Molecular dynamics study on the influence of thermal aging on the mechanical properties of epoxy resins for high voltage bushing.

CONTEXT: Thermal aging significantly deteriorates the mechanical properties and service performance of epoxy resins used for the high-voltage bushing. Current studies on the thermal aging behavior of epoxy resins mainly focus on experimental observations. However, an in-depth understanding of the mechanism of thermal aging of epoxy resins requires the monitoring of structural evolution of epoxy resins during thermal aging at the molecular level. To thoroughly analyze the intrinsic factors affecting structural evolution and the effect of thermal aging on the mechanical properties of epoxy resin for high-voltage bushing, epoxy resin models with different crosslinking degrees were established and thermal aging treatments at various temperatures and time periods were carried out by molecular dynamics simulation. It was found that the tensile strength of the epoxy resin was enhanced with the increase of the crosslinking degree, which was related to the elevation of the proportion of C-N and O-H bonds in its structure. With the increase of thermal aging temperature, the tensile strength of the epoxy resin decreased, which was related to the formation of weak bonds. At the early stage of thermal aging and after a period of high-temperature thermal aging, the strength of epoxy resin significantly decreases. The thermal aging of the epoxy resin is accelerated under external loading. In addition, the crosslinking degree and curing agent also affect the thermal aging resistance of epoxy resins. The results of this study can provide guidance for predicting and improving the thermal aging resistance of epoxy resins. METHODS: Materials Studio was used to construct molecular models and complete crosslinking reactions. DGEBA and 44DDS (or 33DDS) were mixed at a ratio of 2:1, followed by crosslinking reaction. During this process, the Nose method was used to control temperature, the Berendsen method was used to control pressure, and the polymer consistent force field (PCFF) was used to control the motion and force of atoms. Isobaric-isothermal ensemble (NPT ensemble) was used to heat up epoxy resin models to various thermal aging temperatures of 400 K, 500 K, 600 K and 700 K. The models were maintained at these temperatures for different thermal aging times of 100 ps, 200 ps, 300 ps, 400 ps, 500 ps, 600 ps, 700 ps and 800 ps. Afterwards, the models were cooled down to 300 K and subjected to uniaxial tensile testing at this temperature with a strain rate of 1 × 109 s-1. The structural configurations and stress-strain data during the tensile process were recorded. The flow stress of the material was derived by counting the average stress in the 20-50% strain interval.

Study on clinical features and factors related to long-term outcomes of antibody-negative autoimmune encephalitis.

OBJECTIVE: To delineate the clinical characteristics of antibody-negative autoimmune encephalitis (AE) and to investigate factors associated with long-term outcomes among antibody-negative AE. METHODS: Patients diagnosed with antibody-negative AE were recruited from January 2016 to December 2022 at the Second Xiangya Hospital of Central South University. The study assessed the long-term outcomes of antibody-negative AE using the modified Rankin scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Predictors influencing long-term outcomes were subsequently analyzed. External validation of RAPID scores (refractory status epilepticus [RSE], age of onset ≥60 years, ANPRA [antibody-negative probable autoimmune encephalitis], infratentorial involvement, and delay of immunotherapy ≥1 month) was performed. RESULTS: In total, 100 (47 females and 53 males) antibody-negative AE patients were enrolled in this study, with approximately 49 (49%) experiencing unfavorable long-term outcomes (mRS scores ≥3). Antibody-negative AE was subcategorized into ANPRA, autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Psychiatric symptoms were prevalent in LE and ANPRA subtypes, while weakness and gait instability/dystonia were predominant in the ADEM subtype. Higher peak CASE scores (odds ratio [OR] 1.846, 95% confidence interval [CI]: 1.163-2.930, p = 0.009) and initiating immunotherapy within 30 days (OR 0.210, 95% CI: 0.046-0.948, p = 0.042) were correlated with long-term outcomes. Receiver operating characteristic (ROC) analysis returned that the RAPID scores cutoff of 1.5 best discriminated the group with poor long-term outcomes (sensitivity 85.7%, specificity 56.9%). INTERPRETATION: The ANPRA subtype exhibited poorer long-term outcomes compared to LE and ADEM subtypes, and early immunotherapy was crucial for improving long-term outcomes in antibody-negative AE. The use of RAPID scoring could aid in guiding clinical decision making.

