One-Pot Etching Pyrolysis to Defect-Rich Carbon Nanosheets to Construct Multiheteroatom-Coordinated Iron Sites for Efficient Oxygen Reduction.

Constructing multiheteroatom coordination structure in carbonaceous substrates demonstrates an effective method to accelerate the oxygen reduction reaction (ORR) of supported single-atom catalyst. Herein, the novel etching route assisted by potassium thiocyanate (KCNS) is developed to convert metal-organic framework to 2D defect-rich porous N,S-co-doped carbon nanosheets for anchoring atomically dispersed iron sites as the high-performance ORR catalysts (Fe-SACs). The well-designed KCNS-assisted etching route can generate spatial confinement template to direct the carbon nanosheet formation, etching condition to form defect-rich structure, and additional sulfur atoms to coordinate iron species. Spectral and microscopy analysis reveals that the iron element in Fe-SACs is highly isolated on carbon nanosheet and anchored by nitrogen and sulfur atoms in unsymmetrical Fe-S1N3 structure. The optimized Fe-SACs with large specific surface area could show remarkable alkaline ORR performances with a high half-wave potential of 0.920 V versus RHE and excellent durability. The rechargeable zinc-air battery assembled with Fe-SACs air electrodes delivers a large power density of 350 mW cm-2 and a stable voltage platform during charge and discharge over more than 1300 h. This work proposes a novel strategy for the preparation of single-atom catalysts with multiheteroatom coordination structure and highly exposed active sites for efficient ORR.

Pediatric Ocular Myasthenia Gravis: Single-Center Experience.

BACKGROUND: Currently, there is no universally accepted standard treatment for ocular myasthenia gravis (OMG) in children. We aimed to investigate the possible proper regimens and timing of treatment for pediatric OMG cases based on the clinical manifestations: OMG with ptosis only and OMG with other features. METHODS: One hundred and forty two OMG cases attended at the Department of Pediatrics, Xiangya Hospital, Central South University, from 2010 to 2019 were included, and information from medical records was reviewed and recorded. Comparisons of clinical characteristics between patients with OMG with ptosis only and patients with OMG with other features as well as between patients treated with glucocorticoid (GC) within or after six months from disease onset were performed. RESULTS: OMG with other features constituted about 54.9% of the cases, and 66.2% of the patients achieved optimal outcome. Patients with OMG with ptosis only responded to pyridostigmine alone more than patients with OMG with other features who required several therapies (P < 0.001). Patients with OMG with ptosis only had a larger proportion of optimal outcome than the patients with OMG with other features (P = 0.002), and the difference remained significant even when the individual outcome groups were compared (P < 0.001). Patients who received GC within six months had a greater proportion of optimal outcome than those who received it after six months (P < 0.001). CONCLUSIONS: Although OMG with other features is a more common subtype of OMG, it is also more severe than OMG with ptosis only. An earlier addition of GC leads to optimal outcome.

Application of Machine-learning based on Radiomics Features in Differential Diagnosis of Superficial Lymphadenopathy.

OBJECTIVE: The accurate diagnosis of superficial lymphadenopathy is challenging. We aim to explore a non-invasive and accurate machine-learning method for distinguishing benign lymph nodes, lymphoma, and metastatic lymph nodes. METHODS: The clinical data and ultrasound images of 160 patients with superficial lymphadenopathy (58 benign lymph nodes, 62 lymphoma, 40 metastatic lymph nodes) admitted to our hospital from January 2020 to November 2022 were retrospectively studied. Patients were randomly divided into a training set and test set according to the ratio of 6:4. Firstly, the radiomics features of each lymph node were extracted, and then a series of statistical methods were used to avoid over-fitting. Then, the gradient boosting machine(GBM) was used to build the model. The area under receiver(AUC) operating characteristic curve, precision, recall rate and F1 value were calculated to evaluate the effectiveness of the model. RESULTS: Ten robust features were selected to build the model. The AUC values of benign lymph nodes, lymphoma and metastatic lymph nodes in the training set were 1.00, 0.98 and 0.99, and the AUC values of the test set were 0.96, 0.84 and 0.90, respectively. CONCLUSION: It was a reliable and non-invasive method for the differential diagnosis of lymphadenopathy based on the model constructed by machine learning.

Targeted sequencing identifies risk variants in 202 candidate genes for neurodevelopmental disorders.

