for the purification and subsequent reconstitution of three bacterial channels: KcsA and the mechanosensitive channels of large and small conductance (MscL and MscS). We found that channels in NCMN particles, which appeared to be remarkably stable when stored at 4 °C, can be reconstituted into bilayers by simply incubating with lipids. We show that the resulting proteoliposomes can be patched for electrophysiological studies or used for the generation of liposome-based nanodevices. In sum, the findings demonstrate that the NCMN system is a simple and robust membrane protein extraction and reconstitution approach for making high-quality functional proteoliposomes that could significantly impact membrane protein research and the development of nanodevices.

Background: Neural precursor cell-expressed developmentally downregulated 4 (NEDD4) polymorphisms and childhood trauma (CT) are associated with schizophrenia. However, whether NEDD4 interacts with CT on symptoms of schizophrenia remains unknown. This study aimed to investigate the gene–environment interaction effect.Methods: We recruited 289 schizophrenia patients and 487 controls and genotyped rs2303579, rs3088077, rs7162435, rs11550869, and rs62043855 in their NEDD4 gene.Results: We found significant differences in the rs2303579 and rs3088077 between the two groups. Patients with the rs2303579 CC genotype had higher scores compared with other genotype (P = 0.026) in the test of positive schizophrenia syndrome scores, whereas patients with the rs3088077 TT (P = 0.037) and rs7162435 CC genotypes (P = 0.009) had higher scores compared with the other genotypes in the test of excitement factor. Patients with a family history of psychosis (FH+) reported higher negative scores (P = 0.012) than those without. Patients exposed to physical abuse (PA) reported a lower language learning and memory score (P = 0.017) and working memory score (P = 0.047) than those not. Patients exposed to sexual abuse (SA) reported a lower reasoning and problem-solving skills score (P = 0.025); those exposed to emotional neglect (EN) reported a lower social cognition score (P = 0.044); and those exposed to physical neglect reported a lower social cognition score (P = 0.036) but higher visual learning and memory score (P = 0.032). Rs3088077 could interact with EN to increase risk for schizophrenia. Optimal model rs62043855 × EA, rs3088077 × rs7162435 × rs11550869 × SA × EN and rs2303579 × rs7162435 × rs11550869 × rs62043855 × EA × PA could explain positive symptom, excitement symptom and working memory, respectively, in FH+ group.Conclusion: The study highlighted that the combined interaction of NEDD4 and CT may be associated with symptoms of schizophrenia especially for those with FH+.

Background : Previous studies have linked schizophrenia to EAAT1 and EAAT2 genes. The aim of this study was to investigate the relationship between polymorphism of these two genes and schizophrenia in Chinese Han population. Methods : A total of 233 schizophrenic patients and 342 healthy controls were enrolled. Six SNPs including rs2269272、rs2731880、rs12360706、rs3088168、rs12294045、rs10836387 were genotyped by SNaPshot. Clinical features were collected using a general demographic questionnaire. Symptoms were measured by the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by Matrics Consensus Cognitive Battery (MCCB). Results: The allele frequency of EAAT1 rs2731880 was significantly different between patients and controls ( c2 =4.205, R=0.040). The allele and genotype frequency of EAAT2 rs12294045 were significantly different between case and control group (allele: c 2 = 8.144， R = 0.004; genotype: c 2 = 8.054, R = 0.02). Patients with family history of psychosis were more likely to have the CT genotype of rs12294045 than patients without family history of psychosis，while patients with CT genotype of rs12294045 had significantly lower scores of verbal learning and working memory. Conclusions: The polymorphism of EAAT1 and EAAT2 genes in Chinese Han population may be associated with schizophrenia. The CT genotype of EAAT2 rs12294045 may be one of the risk factors for verbal learning memory and working operational memory dysfunction in patients.