Risk stratification and predictive modeling of postoperative delirium in chronic subdural hematoma.

Background- Postoperative delirium is a common complication associated with the elderly, causing increased morbidity and prolonged hospital stay. However, its risk factors in chronic subdural hematoma patients have not been well studied. Methods- A total of 202 consecutive patients with chronic subdural hematoma at Peking University Third Hospital between January 2018 and January 2023 were enrolled. Various clinical indicators were analyzed to identify independent risk factors for postoperative delirium using univariate and multivariate regression analyses. Delirium risk prediction models were developed as a nomogram and a Markov chain. Results- Out of the 202 patients (age, 71 (IQR, 18); female-to-male ratio, 1:2.7) studied, 63 (31.2%) experienced postoperative delirium. Univariate analysis identified age (p < 0.001), gender (p = 0.014), restraint belt use (p < 0.001), electrolyte imbalance (p < 0.001), visual analog scale score (p < 0.001), hematoma thickness (p < 0.001), midline shift (p < 0.001), hematoma side (p = 0.013), hematoma location (p = 0.018), and urinal catheterization (p = 0.028) as significant factors. Multivariate regression analysis confirmed the significance of restraint belt use (B = 7.657, p < 0.001), electrolyte imbalance (B = -3.993, p = 0.001), visual analog scale score (B = 2.331, p = 0.016), and midline shift (B = 0.335, p = 0.007). Hematoma thickness and age had no significant impact. Conclusion- Increased midline shift and visual analog scale scores, alongside restraint belt use and electrolyte imbalance elevate delirium risk in chronic subdural hematoma surgery. Our prediction models may offer reference value in this context.

Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care.

Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of 'predictive, preventive, and personalized' periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

Clinical features of adult patients with positive NMDAR-IgG coexisting with MOG-IgG.

INTRODUCTION: This study was designed to analyze clinical and radiographic features of adult patients coexisting with NMDAR-IgG and MOG-IgG. METHODS: Eleven adult patients coexisting with NMDAR-IgG and MOG-IgG were collected from Xiangya Hospital, Central South University, between June 2017 and December 2021. Fifty-five patients with anti-NMDAR encephalitis and 49 with MOG-AD were served as controls. RESULTS: Onset age was 27 (IQR 20-34) years old. Seizures and psychotic symptoms were prominent symptoms. Ten of eleven patients presented abnormal T2/FLAIR hyperintensity, mainly involving the cortex, brainstem, and optic nerve. Compared with the NMDAR IgG ( +)/MOG IgG ( -) group, the NMDAR IgG ( +)/MOG IgG ( +) group showed more ataxia symptoms (27.3% vs. 3.6%, P = 0.037), while more T2/FLAIR hyperintensity lesions were found in the brainstem (54.5% vs. 7.3%, P < 0.001) and optic nerve (27.3% vs. 1.8%, P = 0.011) with more abnormal MRI patterns (90.9% vs. 41.8%, P = 0.003). In comparison with the NMDAR IgG ( -)/MOG IgG ( +) group, the NMDAR IgG ( +)/MOG IgG ( +) group had more seizures (72.7% vs. 24.5%, P = 0.007) and mental symptoms (45.5% vs. 0, P < 0.001). The NMDAR IgG ( +)/MOG IgG ( +) group tended to be treated with corticosteroids alone (63.6% vs. 20.0%, P = 0.009), more prone to recur (36.5% vs. 7.3%, P = 0.028) and lower mRS score (P = 0.036) at the last follow-up than pure anti-NMDAR encephalitis. CONCLUSION: The symptoms of the NMDAR IgG ( +)/MOG IgG ( +) group were more similar to anti-NMDAR encephalitis, while MRI patterns overlapped more with MOG-AD. Detecting both NMDAR-IgG and MOG-IgG maybe warranted in patients with atypical encephalitis symptoms and demyelinating lesions in infratentorial regions.

