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Abstract Background and objectives Methionine adenosyltransferase I/III deficiency used to be considered a relatively benign disease. This study aims to elucidate the clinical characteristics of methionine adenosyltransferase I/III deficiency patients with neurological manifestations. Methods The clinical data, blood amino acids, plasma total homocysteine, gene variants, brain imaging, treatments and outcomes of 15 patients with methionine adenosyltransferase I/III deficiency were retrospectively analyzed. Results Of these 15 patients, 10 demonstrated neurological abnormalities, with delayed language development, learning difficulties or abnormal brain imaging findings. Eleven patients were identified by newborn screening. Patients with demyelination showed significantly higher blood methionine concentrations at baseline (1102 vs. 396 µmol/L), and their blood methionine remained markedly elevated despite a low-methionine diet. Their plasma total homocysteine was normal to moderate elevated. One patient underwent liver transplantation aged 8 years, which reduced his serum methionine concentration to normal. Compound heterozygous and homozygous MAT1A variants were identified from the patients. Among the 21 variants observed, nine have been reported previously, while 12 were novel. Conclusions Methionine adenosyltransferase I/III deficiency is not just a benign disease. Severe persistent hypermethioninemia can cause brain injuries, especially in the white matter. Liver transplantation may be a potential treatment option for refractory methionine adenosyltransferase I/III deficiency.

目的 评估普罗布考与阿托伐他汀钙联合治疗急性脑梗死（acute cerebral infarction，ACI）的疗效，以提供ACI的治疗参考方案。 方法 回顾性收集2018年1月—2023年9月在重庆市急救医疗中心就诊，发病24 h内住院的ACI患者资料。纳入患者需满足：接受了阿托伐他汀钙（20 mg，每晚1次）单药或联用普罗布考（0.5 mg，每日2次）调节血脂治疗，且治疗周期为3个月以上。根据是否联用普罗布考分为联合治疗组和对照组，比较两组治疗后神经功能（使用NIHSS评估）、神经功能结局（使用mRS评估）、生活能力（使用Barthel指数评估）以及血脂水平的差异。 结果 研究共入组102例患者，其中联合治疗组56例，对照组46例。两组的基线资料差异无统计学意义。治疗后14 d两组的NIHSS评分和血脂水平、治疗3个月后的血脂水平均较本组治疗前显著改善（均P

The imbalance between the supply and demand of pediatric medical resources and health management services in our country has been a long-standing issue, primary healthcare institutions are particularly prominent in this context. How to achieve integration and optimization of pediatric medical resources at the grassroots medical and health institutions is an urgent problem that needs to be addressed. This article primarily summarizes and analyzes the concept and framework of integrated health management services for children, including children's health assessment, early intervention, long-term follow-up, and case studies and practical experiences. Through a review of domestic and international literature, it concludes feasible models of integrated health services for children. This review suggests that integrated health management services have broad potential and promising applications, providing personalized and efficient health management and intervention for children.

Abstract Background The dynamics of mitochondrial respiratory cristae (MRC) and its impact on oxidative phosphorylation (OXPHOS) play a crucial role in driving the progression of high-grade glioma (HGG). However, the underlying mechanism remains unclear. Methods In the present study, we employed machine learning-based transmission electron microscopy analysis of 7141 mitochondria from 54 resected glioma patients. Additionally, we conducted bioinformatics analysis and multiplex immunohistochemical (mIHC) staining of clinical glioma microarrays to identify key molecules involved in glioma. Subsequently, we modulated the expression levels of mitochondrial dynamic-1-like protein (DNM1L/DRP1), and its two receptors, mitochondrial fission protein 1 (FIS1) and mitochondrial fission factor (MFF), via lentiviral transfection to further investigate the central role of these molecules in the dynamics of glioblastoma (GBM) cells and glioma stem cells (GSCs). We then evaluated the potential impact of DNM1L/DRP1, FIS1, and MFF on the proliferation and progression of GBM cells and GSCs using a combination of CCK-8 assay, Transwell assay, Wound Healing assay, tumor spheroid formation assay and cell derived xenograft assay employing NOD/ShiLtJGpt-Prkdc em26Cd52 Il2rg em26Cd22/Gpt (NCG) mouse model. Subsequently, we validated the ability of the DNM1L/DRP1-FIS1 axis to remodel MRC structure through mitophagy by utilizing Seahorse XF analysis technology, mitochondrial function detection, MRC abundance detection and monitoring dynamic changes in mitophagy. Results Our findings revealed that compared to low-grade glioma (LGG), HGG exhibited more integrated MRC structures. Further research revealed that DNM1L/DRP1, FIS1, and MFF played pivotal roles in governing mitochondrial fission and remodeling MRC in HGG. The subsequent validation demonstrated that DNM1L/DRP1 exerts a positive regulatory effect on FIS1, whereas the interaction between MFF and FIS1 demonstrates a competitive inhibition relationship. The down-regulation of the DNM1L/DRP1-FIS1 axis significantly impaired mitophagy, thereby hindering the remodeling of MRC and inhibiting OXPHOS function in glioma, ultimately leading to the inhibition of its aggressive progression. In contrast, MFF exerts a contrasting effect on MRC integrity, OXPHOS activity, and glioma progression. Conclusions This study highlights that the DNM1L/DRP1-FIS1 axis stabilizes MRC structures through mitophagy in HGG cells while driving their OXPHOS activity ultimately leading to robust disease progression. The inhibition of the DNM1L/DRP1-FIS1 axis hinders MRC remodeling and suppresses GBM progression. We propose that down-regulation of the DNM1L/DRP1-FIS1 axis could be a potential therapeutic strategy for treating HGG.

Abstract Background Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear. Methods Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants. Results We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells. Conclusion Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.

Abstract Background Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. Methods Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children’s Medical Center of Peking University First Hospital from September 2014 to August 2023. Results Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. Conclusions Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.

Abstract Background Premature Ventricular Complexes (PVCs) are very common in clinical practice, with frequent PVCs (more than 30 beats per hour) or polymorphic PVCs significantly increasing the risk of mortality. Previous studies have shown that vagus nerve stimulation improves ventricular arrhythmias. Stimulation of the auricular distribution of the vagus nerve has proven to be a simple, safe, and effective method to activate the vagus nerve. Transcutaneous au ricular vagus nerve stimulation (taVNS) has shown promise in both clinical and experimental setting for PVCs; however, high-quality clinical studies are lacking, resulting in insufficient evidence of efficacy. Methods The study is a prospective, randomized, parallel-controlled trial with a 1:1 ratio between the two groups. Patients will be randomized to either the treatment group (taVNS) or the control group (Sham-taVNS) with a 6-week treatment and a subsequent 12-week follow-up period. The primary outcome is the proportion of patients with a ≥ 50% reduction in the number of PVCs monitored by 24-hour Holter. Secondary outcomes include the proportion of patients with a ≥ 75% reduction in PVCs, as well as the changes in premature ventricular beats, total heartbeats, and supraventricular premature beats recorded by 24-hour Holter. Additional assessments compared score changes in PVCs-related symptoms, as well as the score change of self-rating anxiety scale (SAS), self-rating depression scale (SDS), and 36-item short form health survey (SF-36). Discussion The TASC-V trial will help to reveal the efficacy and safety of taVNS for frequent PVCs, offering new clinical evidence for the clinical practice. Trial registration Clinicaltrials.gov: NCT04415203 (Registration Date: May 30, 2020).

Abstract Background and aims To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. Materials and methods This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023. Results Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction. Conclusions A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.

