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Abstract Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Abstract Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like zebrafish, base editors significantly accelerate and refine in vivo analysis of genetic variations. However, base editors are restricted by protospacer adjacent motif (PAM) sequences and specific editing windows, hindering their applicability to a broad spectrum of genetic variants. Additionally, base editors can introduce unintended mutations and often exhibit reduced efficiency in living organisms compared to cultured cell lines. Here, we engineer a suite of adenine base editors (ABEs) called ABE-Ultramax (Umax), demonstrating high editing efficiency and low rates of insertions and deletions (indels) in zebrafish. The ABE-Umax suite of editors includes ABEs with shifted, narrowed, or broadened editing windows, reduced bystander mutation frequency, and highly flexible PAM sequence requirements. These advancements have the potential to address previous challenges in disease modeling and advance gene therapy applications.

Monitoring the building blast vibration signal is an efficient way to determine the power of blast vibration hazards. Due to the harsh measurement environment, noise is inevitably introduced into the recorded signals. This research presents a denoising approach based on Improved complete ensemble empirical mode decomposition with adaptive noise(ICEEMDAN) and Composite Multiscale Permutation Entropy (CMPE). First, the noisy blast vibration signal is decomposed into different intrinsic mode functions using ICEEMDAN; then multiple intrinsic mode functions (IMFs) are separated into pure and noisy using CMPE, the noisy IMFs are denoised using wavelet thresholding; finally the blast wave is reconstructed using the pure and denoised mixed IMFs. The proposed approach was compared with four other approaches (CEEMDAN-CMPE, VMD-CMPE, SVMD-CMPE, and WST). The results indicate that the proposed approach has better performance and can be considered as an effective denoising method for building blast vibration signals.

Abstract Background Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, provide potential biomarkers for the diagnosis and treatment of CHD. However, the mechanisms underlying miRNAs-mediated regulation of cardiac development and CHD malformation remain to be further elucidated. This study aimed to explore the function of microRNA-20b-5p (miR-20b-5p) in cardiac development and CHD pathogenesis. Methods and results miRNA expression profiling identified that miR-20b-5p was significantly downregulated during a 12-day cardiac differentiation of human embryonic stem cells (hESCs), whereas it was markedly upregulated in plasma samples of atrial septal defect (ASD) patients. Our results further revealed that miR-20b-5p suppressed hESCs-derived cardiac differentiation by targeting tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine, leading to a reduction in key cardiac transcription factors including GATA4, NKX2.5, TBX5, MYH6 and cTnT. Additionally, knockdown of TET2 significantly inhibited cardiac differentiation, which could be partially restored by miR-20b-5p inhibition. Conclusions Collectively, this study provides compelling evidence that miR-20b-5p functions as an inhibitory regulator in hESCs-derived cardiac differentiation by targeting TET2, highlighting its potential as a biomarker for ASD.

Abstract Background Coronary heart disease (CHD) is a cardiovascular disease with high mortality. At present, percutaneous coronary intervention (PCI) is considered as the main effective treatment for CHD due to less trauma, shorter course of treatment, and better curative effect. However, PCI alone is not a permanent cure, so cardiac rehabilitation (CR) is needed for a supplement. Nowadays, the evaluation of the nursing-sensitive quality of CR after PCI focuses on the outcomes of patients, lacks a complete evaluation indicator system, and is prone to problems such as nursing management imbalance. Objective A scientific, sensitive, comprehensive and practical nursing-sensitive quality indicator system based on the structure-process-outcome model was constructed to provide a reference for evaluating nursing-sensitive quality of CR after PCI. Methods Firstly, through literature analysis and semi-structured interview, the indicator system was collected, screened and determined. Then, the framework of the indicator system was established, and the draft of nursing-sensitive quality indicator system of CR after PCI was formed. Subsequently, the nursing-sensitive quality indicator system of CR after PCI was initially established using Delphi method. Finally, the specific weight was determined by analytic hierarchy process (AHP), and the nursing-sensitive quality indicator system of CR after PCI was established and perfected. Results Two rounds of expert consultations were separately given 15 questionnaires, and all these questionnaires were returned, with a questionnaire response rate of 100%. Such result indicated that experts were highly motivated. Besides, the authoritative coefficients for two rounds of expert consultations were 0.865 and 0.888, and the coordination coefficients were 0.491 and 0.522, respectively. Hence, the experts’ authority and coordination were high and the results were reliable. After the second round of expert consultation, the nursing-sensitive quality indicator system of CR after PCI was established, eventually. This system consisted of 3 first-level indicators (structural indicator, process indicator and outcome indicator), 11 s-level indicators and 29 third-level indicators. Conclusion A relatively complete and reliable nursing-sensitive quality indicator system of CR after PCI has been established in this study. Such system is scientific and reliable and can provide a reference for the evaluation of clinical teaching quality of CR after PCI.

Abstract Background Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Methods Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. Results A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. Conclusions Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”.