Objective: To investigate the role of serum sex hormone levels (progesterone, testosterone) and heart rate variability (HRV) indicators (SDNN, LF/HF) in women with generalized anxiety disorder (GAD). Methods: A total of 155 female GAD patients admitted to Shandong Mental Health Center were selected as the research group (RG) and all received venlafaxine sustained release tablets. Another 111 female patients who underwent physical examination during the same period were selected as the control group (CG). The progesterone, testosterone, SDNN, LF/HF of the two groups were measured, and the anxiety of the two groups was evaluated by the anxiety self-rating scale (SAS) for analysis. Results: The progesterone, testosterone and standard deviation of NN intervals (SDNN) in the RG were greatly lower than those in the CG, while low-frequency and high-frequency (LF/HF) was the opposite. The area under the curve (AUC) of female GAD diagnosed by progesterone, testosterone, SDNN and LF/HF alone was 0.822, 0.810, 0.826 and 0.803 respectively, and the corresponding AUC of joint diagnosis of progesterone, testosterone combined with SDNN and LF/HF was 0.902, 0.902, 0.900 and 0.906. In the RG, the SAS score was negatively correlated with progesterone, testosterone and SDNN, while it was positively correlated with LF/HF. The post-treatment progesterone, testosterone and SDNN elevated markedly in the RG, while LF/HF was reversed. The AUC of menopause, progesterone, testosterone, SDNN and LF/HF in efficacy prediction of female GAD was 0.869, 0.766, 0.824 and 0.760, and the four were the risk factors affecting the occurrence of female GAD. Conclusion: Serum progesterone and testosterone levels, SDNN, and LF/HF can be used as predictors of diagnosis, anxiety degree, and efficacy of female GAD patients.

Although extracellular force has a profound effect on cell shape, cytoskeleton tension, and cell proliferation through the Hippo signaling effector Yki/YAP/TAZ, how intracellular force regulates these processes remains poorly understood. Here, we report an essential role for spectrin in specifying cell shape by transmitting intracellular actomyosin force to cell membrane. While activation of myosin II in Drosophila melanogaster pupal retina leads to increased cortical tension, apical constriction, and Yki-mediated hyperplasia, spectrin mutant cells, despite showing myosin II activation and Yki-mediated hyperplasia, paradoxically display decreased cortical tension and expanded apical area. Mechanistically, we show that spectrin is required for tethering cortical F-actin to cell membrane domains outside the adherens junctions (AJs). Thus, in the absence of spectrin, the weakened attachment of cortical F-actin to plasma membrane results in a failure to transmit actomyosin force to cell membrane, causing an expansion of apical surfaces. These results uncover an essential mechanism that couples cell shape, cortical tension, and Hippo signaling and highlight the importance of non-AJ membrane domains in dictating cell shape in tissue morphogenesis.

All membrane proteins have dynamic and intimate relationships with the lipids of the bilayer that may determine their activity. Mechanosensitive channels sense tension through their interaction with the lipids of the membrane. We have proposed a mechanism for the bacterial channel of small conductance, MscS, that envisages variable occupancy of pockets in the channel by lipid chains. Here, we analyze protein–lipid interactions for MscS by quenching of tryptophan fluorescence with brominated lipids. By this strategy, we define the limits of the bilayer for TM1, which is the most lipid exposed helix of this protein. In addition, we show that residues deep in the pockets, created by the oligomeric assembly, interact with lipid chains. On the cytoplasmic side, lipids penetrate as far as the pore-lining helices and lipid molecules can align along TM3b perpendicular to lipids in the bilayer. Cardiolipin, free fatty acids, and branched lipids can access the pockets where the latter have a distinct effect on function. Cholesterol is excluded from the pockets. We demonstrate that introduction of hydrophilic residues into TM3b severely impairs channel function and that even “conservative” hydrophobic substitutions can modulate the stability of the open pore. The data provide important insights into the interactions between phospholipids and MscS and are discussed in the light of recent developments in the study of Piezo1 and TrpV4.