The epigenetic reader SntB was identified as an important transcriptional regulator of growth, development, and secondary metabolite synthesis in Aspergillus flavus. However, the underlying molecular mechanism is still unclear. In this study, by gene deletion and complementation, we found SntB is essential for mycelia growth, conidial production, sclerotia formation, aflatoxin synthesis, and host colonization. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis revealed that SntB played key roles in oxidative stress response of A. flavus, influencing related gene activity, especially catC encoding catalase. SntB regulated the expression activity of catC with or without oxidative stress, and was related to the expression level of the secretory lipase (G4B84_008359). The deletion of catC showed that CatC participated in the regulation of fungal morphogenesis, reactive oxygen species (ROS) level, and aflatoxin production, and that CatC significantly regulated fungal sensitive reaction and AFB1 yield under oxidative stress. Our study revealed the potential machinery that SntB regulated fungal morphogenesis, mycotoxin anabolism, and fungal virulence through the axle of from H3K36me3 modification to fungal virulence and mycotoxin biosynthesis. The results of this study shed light into the SntB-mediated transcript regulation pathways of fungal mycotoxin anabolism and virulence, which provided potential strategy to control the contamination of A. flavus and its aflatoxins.

The occurrence and development of central nervous system (CNS) diseases is a multi-factor and multi-gene pathological process, and their diagnosis and treatment have always posed a serious challenge in the medical field. Therefore, exploring the relevant factors in the pathogenesis of CNS and improving the diagnosis and treatment rates has become an urgent problem. Piezo1 is a recently discovered mechanosensitive ion channel that opens in response to mechanical stimuli. A number of previous studies have shown that the Piezo channel family plays a crucial role in CNS physiology and pathology, especially in diseases related to CNS development and mechanical stimulation. This article comprehensively describes the biological properties of Piezo1, focuses on the potential association between Piezo1 and CNS disorders, and explores the pharmacological roles of Piezo1 agonists and inhibitors in treating CNS disorders.

Abstract Objectives This study aimed to design a modified passive-deflation sealer injection needle and investigate its ability to improve obturation quality of single-cone technique through assessing the distribution of voids in root canals using micro-computed tomography (micro-CT). Materials and methods Forty-eight mandibular incisors were divided into eight groups (n = 6), according to the taper of root canal preparation (0.06 or 0.04), the needle used for sealer injection (modified or commercial iRoot SP injection needle), and the obturation method (iRoot SP sealer-only or single-cone obturation). After obturation, each specimen was scanned by micro-CT. The volumetric percentage and distribution of all voids were first analyzed and compared among groups, then the open and closed voids were separately analyzed and compared among single-cone obturation groups. Results Compared to commercial needle groups, modified needle groups showed much less voids, especially in the apical root canal part (P

Abstract Background Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported. Results Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR. Conclusions Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

BackgroudRoutine metabolic assessments for methylmalonic acidemia (MMA), propionic acidemia (PA), and homocysteinemia involve detecting metabolites in dried blood spots (DBS) and analyzing specific biomarkers in serum and urine. This study aimed to establish a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous detection of three specific biomarkers (methylmalonic acid, methylcitric acid, and homocysteine) in DBS, as well as to appraise the applicability of these three DBS metabolites in monitoring patients with MMA, PA, and homocysteinemia during follow-up.MethodsA total of 140 healthy controls and 228 participants were enrolled, including 205 patients with MMA, 17 patients with PA, and 6 patients with homocysteinemia. Clinical data and DBS samples were collected during follow-up visits.ResultsThe reference ranges (25th–95th percentile) for DBS methylmalonic acid, methylcitric acid, and homocysteine were estimated as 0.04–1.02 μmol/L, 0.02–0.27 μmol/L and 1.05–8.22 μmol/L, respectively. Following treatment, some patients achieved normal metabolite concentrations, but the majority still exhibited characteristic biochemical patterns. The concentrations of methylmalonic acid, methylcitric acid, and homocysteine in DBS showed positive correlations with urine methylmalonic acid (r = 0.849, p

Abstract Background Mitochondrial diseases are heterogeneous in terms of clinical manifestations and genetic characteristics. The dynamin 1-like gene (DNM1L) encodes dynamin-related protein 1 (DRP1), a member of the GTPases dynamin superfamily responsible for mitochondrial and peroxisomal fission. DNM1L variants can lead to mitochondrial fission dysfunction. Case presentation Herein, we report a distinctive clinical phenotype associated with a novel variant of DNM1L and review the relevant literature. A 5-year-old girl presented with paroxysmal hemiplegia, astigmatism, and strabismus. Levocarnitine and coenzyme Q10 supplement showed good efficacy. Based on the patient’s clinical data, trio whole-exome sequencing (trio-WES) and mtDNA sequencing were performed to identify the potential causative genes, and Sanger sequencing was used to validate the specific variation in the proband and her family members. The results showed a novel de novo heterozygous nonsense variant in exon 20 of the DNM1L gene, c.2161C>T, p.Gln721Ter, which is predicted to be a pathogenic variant according to the ACMG guidelines. The proband has a previously undescribed clinical manifestation, namely hemiparesis, which may be an additional feature of the growing phenotypic spectrum of DNM1L-related diseases. Conclusion Our findings elucidate a novel variant in DNM1L-related disease and reveal an expanding phenotypic spectrum associated with DNM1L variants. This report highlights the necessity of next generation sequencing for early diagnosis of patients, and that further clinical phenotypic and genotypic analysis may help to improve the understanding of DNM1L-related diseases.

Optical instruments require extremely high precision, and even minor surface contamination can severely impact their performance. Peelable coatings offer an effective and non-damaging method for removing contaminants from optical surfaces. In this study, an amphiphilic polyacrylate copolymer (PMLEA) was synthesized via solution radical copolymerization using the lipophilic monomer lauryl acrylate (LA) and hydrophilic monomers ER-10, methyl methacrylate (MMA), and butyl acrylate (BA). The structure and molecular weight of the copolymer were characterized using Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and gel permeation chromatography (GPC). The hydrophilic–lipophilic balance, surface tension, and wettability of the copolymer were analyzed through water titration, the platinum plate method, and liquid contact angle tests. The cleaning performance of the copolymer coating on quartz glass surface contaminants was evaluated using optical microscopy and Ultraviolet-Visible Near-Infrared (UV-Vis-NIR) spectroscopy. The study examined the effect of varying the ratio of LA to ER-10 on the hydrophilicity, lipophilicity, cleaning efficiency, and mechanical properties of the copolymer coating. The results showed that when the mass ratio of LA to ER-10 was 1:2, the synthesized copolymer exhibited optimal performance in removing dust, grease, and fingerprints from quartz glass surfaces. The coating had a tensile strength of 2.57 MPa, an elongation at break of 183%, and a peeling force of 2.07 N m−1.

Background: Neurofilaments are neuron specific skeleton proteins maintaining axon transduction speed, leaked into cerebrospinal fluid and serum after axonal injury or neuron death. Sleep duration change has long related to many health issues but lack laboratory examination. Methods: This study enrolled total 10,175 participants from 2013 to 2014 National Health and Nutrition Examination Survey and used a multi-variable linear model to analyze the relationship between sleep duration and serum neurofilament light chain (sNfL) level. Results: There was a fixed relationship between sleep duration and sNfL level (β = 0.65, p = 0.0280). After adjusted for covariates, this relationship still (β = 0.82, p = 0.0052). Segmented regression showed that the turning point of sleep duration was 7 h 1 h decrease in sleep duration was significantly associated with −1.26 higher sNfL level (95 % CI: 2.25, −0.28; p = 0.0115) when sleep duration 7 h. Furthermore, the stratified analysis indicated that the associations between sleep duration and sNfL level were stronger among those normal body mass index and trouble sleeping (p-interaction

Abrus cantoniensis Hance (AC) is popularly consumed as a kind of medicine homologous food plant. This paper was to examine the hepatoprotective effects and mechanism of AC against liver damage triggered by APAP. Results displayed that AC extract could significantly reduce AST and ALT activities and alleviate histopathological injury via attenuating oxidative stress, hepatocyte apoptosis, and inflammation. In vitro, AC extract inhibited the ROS production and apoptosis by inhibiting MAPK signaling pathway in APAP-induced HepG2. Inflammation was relieved via blocking NF-κB signaling pathways in LPS-induced THP-1 cell. Furthermore, we found that AC extract was capable of regulating the expression of APAP metabolism-related enzymes, thus promoting the excretion and detoxification of APAP. Finally, a reliable UPLC-MS/MS method was set up for the chemical profiling of AC extract. These results indicated that AC is expected to be developed as a functional food or health product for the prevention and treatment of APAP poisoning.