Primate tourism brings many benefits, but also some problems. How to better evaluate primate tourism is of significance for formulating tourism management strategies. In this study, we compared the aggressive behavior of three Sichuan snub-nosed monkey groups that encounter ecotourists and found that male aggressive behavior is a useful indicator for assessing ecotourism of these and, by inference, other groups. In high-risk tourism groups multiple monkeys direct aggression towards tourists, whereas low-risk tourism groups are characterized by low rates of such aggression. We found that tourists touching or attempting to touch the monkeys can trigger aggressive behaviors in all groups, while carrying food and eating have different effects across groups. In well-managed groups, tourist-directed aggressive behaviors are milder than in less well-managed groups. We propose that male monkey aggressive behavior elicited by tourists’ behavior is a useful indicator in assessing primate tourism, and can help guide further improvements in tourism management.

The effect of equal channel angular pressing (ECAP) and further cold upsetting (CU) process on the kinetics of precipitation during aging of solid solution treated 7050 Al alloy were studied using differential scanning calorimetry and transmission electron microscopy. Results indicate that the activation energy of η′ phase was reduced from 120.371 kJ/mol to 73.387 kJ/mol after ECAP process and to 59.740 kJ/mol after CU process, because of the accumulation of dislocations. Thus, the peak aging time was shortened from 333 h to 7 h and 3 h after ECAP and ECAP−CU composite process respectively. Additionally, the precipitation of the η phase was suppressed after ECAP, but accelerated after ECAP−CU process, with the change of activation energy from 185.323 kJ/mol to 208.266 kJ/mol and 156.060 kJ/mol respectively. The annihilation of dislocations and precipitation of phases during aging treatment led to the competition of softening and strengthening of mechanical strength, indicating that the increasement of elongation is coupled with slight reduction of strength. After peak aging treatment, the tensile strength remained approximately unchanged of 546 ± 14 MPa, while the uniform elongation increased by about 35.3% from 5.1 ± 0.6 to 6.9 ± 1.5.

Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.

Abstract The development of lithium (Li) metal batteries has been severely limited by the formation of lithium dendrites and the associated catastrophic failure and inferior Coulombic efficiency which caused by non‐uniform or insufficient Li+ supply across the electrode–electrolyte interface. Therefore, a rational strategy is to construct a robust electrolyte that can allow efficient and uniform Li+ transport to ensure sufficient Li+ supply and homogenize the Li plating/stripping. Herein, we report an ion‐percolating electrolyte membrane that acts as a stable Li+ reservoir to ensure a near‐single Li+ transference number (0.78) and homogenizes Li+ migration to eradicate dendrite growth, endowing Li//LFP cell with an ultrahigh average Coulombic efficiency (ca. 99.97%) after cycling for nearly half of a year and superior cycling stability when pairing with LiCoO2 with limited Li amount and LiNi0.8Mn0.1Co0.1O2. These estimable attributes demonstrate significant potential of utility value for the ion‐percolating electrolyte.

ABSTRACTThe gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.

PurposeChina adjusted and optimized its prevention and control strategies in December 2022, and it entered a new era of the coronavirus epidemic. Here, we describe the general and otolaryngology-related symptoms of coronavirus disease 2019 (COVID-19) in children during the first pandemic in the post-epidemic era, focusing on the frequency and severity of smell and taste loss, as well as the recovery process and its influencing factors.Patients and methodsFrom 2 January to 7 January 2023, we conducted a cross-sectional online questionnaire survey through Questionnaire Stars in order to collect relevant information about COVID-19 in children in Shenzhen.ResultsA total of 1,247 valid questionnaires were received, with an effective response rate of 78.72%. All of the diagnoses were confirmed by nucleic acid or antigen test for COVID-19. Among the subjects, the sex ratio of male to female was more inclined to male (1.35:1), and the age was 3–16 years, with an average of 10.13 ± 2.82 years old. The most common symptoms were cough (58.24%), stuffy nose (56.18%), headache (42.09%), fatigue (40.44%), and sore throat (31.63%). Approximately 6.43% of the children reported dysosmia, the mean time of the duration of dysosmia was 5.38 ± 2.92 days, and the mean score of the severity of the dysosmia as assessed by visual analogue scale (VAS) was 4.63 ± 2.29. Approximately 13.34% reported dysgeusia, the mean time of the duration of dysgeusia was 4.77 ± 3.98 days, and the mean score of the severity of the dysgeusia as assessed by VAS was 5.12 ± 2.29. Univariate and multivariate logistic regression analysis showed that the prevalence of taste and olfactory disorders increased with age, mainly in children with severe symptoms and older children.ConclusionIn the post-epidemic era, due to weakening of the pathogenicity of the subvariant of Omicron, overall condition of children with COVID-19 was mild, incidence of olfactory and taste disorders was low, recovery was faster, and prognosis was better. In our study, cough, runny nose, and sore throat were the most common symptoms, and the prevalence of taste and olfactory disorders increased with age, mainly in older children with severe symptoms.

