Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

First copy number variant in trans with single nucleotide variant in CCN6 causing progressive pseudorheumatoid dysplasia revealed by genome sequencing and deep phenotyping in monozygotic twins.

Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis.

Enhancement of the function of mesenchymal stem cells by using a GMP-grade three-dimensional hypoxic large-scale production system.

Background: Efficiently increasing the production of clinical-grade mesenchymal stem cells (MSCs) is crucial for clinical applications. Challenges with the current planar culture methods include scalability issues, labour intensity, concerns related to cell senescence, and heterogeneous responses. This study aimed to establish a large-scale production system for MSC generation. In addition, a comparative analysis of the biological differences between MSCs cultured under various conditions was conducted. Methods and materials: We developed a GMP-grade three-dimensional hypoxic large-scale production (TDHLSP) system for MSCs using self-fabricated glass microcarriers and a multifunctional bioreactor. Different parameters, including cell viability, cell diameter, immunophenotype, morphology, karyotype, and tumourigenicity were assessed in MSCs cultured using different methods. Single-cell RNA sequencing (scRNA-seq) revealed pathways and genes associated with the enhanced functionality of MSCs cultured in three dimensions under hypoxic conditions (3D_Hypo MSCs). Moreover, CD142 knockdown in 3D_Hypo MSCs confirmed its in vitro functions. Results: Inoculating 2 × 108 MSCs into a 2.6 L bioreactor in the TDHLSP system resulted in a final scale of 4.6 × 109 3D_Hypo MSCs by day 10. The 3D_Hypo MSCs retained characteristics of the 2D MSCs, demonstrating their genomic stability and non-tumourigenicity. Interestingly, the subpopulations of 3D_Hypo MSCs exhibited a more uniform distribution and a closer relationship than those of 2D MSCs. The heterogeneity of MSCs was strongly correlated with 'cell cycle' and 'stroma/mesenchyme', with 3D_Hypo MSCs expressing higher levels of activated stroma genes. Compared to 2D MSCs, 3D_Hypo MSCs demonstrated enhanced capabilities in blood vessel formation, TGF-ß1 secretion, and inhibition of BV2 proliferation, with maintenance of Senescence-Associated ß-Galactosidase (SA-ß-gal) negativity. However, the enhanced functions of 3D_Hypo MSCs decreased upon the downregulation of CD142 expression. Conclusion: The TDHLSP system led to a high overall production of MSCs and promoted uniform distribution of MSC clusters. This cultivation method also enhanced key cellular properties, such as angiogenesis, immunosuppression, and anti-aging. These functionally improved and uniform MSC subpopulations provide a solid basis for the clinical application of stem cell therapies.

Transcriptome analysis revealed SMURF2 as a prognostic biomarker for oral cancer.

BACKGROUND: The activation of TGF-ß pathway can facilitate tumorigenesis. Understanding the TGF-related genes (TRGs) in oral cancer and determining their prognostic value is of utmost importance. METHODS: The TRGs were selected to develop a prognostic model based on lasso regression. Oral cancer patients were classified into high-risk and low-risk groups based on the risk model. Subsequently, multivariate COX regression was employed to identify the prognostic marker. Additionally, the expression of SMURF2 was validated using quantitative real-time polymerase chain reaction (qRT-PCR) and the Human Protein Atlas (HPA) database. To investigate the relationship between SMURF2 expression and immune cell infiltrations, we conducted single-sample Gene Set Enrichment Analysis (ssGSEA) analyses. RESULTS: We identified 16 differentially expressed TRGs in oral cancer, all of which showed upregulation. From these, we selected eight TRGs as prognostic signatures. Furthermore, the high-risk group demonstrated lower infiltration levels of immune cells, immune score, and higher tumor purity. Interestingly, we also found that SMURF2 serves as an independent prognostic biomarker. SMURF2 was upregulated in oral cancer, as confirmed by public databases and qRT-PCR analysis. Importantly, our results indicate a close association between SMURF2 expression and the immune microenvironment. CONCLUSION: The 8-TRG signature prognosis model that we constructed has the ability to predict the survival rate and immune activity of oral cancer patients. SMURF2 could be effective in recognizing prognosis and evaluating immune efficacy for oral cancer.

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear. METHODS: Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation. RESULTS: SLC16A8, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious SLC16A8 variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings. CONCLUSION: This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.

Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities. MAIN BODY: Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term "Ehlers Danlos". A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more "normalized" life. CONCLUSION: The first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.

A smartphone-based diagnostic analyzer for point-of-care milk somatic cell counting.