Abstract Cognitive impairment is a multifactorial and multi-step pathological process that places a heavy burden on patients and the society. Neuroinflammation is one of the main factors leading to cognitive impairment. The inflammasomes are multi-protein complexes that respond to various microorganisms and endogenous danger signals, helping to initiate innate protective responses in inflammatory diseases. NLRP3 inflammasomes produce proinflammatory cytokines (interleukin IL-1β and IL-18) by activating caspase-1. In this review, we comprehensively describe the structure and functions of the NLRP3 inflammasome. We also explore the intrinsic relationship between the NLRP3 inflammasome and cognitive impairment, which involves immune cell activation, cell apoptosis, oxidative stress, mitochondrial autophagy, and neuroinflammation. Finally, we describe NLRP3 inflammasome antagonists as targeted therapies to improve cognitive impairment.

Abstract Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

BackgroundNonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown.MethodsUsing the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes.ResultsSeven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the ‘cholesterol homeostasis’ pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression.ConclusionIn summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.

Background: Osteoporosis (OP) is a chronic bone metabolic disease and a serious global public health problem. Several studies have shown that mitophagy plays an important role in bone metabolism disorders; however, its role in osteoporosis remains unclear.Methods: The Gene Expression Omnibus (GEO) database was used to download GSE56815, a dataset containing low and high BMD, and differentially expressed genes (DEGs) were analyzed. Mitochondrial autophagy-related genes (MRG) were downloaded from the existing literature, and highly correlated MRG were screened by bioinformatics methods. The results from both were taken as differentially expressed (DE)-MRG, and Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed. Protein-protein interaction network (PPI) analysis, support vector machine recursive feature elimination (SVM-RFE), and Boruta method were used to identify DE-MRG. A receiver operating characteristic curve (ROC) was drawn, a nomogram model was constructed to determine its diagnostic value, and a variety of bioinformatics methods were used to verify the relationship between these related genes and OP, including GO and KEGG analysis, IP pathway analysis, and single-sample Gene Set Enrichment Analysis (ssGSEA). In addition, a hub gene-related network was constructed and potential drugs for the treatment of OP were predicted. Finally, the specific genes were verified by real-time quantitative polymerase chain reaction (RT-qPCR).Results: In total, 548 DEGs were identified in the GSE56815 dataset. The weighted gene co-expression network analysis(WGCNA) identified 2291 key module genes, and 91 DE-MRG were obtained by combining the two. The PPI network revealed that the target gene for AKT1 interacted with most proteins. Three MRG (NELFB, SFSWAP, and MAP3K3) were identified as hub genes, with areas under the curve (AUC) 0.75, 0.71, and 0.70, respectively. The nomogram model has high diagnostic value. GO and KEGG analysis showed that ribosome pathway and cellular ribosome pathway may be the pathways regulating the progression of OP. IPA showed that MAP3K3 was associated with six pathways, including GNRH Signaling. The ssGSEA indicated that NELFB was highly correlated with iDCs (cor = −0.390, p < 0.001). The regulatory network showed a complex relationship between miRNA, transcription factor(TF) and hub genes. In addition, 4 drugs such as vinclozolin were predicted to be potential therapeutic drugs for OP. In RT-qPCR verification, the hub gene NELFB was consistent with the results of bioinformatics analysis.Conclusion: Mitophagy plays an important role in the development of osteoporosis. The identification of three mitophagy-related genes may contribute to the early diagnosis, mechanism research and treatment of OP.

Magnetoencephalography (MEG) is a non-invasive technique that can precisely capture the dynamic spatiotemporal patterns of the brain by measuring the magnetic fields arising from neuronal activity along the order of milliseconds. Observations of brain dynamics have been used in cognitive neuroscience, the diagnosis of neurological diseases, and the brain-computer interface (BCI). In this study, we outline the basic principle, signal processing, and source localization of MEG, and describe its clinical applications for cognitive assessment, the diagnoses of neurological diseases and mental disorders, preoperative evaluation, and the BCI. This review not only provides an overall perspective of MEG, ranging from practical techniques to clinical applications, but also enhances the prevalent understanding of neural mechanisms. The use of MEG is expected to lead to significant breakthroughs in neuroscience.

Abstract Purpose There are few studies on the risk factors of postoperative complications after surgical treatment of hepatic hemangioma (HH). This study aims to provide a more scientific reference for clinical treatment. Methods The clinical characteristics and operation data of HH patients undergoing surgical treatment in the First Affiliated Hospital of Air Force Medical University from January 2011 to December 2020 were retrospectively collected. All enrolled patients were divided into two groups based on the modified Clavien-Dindo classification: Major group (Grade II/III/IV/V) and Minor group (Grade I and no complications). Univariate and multivariate regression analysis was used to explore the risk factors for massive intraoperative blood loss (IBL) and postoperative Grade II and above complications. Results A total of 596 patients were enrolled, with a median age of 46.0 years (range, 22–75 years). Patients with Grade II/III/IV/V complications were included in the Major group (n = 119, 20%), and patients with Grade I and no complications were included in the Minor group (n = 477, 80%). The results of multivariate analysis of Grade II/III/IV/V complications showed that operative duration, IBL, and tumor size increased the risk of Grade II/III/IV/V complications. Conversely, serum creatinine (sCRE) decreased the risk. The results of multivariate analysis of IBL showed that tumor size, surgical method, and operative duration increased the risk of IBL. Conclusions Operative duration, IBL, tumor size, and surgical method are independent risk factors that should be paid attention to in HH surgery. In addition, as an independent protective factor for HH surgery, sCRE should attract more attention from scholars.

Antiviral responses are often accompanied by translation inhibition and formation of stress granules (SGs) in infected cells. However, the triggers for these processes and their role during infection remain subjects of active investigation. Copy-back viral genomes (cbVGs) are the primary inducers of the mitochondrial antiviral signaling (MAVS) pathway and antiviral immunity during Sendai virus (SeV) and respiratory syncytial virus (RSV) infections. The relationship between cbVGs and cellular stress during viral infections is unknown. Here, we show that SGs form during infections containing high levels of cbVGs, and not during infections with low levels of cbVGs. Moreover, using RNA fluorescent in situ hybridization to differentiate accumulation of standard viral genomes from cbVGs at a single-cell level during infection, we show that SGs form exclusively in cells that accumulate high levels of cbVGs. Protein kinase R (PKR) activation is increased during high cbVG infections and, as expected, is necessary for virus-induced SGs. However, SGs form independent of MAVS signaling, demonstrating that cbVGs induce antiviral immunity and SG formation through 2 independent mechanisms. Furthermore, we show that translation inhibition and SG formation do not affect the overall expression of interferon and interferon stimulated genes during infection, making the stress response dispensable for global antiviral immunity. Using live-cell imaging, we show that SG formation is highly dynamic and correlates with a drastic reduction of viral protein expression even in cells infected for several days. Through analysis of active protein translation at a single-cell level, we show that infected cells that form SGs show inhibition of protein translation. Together, our data reveal a new cbVG-driven mechanism of viral interference where cbVGs induce PKR-mediated translation inhibition and SG formation, leading to a reduction in viral protein expression without altering overall antiviral immunity.