With the continuous deepening of genetic research on neurodevelopmental disorders (NDDs), more patients have been identified the causal or candidate genes. However, it is still urgent needed to increase the sample size to confirm the associations between variants and clinical manifestations. We previously performed molecular inversion probe sequencing of autism spectrum disorder (ASD) candidate genes in 1543 ASD patients. In this study, we used the same method to detect de novo variants (DNVs) in 665 NDD patients with intellectual disability (ID) and/or epilepsy (EP) for genetic analysis and diagnosis. We compared findings from ID/EP and ASD patients to improve our understanding of different subgroups of NDDs. We identified 72 novel variants and 39 DNVs. A totally of 5.71 % (38/665) of the patients were genetically diagnosed by this sequencing strategy. ID/EP patients demonstrated a higher prevalence of likely gene disruptive DNVs in ASD genes than the healthy population. Regarding high-risk genes, SCN1A and CKDL5 were more frequently mutated in ID/EP patients than in ASD patients. Our data provide an overview of the mutation burden in ID/EP patients from the perspective of high risk ASD genes, indicating the differences and association of NDDs subgroups.

Clinical and radiological features, treatment responses and prognosis in pediatric patients with co-existing anti-N-methyl-D-aspartate receptor and myelin oligodendrocyte glycoprotein antibody-associated encephalitis: A single center study.

OBJECTIVES: To characterize the clinical and radiological features, treatment responses and outcomes of children with co-existing anti-N-methyl-D-aspartate receptor(NMDAR) and myelin oligodendrocyte glycoprotein(MOG) antibody-associated encephalitis. METHODS: Clinical manifestations, imaging features, effectiveness of treatment and outcomes of patients who were cerebral spinal fluid(CSF)-positive for NMDAR-antibody(NMDAR-ab) and seropositive for MOG-antibody(MOG-ab) were analyzed. RESULTS: Twelve patients including 8 females and 4 males were enrolled. The median onset age was 9 years, ranging from 2.2 to 12.8 years. Behavioral changes and/or psychiatric symptoms (n = 8/12), seizures (n = 8/12), encephalopathy (n = 7/12) were 3 of the most common symptoms. Brain magnetic resonance imaging(MRI) of all the patients showed T2/fluid attenuation inversion recovery(FLAIR) abnormal signal in the cerebral white matter at least once in the courses of disease, 2 of whom developed new brain lesions which were asymptomatic. All of the patients had supratentorial lesions. Spinal cord MRI was performed in 7 patients. Only 1 patient showed related abnormalities with increased T2 signal in the spinal cord C1-5. Nine patients underwent optic nerve MRI; 5 patients demonstrated abnormal results, among whom 4 exhibited T2 abnormal signal (2 were symptom-free) and 1 showed a little effusion in bilateral optic nerve sheats. Intravenous immunoglobulin (IVIG) and intravenous methylprednisolone (IVMP) were the most common used therapies in those patients. Nine patients were treated with second-line therapy to prevent relapses. For total 29 clinical attacks, the median modified Rankin Scale (mRS) before treatment and after therapy of acute stage was 1 and 0, respectively. Seven of 12 patients(58.3 %) experienced clinical relapses. In terms of outcome, all of the patients' mRS of last follow-up (≥6 months) was ≤2. CONCLUSIONS: Behavioral changes and/or psychiatric symptoms, seizures and encephalopathy were common in children with co-existing anti-NMDAR and MOG antibody-associated encephalitis. A minority of subjects may develop asymptomatic lesions on brain and optic nerve MRI. The relapse rate of this disease is relatively high. The majority of patients responded well to the immunotherapies and had a good outcome(mRS of last follow-up≤2).

A glucose-mediated antibiotic resistance metabolic flux from glycolysis, the pyruvate cycle, and glutamate metabolism to purine metabolism.

