Author Correction: Structure of human GABAB receptor in an inactive state.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structure of human GABAB receptor in an inactive state.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Symmetric activation and modulation of the human calcium-sensing receptor.

The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.

Characteristics and influencing factors of social isolation in patients with breast cancer: a latent profile analysis.

PURPOSE: The goal of this study is to investigate the social isolation (SI) subtypes of patients with breast cancer (BC) and to explore its influencing factors. METHODS: A sample of 303 BC patients participated in the study from September to December, 2021. Latent profile analysis (LPA) was performed to identify SI clusters based on the three sub-scales of the Chinese version of the Social Anxiety Scale, the Chinese version of the Social Avoidance and Distress Scale, and the Chinese version of the Loneliness Scale. RESULTS: We found that SI can be divided into three categories: high-level (Class 1), middle-level (Class 2), and low-level (Class 3), accounting for 20.46%, 33.00%, and 46.54%, respectively. Compared to Class 3, Class 1, which had the lower average monthly income per family member (RMB) (< 3000: OR = 5.298, P = .021; 3000 ~ 5000: OR = 5.320, P = .018), was more likely to suffer from SI due to occupation (Laborer: OR = 12.023, P = .009). Surgery (OR = 14.138, P < .001; OR = 2.777, P = .020), chemotherapy (OR = 10.224, P = .001; OR = 3.545, P = .001); poorer family functioning (OR = .671, P < .001; OR = .801, P = .002), and lower levels of self-transcendence (OR = .806, P < .001; OR = .911, P < .001) were important influencing factors for SI in Class 1 and Class 2 compared to Class 3. CONCLUSION: SI is classifiably heterogeneous among patients with BC. Strategies that identify characteristics of SI and give targeted intervention focusing on family functioning and improving self-transcendence levels contribute to the prevention of SI among patients with BC.

Relationship of sleep-quality and social-anxiety in patients with breast cancer: a network analysis.

BACKGROUND: There is a complex relationship between social anxiety and sleep quality. However, network analysis studies of associations between social anxiety and sleep quality are lacking, particularly among patients with breast cancer. The current study aimed to extend this research to a sample of patients with breast cancer and to examine symptom-level associations between social anxiety and sleep quality using network analysis. METHODS: Network analysis was conducted to explore their associations and identify bridge items of social anxiety and sleep quality. RESULTS: The network structure revealed 9 important edges between social anxiety and sleep quality. "Subjective sleep quality" had the highest EI value in the network. "Working difficulty under watching" and "Sleep disorders" had the highest BEI values in their own communities. CONCLUSION: There are complex pathological correlation pathways between social anxiety and sleep quality in breast cancer patients. "Subjective sleep quality", "Working difficulty under watching" and "Sleep disorders" have the potential to be intervention targets for sleep disorder-social anxiety comorbidity. Medical staff can take corresponding interventions according to the the centrality indices and bridge centrality indicators identified in this study, which is likely to effectively reduce the comorbidity of sleep disorders and social anxiety.

Effectiveness of three exercise programs and intensive follow-up in improving quality of life, pain, and lymphedema among breast cancer survivors: a randomized, controlled 6-month trial.

PURPOSE: Postoperative complications of breast cancer (BC) seriously affect the quality of life (QOL) of survivors. Physical activity is related to prevention of complications and improvement of QOL. Follow-up can keep patients motivated to exercise. This study aimed to (1) compare the effect of three exercise programs on lymphedema, pain, and QOL in BC patients and (2) explore the effect of intensive follow-up on the outcomes of exercise programs. METHODS: A single-blind randomized parallel controlled trial with a 6-month intervention was carried out in China in 2021. The study sample included 200 women with BC. The patients were randomly divided into 4 groups. G0 (control group) was joint mobility exercise (JME) group; G1 was joint mobility exercise + intensive follow-up (IF) group; G2 was JME + aerobic exercise (AE) + IF group; and G3 was JME + progressive resistance exercise (PRE) + IF group. Outcome measures were evaluated at baseline (T1), 3 months post-intervention (T2), and 6 months post-intervention (T3). The following instruments and measurements were administered before and after the intervention: the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument, the numerical rating scale (NRS), and the relative volume change (RVC). Verificating aim 1 is by comparing the results of G1, G2, and G3, and verificating aim 2 is achieved by comparing G0 and G1. Differences before and after the intervention were determined by analysis of variance of repeated measures and Kruskal-Wallis nonparametric analysis of variance. RESULTS: Among the exercise programs, JME + PRE + IF resulted in the best improvement in QOL (T2: ΔG3-G0 = 13.032, P = 0.008; T2: ΔG3-G1 = 13.066, P < 0.001; ΔG3-G0 = 17.379, P < 0.001). For pain relief, JME + AE + IF had the best improvement (T3: ΔG2-G1 = - 0.931, P = 0.010; ΔG2-G0 = - 1.577, P < 0.001). For the prevention of lymphedema, JME + AE + IF (Z = 2.651, P = 0.048) and JME + PRE + IF (Z = 3.277, P = 0.006) had the similar effect, but JME + PRE + IF is better than JME + AE + IF. CONCLUSION: JME + PRE have the best effect in improving the QOL and preventing lymphedema after surgery. In improving pain, the effect of JME + AE appears earlier, and the overall effect of JME + PRE is better. In addition, long-term and planned monitoring and follow-up are also important.