Some studies have shown that sorafenib could significantly prolong the overall survival of patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE). However, other studies revealed that patients had no access to sorafenib-related survival benefits after TACE. To identify the predictive biomarkers of therapeutic efficacy of sorafenib, we explored the potential predictive value of vascular endothelial growth factor (VEGF) and other clinical variables for survival benefits from sorafenib in patients treated with TACE previously. The results demonstrated that patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L showed significant survival benefits from sorafenib after TACE treatment compared with those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L. Meanwhile, patients with VEGF > 131.09 pg/mL may obtain sorafenib-associated survival benefits after TACE when compared to those with VEGF ≤ 131.09 pg/mL, which needs further confirmation. The abovementioned results are helpful to confirm the specific population who are sensitive to targeted therapy. (1) Background: VEGF plays a crucial role in modulating proliferation and metastasis in HCC. We aimed to explore the relationship between VEGF and the prognosis, as well as the mortality risk of HCC patients who received TACE, and whether it and other variables could be considered as potential biomarkers for predicting the benefits from sorafenib. (2) Method: A total of 230 consecutive newly diagnosed patients with unresectable HCC treated with either TACE or TACE–sorafenib were collected retrospectively. Cox regression analyses were performed to evaluate the prognostic value of VEGF. Furthermore, restricted cubic splines were fitted to assess the nonlinear associations between VEGF and OS, and the threshold effect analysis was subsequently performed. Lastly, the potential factors for predicting the survival benefits from sorafenib after the TACE procedure were identified using the Cox proportional hazard model with an interaction term. (3) Results: VEGF was recognized as an independent prognostic factor for OS in the TACE alone cohort (HR = 3.237, p = 0.013). A nonlinear relationship was observed between VEGF and OS in HCC patients with TACE administration after adjustment for confounders (p for nonlinearity = 0.030); the mortality risk increased with increasing the baseline VEGF before the inflection point, and the HR for death was 1.008. There was no significant interaction between the VEGF levels and treatment modality (p for interaction = 0.233), and further studies are needed to identify its predictive value on the efficacy of sorafenib. Patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L derived significant sorafenib-related benefits in OS when compared to those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L (p for interaction = 0.004 and 0.031, respectively). (4) Conclusions: Within a certain concentration range, elevated baseline VEGF meant an increased risk of death in HCC patients treated with TACE. Significant improvements in OS associated with sorafenib were observed in patients with higher tumor size and lower total bilirubin after TACE treatment.

Abstract Background cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investigate the clinical features of patients with late-onset cblC deficiency and explore diagnosis and management strategies around puberty. Results This study included 56 patients (35 males and 21 females) with late-onset cblC deficiency who were admitted to our clinic between 2002 and September 2021. The diagnosis was confirmed by metabolic and genetic tests. The clinical and biochemical features, disease triggers, outcome, and associated genetic variants were examined. The onset age ranged from 10 to 20 years (median age, 12 years). Fifteen patients (26.8%) presented with symptoms after infection or sports training. Further, 46 patients (82.1%) had neuropsychiatric diseases; 11 patients (19.6%), cardiovascular diseases; and 6 patients (10.7%), pulmonary hypertension. Renal damage was observed in 6 cases (10.7%). Genetic analysis revealed 21 variants of the MMACHC gene in the 56 patients. The top five common variants detected in 112 alleles were c.482G > A (36.6%), c.609G > A (16.1%), c.658_660delAAG (9.8%), c.80A > G (8.0%), and c.567dupT (6.3%). Thirty-nine patients carried the c.482G > A variant. Among 13 patients who exhibited spastic paraplegia as the main manifestation, 11 patients carried c.482G > A variants. Six patients who presented with psychotic disorders and spastic paraplegia had compound heterozygotic c.482G > A and other variants. All the patients showed improvement after metabolic treatment with cobalamin, l-carnitine, and betaine, and 30 school-aged patients returned to school. Two female patients got married and had healthy babies. Conclusions Patients with late-onset cblC deficiency present with a wide variety of neuropsychiatric symptoms and other presentations, including multiple organ damage. As a result, cb1C deficiency can easily be misdiagnosed as other conditions. Metabolic and genetic studies are important for accurate diagnosis, and metabolic treatment with cobalamin, l-carnitine, and betaine appears to be beneficial.

Periodontitis is an inflammatory disease initiated by periodontopathogenic bacteria in the dental plaque biofilms. Understanding the role of Porphyromonas gingivalis (P. gingivalis), a keystone pathogen associated with chronic periodontitis, in the inflammatory response is crucial. Herein, we investigated whether P. gingivalis infection triggers the expression of the type I IFN gene and various cytokines and leads to activation of the cGAMP synthase–stimulator of IFN genes (cGAS-STING) pathway both in vitro and in a mouse model. Additionally, in an experimental model of periodontitis using P. gingivalis, StingGt mice showed lower levels of inflammatory cytokines and bone resorption than wild-type mice. Furthermore, we report that a STING inhibitor (SN-011) significantly decreased inflammatory cytokine production and osteoclast formation in a periodontitis mouse model with P. gingivalis. In addition, STING agonist (SR-717) -treated periodontitis mice displayed enhanced macrophage infiltration and M1 macrophage polarization in periodontal lesions compared with that in vehicle-treated periodontitis mice. In conclusion, our results demonstrate that the cGAS-STING signaling pathway may be one of the key mechanisms crucial for the P. gingivalis-induced inflammatory response that leads to chronic periodontitis.

Objective: To explore the related risk factors of serous exudation after antibiotic-loaded calcium sulfate treatment of fracture-related infections and to provide a theoretical basis for clinical treatment and prevention of serous exudation complications.Methods: The clinical data of 145 patients with limb fracture-related infection treated with antibiotic-loaded calcium sulfate in Xi’an Honghui Hospital from January 2019 to December 2022 were retrospectively analyzed. All patients were diagnosed with fracture-related infection by preoperative magnetic resonance examination, bacterial culture and gene detection and received antibiotic-loaded calcium sulfate implantation. The postoperative serous exudation was recorded through hospitalization observation, outpatient review or follow-up. The collected clinical data were sorted out, and the patient data were divided into serous exudation groups and non-exudation groups. Firstly, the clinical data of the two groups were compared by single-factor analysis to screen out the risk factors. Then multivariate binary Logistic regression analysis determined the independent risk factors and protective factors.Results: 1) According to the inclusion and exclusion criteria, there were 145 cases with complete clinical data, including 27 cases in the non-infectious exudation group and 118 cases in the non-exudative group; 2) Univariate analysis showed that the history of diabetes, smoking history, calcium sulfate implantation, drainage time, combined flap surgery, geometric shape of implanted calcium sulfate, and thickness of soft tissue covered by the surgical area were all associated with the occurrence of non-infectious exudation after antibiotic-loaded calcium sulfate implantation (p < 0.05); 3) The amount of implanted calcium sulfate was more [OR = 5.310, (1.302–21.657), p = 0.020], combined with flap surgery [OR = 3.565, (1.195–10.641), p = 0.023], and the thickness of soft tissue coverage in the operation area was thinner [OR = 5.305, (1.336–21.057), p = 0.018]. Longer drainage time [OR = 0.210, (0.045–0.967), p = 0.045] was a protective factor for non-infectious exudation after antibiotic-loaded calcium sulfate implantation.Conclusion: 1) The probability of serous exudation in patients with fracture-associated infection after antibiotic-loaded calcium sulfate surgery was 18.62%. This complication may cause a heavier economic and psychological burden on patients; 2) With the increase of bone infection area and the application of more calcium sulfate, the incidence of serous exudation after antibiotic-loaded calcium sulfate surgery in patients with the fracture-related infection will increase, so we should use the amount of calcium sulfate reasonably on the premise of sufficient control of infection in clinical work, and the incidence of serous exudation will also increase due to the recent skin flap surgery and the thinner soft tissue coverage of calcium sulfate implantation area; 3) Under the premise of being able to drain the drainage from the surgical area, the longer drainage time of the drainage tube has a positive effect on preventing the occurrence of serous exudation.