From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review.

In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.

Genetic evidence strengthens the bidirectional connection between gut microbiota and periodontitis: insights from a two-sample Mendelian randomization study.

BACKGROUND: Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis. MATERIALS AND METHODS: A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation. RESULTS: 2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10-1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05-1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03-1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01-1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00-1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70-0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated. CONCLUSIONS: The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.

OCT4's role and mechanism underlying oral squamous cell carcinoma. / OCT4åœ¨å£è ”é³žçŠ¶ç»†èƒžç™Œå‘ç— æœºåˆ¶ä¸­çš„ä½œç”¨.

Oral squamous cell carcinoma (OSCC), a common malignancy of the head and neck, ranks sixth worldwide in terms of cancers with the most negative impact, owing to tumor relapse rates, cervical lymphnode metastasis, and the lack of an efficacious systemic therapy. Its prognosis is poor, and its mortality rate is high. Octamer-binding transcription factor 4 (OCT4) is a member of the Pit-Oct-Unc (POU) family and is a key reprogramming factor that produces a marked effect in preserving the pluripotency and self-renewal state of embryonic stem cells (ESCs). According to recent studies, OCT4 participates in retaining the survival of OSCC cancer stem cells (CSCs), which has far-reaching implications for the occurrence, recurrence, metastasis, and prognosis of oral carcinogenesis. Therefore, we summarize the structure, subtypes, and function of OCT4 as well as its role in the occurrence, progression, and prognosis of OSCC.

A novel postoperative nomogram and risk classification system for individualized estimation of survival among patients with parotid gland carcinoma after surgery.

BACKGROUND: Parotid gland carcinoma (PGC) is a rare but aggressive head and neck cancer, and the prognostic model associated with survival after surgical resection has not yet been established. This study aimed to construct a novel postoperative nomogram and risk classification system for the individualized prediction of overall survival (OS) among patients with resected PGC. METHODS: Patients with PGC who underwent surgery between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were randomized into training and validation cohorts (7:3). A nomogram developed using independent prognostic factors based on the results of the multivariate Cox regression analysis. Harrell's concordance index (C-index), time-dependent area under the curve (AUC), and calibration plots were used to validate the performance of the nomogram. Moreover, decision curve analysis (DCA) was performed to compare the clinical use of the nomogram with that of traditional TNM staging. RESULTS: In this study, 5077 patients who underwent surgery for PGC were included. Age, sex, marital status, tumor grade, histology, TNM stage, surgery type, radiotherapy, and chemotherapy were independent prognostic factors. Based on these independent factors, a postoperative nomogram was developed. The C-index of the proposed nomogram was 0.807 (95% confidence interval 0.797-0.817). Meanwhile, the time-dependent AUC (> 0.8) indicated that the nomogram had a satisfactory discriminative ability. The calibration curves showed good concordance between the predicted and actual probabilities of OS, and DCA curves indicated that the nomogram had a better clinical application value than the traditional TNM staging. Moreover, a risk classification system was built that could perfectly classify patients with PGC into three risk groups. CONCLUSIONS: This study constructed a novel postoperative nomogram and corresponding risk classification system to predict the OS of patients with PGC after surgery. These tools can be used to stratify patients with high or low risk of mortality and provide high-risk patients with more directed therapies and closer follow-up.

Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula.

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.

CFD Simulations of Ventilation and Interunit Dispersion in Dormitory Complex: A Case Study of Epidemic Outbreak in Shanghai.