The social support, psychological resilience and quality of life of nurses in infectious disease departments in China: A mediated model.

AIM: This paper aimed to investigate the relationship between social support and quality of life for nurses in infectious disease departments in China, as well as the function of psychological resilience in mediating this relationship. BACKGROUND: Nurses in infectious disease departments play a critical role in the prevention and control of infectious diseases and in public health care services in general, and their quality of life can affect the quality of clinical nursing work they do. However, there are few studies on the relationship between nurses' social support networks and their quality of life. METHODS: A cross-sectional study was conducted using a sample of 866 clinical nurses from the infectious disease departments of 10 general hospitals in China. Data were collected using a questionnaire survey from January to May 2021. The mediating influence of psychological resilience on social support and quality of life was investigated using structural equation modelling. RESULTS: The score of quality of life was (36.36 ± 7.64). Quality of life was positively correlated with social support and psychological resilience (r1 = 0.521, r2 = 0.583; p < .01), and psychological resilience was positively correlated with social support (r = 0.426; p < .01) as well. The mediating effect of psychological resilience between social support and quality of life was 0.233, accounting for 37% of the total effect. CONCLUSION: The quality of life of nurses working in infectious disease departments is in the middle level. Psychological resilience is a mediating variable between social support and quality of life. IMPLICATIONS FOR NURSING MANAGEMENT: Managers can improve the quality of life of nurses by both increasing social support and strengthening psychological resilience. Managers should pay attention to the degree of social support provided to nurses and take proactive measures to build psychological resilience so that nurses can effectively manage stress and negative emotions from work and life in order improve their quality of life.

Career identity and career success among Chinese male nurses: The mediating role of work engagement.

AIM: This study aimed to investigate the effect of career identity on career success among Chinese male nurses and to examine the mediating role of work engagement in this relationship. BACKGROUND: Recently, with the development of the nursing career, male nurses take up a higher share and play a more important role in the nursing team. With its own particularity and advantages, this group's stability closely relates to the future of the nursing team. Therefore, promoting the career success of the male nurses is essential to the nursing team development. METHODS: The data were collected in China. A sample of 557 male nurses completed measures of career identity, work engagement and career success scale. Structural equation model was adopted to verify the research hypotheses. RESULTS: Career identity was significantly and positively related to male nurses' work engagement and career success (p < .01). And work engagement partially mediated the association between career identity and career success. CONCLUSION: Career identity is critical to predicting and enhancing male nurses' career success. Work engagement plays an intervening mechanism explaining how career identity promotes career success among male nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing management should minimize the impact of the traditional concept, implement the gender equality and provide moderate care for male nurses to facilitate balanced development of gender by upgrading the management system. The administrators should carry out skill training based on male nurses' features and the need of the department. Given full play to their respective advantages, male nurses will make great progress in professional development and achieve greater career identity and work engagement. Meanwhile, the further exploration of better incentive mechanism also makes sense in improving career identity and work engagement by the reform of performance appraisal mechanism and salary adjustment according to their ability.

Effects of co-exposure to lead and manganese on learning and memory deficits.

Lead (Pb) and manganese (Mn) are common neurotoxins. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats were given ad libitum access to drinking water solutions containing Pb (100 mg/L), Mn (2.5 mg/mL) or a mixture, and each treatment had its own minocycline (50 mg/(kg•day)) supplement group. The results showed a significant difference in spatial memory and induction levels of hippocampal long-term potentiation (LTP) in all exposure groups when compared with controls. The combined-exposure group exhibited the most pronounced effect when compared with each of the single-metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5, accompanied by decreased expression levels of GLAST, GLT-1, and GS. Furthermore, the levels of glutamate in the synaptic cleft increased significantly. When microglial activation was inhibited by minocycline, the activation of astrocytes and the expression of GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment, hippocampal LTP impairment and cognitive injury were significantly alleviated in each of the exposure groups. These results suggest that combined exposure to Pb and Mn can cause greater effects on cognition and synaptic plasticity when compared to single-metal exposure groups. The reason may involve abnormal activation of microglia leading to excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and leading to perturbed cognition and synaptic plasticity.