The development of catalysts for low-temperature methane combustion is crucial in addressing the greenhouse effect. An effective industrial catalyst strategy involves optimizing noble metal utilization and boosting metal–metal interaction. Here, the PdNi-H catalyst was synthesized using the self-assembly method, achieving the high dispersion and close proximity of Pd and Ni atoms compared to the counterparts prepared by the impregnation method, as confirmed by EDS mapping. The XRD and TEM results revealed Pd2+ and Ni2+ doping within the CeO2 lattice, causing distortions and forming Pd-O-Ce or Ni-O-Ce structures. These structures promoted oxygen vacancy formation in CeO2, and this was further confirmed by the Raman and XPS results. Consequently, the PdNi-H catalyst demonstrated an excellent redox ability and catalytic activity, achieving lower ignition and complete methane burning temperatures at 282 and 387 °C, respectively. The highly dispersed PdNi species played a pivotal role in activating methane for enhanced redox ability. Additionally, the narrow size distribution range contributed to more vacancies on the surface of CeO2, as confirmed by the XPS results, thereby facilitating the activation of gas phase oxygen to form oxygen species (O2−). This collaborative catalytic approach presents a promising strategy for developing efficient and stable methane combustion catalysts at low temperatures.

Abstract Objective The application of double plating in olecranon fractures is becoming increasingly widespread. There is no research comparing this technique with traditional tension band wiring (TBW) and the single plate technique. The purpose of this study was to compare the efficacy of three fixation techniques in olecranon fractures. Materials and methods From March 2016 to May 2020, we collected the clinical data of 95 patients with olecranon fractures who underwent surgical treatment. Thirty-five patients received TBW surgery (TBW Group), 32 patients received a 3.5 mm locking compression plate (LCP, 3.5 mm LCP Group), and 28 patients received double mini-locking plate treatment (DP Group). The operation time, fracture union time, time of return to work, range of motion (ROM), soft tissue stimulation to remove internal fixation, and patient-related functional results (the Weseley score, Mayo Elbow Performance Score [MEPS], and Disabilities of Arm, Shoulder and Hand Score [DASH]) were recorded. The clinical results and complications of the three internal fixation techniques were compared. Results The average follow-up time was 15.011.82 months (12–18 months). All patients’ fractures healed by first intention. There were no statistically significant differences in the operation time, fracture union time, ROM, Weseley score, MEPS or DASH scores of the three groups of patients. The postoperative return time for patients in the TBW group was 10.002.15 weeks, the 3.5 mm LCP group was 9.561.93 weeks, and the DP group was 8.432.38 weeks (P = 0.014); 12 patients in the TBW group required removal of plant due to soft tissue stimulation, the 3.5 mm LCP group had 8 cases, and the DP group had 2 cases (P = 0.038). Conclusion The postoperative clinical results and elbow joint function of patients with olecranon fractures fixed by tension band wiring, 3.5 mm LCP and double mini-locking plate are similar, which indicates that double-plate technology can be used as an alternative to the two groups of traditional techniques. In addition, double-plate technology also helps patients return to work earlier and has a lower incidence of soft tissue stimulation.

Abstract Objective An inferior pole fracture of the patella requires surgical treatment to restore the knee extension mechanism of the knee joint. Different from other types of patellar fractures, inferior pole fractures are usually comminuted, and other traditional fixation methods, such as tension band wiring, may not meet the fixation needs. We propose fixing inferior pole fractures of the patella with a custom-made anchor-like plate combined with cerclage and report the surgical outcomes. Material and methods This is a retrospective clinical study. From June 2018 to August 2020, 21 patients with inferior patella fracture treated at Hong Hui Hospital Affiliated to Xi’an Jiaotong University received a custom-made anchor-like plate combined with cerclage. Complications of the surgical fixation methods and final knee function were used as the main outcome measures. Results All fractures achieved good union, and the union time ranged from 8 to 12 weeks. No patients had serious complications, such as internal fixation failure or infection. The average duration of surgery of patients was 75.05 7.26 min, and the intraoperative blood loss was 60.099.49 ml. At the last follow-up, the range of motion of the knee was 120°-140°, with an average of 131.436.92°, the Bostman score was 27–30, and the Lysholm score ranged from 82 to 95. All patients showed good knee function one year after the operation. Conclusion We used a modified T-shaped plate combined with cerclage technology to fix inferior fractures pole of the patella, providing reliable fixation, allowing early functional exercise of the knee joint, and providing patients with good knee joint function after surgery.

Spontaneous migration of H-atoms from metal particles to a nonreducible oxide support is generally limited by thermodynamics. Here, small oxygenate molecules are found to act as effective H-carriers to promote this process and lead to much improved hydrodeoxygenation rates on Pt-Fe/SiO2 catalysts.

Abstract Background Propionic acidemia is a severe inherited metabolic disorder, caused by the deficiency of propionyl-CoA carboxylase which encoded by the PCCA and PCCB genes. The aim of the study was to investigate the clinical features and outcomes, molecular epidemiology and phenotype-genotype relationship in Chinese population. Methods We conducted a retrospective study of 60 Chinese patients diagnosed at Peking University First Hospital from 2007 to 2020. Their clinical and laboratory data were reviewed. The next-generation sequencing was conducted on blood samples from 58 patients. Results Only 5 (8.3%) patients were identified by newborn screening. In the rest 55 patients, 25 had early-onset (≤ 3 months) disease and 30 had late-onset (> 3 months) disease. Neurological abnormalities were the most frequent complications. Five cases detected by newborn screening had basically normal development. Nine (15%) cases died in our cohort. 24 patients (41.4%) harbored PCCA variants, and 34 (58.6%) harbored PCCB variants. 30 (11 reported and 19 novel) variants in PCCA and 28 (18 reported and 10 novel) variants in PCCB mere identified. c.2002G>A and c.937C>T in PCCA, and c.838dupC in PCCB were the most common variants in this cohort, with the frequency of 13.9% (6/44 alleles), 13.9% (6/44 alleles) and 12.5% (8/64 alleles), respectively. There was no difference in clinical features and outcomes between patients with PCCA and PCCB variants. Certain variants with high frequencies and homozygotes may be associated with early-onset or late-onset propionic acidemia. Conclusions Although the genotype–phenotype correlation is still unclear, certain variants seemed to be related to early-onset or late-onset propionic acidemia. Our study further delineated the complex clinical manifestations of propionic acidemia and expanded the spectrum of gene variants associated with propionic acidemia.

As a filamentous pathogenic fungus with high-yield of aflatoxin B1, Aspergillus flavus is commonly found in various agricultural products. It is crucial to develop effective strategies aimed at the prevention of the contamination of A. flavus and aflatoxin. Hexokinase AfHxk1 is a critical enzyme in fungal glucose metabolism. However, the role of AfHxk1 in A. flavus development, aflatoxin biosynthesis, and virulence has not yet been explored. In this study, afHxk1 gene deletion mutant (ΔafHxk1), complementary strain (Com-afHxk1), and the domain deletion strains (afHxk1ΔD1 and afHxk1ΔD2) were constructed by homologous recombination. Phenotype study and RT-qPCR revealed that AfHxk1 upregulates mycelium growth and spore and sclerotia formation, but downregulates AFB1 biosynthesis through related classical signaling pathways. Invading models and environmental stress analysis revealed that through involvement in carbon source utilization, conidia germination, and the sensitivity response of A. flavus to a series of environmental stresses, AfHxk1 deeply participates in the regulation of pathogenicity of A. flavus to crop kernels and Galleria mellonella larvae. The construction of domain deletion strains, afHxk1ΔD1 and afHxk1ΔD2, further revealed that AfHxk1 regulates the morphogenesis, mycotoxin biosynthesis, and the fungal pathogenicity mainly through its domain, Hexokinase_2. The results of this study revealed the biological role of AfHxk1 in Aspergillus spp., and might provide a novel potential target for the early control of the contamination of A. flavus.