Background Schizophrenia is a complex psychiatric disorder with unknown etiology. A number of recent studies have shown that the polymorphism of the neural precursor cell expressed developmentally down-regulated 4 ( NEDD4 ) gene is associated with a variety of neuropsychiatric disorders, such as schizophrenia, and may also be associated with cognitive dysfunction in these diseases. Methods A case-control study was carried out, the alleles and genotypes distributions of five loci (rs3088077, rs2303579, rs7162435, rs11550869, rs62043855) of the NEDD4 gene from 296 schizophrenia patients and 320 healthy controls were detected by using Taqman single-nucleotide polymorphism (SNP) genotyping technology. The clinical data of case and control group members were collected by self-made questionnaire and the psychotic symptoms of case group members were assessed by the Positive and Negative Syndrome Scale (PANSS). The Matrics Consensus Cognitive Battery (MCCB) was used to test the cognitive function of case group members. Results The alleles and genotypes frequency of two loci (rs3088077, rs2303579) between case and control group showed significant differences ( P < 0.05). There was no significant difference in MCCB scores of patients with different genotypes at rs3088077, rs11550869 and rs7162435 loci in case group. The study of rs2303579 locus showed that, patients’ scores with CT genotype were significantly lower than those with CC and TT genotypes ( P < 0.05) in the test of Wechsler Memory Scale-Third Edition (WMS-III): Spatial Span, the scores of patients with TT genotype were significantly higher than those with CT genotype ( P < 0.05) in the test of Hopkins Verbal Learning Test-Revised (HVLT-R). The study of rs62043855 locus showed that patients with TG genotype had significantly lower scores than those with GG genotype ( P < 0.05) in the test of Neuropsychological Assessment Battery (NAB): Mazes. Conclusions Our study showed that in schizophrenia patients of Chinese Han population, the polymorphisms of rs3088077 and rs2303579 loci were related to the pathogenesis of schizophrenia, while the polymorphisms of rs2303579 and rs62043855 loci were associated with cognitive dysfunction.

Abstract The gene – environment (G × E) interaction effect is involved in severe mental disorders. However, whether the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism participates in the childhood-abuse influenced schizophrenic symptoms remains unclear. We examined the interaction between BDNF Val66Met, and childhood trauma (ChT) on psychotic symptoms in a Chinese Han population. To estimate the G × E interaction, psychiatric interviews, self-report questionnaires for ChT, and genotyping for BDNF Val66Met were carried out on 201 schizophrenic patients. G × E interactions were analyzed by generalized multifactor dimensionality reduction (GMDR). Among all patients, 11.9%, 19.4%, 23.4%, 26.4%, and 73.6% reported emotional abuses, physical abuses (PA), sexual abuses (SA), emotional neglects (EN), and physical neglects (PN), respectively. Significant negative correlations were observed between anxiety/depression factors, and ChT total scores. Patients with 3 different BDNF genotypes showed significant differences in anxiety/depression scores. Significant 2-way interactions were found for Val66Met × PN, 3-way interactions were found for Val66Met × PN × PA, and four-way interactions were found for Val66Met × PN × PA × EN with regard to the excitement scores. Our findings suggested an involvement of BDNF Val66Met polymorphism after ChT in terms of risk for schizophrenia symptoms.

The epithelial Na+ channel (ENaC) is a heteromeric channel composed of three subunits (α, β, γ). At the C-terminus of each subunit, a PY-motif allows binding of the ubiquitin ligase Nedd4-2 which plays a key role in promoting ENaC retrieval from the plasma membrane. Phosphorylation of Nedd4-2 by the serum and glucocorticoid-inducible kinase 1 (Sgk1) reduces Nedd4-2 binding to the PY-motifs. In β and γENaC, threonine residues (βT613, γT623) belong to an extracellular signal-regulated kinase (ERK) motif and directly precede the PY-motifs. Thus, phosphorylation of these residues may modulate the interaction of their adjacent PY-motifs with Nedd4-2. In this study, a phosphospecific antibody was used to demonstrate phosphorylation of βT613 in Xenopus laevis oocytes heterologously expressing rat αβγENaC. Treating the oocytes with progesterone to stimulate ERK increased phosphorylation of βT613. Inactivation of the putative phosphorylation sites by mutating both threonine residues to alanine (βT613A/γT623A) increased ENaC-mediated amiloride-sensitive whole-cell currents (ΔIami) and expression of βENaC at the cell surface. Co-expression of Nedd4-2 largely reduced ΔIami in oocytes expressing αβγENaC or channels with mutated PY-motifs in α and γENaC or in α and βENaC. Importantly, the inhibitory effect of co-expressed Nedd4-2 was largely reduced in channels with mutated PY-motifs in α and γENaC when combined with the βT613A mutation but conserved in channels with mutated PY-motifs in α and βENaC combined with the γT623A mutation. These results suggest that phosphorylation and dephosphorylation of βT613 play a prominent role in regulating Nedd4-2-mediated ENaC retrieval from the plasma membrane.