Introduction: Bacterial metabolic environment influences antibiotic killing efficacy. Thus, a full understanding for the metabolic resistance mechanisms is especially important to combat antibiotic-resistant bacteria. Methods: Isobaric tags for relative and absolute quantification-based proteomics approach was employed to compare proteomes between ceftazidime-resistant and -sensitive Edwarsiella tarda LTB4 (LTB4-RCAZ and LTB4-S, respectively). Results: This analysis suggested the possibility that the ceftazidime resistance mediated by depressed glucose is implemented through an inefficient metabolic flux from glycolysis, the pyruvate cycle, glutamate metabolism to purine metabolism. The inefficient flux was demonstrated by the reduced expression of genes and the decreased activity of enzymes in the four metabolic pathways. However, supplement upstream glucose and downstream guanosine separately restored ceftazidime killing, which not only supports the conclusion that the inefficient metabolic flux is responsible for the resistance, but also provides an effective approach to reverse the resistance. In addition, the present study showed that ceftazidime is bound to pts promoter in E. tarda. Discussion: Our study highlights the way in fully understanding metabolic resistance mechanisms and establishing metabolites-based metabolic reprogramming to combat antibiotic resistance.

The genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews.

Background: Genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders such as global developmental delay (GDD)/intellectual disability (ID), epileptic encephalopathy (EE), and autism spectrum disorder (ASD) are unknown. We aimed to summarize genotype-phenotype correlations and potential treatment for CACNA1A-related neurodevelopmental disorders. Methods: Six children diagnosed with CACNA1A-related neurodevelopmental disorders at Xiangya Hospital, Central South University from April 2018 to July 2021 were enrolled. The PubMed database was systematically searched for all reported patients with CACNA1A-related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison. Results: Six patients were recruited from our hospital. Three cases presented with epilepsy, five with GDD/ID, five with ataxia, and two with ASD. The variants included p.G701R, p.R279C, p.D1644N, p.Y62C, p.L1422Sfs*8, and p. R1664Q [two gain-of-function (GOF) and four loss-of-function (LOF) variants]. About 187 individuals with GDD/ID harboring 123 variants were found (case series plus data from literature). Of those 123 variants, p.A713T and p.R1664* were recurrent, 37 were LOF, and 7 were GOF. GOF variants were linked with severe-profound GDD/ID while LOF variants were associated with mild-moderate GDD/ID (p = 0.001). The p.A713T variant correlated with severe-profound GDD/ID (p = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus (n = 64), provoked seizures (n = 49), focal seizures (n = 37), EE (n = 29), absence seizures (n = 26), and myoclonic seizures (n = 10). About 49 (42.20%) patients had controlled seizures while 67 (57.80%) individuals remained with refractory seizures. Status epilepticus correlated with variants located on S4, S5, and S6 (p = 0.000). Among the 83 epilepsy-related variants, 23 were recurrent, 32 were LOF, and 11 were GOF. Status epilepticus was linked with GOF variants (p = 0.000). LOF variants were associated with absence seizures (p = 0.000). Six patients died at an early age (3 months to ≤5 years). We found 18 children with ASD. Thirteen variants including recurrent ones were identified in those 18 cases. GOF changes were more linked to ASD. Conclusion: The p.A713T variant is linked with severe-profound GDD/ID. More than half of CACNA1A-related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.

Interferon-gamma treatment of human umbilical cord mesenchymal stem cells can significantly reduce damage associated with diabetic peripheral neuropathy in mice.

BACKGROUND: Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. METHODS: Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. RESULTS: The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. CONCLUSION: Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.

Individual bat virome analysis reveals co-infection and spillover among bats and virus zoonotic potential.

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within individual bats, and hence the frequency of virus co-infection and spillover among them. We characterize the mammal-associated viruses in 149 individual bats sampled from Yunnan province, China, using an unbiased meta-transcriptomics approach. This reveals a high frequency of virus co-infection (simultaneous infection of bat individuals by multiple viral species) and spillover among the animals studied, which may in turn facilitate virus recombination and reassortment. Of note, we identify five viral species that are likely to be pathogenic to humans or livestock, based on phylogenetic relatedness to known pathogens or in vitro receptor binding assays. This includes a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV and SARS-CoV-2. In vitro assays indicate that this recombinant virus can utilize the human ACE2 receptor such that it is likely to be of increased emergence risk. Our study highlights the common occurrence of co-infection and spillover of bat viruses and their implications for virus emergence.

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells.