ObjectiveCblC deficiency, the most common cobalamin metabolic abnormality, is caused by pathogenic variants in the MMACHC gene. The renal complications of this disease have been described only in a small number of cases. This study aimed to better delineate renal phenotype and genetic characteristics in Chinese children with cblC defect.MethodsChildren with cblC deficiency who manifested as kidney damage were enrolled. Clinical, renal pathological, and genetic data were reviewed in detail.ResultsSeven cases were enrolled. Ages at disease onset ranged from 9 months to 5 years. All patients presented with hematuria and proteinuria, and 2/7 cases presented with nephrotic syndrome. Renal dysfunction was observed in 4/7 cases. Renal biopsy was performed in 5/7 cases, and all of them had renal thrombotic microangiopathy. Macrocytic anemia was detected in all seven patients. Six out of seven cases had hypertension, and 2/7 cases presented with pulmonary hypertension. Two of them had a mild intellectual disability, and one suffered from epilepsy. Increased urine methylmalonic acid and plasma homocysteine were detected in seven cases, while two patients had normal levels of urine methylmalonic acid at the initial evaluation. After diagnosis, all seven cases were treated with hydroxocobalamin IM. Six cases were followed-up for 3–8 years. After treatments, anemia was the first to be recovered, followed by proteinuria. Renal function recovered after 1 year in two cases, whereas patient 2 progressed to stage 2 chronic kidney disease 13 years after onset. While a case presented with end-stage kidney disease because of late diagnosis, one case died 3 months after disease onset due to giving up treatment. Three MMACHC pathogenic variants c.80A > G (8/14), c.609G > A (4/14), and c.658_660delAAG (2/14) were detected in all seven children.ConclusionMMACHC variant c.80A > G may be associated with prominent renal complications in Chinese cblC patients. Macrocytic anemia and hyperhomocysteinemia are useful clues for patients with hematuria and proteinuria caused by cblC defect. The most frequent renal pathological manifestation is thrombotic microangiopathy. Early diagnosis and treatment resulted in improving renal and hematological signs.

Abstract The active and stable palladium (Pd) based catalysts for CH4 conversion are of great environmental and industrial significance. Herein, we employed N2 as an optimal activation agent to develop a Pd nanocluster exsolved Ce‐incorporated perovskite ferrite catalyst toward lean methane oxidation. Replacing the traditional initiator of H2, the N2 was found as an effective driving force to selectively touch off the surface exsolution of Pd nanocluster from perovskite framework without deteriorating the overall material robustness. The catalyst showed an outstanding T50 (temperature of 50% conversion) plummeting down to 350°C, outperforming the pristine and H2‐activated counterparts. Further, the combined theoretical and experimental results also deciphered the crucial role that the atomically dispersed Ce ions played in both construction of active sites and CH4 conversion. The isolated Ce located at the A‐site of perovskite framework facilitated the thermodynamic and kinetics of the Pd exsolution process, lowering its formation temperature and promoting its quantity. Moreover, the incorporation of Ce lowered the energy barrier for cleavage of C─H bond, and was dedicated to the preservation of highly reactive PdOx moieties during stability measurement. This work successfully ventures uncharted territory of in situ exsolution to provide a new design thinking for a highly performed catalytic interface.

Abstract Background Immunotherapy is a valuable option for cancer treatment, and the curative effect of anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using 68Ga-NOTA-Nb109 nanobody. 68Ga-NOTA-Nb109 was generated by radionuclide (68Ga) labeling of Nb109 using a NOTA chelator. To facilitate clinical trials, we explored the optimal dose range of 68Ga-NOTA-Nb109 in BALB/c A375-hPD-L1 tumor-burdened nude mice and C57-hPD-L1 transgenic MC38-hPD-L1 tumor-burdened mice by administration of a single intravenous dose of 68Ga-NOTA-Nb109 and confirmed the dose in cynomolgus monkeys. The biodistribution data of cynomolgus monkey PET images were extrapolated to estimate the radiation dose for the adult male and female using OLINDA2.1 software. Results 68Ga-NOTA-Nb109 was stable in physiologic media and human serum. Ex vivo biodistribution studies showed rapid and specific uptake in A375-hPD-L1 or MC38-hPD-L1 tumors. The estimated ED50 was approximately 5.4 µg in humanized mice. The injected mass (0.3–100 µg in nude mice and approximately 1–100 µg in humanized mice) greatly influenced the general biodistribution, with a better tumor-to-background ratio acquired at lower doses of Nb109 (0.3–10 µg in nude mice and approximately 1 µg in humanized mice), indicating maximum uptake in tumors at administered mass doses below the estimated ED50. Therefore, a single 15-μg/kg dose was adopted for the PET/CT imaging in the cynomolgus monkey. The highest specific and persistent uptake of the tracer was detected in the spleen, except the levels in the kidney and urine bladder, which was related to metabolism and excretion. The spleen-to-muscle ratio of the tracer exceeded 10 from immediately to 4 h after administration, indicating that the dose was appropriate. The estimated effective dose was calculated to yield a radiation dose of 4.1 mSv to a patient after injecting 185 MBq of 68Ga-NOTA-Nb109. Conclusion 68Ga-NOTA-Nb109 showed specific accumulation in hPD-L1 xenografts in ex vivo biodistribution studies and monkey PET/CT imaging. The dose escalation distribution data provided a recommended dose range for further use, and the safety of the tracer was confirmed in dosimetry studies.

Objective: This study aimed to compare the biomechanical stability and clinical efficacy of the Kirschner-wire (K-wire) tension band combined with patellar cerclage and an anchor-loop plate (ALP) in treating inferior-pole patellar fracture.Methods: The finite element model was established to analyze the mechanical properties of a K-wire tension band combined with patellar cerclage and ALP fixation in the treatment of inferior patellar pole fracture. The clinical data of 49 patients with patellar inferior-pole fracture (AO/OTA 34 A1) admitted to our hospital from January 2017 to July 2021 were retrospectively analyzed. Among these, 28 cases were fixed with ALPs (ALP group) and 21 cases were fixed with K-wire tension bands combined with patellar cerclage (K-wire group). By reviewing the medical records and follow-up results, we compared the operation time, final knee joint activity, incidence of secondary surgery, postoperative complications, and joint function recovery between the two groups.Results: The biomechanical analysis of the finite element model showed that the maximum displacement of the K-wire group was 1.87 times that of the ALP group. The maximum stress of the K-wire group was 1.34 times that of the ALP group. The maximum stress of the pole bone in the K-wire group was 13.89 times that of the ALP group. The average follow-up times of the K-wire group and ALP group were similar (p > 0.05), and the average ages of the two groups were similar (p > 0.05). The operation time of the ALP group was significantly shorter than that of the K-wire group (p < 0.05).The final knee joint activity of the ALP group was significantly greater than that of the K-wire group (p < 0.05). The Bostman patellar fracture function score of the ALP group was significantly better than that of the K-wire group at 3 and 9 months after operation (p < 0.05). Postoperative complications of the two groups included 1 case (3.6%) in the ALP group with internal fixation-stimulation complications and, in the K-wire group, 3 cases (14.3%) with internal fixation stimulation complications and 1 case (4.8%) with infection.Conclusion: The ALP and K-wire tension band combined with patella cerclage models were tested at 500 N, and no damage occurred, indicating that the newly designed ALP is safe in mechanical structure. The ALP has better therapeutic effect in biomechanical stability, postoperative complications, secondary surgery, and knee function. This technique is an effective method for the treatment of inferior-pole patellar fracture.