The ability to reversibly and non-invasively modulate region-specific brain activity in vivo suggests Low Intensity Focused Ultrasound (LIFU) as potential therapeutics for neurological dysfunctions such as epilepsy and Parkinson's disease. While in vivo studies provide evidence of the bioeffects of LIFU on neuronal activity, they merely hint at potential mechanisms but do not fully explain how this technology achieves these effects. One potential hypothesis is that LIFU produces local membrane depolarization by mechanically perturbing the neuronal cell membrane, or activating channels or other proteins embedded in the membrane. Proteins that sense mechanical perturbations of the membrane, such as those gated by membrane tension, are prime candidates for activating in response to LIFU and thus leading to the neurological responses that have been measured. Here we use the bacterial mechanosensitive channel MscL, which has been purified and reconstituted in liposomes, to determine how LIFU may affect the activation of this membrane-tension gated channel. Two bacterial voltage-gated channels, KvAP and NaK2K F92A channels were also studied. Surprisingly, the results suggest that ultrasound modulation and membrane perturbation does not induce channel gating, but rather induces pore formation at the membrane protein-lipid interface. However, in vesicles with high MscL mechanosensitive channel concentrations, apparent decreases in pore formation are observed, suggesting that this membrane-tension-sensitive protein may serve to increase the elasticity of the membrane, presumably because of expansion of the channel in the plane of the membrane independent of channel gating.

MscL is a bacterial mechanosensitive channel that serves as a cellular emergency release valve, protecting the cell from lysis upon a drop in external osmolarity. The channel has an extremely large pore (30 Å) and can be purified and reconstituted into artificial membranes. Moreover, MscL is modified to open in response to alternative external stimuli including changes in pH. These properties suggest this channel's potential as a triggered "nanopore" for localized release of vesicular contents such as magnetic resonance imaging (MRI) contrast agents and drugs. Toward this end, several variants of pH-triggered MscL nanovalves are engineered. Stealth vesicles previously been shown to evade normal in vivo clearance and passively accumulate in inflamed and malignant tissues are reconstituted. These vesicles are loaded with 1,4,7,10-tetraazacyclododecane tetraacetic acid gadolinium complex (Gd-DOTA), an MRI contrast reagent, and the resulting nanodevices tested for their ability to release Gd-DOTA as evidenced by enhancement of the longitudinal relaxation rate (R1 ) of the bulk water proton spins. Nanovalves that are responsive to physiological pH changes are identified, but differ in sensitivity and efficacy, thus giving an array of nanovalves that could potentially be useful in different settings. These triggered nanodevices may be useful in delivering both diagnostic and therapeutic agents.

MscL, the highly conserved bacterial mechanosensitive channel of large conductance, is one of the best studied mechanosensors. It is a homopentameric channel that serves as a biological emergency release valve that prevents cell lysis from acute osmotic stress. We previously showed that the periplasmic region of the protein, particularly a single residue located at the TM1/periplasmic loop interface, F47 of Staphylococcus aureus and I49 of Escherichia coli MscL, plays a major role in both the open dwell time and mechanosensitivity of the channel. Here, we introduced cysteine mutations at these sites and found they formed disulfide bridges that decreased the channel open dwell time. By scanning a likely interacting domain, we also found that these sites could be disulfide trapped by addition of cysteine mutations in other locations within the periplasmic loop of MscL, and this also led to rapid channel kinetics. Together, the data suggest structural rearrangements and protein-protein interactions that occur within this region upon normal gating, and further suggest that locking portions of the channel into a transition state decreases the stability of the open state.

Background Although several lines of evidences suggest that the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be involved in the pathophysiology of schizophrenia, this association remains controversial. Here, we aim to investigate the genetic association between the BDNF Val66Met polymorphism and schizophrenia and to explore whether this polymorphism could influence the severity of clinical symptoms in schizophrenic patients in a Chinese Han population. Patients and methods Genotyping of the BDNF Val66Met polymorphism was carried out in 456 schizophrenic patients and 483 controls using the fluorescence resonance energy transfer method. The patients’ psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. The general clinical data of schizophrenic patients were analyzed. Results There were significant differences in the genotype distribution and allelic frequencies of the BDNF Val66Met polymorphism between the schizophrenia group and the controls. Multiple linear regression analysis showed that the BDNF Val66Met polymorphism explained ∼16% of the variance in anxiety/depression symptoms in schizophrenic patients. Conclusion Our data provide evidence that the BDNF Val66Met polymorphism may be involved in the etiology of schizophrenia in a Chinese Han population. Furthermore, the BDNF Val66Met polymorphism is a significant factor influencing the severity of anxiety/depression symptoms in schizophrenic patients.