Objective: To investigate the pathogenesis of three novel de novo CACNA1C variants (p.E411D, p.V622G, and p.A272V) in causing neurodevelopmental disorders and arrhythmia. Methods: Several molecular experiments were carried out on transfected human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells to explore the effects of p.E411D, p.V622G, and p.A272V variants on electrophysiology, mitochondrial and lysosomal functions. Electrophysiological studies, RT-qPCR, western blot, apoptosis assay, mito-tracker fluorescence intensity, lyso-tracker fluorescence intensity, mitochondrial calcium concentration test, and cell viability assay were performed. Besides, reactive oxygen species (ROS) levels, ATP levels, mitochondrial copy numbers, mitochondrial complex I, II, and cytochrome c functions were measured. Results: The p.E411D variant was found in a patient with attention deficit-hyperactive disorder (ADHD), and moderate intellectual disability (ID). This mutant demonstrated reduced calcium current density, mRNA, and protein expression, and it was localized in the nucleus, cytoplasm, lysosome, and mitochondria. It exhibited an accelerated apoptosis rate, impaired autophagy, and mitophagy. It also demonstrated compromised mitochondrial cytochrome c oxidase, complex I, and II enzymes, abnormal mitochondrial copy numbers, low ATP levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, and elevated mitochondrial calcium ions. The p.V622G variant was identified in a patient who presented with West syndrome and moderate global developmental delay. The p.A272V variant was found in a patient who presented with epilepsy and mild ID. Both mutants (p.V622G and p.A272V) exhibited reduced calcium current densities, decreased mRNA and protein expressions, and they were localized in the nucleus, cytoplasm, lysosome, and mitochondria. They exhibited accelerated apoptosis and proliferation rates, impaired autophagy, and mitophagy. They also exhibited abnormal mitochondrial cytochrome c oxidase, complex I and II enzymes, abnormal mitochondrial copy numbers, low ATP, high ROS levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, as well as elevated mitochondrial calcium ions. Conclusion: The p.E411D, p.V622G and p.A272V mutations of human CACNA1C reduce the expression level of CACNA1C proteins, and impair mitochondrial and lysosomal functions. These effects induced by CACNA1C variants may contribute to the pathogenesis of CACNA1C-related disorders.

A glucose-responsive nitric oxide release hydrogel for infected diabetic wounds treatment.

Bacteria-infected chronic wound is one of the most serious complications of diabetes and characterized with high morbidity and risk of lower extremity amputation. Nitric oxide (NO) represents a promising strategy to accelerate wound healing through down-regulating inflammation, promoting angiogenesis and bacterial eradication. However, stimuli-responsive and control release of NO at the wound microenvironment remains a challenge. In this work, an injectable, self-healing and antibacterial hydrogel characterized with glucose-responsive and constant NO release behaviors has been engineered for diabetic wound management. The hydrogel (CAHG) is prepared by in situ crosslinking of L-arginine (L-Arg)-coupled chitosan and glucose oxidase (GOx)-modified hyaluronic acid based on Schiff-base reaction. The system is capable of mediating a continuous release of hydrogen peroxide (H2O2) and NO by the cascaded consumption of glucose and L-Arg in the presence of hyperglycemia environment. In vitro studies demonstrate that bacteria proliferation is significantly inhibited by CAHG hydrogel involving in the cascaded release of H2O2 and NO. More importantly, a full-thickness skin wound model on a diabetic mouse demonstrates that H2O2 and NO release from CAHG hydrogel exhibits a superior efficiency for wound healing through bacterial inhibition, down-regulation of pro-inflammatory factors and the elevation of M2-type macrophage, contributing to the collagen deposition and angiogenesis. In conclusion, CAHG hydrogel with excellent biocompatibility and glucose-responsive NO release characteristic can serve as a highly efficient therapeutic strategy for diabetic wound treatment.

Prevalence and Characteristics of Novel Pathogenic Leptospira Species in Bats in Yunnan Province, China.

Leptospirosis has been identified as a zoonotic disease caused by pathogenic spirochetes of the bacterial genus Leptospira. Rodents are considered the primary hosts of these bacteria, whereas many recent studies suggest that bats may serve as potential natural reservoirs. However, studies on pathogenic spirochetes hosted by bat populations still need to be completed in China. In this study, a total of 276 bats belonging to five genera collected in Yunnan Province (Southwest China) from 2017 to 2021 were included in the screening. Pathogenic spirochetes were detected by PCR amplification and sequencing targeting four genes (rrs, secY, flaB, and LipL32), resulting in 17 positive samples. Phylogenetic analysis based on multi-loci concatenated sequences, inferred by MLST approach, identified the strains as two novel Leptospira species within the pathogenic group. Of note, only Rousettus leschenaultii was found to harbor these spirochetes, suggesting it may be one of the potential natural reservoirs in circulating leptospires in this region. Nevertheless, the pathogenesis and transmission dynamics still need to be fully understood, requiring in-depth studies on other animals and the surrounding population.