Abstract Background UTP-glucose-1-phosphoryl transferase (UGPase) catalyzes the synthesis of UDP-glucose, which is essential for generating the glycogen needed for the synthesis of bacterial lipopolysaccharide (LPS) and capsular polysaccharide, which play important roles in bacterial virulence. However, the molecular function of UGPase in Brucella is still unknown. Results In this study, the ubiquitination modification of host immune-related protein in cells infected with UGPase-deleted or wild-type Brucella was analyzed using ubiquitination proteomics technology. The ubiquitination modification level and type of NF-κB Essential Modulator (NEMO or Ikbkg), a molecule necessary for NF-κB signal activation, was evaluated using Coimmunoprecipitation, Western blot, and dual-Luciferase Assay. We found 80 ubiquitin proteins were upregulated and 203 ubiquitin proteins were downregulated in cells infected with B. melitensis 16 M compared with those of B. melitensis UGPase-deleted strain (16 M-UGPase−). Moreover, the ubiquitin-modified proteins were mostly enriched in the categories of regulation of kinase/NF-κB signaling and response to a bacterium, suggesting Brucella UGPase inhibits ubiquitin modification of related proteins in the host NF-κB signaling pathway. Further analysis showed that the ubiquitination levels of NEMO K63 (K63-Ub) and Met1 (Met1-Ub) were significantly increased in the 16 M-UGPase−-infected cells compared with that of the 16 M-infected cells, further confirming that the ubiquitination levels of NF-κB signaling-related proteins were regulated by the bacterial UGPase. Besides, the expression level of IκBα was decreased, but the level of p-P65 was significantly increased in the 16 M-UGPase−-infected cells compared with that of the 16 M- and mock-infected cells, demonstrating that B. melitensis UGPase can significantly inhibit the degradation of IκBα and the phosphorylation of p65, and thus suppressing the NF-κB pathway. Conclusions The results of this study showed that Brucella melitensis UGPase inhibits the activation of NF-κB by modulating the ubiquitination of NEMO, which will provide a new scientific basis for the study of immune mechanisms induced by Brucella.

In this work, La-doped Mg-Ni multiphase alloys were prepared by resistance melting furnace (RMF) and then modified by high-energy ball milling (HEBM). The hydrolysis H2 generation kinetics/thermodynamics of prepared alloys in NaCl solutions have been investigated with the help of nonlinear and linear fitting by Avrami-Erofeev and Arrhenius equations. Combining the microstructure information before and after hydrolysis and thermodynamics fitting results, the hydrolysis H2 generation mechanism based on nucleation & growth has been elaborated. The final H2 generation capacities of 0La, 5La, 10La and 15 La alloys are 677, 653, 641 and 770 mL·g − 1 H2 in 240 min at 291 K, respectively. While, the final H2 generation capacities of HEBM 0La, 5La, 10La and 15 La alloys are 632, 824, 611 and 653 mL·g − 1 H2 in 20 min at 291 K, respectively. The as-cast 15La alloy and HEMB 5La alloy present the best H2 production rates and final H2 production capacities, especially the HEBM 5La can rapidly achieve high H2 generation capacity (670 and 824 mL·g − 1 H2) at low temperature (291 K) within short time (5 and 20 min). The difference between the H2 generation capacities is mainly originated from the initial nucleation rate of Mg(OH)2 and the subsequent processes affected by the microstructures and phase compositions of the hydrolysis alloys. Relative low initial nucleation rate and fully growth of Mg(OH)2 nucleus are the premise of high H2 generation capacity due to the hydrolysis H2 generation process consisted by the nucleation, growth and contacting of Mg(OH)2 nucleus. To utilization H2 by designing solid state H2 generators using optimized Mg-based alloys is expected to be a feasible H2 generation strategy at the moment.

Surfactants are increasingly used in systems that come into contact with the human body, such as food, pharmaceuticals, cosmetics and personal hygiene products. Increasing attention is being devoted to the toxic effects of surfactants in various human contact formulations, as well as the removal of residual surfactants. In the presence of ozone (O3), anion surfactants—a characteristic micro-pollutant—such as sodium dodecylbenzene sulfonate (SDBS) in greywater, can be removed using radical advanced oxidation. Herein, we report a systematic study of the SDBS degradation effect of O3 activated by vacuum ultraviolet (VUV) irradiation and the influence of water composition on VUV/O3, and determined the contribution of radical species. We show a synergistic effect of VUV and O3, while VUV/O3 reached a higher mineralization (50.37%) than that of VUV (10.63%) and O3 (29.60%) alone. The main reactive radicals of VUV/O3 were HO•. VUV/O3 had an optimal pH of 9. The addition of SO42− had almost no effect on the degradation of SDBS by VUV/O3, Cl− and HCO3− slightly reduced the reaction rate, and NO3− had a significant inhibition on the degradation. In total, SDBS had three isomers, with which the three degradation pathways were very comparable. Compared with SDBS, the toxicity and harmfulness of the degradation by-products of the VUV/O3 process decreased. Additionally, VUV/O3 could degrade synthetic anion surfactants from laundry greywater effectively. Overall, the results show the potential of VUV/O3 in safeguarding humans from residual surfactant hazards.

The henipaviruses, including Nipah virus (NiV) and Hendra virus (HeV), are biosafety level 4 (BSL-4) zoonotic pathogens that cause severe neurological and respiratory disease in humans. To study the replication machinery of these viruses, we developed robust minigenome systems that can be safely used in BSL-2 conditions. The nucleocapsid (N), phosphoprotein (P), and large protein (L) of henipaviruses are critical elements of their replication machinery and thus essential support components of the minigenome systems. Here, we tested the effects of diverse combinations of the replication support proteins on the replication capacity of the NiV and HeV minigenomes by exchanging the helper plasmids coding for these proteins among the two viruses. We demonstrate that all combinations including one or more heterologous proteins were capable of replicating both the NiV and HeV minigenomes. Sequence alignment showed identities of 92% for the N protein, 67% for P, and 87% for L. Notably, variations in amino acid residues were not concentrated in the N-P and P-L interacting regions implying that dissimilarities in amino acid composition among NiV and HeV polymerase complex proteins may not impact their interactions. The observed indiscriminate activity of NiV and HeV polymerase complex proteins is different from related viruses, which can support the replication of heterologous genomes only when the whole polymerase complex belongs to the same virus. This newly observed promiscuous property of the henipavirus polymerase complex proteins likely attributed to their conserved interaction regions could potentially be harnessed to develop universal anti-henipavirus antivirals. IMPORTANCE Given the severity of disease induced by Hendra and Nipah viruses in humans and the continuous emergence of new henipaviruses as well as henipa-like viruses, it is necessary to conduct a more comprehensive investigation of the biology of henipaviruses and their interaction with the host. The replication of henipaviruses and the development of antiviral agents can be studied in systems that allow experiments to be performed under biosafety level 2 conditions. Here, we developed robust minigenome systems for the Nipah virus (NiV) and Hendra virus (HeV) that provide a convenient alternative for studying NiV and HeV replication. Using these systems, we demonstrate that any combination of the three polymerase complex proteins of NiV and HeV could effectively initiate the replication of both viral minigenomes, which suggests that the interaction regions of the polymerase complex proteins could be effective targets for universal and effective anti-henipavirus interventions. [ABSTRACT FROM AUTHOR]