Association of serum Gasdermin D with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti-NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti-NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow-up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti-NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti-NMDAR encephalitis than in healthy controls (p = 0.002, padjusted  = 0.009), especially in males (p = 0.001, padjusted  = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = -0.419 and -0.426, p = 0.011 and 0.012, respectively). Furthermore, 3-month follow-up evaluation revealed that after treatment, anti-NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = -0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti-NMDAR encephalitis and are associated with disease prognosis.

Effects of a 4-week Omaha System transitional care programme on rheumatoid arthritis patients' self-efficacy, health status, and readmission in mainland China: A randomized controlled trial.

BACKGROUND AND AIM: To our knowledge, the practice of transitional care was not common in mainland China. This study was designed to test the intervention effects of a specific dose (4 weeks) of an Omaha-based system transitional care programme for Chinese patients suffering from rheumatoid arthritis. METHODS: The intervention group adopted a 4-week nurse-led transitional care intervention based on the Omaha System. The control group used a comparable length of routine care. The outcome indexes were a Chinese version of the Arthritis Self-Efficacy Scale-8, Health Assessment Questionnaire-Disability Index, and hospital readmission rates. Data were collected from June 2018 to December 2018. RESULTS: Finally, 88 patients (44 in the intervention group and 44 in the control group) entered the data analysis. Baseline sociodemographic data for both groups were not found to be statistically significant. The self-efficacy and HAQ-DI of the intervention group were significantly different from the control group. Although the readmission rates of the intervention group were lower than that of the control group, it was not statistically significant. CONCLUSIONS: This 4-week transitional care intervention dose is sufficient to provide evidence for improving self-efficacy to implement disease management and enhancing physical function of patients diagnosed with rheumatoid arthritis.

Structure of the nonameric bacterial amyloid secretion channel.

Various strains of bacteria are able to produce a unique class of functional amyloids termed curli, which are critical for biofilm formation, host cell adhesion, and colonization of inert surfaces. Curli are secreted via the type VIII bacterial secretion system, and they share biochemical and structural characteristics with amyloid fibers that have been implicated in deleterious disease in humans. Here, we report the crystal structure of Escherichia coli CsgG, which is an essential lipoprotein component of the type VIII secretion system and which forms a secretion channel in the bacterial outer membrane for transporting curli subunits. CsgG forms a crown-shaped, symmetric nonameric channel that spans the outer membrane via a 36-strand ß-barrel, with each subunit contributing four ß-strands. This nonameric complex contains a central channel with a pore located at the middle. The eyelet of the pore is ∼12 Å in diameter and is lined with three stacked nine-residue rings consisting of Tyr-66, Asn-70, or Phe-71. Our structure-based functional studies suggest that Tyr-66 and Phe-71 residues function as gatekeepers for the selective secretion of curli subunits. Our study describes in detail, to our knowledge, the first core structure of the type VIII bacterial secretion machinery. Importantly, our structural analysis suggests that the curli subunits are secreted via CsgG across the bacterial outer membrane in an unfolded form.

Structural and functional analysis of the ß-barrel domain of BamA from Escherichia coli.

In gram-negative bacteria, the assembly of outer membrane proteins (OMPs) requires a ß-barrel assembly machinery (BAM) complex, of which BamA is an essential and evolutionarily conserved component. To elucidate the mechanism of BamA-mediated OMP biogenesis, we determined the crystal structure of the C-terminal transmembrane domain of BamA from Escherichia coli (EcBamA) at 2.6 Å resolution. The structure reveals 2 distinct features. First, a portion of the extracellular side of the ß barrel is composed of 5 markedly short ß strands, and the loops stemming from these ß strands form a potential surface cavity, filled by a portion of the L6 loop that includes the conserved VRGF/Y motif found in the Omp85 family. Second, the 4 extracellular loops L3, L4, L6, and L7 of EcBamA form a dome over the barrel, stabilized by a salt-bridge interaction network. Functional data show that hydrophilic-to-hydrophobic mutations of the potential hydrophilic surface cavity and a single Arg547Ala point mutation that may destabilize the dome severely affect the function of EcBamA. Our structure of the EcBamA ß barrel and structure-based mutagenesis studies suggest that the transmembrane ß strands of OMP substrates may integrate into the outer membrane at the interface of the first and last ß strands of the EcBamA barrel, whereas the soluble loops or domains may be transported out of the cell via the hydrophilic surface cavity on dislocation of the VRGF/Y motif of L6. In addition, the dome over the barrel may play an important role in maintaining the efficiency of OMP biogenesis.