A two-center retrospective study: association of early caffeine administration and oxygen radical diseases in neonatology in Chinese preterm neonates.

Introduction: Since December 2012, the prophylactic use of caffeine to treat AOP in preterm infants has been approved in China. This study aimed to investigate the relationship between early caffeine treatment initiation and the incidence of oxygen radical diseases in neonatology (ORDIN) in Chinese preterm infants. Methods: A retrospective study was conducted at two hospitals in South China, involving 452 preterm infants with gestational ages less than 37 weeks. The infants were divided into early (227 cases, initiating within 48 h after birth) and late (225 cases, initiating over 48 h after birth) caffeine treatment group. Logistic regression analysis and Receiver Operating Characteristic (ROC) curves were used to evaluate the association between early caffeine treatment and the incidence of ORDIN. Results: The results showed that extremely preterm infants in early treatment group had a lower incidence of PIVH and ROP compared to those in the late treatment group (PIVH, 20.1% versus 47.8%, P = 0.02; ROP, 70.8% versus 89.9%, P = 0.025). Very preterm infants in the early treatment group had a lower incidence of BPD and PIVH compared to those in the late treatment group (BPD, 43.8% versus 63.1%, P = 0.002; PIVH, 9.0% versus 22.3%, P = 0.001). Moreover, VLBW infants who received early caffeine treatment exhibited a decreased incidence of BPD (55.9% versus 80.9%, P = 0.000), PIVH (11.8% versus 33.1%, P = 0.000), and ROP (69.9% versus 79.8%, P = 0.043) compared to those in the late treatment group. Infants in the early caffeine treatment showed a reduced likelihood of PIVH (adjusted odds ratio, 0.407; 95%CI, 0.188-0.846) but did not exhibit a significant association with other terms of ORDIN. ROC analysis revealed that early initiation of caffeine treatment was associated with lower risk of BPD, PIVH, and ROP in preterm infants. Discussion: In conclusion, this study demonstrates that early initiation of caffeine treatment is associated with a decreased incidence of PIVH in Chinese preterm infants. Further prospective investigations are necessary to verify and elucidate the precise effects of early caffeine treatment on complications in preterm Chinese infants.

Tuning Carbon Defect in Copper Single-Atom Catalysts for Efficient Oxygen Reduction.

Defect chemistry in carbon matrix shows great potential for promoting the oxygen reduction reaction (ORR) of metal single-atom catalysts. Herein, a modified pyrolysis strategy is proposed to tune carbon defects in copper single-atom catalysts (Cu-SACs) to fully understand their positive effect on the ORR activity. The optimized Cu-SACs with controllable carbon defect degree and enhanced active specific surface area can exhibit improved ORR activity with a half-wave potential of 0.897 VRHE , ultrahigh limiting current density of 6.5 mA cm-2 , and superior turnover frequency of 2.23 e site-1 s-1 . The assembled Zn-air batteries based on Cu-SACs can also show well-retained reversibility and voltage platform over 1100 h charge/discharge period. Density functional theory calculations reveal that suitable carbon defects can redistribute charge density of Cu-N4 active sites to weaken the O-O bond in adsorbed OOH* intermediate and thus reduce its dissociation energy. This discovery offers a universal strategy for fabricating superior single-atom catalysts with high-efficiency active sites toward energy-directed applications.

Genotype-phenotype correlations of STXBP1 pathogenic variants and the treatment choices for STXBP1-related disorders in China.