Abstract Background Although immunotherapy has revolutionized treatment strategies for some types of cancers, most patients failed to respond or obtain long-term benefit. Tumor-infiltrating CD8+ T lymphocytes are closely related to the treatment outcome and prognosis of patients. Therefore, noninvasive elucidation of both systemic and tumor-infiltrating CD8+ T lymphocytes is of extraordinary significance for patients during cancer immunotherapy. Herein, a panel of 68Ga-labeled Nanobodies were designed and investigated to track human CD8+ T cells in vivo through immuno-positron emission tomography (immunoPET). Results Among the screened Nanobodies, SNA006a showed the highest binding affinity and specificity to both human CD8 protein and CD8+ cells in vitro, with the equilibrium dissociation constant (K D ) of 6.4 × 10−10 M and 4.6 × 10−10 M, respectively. 68Ga-NOTA-SNA006 was obtained with high radiochemical yield and purity, and stayed stable for at least 1 h both in vitro and in vivo. Biodistribution and Micro-PET/CT imaging studies revealed that all tracers specifically concentrated in the CD8+ tumors with low accumulation in CD8− tumors and normal organs except the kidneys, where the tracer was excreted and reabsorbed. Notably, the high uptake of 68Ga-NOTA-SNA006a in CD8+ tumors was rapid and persistent, which reached 24.41 ± 1.00% ID/g at 1.5 h after intravenous injection, resulting in excellent target-to-background ratios (TBRs). More specifically, the tumor-to-muscle, tumor-to-liver, and CD8+ to CD8− tumor was 28.10 ± 3.68, 5.26 ± 0.86, and 19.58 ± 2.70 at 1.5 h, respectively. Furthermore, in the humanized PBMC-NSG and HSC-NPG mouse models, 68Ga-NOTA-SNA006a accumulated in both CD8+ tumors and specific tissues such as liver, spleen and lung where human CD8 antigen was overexpressed or CD8+ T cells located during immunoPET imaging. Conclusions 68Ga-NOTA-SNA006a, a novel Nanobody tracer targeting human CD8 antigen, was developed with high radiochemical purity and high affinity. Compared with other candidates, the long retention time, low background, excellent TBRs of 68Ga-NOTA-SNA006a make it precisely track the human CD8+ T cells in mice models, showing great potential for immunotherapy monitoring and efficacy evaluation.

New ventures have stronger learning motivation but higher failure rates. In the era of the digital economy, it is necessary to clarify whether and how learning orientation gives scientific guidance for new ventures. We developed a chain multiple intermediary model following the paradigm of “orientation → capability → performance,” which was empirically analyzed using data from 214 Chinese new ventures. The results show that learning orientation not only has a direct positive impact on new venture performance (NVP) but also has an indirect positive effect through the chain-mediating effect of absorptive capacity and innovation capacity. The study advances theoretical understanding of the effect and path of learning orientation on NVP, fosters in-depth research on organizational learning and dynamic capability, and provides targeted organizational learning solutions for new ventures in emerging economies.

Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare autosomal recessive metabolic disorder caused by mutations of the HMGCS2 gene. To date, no more than 60 patients have been reported throughout the world.Purpose: To analyze the clinical, biochemical, molecular, and outcome features of HMGCS2D in a case series of 10 new Chinese patients.Methods: This retrospective study includes 10 Chinese patients diagnosed with HMGCS2D. We collected and analyzed clinical data for all patients. We also reviewed clinical data for 39 cases that had been reported previously.Results: All of our patients had experienced their first metabolic crisis before 12 months old. The most common clinical manifestations were anorexia, dyspnea, and disturbance of consciousness (10/10), followed by vomiting (8/10), fever (7/10), cough (4/10), diarrhea, and seizures (3/10). Each patient (10/10) had a different degree of hepatomegaly and increased aminotransferase, severe metabolic acidosis, and hypofibrinogenemia. 9 patients presented with severe hypoglycemia and weak positives on qualitative tests of urinary ketone body. Patient 3 was the only one without hypoglycemia. Five patients had hypocalcemia, five patients had hyperammonemia, four patients had hyperuricemia, and three had hypertriglyceridemia. During the metabolic acidosis episode, we observed high dicarboxylic acid values in urine, and the elevated ratio of blood acetylcarnitine to free carnitine may have been an additional biochemical signature. However, all returned to normal during the interictal interval. Molecular analysis identified 15 variants in the HMGCS2 gene, of which 10 were novel (c.220G>A/p.E74K, c.407A>G/p.D136G, c.422T>A/p.V141D, c.719A>C/p.D240A, c.821G>A/p.R274H, c.39dupA/p.L14Tfs*59, c.1394delA/p.N465Tfs*10, c.788delT/p.L263Cfs*36, c.717T>G/p.Y239*, and c.1017-2A>G). Combining these with previous cases, the known mutation c.1201G>T/p.E401* has been found in 6/40 (15.0%) of mutated alleles in 21 Chinese patients from 20 families, while none have been found in other populations. We found that patients with biallelic truncation mutation appeared to show a more severe clinical condition through a literature review.Conclusion: This study analyzed the phenotypic and genetic features of HMGCS2D in a Chinese case series. We also expanded the HMGCS2 mutational spectrum with 10 novel variants. The c.1201G>T/p.E401* mutation was the most frequent, representing 15.0% of the mutated alleles in reported unrelated Chinese patients, and thus, it may be a hot spot mutation.

Abstract Background Progressive myoclonic epilepsy (PME) is a group of neurodegenerative diseases with genetic heterogeneity and phenotypic similarities, and many cases remain unknown of the genetic causes. This study is aim to summarize the clinical features and study the genetic causes of PME patients. Methods Sanger sequencing of the target gene, Next Generation Sequencing (NGS) panels of epilepsy, trio-based Whole Exome Sequencing (WES) and detection of cytosine-adenine-guanine (CAG) repeat number were used to investigate the genetic causes of PME patients. Results Thirty-eight children with PME whose seizure onset age ranged from 3 months to 12 years were collected from February 2012 to November 2019 in three hospitals in Beijing, China. The seizure types included myoclonic seizures (n = 38), focal seizures (n = 19), generalized tonic-clonie seizure (GTCS) (n = 13), absence seizures (n = 4), atonic seizures (n = 3), epileptic spasms (n = 2) and tonic seizures (n = 1). Twenty-seven cases were sporadic and 11 had family members affected. Established PME-related genes were identified in 30 out of 38 (78.9%) patients who had either recessively inherited or de novo heterozygous mutations. Among these 30 cases, there were 12 cases (31.6%) of neuronal ceroid lipofuscinoses (the causing gene contains TPP1, PPT1, CLN5, CLN6 and MFSD8), two cases of sialidosis (the causing gene is NEU1), two cases of neuronopathic Gaucher disease (the causing gene is GBA), one case of spinal muscular atrophy-progressive myoclonic epilepsy (the causing gene is ASAH1), four cases of KCNC1 mutation-related PME, four cases of KCTD7 mutation-related PME, two cases of TBC1D24 mutation-related PME, one case of GOSR2 related PME, and two of dentatorubral-pallidoluysian atrophy (the causing gene is ATN1). In total, 13 PME genes were identified in our cohort. The etiology was not clear in eight patients. Conclusion PME is a group of clinically and genetically heterogeneous diseases. Genetic diagnosis was clear in 78.9% of PME patients. Various of genetic testing methods could increase the rate of genetic diagnosis. Neuronal ceroid lipofuscinoses (NCL) is the most common etiology of PME in children. Nearly one third PME children were diagnosed with NCL. GOSR2 related PME was in our cohort in Asia for the first time.