Unraveling the regulatory network of the MADS box transcription factor RIN in fruit ripening.

The MADS box transcription factor RIN is a global regulator of fruit ripening. However, the direct targets modulated by RIN and the mechanisms underlying the transcriptional regulation remain largely unknown. Here we identified 41 protein spots representing 35 individual genes as potential targets of RIN by comparative proteomic analysis of a rin mutant in tomato fruits. Gene expression analysis showed that the mRNA level of 26 genes correlated well with the protein level. After examining the promoter regions of the candidate genes, a variable number of RIN binding sites were found. Five genes (E8, TomloxC, PNAE, PGK and ADH2) were identified as novel direct targets of RIN by chromatin immunoprecipitation. The results of a gel mobility shift assay confirmed the direct binding of RIN to the promoters of these genes. Of the direct target genes, TomloxC and ADH2, which encode lipoxygenase (LOX) and alcohol dehydrogenase, respectively, are critical for the production of characteristic tomato aromas derived from LOX pathway. Further study indicated that RIN also directly regulates the expression of HPL, which encodes hydroperoxide lyase, another rate-limiting enzyme in the LOX pathway. Loss of function of RIN causes de-regulation of the LOX pathway, leading to a specific defect in the generation of aroma compounds derived from this pathway. These results indicate that RIN modulates aroma formation by direct and rigorous regulation of expression of genes in the LOX pathway. Taken together, our findings suggest that the regulatory effect of RIN on fruit ripening is achieved by targeting specific molecular pathways.

Effect of exercise on rehabilitation of breast cancer surgery patients: A systematic review and meta-analysis of randomized controlled trials.

AIM: To determine the effective exercise methods for different complications of breast cancer patients after surgery. DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive electronic search was carried out with no time limit until May 2020. Studies must have been randomized controlled trials of patients after breast cancer surgery, without limit to the way of exercise. Literature quality was evaluated by the modified Jadad scale. The meta-analysis was conducted with CMA2.0 software. RESULTS: Aerobic exercise reduced the intensity of the pain (MD = -1.043), improved shoulder flexion (MD = 3.398) and internal rotation range (MD = 3.868), lessened upper limb dysfunction (MD = -5.231) and improved muscle strength during flexion (MD = 1.076) and abduction (MD = 0.991). Shoulder elbow movement improved the range of shoulder external rotation (MD = 2.691) and reduced the incidence of arm lymphedema (RR = 0.343). Anti-resistance exercise also lessened upper limb dysfunction (MD = - 4.094).

Network analysis of somatic symptoms in Chinese patients with depressive disorder.

Introduction: Network theory conceptualizes somatic symptoms as a network of individual symptoms that are interconnected and influenced by each other. In this conceptualization, the network's central symptoms have the strongest effect on other symptoms. Clinical symptoms of patients with depressive disorders are largely determined by their sociocultural context. To our knowledge, no previous study has investigated the network structure of somatic symptoms among Chinese patients with depressive disorders. The aim of this study was to characterize the somatic symptoms network structure in patients with depressive disorders in Shanghai, China. Method: A total of 177 participants were recruited between October 2018 and June 2019. The Chinese version of the Patient Health Questionnaire-15 was used to assess somatic symptoms. In order to quantify the somatic symptom network structure, indicators of "closeness," "strength," and "betweenness" were employed as identifiers for network-central symptoms. Result: The symptoms of "feeling your heart pound or race," "shortness of breath," and "back pain" had the highest centrality values, indicating that these symptoms were central to the somatic symptom networks. Feeling tired or mentally ill had the strongest positive correlation with insomnia or other sleep problems (r = 0.419), followed by chest pain and breathlessness (r = 0.334), back pain, and limb or joint pain (r = 0.318). Discussion: Psychological and neurobiological research that offers insights into somatic symptoms may focus on these central symptoms as targets for treatment and future research.

Knowledge, attitudes and behaviors toward healthy eating among Chinese cancer patients treated with chemotherapy: A systematic review.