BACKGROUND: We aimed to analyze the genotype-phenotype correlations of STXBP1 pathogenic variants, prognostic factors and the treatment choices in a case-series of STXBP1-related disorders from China. METHODS: The clinical data and genetic results of the children diagnosed with STXBP1-related disorders at Xiangya hospital from 2011 to 2019 were collected retrospectively, and analyzed. We divided our patients into groups for comparison purposes: patients with missense variants and nonsense variants, patients who are seizure-free and not seizure-free, patients with mild to moderate intellectual disability (ID) and severe to profound global developmental delay (GDD). RESULTS: Nineteen patients were enrolled: 17 (89.5%) unrelated and 2 (10.5%) familial. Twelve (63.2%) were females. Developmental epileptic encephalopathy (DEE) was observed in 18 (94.7%) patients and ID alone in 1 (5.3%) individual. Thirteen patients (68.4%) had profound ID/GDD, 4 (23.53%) severe, 1 (5.9%) moderate and 1 (5.9%) mild. Three patients (15.8%) with profound ID died. A total of 19 variants were detected: pathogenic (n = 15) and likely pathogenic (n = 4). Seven were novel variants: c.664-1G>-, M486R, H245N, H498Pfs*44, L41R, L410del, and D90H. Of the 8 previous reported variants, 2 were recurrent: R406C and R292C. Anti-seizure medications were used in combinations, and 7 patients became seizure-free, and most of them achieved seizure freedom within the first 2 years of life irrespective of the type of the mutation. Effective medications for the seizure-free individuals included adrenocorticotropic (ACTH) and/or levetiracetam and/or phenobarbital and/or sodium valproate and/or topiramate and/or vigabatrin and/or nitrazepam. There was no correlation between the types of pathogenic variants and the phenotypes. CONCLUSION: Our case-series showed that there is no genotype-phenotype correlation in patients with STXBP1-related disorders. This study adds 7 novel variants which expand the spectrum of STXBP1-related disorders. Combinations of levetiracetam and/or sodium valproate and/or ACTH and/or phenobarbital and/or vigabatrin and/or topiramate and/or nitrazepam were more often associated with seizure freedom in our cohort within 2 years of life.

Multimorbidity of Allergic Conditions in Urban Citizens of Southern China: A Real-World Cross-Sectional Study.

BACKGROUND: Extensive knowledge of allergic multimorbidities is required to improve the management of allergic diseases with the industrialization of China. However, the demography and allergen distribution patterns of allergic multimorbidities in China remain unclear, despite the increasing prevalence of allergies. METHODS: This was a real-world, cross-sectional study of 1273 outpatients diagnosed with one or more allergic diseases in Guangzhou, the most populated city of southern China, with leading industrial and commercial centers, between April 2021 and March 2022. Seven allergic diseases (allergic rhinitis (AR), asthma (AS)/cough variant asthma (CVA), atopic dermatitis (AD)/eczema, food allergy (FA), allergic conjunctivitis (AC), drug allergy (DA), and anaphylaxis) were assessed. Positive rates of sensitization to different allergens were measured using an allergen detection system of the UniCAP (Pharmacia Diagnostics, Sweden) instrument platform to compare the groups of allergic multimorbidities against a single entity. RESULTS: There were 659 (51.8%) males and 614 (48.2%) females aged from 4 months to 74 years included in the analysis. The study participants who were diagnosed with allergic diseases had an average of 1.6 diagnoses. Overall, 46.5% (592 of 1273) of the patients had more than one allergic condition, and allergic rhinitis was the most common type of multimorbidity. Women were more likely to suffer from an allergic disease alone, whereas allergic multimorbidities were more likely to be diagnosed in men (p = 0.005). In addition, allergic multimorbidities were common in all age groups, with an incidence ranging from 37.1% to 57.4%, in which children and adolescents were more frequently diagnosed with allergic multimorbidities than adults (18-60 years old) (all p < 0.05). Allergic multimorbidity was observed throughout the year. A difference in the positive rate of allergens sensitization and total immunoglobulin E (tIgE) levels between different allergic multimorbidities was observed. CONCLUSIONS: Allergic multimorbidities were very commonly found in nearly half of all patients with allergies. The proportion of allergic multimorbidities varied with the type of disease, sex, age, and allergen distribution pattern. These findings may help clinicians to develop "One health" strategies for the clinical management of allergic diseases.

Macromolecular NO-Donor Micelles for Targeted and Augmented Chemotherapy against Prostate Cancer.

Mitoxantrone (MTO) is clinically utilized for treating hormone-refractory prostate cancer (PCa), however, the therapeutic outcome is far from optimal due to the lack of proper drug carrier as well as the inherent MTO detoxification mechanisms of DNA lesion repair and anti-oxidation. Herein, a bombesin-installed nanoplatform combining the chemotherapeutic MTO and the chemotherapeutic sensitizer of nitric oxide (NO) is developed based on MTO-loaded macromolecular NO-donor-containing polymeric micelles (BN-NMMTO ) for targeted NO-sensitized chemotherapy against PCa. BN-NMMTO actively target and accumulates in PCa sites and are internalized into the tumor cells. The macromolecular NO-donor of BN-NMMTO undergoes a reductive reaction to unleash NO upon intracellular glutathione (GSH), accompanying by micelle swelling and MTO release. The targeted intracellular MTO release induces DNA lesion and reactive oxygen species (ROS) generation in tumor cells without damage to the normal cells, and MTO's cytotoxicity is further augmented by NO release via the inhibition of both DNA repair and anti-oxidation pathways as compared with traditional MTO therapies.