BACKGROUND: Mastitis, a pervasive and detrimental disease in dairy farming, poses a significant challenge to the global dairy industry. Monitoring the milk somatic cell count (SCC) is vital for assessing the incidence of mastitis and the quality of raw cow's milk. However, existing SCC detection methods typically require large-scale instruments and specialized operators, limiting their application in resource-constrained settings such as dairy farms and small-scale labs. To address these limitations, this study introduces a novel, smartphone-based, on-site SCC testing method that leverages smartphone capabilities for milk somatic cell identification and enumeration, offering a portable and user-friendly testing platform. RESULTS: The central findings of our study demonstrate the effectiveness of the proposed method for counting milk somatic cells. Its on-site applicability, facilitated by the microfluidic chip, optical system, and smartphone integration, heralds a paradigm shift in point-of-care testing (POCT) for dairy farms and smaller laboratories. This approach bypasses complex processing and presents a user-friendly solution for real-time SCC monitoring in resource-limited settings. This device boasts several unique features: small size, low cost (<$1,000 total manufacturing cost and <$1 per test), and high accuracy. Remarkably, it delivers test results within just 2 min. Actual-sample testing confirmed its consistency with results from the commercial Bentley FTS/FCM cytometer, affirming the reliability of the proposed method. Overall, these results underscore the potential for transformative change in dairy farm management and laboratory testing practices. SIGNIFICANCE: In summary, this study concludes that the proposed smartphone-based method significantly contributes to the accessibility and ease of SCC testing in resource-limited environments. By fostering the use of POCT technology in food safety control, particularly in the dairy industry, this innovative approach has the potential to revolutionize the monitoring and management of mastitis, ultimately benefiting the global dairy sector.

Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Investigation of clinical significance of ST-segment depression during paroxysmal supraventricular tachycardia.

INTRODUCTION: There are great differences in ST-segment depression during PSVT episodes. The aim of this study is to investigate the clinical significance of ST segment depression during PSVT. METHODS: The study enrolled 333 consecutive patients who were diagnosed with PSVT by electrophysiological test from Jan 1, 2021 to July 31, 2022. The range, magnitude and morphology of ST-segment depression were described. The correlation between ST-segment depression and symptoms of chest tightness, chest pain or hypotension, the correlation between ST-segment depression and coronary stenosis, and the possible influencing factors were analyzed. In addition, the diagnostic efficacy of ST-segment depression for AVRT was determined. RESULTS: ST-segment depression was present in 85% of patients, in 70% of which the depression range was more than six leads. The magnitude of the depression was more significant in precordial leads (P < 0.001). ST-segment depression of >1 mm in limb leads and precordial leads was found in 36.0% and 49.8% of the patients, respectively, while >3 mm was found in 2.4% and 9.6%, respectively. The morphology of ST-segment depression in limb leads was different from that in precordial leads (P < 0.001). Downsloping ST-segment depression was more common in limb leads (limb vs. precordial: 40.5% vs. 12.6%), whereas upsloping depression was more common in precordial leads (limb vs. precordial: 3.0% vs. 23.1%). Correlation analysis showed that ST-segment depression was not correlated with symptoms of chest tightness and pain, nor was it correlated with coronary artery stenosis. The most important influencing factor is the type of PSVT, especially affecting the morphology of depression in limb leads (OR = 10.27 [5.93-17.79], P < 0.001). The sensitivity and specificity of downsloping ST-segment depression in limb leads for diagnosis of AVRT were 75.5% and 76.7%. CONCLUSION: ST-segment depression is a common ECG change during PSVT episodes, and it's not associated with severe coronary stenosis. The type of PSVT has a significant effect on the manifestation of ST-segment depression. The downslope morphology of ST-segment depression in limb leads is helpful in differentiating AVRT from AVNRT.

Utilizing the Adsorbability of Pseudoboehmite for Tailoring the Stability of an Aluminum Sulfate Alkali-free Accelerator for Shotcrete.

Shotcrete is widely used in tunnels, bridges, culverts, and other large-scale projects. The accelerator is an additive employed to expedite the setting time of shotcrete. Previous research primarily concentrated on enhancing the early strength of accelerators, whereas their long-term stability has been inadequately investigated. In this study, pseudoboehmite (PB) and amorphous aluminum hydroxide (AAH) were incorporated into the accelerator to enhance its stability over a period of 90 days without any signs of crystallization or delamination. Furthermore, the accelerator exhibited an initial setting time of 170 s, a final setting time of 550 s, and a compressive strength of 11.58 MPa after 1 day. The mechanism of effects was studied by isothermal calorimetry, FTIR, XRD, TG-DTG, and SEM analysis. The enhancement in stability is attributed to the distinctive adsorption and thixotropic properties of PB, which facilitate the formation of an electrical double-layer structure in acidic solutions. The expedited setting and hardening are primarily due to the equilibrium between Al3+, SO42-, and Ca2+ ions, which accelerates the hydration process of cement. This research offers a methodology for developing a high-performance, alkali-free liquid accelerator.