Side effects from chemotherapy may disturb healthy eating. There are many food taboos among Chinese patients with cancer treated with chemotherapy; they may be conservative in food intake and seek help from traditional Chinese medicine to adjust to healthy eating. Differences in eating cultures may lead Chinese patients with cancer to generate different knowledge, attitudes, and behaviors toward healthy eating. This systematic review explored the knowledge, attitudes, and behaviors toward healthy eating and summarized influencing factors among Chinese patients with cancer treated with chemotherapy. Two English and three Chinese databases were searched since 2007. The eligibility criteria were quantitative descriptive studies, participants who were adult Chinese patients with cancer who received chemotherapy, and primary outcomes that included knowledge, attitudes, or behaviors toward healthy eating. A total of 12 studies were identified. The 11-item tool from the Agency for Healthcare Research and Quality was used to assess quality. All studies were of moderate quality. Narrative qualitative analysis was considered to summarize the findings, and the results were reported by scores or percentages. Four studies measured knowledge, and the information about what to eat and how much to eat was contradictory and confused patients, with little known about Chinese food therapy. Ten studies involved attitudes, and patients were aware of the importance and willingness for eating guidance before, during, and after chemotherapy. Strategies to relieve vomiting and nausea, engage in healthy food choices, and seek food therapy were the main behaviors. The influencing factors were found only in behaviors, including demographic and psychological factors. Knowledge, attitudes, and behaviors toward healthy eating are not satisfactory and need to be improved. More high-quality studies should regard health behavior as a distal outcome and explore the influences of knowledge and attitudes on behaviors.

The Relationship between Trait Impulsivity and Everyday Executive Functions among Patients with Type 2 Diabetes Mellitus: The Mediating Effect of Negative Emotions.

Background: In recent years, the incidence of type 2 diabetes mellitus (T2DM) has dramatically increased, imposing a heavy financial burden on society and individuals. The most cost-effective way to control diabetes is diabetes self-management, which depends on patients' executive functions (EFs). However, the level of EFs among patients with T2DM varies greatly. In addition to diabetes-related factors contributing to a decline in EFs, trait impulsivity as a relatively stable personality trait may explicate individual differences in EFs. The objective of this study was to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs among patients with T2DM in China. Methods: A total of 305 patients with T2DM were enrolled consecutively from the endocrinology departments of three tertiary hospitals in China using convenience sampling. The participants completed the Sociodemographic Questionnaire, Mini-Mental State Examination (MMSE), Barratt Impulsiveness Scale-Brief (BIS-Brief), Depression Anxiety and Stress Scales with 21 items (DASS-21), and Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) version. A structural equation modeling was used to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs. Results: A total of 32.46% of the participants experienced at least one aspect of daily EF decline. The mediating effect of trait impulsivity on the Behavioral Regulation Index (BRI) of EFs through negative emotions was significant, accounting for 29.57% of the total effect. The mediating effect of trait impulsivity on the Metacognitive Index (MI) of EFs through negative emotions was significant, accounting for 31.67% of the total effect. Conclusions: Trait impulsivity can positively predict EF decline, which can be alleviated by improving the negative emotions of patients with T2DM. Future research exploring interventions to improve the EFs of patients with T2DM should therefore consider their trait impulsivity and negative emotions.

Cerebrospinal fluid uric acid levels associated with disease severity in patients with anti-N-methyl-d-aspartate receptor encephalitis.

INTRODUCTION: Uric acid (UA) is an important natural antioxidant and strong peroxynitrite scavenger, but little is known about central nervous system (CNS) levels of UA in patients with anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). METHODS: Cerebrospinal fluid (CSF) and serum levels of UA were determined in 72 patients with anti-NMDARE and 111 controls with non-inflammatory neurological diseases (NINDs). Serum UA levels were also evaluated in 132 healthy controls (HCs). CSF neuron-specific enolase (NSE) and blood-brain barrier (BBB) index were evaluated in patients with anti-NMDARE. The association of CSF UA levels with anti-NMDARE and its clinical parameters were evaluated in the patients. RESULTS: CSF UA levels were lower in patients with anti-NMDARE than in patients with NINDs, especially in patients with severe impairments (modified Rankin Scale [mRS] scores >3 vs. ≤ 3, p = 0.006). Furthermore, serum UA levels in patients with anti-NMDARE were significantly lower than in patients with NINDs and HCs. CSF UA levels were significantly associated with mRS scores, and serum UA levels in patients with anti-NMDARE. Furthermore, CSF/serum UA ratio was significantly associated with BBB index. CONCLUSIONS: CSF UA levels associated with disease severity and serum UA levels in patients with anti-NMDARE. And CSF/serum UA ratio correlated with BBB index, indicating that CSF and serum UA levels change similarly with BBB permeability in anti-NMDARE patients.

BJTJ-1837, a novel FXI activation-blocking antibody.

Background: Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. Objectives: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Methods: Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. Results: A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. Conclusion: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.