Highlights 1. Elevated PP was associated with an increased risk of diabetes in females but not in males according to the multiple Cox regression model. 2. Sex differences in the association between PP and diabetes risk are not significantly affected by age.

Abstract Objective Incomplete Kawasaki disease (IKD) initially presenting as retropharyngeal abnormality is very rare and is prone to misdiagnosis and missed diagnosis, often leading to poor prognosis. Most patients were misdiagnosed with retropharyngeal abscesses. Here, we describe and compare IKD patients initially presenting with retropharyngeal abnormalities, typical KD patients without retropharyngeal abnormalities and retropharyngeal abscess patients. Methods We performed a retrospective case–control study comparing IKD patients initially presenting with retropharyngeal abnormalities to both KD patients without retropharyngeal abnormalities and retropharyngeal abscess patients admitted to Shenzhen Children’s Hospital between January 2016 and December 2021. Results We evaluated data from 10 IKD patients initially presenting with retropharyngeal abnormalities (Group A), 20 typical KD patients (Group B) and 16 surgical drainage confirmed retropharyngeal abscess patients (Group C). Compared to Group B, we observed that Group A was older and had a more intense inflammatory response. On the day of admission, Groups A and C had similar early clinical presentations, and there were no significant differences in any major signs or symptoms. Close observation for the development of new KD signs and symptoms and unresponsiveness to empirical antibiotic therapy after 3 days is extremely important. The CRP (p = 0.011), AST (p = 0.002) and ALT (p = 0.013) levels were significantly higher and the WBC (P = 0.040) levels were significantly lower in Group A than in Group C. Neck radiological findings, such as the presence of ring enhancement (p = 0.001) and mass effects on the airway, are also useful tools for distinguishing these two diseases. Conclusion The careful observation of the signs and symptoms of this disease and the comprehensive analysis of the laboratory tests and neck radiological findings may help clinicians become aware of retropharyngeal abnormality as an atypical presentation of KD. Then, unnecessary treatments could be reduced, and the occurrence of serious complications can be avoided.

Abstract Objective Oesophageal foreign bodies (EFBs) are a common emergency issue in paediatrics, and few studies have revealed its clinical features and treatment methods. We conducted this retrospective study to provide our 10-year clinical evidence for the diagnosis and treatment of EFB and reduce the incidence of complications. Methods We retrospectively reviewed all paediatric cases diagnosed with EFB from January 2012 to December 2021 at Shenzhen Children’s Hospital. The age and sex of the patients, types of foreign bodies (FBs), preoperative examination, location and duration of FB impaction, clinical symptoms, surgical methods, therapeutic effects and complications were analysed. Results Among the 1355 cases, 759 were boys and 596 were girls, with a median age of 2.9 years (4 months to 16 years). The shortest FB lodged time was 1 hour, while the longest time was 3 months. The types of foreign bodies included coins and blunt objects (812,59.9%), bones and sharp objects (278,20.5%), button batteries (86,6.3%), food impactions (84,6.2%), toys (51,3.8%) and plastic objects (44,3.2%). A total of 720 of 812 cases impacted by coins and blunt subjects were successfully treated with a Foley catheter without any complications. A total of 558 patients underwent rigid oesophageal endoscopy under general anaesthesia, and foreign bodies were successfully removed in 525 cases. No FB was found in 33 cases, and FBs pushed into the lower digestive tract during operation in 5 cases. Oesophageal injury was found in 130 cases (23.3%). Our study showed that the age of the patient, time of foreign body incarceration, type of foreign body, location of the lodged foreign body, and fever or cough were risk factors leading to oesophageal foreign body complications, and the differences were statistically significant (P

Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.

Abstract Background Kawasaki disease (KD) is a prevalent form of systemic vasculitis that can damage various organs and systems in children. Typical KD is not difficult to diagnose in clinical practice. In recent years, it has been shown that an increasing number of children do not satisfy the diagnostic criteria for typical KD. This condition is known as incomplete KD (IKD). It is challenging to promptly diagnose and treat such children in clinical practice. Case Description A 10‐year‐old girl was admitted to the hospital due to fever and abdominal pain. She presented with shock symptoms. An enhanced abdominal computed tomography scan revealed intestinal pneumatosis, effusion, and gallbladder enlargement, indicating intestinal obstruction. Due to the poor outcome following an emergency laparoscopic cholecystectomy, IKD was suspected. A 3‐month‐old male pediatric patient was admitted to the hospital due to a fever. Patchy, congestive rashes formed on the patient's body as KD progressed. IKD was suspected based on the clinical signs of fever, rash, and hyperemia of the lips. The two patients were then treated with human immunoglobulin and aspirin treatment. The prognosis for the two children was favorable following prompt treatment. Conclusion Due to the fact that IKD is frequently misdiagnosed, it is vital to (1) improve the patient prognosis for the early identification of children with KD with prolonged fever and anti‐infection failure as the initial manifestation and (2) perform timely diagnosis and comprehensive treatment.

Summary: TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.