Since the beginning of March 2022, a new round of COVID-19 outbreaks in Shanghai has led to a sharp increase in the number of infected people. It is important to identify possible pollutant transmission routes and predict potential infection risks for infectious diseases. Therefore, this study investigated the cross-diffusion of pollutants caused by natural ventilation, including external windows and indoor ventilation windows, under three wind directions in a densely populated building environment with the CFD method. In this study, CFD building models were developed based on an actual dormitory complex and surrounding buildings under realistic wind conditions to reproduce the airflow fields and transmission paths of pollutants. This paper adopted the Wells-Riley model to assess the risk of cross-infection. The biggest risk of infection was when a source room was located on the windward side, and the risk of infection in other rooms on the same side as the source room was large in the windward direction. When pollutants were released from room 8, north wind resulted in the highest concentration of pollutants in room 28, reaching 37.8%. This paper summarizes the transmission risks related to the indoor and outdoor environments of compact buildings.

Cerebellar functional disruption and compensation in mesial temporal lobe epilepsy.

Background: Cerebellar functional alterations are common in patients with mesial temporal lobe epilepsy (MTLE), which contribute to cognitive decline. This study aimed to deepen our knowledge of cerebellar functional alterations in patients with MTLE. Methods: In this study, participants were recruited from an ongoing prospective cohort of 13 patients with left TLE (LTLE), 17 patients with right TLE (RTLE), and 30 healthy controls (HCs). Functional magnetic resonance imaging data were collected during a Chinese verbal fluency task. Group independent component (IC) analysis (group ICA) was applied to segment the cerebellum into six functionally separated networks. Functional connectivity was compared among cerebellar networks, cerebellar activation maps, and the centrality parameters of cerebellar regions. For cerebellar functional profiles with significant differences, we calculated their correlation with clinical features and neuropsychological scores. Result: Compared to HCs and patients with LTLE, patients with RTLE had higher cerebellar functional connectivity between the default mode network (DMN) and the oculomotor network and lower cerebellar functional connectivity from the frontoparietal network (FPN) to the dorsal attention network (DAN) (p < 0.05, false discovery rate- (FDR-) corrected). Cerebellar degree centrality (DC) of the right lobule III was significantly higher in patients with LTLE compared to HC and patients with RTLE (p < 0.05, FDR-corrected). Higher cerebellar functional connectivity between the DMN and the oculomotor network, as well as lower cerebellar degree centrality of the right lobule III, was correlated with worse information test performance. Conclusion: Cerebellar functional profiles were altered in MTLE and correlated with long-term memory in patients.

A Case of Anti-GAD 65 Autoimmune Encephalitis Associated with Focal Segmental Stiff-Person Syndrome.

Glutamic acid decarboxylase (GAD) antibody-related encephalitis is an autoimmune disease associated with intracellular neuronal antigens. We report on a rare case of GAD antibody-associated encephalitis complicated with focal segmental stiffness-person syndrome (SPS) in a middle-aged woman. The disease course lasted for >10 years, initially presenting with drug-resistant epilepsy, followed by stiffness of the right lower limb, and right upper limb involvement. The patient experienced anxiety and depression symptoms due to long-term illness. During hospitalization, serum and cerebrospinal fluid GAD antibodies were positive and no tumor was found. The symptoms were significantly relieved after corticosteroid therapy and intravenous immunoglobulin immunomodulation therapy. To the best of our knowledge, this case is the first to discuss the early recognition and treatment of chronic epilepsy and focal segmental SPS caused by anti-GAD antibody-related encephalitis.

Magnetic SERS Strip Based on 4-mercaptophenylboronic Acid-Modified Fe3O4@Au for Active Capture and Simultaneous Detection of Respiratory Bacteria.