Subarachnoid haemorrhage-induced reversible cardiac dysfunction: time course and potential mechanisms.

AIMS: Cardiac dysfunction is commonly observed in patients with subarachnoid haemorrhage (SAH). However, the specific timeline of cardiac remodelling and the underlying mechanisms responsible for this effect following SAH remain unknown. This study aims to explore the impact of SAH on cardiac dysfunction and its potential mechanisms over time. METHODS AND RESULTS: In Protocol 1, we investigated cardiac function and potential mechanisms in a Sprague-Dawley rat model of SAH at six time points (baseline and Days 1, 3, 7, 14, and 28) while exploring the underlying mechanisms. Our assessments included the haemodynamic profile, echocardiography, and the concentrations of plasma biomarkers at various time points post-SAH. We determined neuropeptide Y (NPY) 1-5 receptor protein expression levels through western blotting. In Protocol 2, we administered an NPY1 receptor antagonist to evaluate the effects of cardiac dysfunction induced by SAH on Day 3. In Protocol 1, SAH gradually provoked cardiac systolic dysfunction during the acute phase, reaching its peak on Day 3 without concurrent alterations in wall thickness. However, no significant changes were observed from Days 14 to 28 compared with Day 0. The changes in cardiac dysfunction were consistent with myocardial injury, inflammatory biomarkers, and NPY levels. SAH resulted in a heightened heart rate and systolic blood pressure, correlating with elevated epinephrine and norepinephrine levels. In Protocol 2, the administration of the NPY1 receptor antagonist effectively ameliorated cardiac dysfunction. CONCLUSIONS: SAH induces transient cardiac dysfunction in the acute phase, and the underlying mechanisms for this response involve the NPY-NPY1 receptor pathway, otherwise known as catecholamines.

Help-Seeking Preferences and Influencing Factors Among Chinese Nurses Exposed to COVID-19: A Person-Centered Approach.

PURPOSE: This study aimed to explore help-seeking preference categories and crucial influencing factors among community nurses exposed to COVID-19 in China using a new person-centered approach. DESIGN: A cross-sectional design including an online self-reported questionnaire survey was used. METHODS: A total of 667 nurses who participated in COVID-19 prevention and control work were recruited. Latent class analysis and logistic regression were used to analyze the data using Mplus and SPSS. FINDINGS: Two latent classes of help-seeking preferences were identified: high help-seeking preferences (33.58%) and low help-seeking preferences (66.42%). Most sampled nurses had relatively low help-seeking preferences when facing psychological threats during COVID-19. Logistic regression showed that career duration, perceived social support, online help-seeking intention, and social media exposure negatively affected low help-seeking preferences. CONCLUSIONS: Career duration, perceived social support, online help-seeking intention, and social media exposure could be key factors influencing help-seeking preferences among Chinese nurses exposed to public emergencies. It is necessary to implement relevant intervention measures, such as focusing on nurses whose career durations are shorter, improving nurses' perceived social support, strengthening positive media publicity, and developing comprehensive online mental health services that promote nurses' help-seeking preferences and behaviors to reduce mental illness during public health emergencies. CLINICAL EVIDENCE: Help-seeking preferences are relatively low among Chinese nurses during public emergencies. Based on the major influencing factors of help-seeking preferences, including social support and social media exposure, more interventions must be developed for prompting psychological help-seeking intentions among Chinese nurses.

Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine.

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.

A highly integrated digital PCR system with on-chip heating for accurate DNA quantitative analysis.

Digital polymerase chain reaction (dPCR) is extensively used for highly sensitive disease diagnosis due to its single-molecule detection ability. However, current dPCR systems require intricate DNA sample distribution, rely on cumbersome external heaters, and exhibit sluggish thermal cycling, hampering efficiency and speed of the dPCR process. Herein, we presented the development of a microwell array based dPCR system featuring an integrated self-heating dPCR chip. By utilizing hydrodynamic and electrothermal simulations, the chip's structure is optimized, resulting in improved partitioning within microwells and uniform thermal distribution. Through strategic hydrophilic/hydrophobic modifications on the chip's surface, we effectively secured the compartmentalization of sample within the microwells by employing an overlaying oil phase, which renders homogeneity and independence of samples in the microwells. To achieve precise, stable, uniform, and rapid self-heating of the chip, the ITO heating layer and the temperature control algorithm are deliberately designed. With a capacity of 22,500 microwells that can be easily expanded, the system successfully quantified EGFR plasmid solutions, exhibiting a dynamic linear range of 105 and a detection limit of 10 copies per reaction. To further validate its performance, we employed the dPCR platform for quantitative detection of BCR-ABL1 mutation gene fragments, where its performance was compared against the QuantStudio 3D, and the self-heating dPCR system demonstrated similar analytical accuracy to the commercial dPCR system. Notably, the individual chip is produced on a semiconductor manufacturing line, benefiting from mass production capabilities, so the chips are cost-effective and conducive to widespread adoption and accessibility.