Meta-transcriptomics for the diversity of tick-borne virus in Nujiang, Yunnan Province.

Ticks, an arthropod known for transmitting various pathogens such as viruses, bacteria, and fungi, pose a perpetual public health concern. A total of 2,570 ticks collected from Nujiang Prefecture in Yunnan Province between 2017 and 2022 were included in the study. Through the meta-transcriptomic sequencing of four locally distributed tick species, we identified 13 RNA viruses belonging to eight viral families, namely, Phenuiviridae, Nairoviridae, Peribunyaviridae, Flaviviridae, Chuviridae, Rhabdoviridae, Orthomyxoviridae, and Totiviridae. The most prevalent viruses were members of the order Bunyavirales, including three of Phenuiviridae, two were classified as Peribunyaviridae, and one was associated with Nairoviridae. However, whether they pose a threat to human health still remains unclear. Indeed, this study revealed the genetic diversity of tick species and tick-borne viruses in Nujiang Prefecture based on COI gene and tick-borne virus research. These data clarified the genetic evolution of some RNA viruses and furthered our understanding of the distribution pattern of tick-borne pathogens, highlighting the importance and necessity of monitoring tick-borne pathogens.

Individual bat viromes reveal the co-infection, spillover and emergence risk of potential zoonotic viruses.

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within bats at the level of individual animals, and hence the frequency of virus co-infection and inter-species transmission. Using an unbiased meta-transcriptomics approach we characterised the mammalian associated viruses present in 149 individual bats sampled from Yunnan province, China. This revealed a high frequency of virus co-infection and species spillover among the animals studied, with 12 viruses shared among different bat species, which in turn facilitates virus recombination and reassortment. Of note, we identified five viral species that are likely to be pathogenic to humans or livestock, including a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV-2 and SARS-CoV, with only five amino acid differences between its receptor-binding domain sequence and that of the earliest sequences of SARS-CoV-2. Functional analysis predicts that this recombinant coronavirus can utilize the human ACE2 receptor such that it is likely to be of high zoonotic risk. Our study highlights the common occurrence of inter-species transmission and co-infection of bat viruses, as well as their implications for virus emergence.

Molecular Detection and Phylogenetic Analyses of Diverse Bartonella Species in Bat Ectoparasites Collected from Yunnan Province, China.

Bartonella species has been validated as blood-borne bacteria in mammals and has a substantial opportunity to be harbored by a variety of hematophagous arthropod vectors. Bats, along with their ectoparasites, are recognized worldwide as one of the natural reservoir hosts for these bacteria. However, there have been few investigations of Bartonella bacteria toward a broad range of obligated bat ectoparasites in China. Here, molecular detection of Bartonella species was performed to survey the infection among bat ectoparasites and follow-up phylogenetic analyses to further characterize the evolutionary relationships of the genus. A total of 434 bat ectoparasites involving four types of arthropods, namely, bat mites, bat tick, bat fleas, and bat flies (further divided into traditionally fly-like bat flies and wingless bat flies) were collected in 10 trapping sites in Yunnan Province, southwestern China. Bartonella was detected by PCR amplification and sequencing through four gene target fragments (gltA, ftsZ, rpoB, and ITS). Accordingly, diverse Bartonella species were discovered, including both the validated species and the novel genotypes, which were characterized into several geographical regions with high prevalence. Phylogenetic analyses based on gltA and multi-locus concatenated sequences both demonstrated strong phylogeny-trait associations of Bartonella species from bats and their parasitic arthropods, suggesting the occurrence of host switches and emphasizing the potential connecting vector role of these ectoparasites. Nevertheless, the maintenance and transmission of Bartonella in both bat and hemoparasite populations have not been fully understood, as well as the risk of spillage to humans, which warrants in-depth experimental studies focusing on these mammals and their ectoparasites.