The rapid diagnosis and detection of respiratory bacteria at the early stage can effectively control the epidemic spread and bacterial infection. Here, we designed a rapid, ultrasensitive, and quantitative lateral flow immunoassay (LFA) strip for simultaneous detection of respiratory bacteria S. aureus and S. pneumoniae. In this assay, the surface enhanced Raman scattering (SERS) tags were designed through combining magnetite Raman enhancement nanoparticle Fe3O4@Au/DTNB and recognition element 4-mercaptophenylboronic acid (4-MPBA). Further, 4-MPBA could capture multiple bacteria in a complex environmental solution. Based on the strategies, Fe3O4@Au/DTNB-mediated magnetic enrichment and 4-MPBA-mediated universal capture capabilities improved the detection sensitivity, the limits of detection for S. aureus and S. pneumoniae were as low as 8 and 13 CFU mL-1, respectively, which were more sensitive than those of colloidal gold method. The Fe3O4@Au/DTNB/Au/4-MPBA-LFA also exhibited good reproducibility, excellent specificity, and high recovery rates in sputum samples, indicating its potential application in the detection of respiratory bacteria samples.

Simultaneously ultrasensitive and quantitative detection of influenza A virus, SARS-CoV-2, and respiratory syncytial virus via multichannel magnetic SERS-based lateral flow immunoassay.

Respiratory viruses usually induced similar clinical symptoms at early infection. Herein, we presented a multichannel surface-enhanced Raman scattering-based lateral flow immunoassay (SERS-based LFA) using high-performance magnetic SERS tags for the simultaneous ultrasensitive detection of respiratory viruses, namely influenza A virus (H1N1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) in biological samples. As-prepared magnetic SERS tags can directly enrich and capture target viruses without pretreatment of samples, avoiding the interference of impurities in the samples as well as improving the sensitivity. With the capture-detection method, the detection limits of the proposed assay reached 85 copies mL-1, 8 pg mL-1, and 8 pg mL-1 for H1N1, SARS-CoV-2 and RSV, respectively. Moreover, the detection properties of the proposed method for target viruses in throat swab samples were verified, suggesting its remarkable potential for the early and rapid differential diagnosis of respiratory viruses.

Research progress and application of rodents model construction of peri-implantitis / 口腔医学

@#With the increasing popularity of dental implants, prevalence of peri-implantitishas also been increasing in recent years. However, a deeper understanding of the pathogenesis of peri-implantitis is still lacking. Animal models are a good bridge for studying the pathogenesis of clinical diseases. Animals such as mini-pigs, canines, non-human primates and rodents are used to construct animal models of peri-implantitis. Among them, rodents are easy to obtain and feed, and have a wide range of applications for research. In this review, we summarize the construction of rodent modelswithperi-implantitis as well as the research progress and applications.

Corrigendum: Case report: Challenges in the diagnosis of a case of Mal de Meleda and a therapeutic attempt of ixekizumab and Adalimumab.

[This corrects the article DOI: 10.3389/fmed.2022.821301.].

De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.

Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.

Case Report: Challenges in the Diagnosis of a Case of Mal de Meleda and a Therapeutic Attempt of Ixekizumab and Adalimumab.

Background: Mal de Meleda (MDM, OMIM 248300) is an autosomal recessive disease characterized by symmetrical and progressive palmoplantar hyperkeratosis soon after birth. Mutations in SLURP1 gene could lead to MDM. Clinically, MDM is easily misdiagnosed as other types of keratoderma due to phenotypic variation and overlap. Objective and Methods: A patient with suspected MDM was confirmed by the combination of next-generation sequencing and Exomiser, and the patient was attempted with the treatment of Ixekizumab and Adalimumab. Results: A homozygous mutation c.256G>A (p.Gly86Arg) in the SLURP1 gene was identified in the patient. The inflammatory erythemas on his hands, feet and buttocks were mildly relieved after the treatment of high dose of Ixekizumab. Conclusions: Our findings helps to enhance the understanding of MDM. Ixekizumab may be a potential strategy to treat MDM.

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients.

Aim: De novo DDX3X variants account for 1-3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X neurodevelopmental disorder in the Chinese cohort have not been characterized. Method: A total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 de novo DDX3X deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of DDX3X patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD). Result: A total of 17 DDX3X variants were novel and 22 were de novo. Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the "at-risk" threshold for ASD. Interpretation: Although a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.