SIGMA leverages protein structural information to predict the pathogenicity of missense variants.

Leveraging protein structural information to evaluate pathogenicity has been hindered by the scarcity of experimentally determined 3D protein. With the aid of AlphaFold2 predictions, we developed the structure-informed genetic missense mutation assessor (SIGMA) to predict missense variant pathogenicity. In comparison with existing predictors across labeled variant datasets and experimental datasets, SIGMA demonstrates superior performance in predicting missense variant pathogenicity (AUC = 0.933). We found that the relative solvent accessibility of the mutated residue contributed greatly to the predictive ability of SIGMA. We further explored combining SIGMA with other top-tier predictors to create SIGMA+, proving highly effective for variant pathogenicity prediction (AUC = 0.966). To facilitate the application of SIGMA, we pre-computed SIGMA scores for over 48 million possible missense variants across 3,454 disease-associated genes and developed an interactive online platform (https://www.sigma-pred.org/). Overall, by leveraging protein structure information, SIGMA offers an accurate structure-based approach to evaluating the pathogenicity of missense variants.

Comprehensive assessment of occurrence, temporal-spatial variations, and ecological risks of heavy metals in Jiaozhou Bay, China: A comprehensive study.

Heavy metals play a significant role in marine ecosystems, exerting notable impacts on the environment and human health. In this study, water, sediment, and aquatic organism samples from Jiaozhou Bay were investigated to comprehensively assess the distribution, temporal-spatial variations, and ecological risks of heavy metals. The results indicate that pollution from industrial wastewater discharge contributes to regional differences in the distribution of heavy metals, possibly being a major source of Zn, Cr, Cd, and Hg (r > 0.7, p < 0.05). Biological and physicochemical processes influence the distribution of Zn, Cr, and Pb in the water and sediment. Hg exhibits a polluted state in both the water and sediment, with As and Hg being the two highest-risk heavy metals in water and sediment, respectively. Among the organisms, crustaceans show significantly higher levels of heavy metal content and accumulation compared to mollusks and fish (p < 0.05), and the bioamplification of heavy metals occurs in the sediment-Rapana venosa-Portunus trituberculatus biological pathway. Portunus trituberculatus, Charybdis japonica, Oratosquilla oratoria, and Octopus ocellatus could pose risks to human health, especially for children and vulnerable populations. This study aims to enhance our understanding of the current status of heavy metal pollution in Jiaozhou Bay and to provide a scientific basis and favorable support for the ecological environmental protection and prevention of ecological risks associated with heavy metal pollution in Jiaozhou Bay and other bays in China.

Impaired glycine neurotransmission causes adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multigeneration families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine-uptake activity in cells, leading to increased extracellular glycine levels and aberrant glycinergic neurotransmission. Slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, a phenotype resembling human patients. The penetrance and severity of curvature were sensitive to the dosage of functional glyt1. Administration of a glycine receptor antagonist or a clinically used glycine neutralizer (sodium benzoate) partially rescued the phenotype. Our results indicate a neuropathic origin for "idiopathic" scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS. Our work further suggests avenues for early diagnosis and intervention of AIS in preadolescents.

The comparison between the novel technique and conventional method in the catheter ablation of premature ventricular contractions originating from the free wall of tricuspid annulus.

BACKGROUND: This study aimed to assess the safety and effectiveness of a novel technique for catheter ablation in patients with premature ventricular contraction (PVC) from the free wall of tricuspid annulus (TV). HYPOTHESIS: We hypothesized that the novel technique is more efficacious than the traditional approach. METHODS: We retrospectively investigated 59 consecutive patients with PVC originating from the free wall of TV between January 2013 and November 2021. The patients were divided into two groups: the reversed S-curve technique group (RST, n = 26) and the reversed C-curve technique group (RCT, n = 33). The RST under the support of a steerable sheath was used in RST group, while the RCT under the support of a nonsteerable sheath was used in the RCT group. Systematic mapping and radiofrequency ablation were preferentially performed under the valve in all patients. RESULTS: Compared to the RCT group, total procedural time and fluoroscopic exposure time were significantly shorter in RST group. Two patients experienced cardiac tamponade in the RCT group, while no complications were observed in RST group (p = .498). The success rate was significantly higher in RST group compared to RCT group (81.9% vs. 100%, p = .029). Three patients in RCT group failed to ablate during the operation but were successfully ablated using the novel method. During regular follow-up, no patients in the RST group had a recurrence, while three patients in the RCT group did (p = .274). CONCLUSIONS: It suggests that the reserved S-curve technique, supported by a steerable sheath, is a feasible and effective method for ablating PVC originating from the free wall of TV.