Efficacy of antihypertensive treatment for target organ protection in patients with masked hypertension (ANTI-MASK): a multicentre, double-blind, placebo-controlled trial.

Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30-70 years with an office blood pressure (BP) of <140/<90 mm Hg and 24-h, daytime or nighttime ambulatory BP of ≥130/≥80, ≥135/≥85, or ≥120/≥70 mm Hg were enrolled. Patients had ≥1 sign of TOD: electrocardiographic left ventricular hypertrophy (LVH), brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, or urinary albumin-to-creatinine ratio (ACR) ≥3.5 mg/mmol in women and ≥2.5 mg/mmol in men. Exclusion criteria included secondary hypertension, diabetic nephropathy, serum creatinine ≥176.8 µmol/L, and cardiovascular disease within 6 months of screening. After stratification for centre, sex and the presence of nighttime hypertension, eligible patients were randomly assigned (1:1) to receive antihypertensive treatment or placebo. Patients and investigators were masked to group assignment. Active treatment consisted of allisartan starting at 80 mg/day, to be increased to 160 mg/day at month 2, and to be combined with amlodipine 2.5 mg/day at month 4, if the ambulatory BP remained uncontrolled. Matching placebos were used likewise in the control group. The primary endpoint was the improvement of TOD, defined as normalisation of baPWV, ACR or LVH or a ≥20% reduction in baPWV or ACR over the 48-week follow-up. The intention-to-treat analysis included all randomised patients, the per-protocol analysis patients who fully adhered to the protocol, and the safety analysis all patients who received at least one dose of the study medication. This study is registered with ClinicalTrials.gov, NCT02893358. Findings: Between February 14, 2017, and October 31, 2020, 320 patients (43.1% women; mean age ± SD 53.7 ± 9.7 years) were enrolled. Baseline office and 24-h BP averaged 130 ± 6.0/81 ± 5.9 mm Hg and 136 ± 8.6/84 ± 6.1 mm Hg, and the prevalence of elevated baPWV, ACR and LVH were 97.5%, 12.5%, and 7.8%, respectively. The 24-h BP decreased on average (±SE) by 10.1 ± 0.9/6.4 ± 0.5 mm Hg in 153 patients on active treatment and by 1.3 ± 0.9/1.0 ± 0.5 mm Hg in 167 patients on placebo. Improvement of TOD occurred in 79 patients randomised to active treatment and in 49 patients on placebo: 51.6% (95% CI 43.7%, 59.5%) versus 29.3% (22.1, 36.5%; p < 0.0001). Per-protocol and subgroup analyses were confirmatory. Adverse events were generally mild and occurred in 38 (25.3%) and 43 (26.4%) patients randomised to active treatment and placebo, respectively (p = 0.83). Interpretation: Our results suggest that antihypertensive treatment improves TOD in patients with masked hypertension, highlighting the need of treatment. However, the long-term benefit in preventing cardiovascular complications still needs to be established. Funding: Salubris China.

Xylooligosaccharides alleviate the carbohydrate-enriched diet-induced intestinal barrier dysfunction in carp Megalobrama amblycephala by promoting intestinal development, immunity and gut microbiota.

To date, although the high-carbohydrate (HC) feed has been extensively adopted in the aquaculture industry, its effects on the intestinal function and development of aquatic animals still remain unclear. In addition, the corresponding nutritional intervention is still barely reported. This study aimed to evaluate the influence of xylooligosaccharides (XOS) on the intestinal health of Megalobrama amblycephala subjected to a HC feeding. Fish (average weight: 44.55 ±â€¯0.15 g) were randomly offered 3 diets, including a control one (29 % carbohydrate), a HC one (41 % carbohydrate), and a XOS supplemented one (HC + 1.0 % XOS, HCX) respectively for 12 weeks. The HC feeding caused morphological abnormalities of intestine, an increased intestinal permeability, and the intestinal immunosuppression, all of which were markedly reversed by XOS administration. In addition, compared with the HC group, HCX feeding remarkably promoted the intestinal activities of digestive and brush border enzymes, and the expressions of cell proliferation-related proteins (Wnt10b and Cyclin D1). The 16s rDNA sequencing also revealed that XOS administration increased the abundance of beneficial bacteria, and decreased that of pathogenic ones. In conclusion, dietary supplementation of XOS improved the intestinal histomorphology, barrier function, cell proliferation and bacterial communities of carbohydrate-overloaded fish Megalobrama amblycephala.

Intracapsular Enucleation of Cervical Sympathetic Chain Schwannoma: Improved Strategy of Intraoperative Hemostasis and Better Outcome.

Objective: Intracapsular enucleation (ICE) of cervical sympathetic chain schwannoma (CSCS) is associated with technical difficulties, with diffuse hemorrhage being the main challenge in our previous attempts. This article presents our new strategy for achieving better hemostasis during ICE procedures in CSCS cases. Methods: A retrospective review of CSCS cases treated at our tertiary medical institution was undertaken between April 2018 and February 2024. Only cases with successful ICE were included. Results: A total of 8 cases were included, with 4 male and 4 female patients and an age range of 23 to 77 (average and median ages were 48.5 and 49.5 years, respectively). The presenting symptom was a neck mass for all the patients, with 4 masses on the left and 4 on the right sides. Enucleation was first undertaken for the first 3 cases (before March 2022), followed by hemostasis; this strategy was quite difficult and time-consuming. For the remaining 5 cases, a new strategy was developed to preemptively manage any potential nourishing vessel between the capsule and tumor parenchyma, which significantly decreased operation time (P = .0155) and facilitated hemorrhage control. First bite syndrome (FBS) was avoided in all cases. Postoperative Horner's syndrome (HS) was avoided in 1 patient (Case 6, new strategy) but occurred in 7 patients, taking 8 days to 1 month to recover with the new strategy (4 patients), significantly shorter (P = .0364) than before (3 patients, 1-3 months). The median duration of follow-up was 20 months. No recurrence was documented. Conclusions: ICE was achieved for CSCS cases, especially with our newly developed strategy, by preemptively and securely managing potential nourishing vessels. Operation time and duration of recovery of postoperative HS could both be shortened. Moreover, FBS could be avoided.

Study on the Underlying Mechanism of Yinhua Gout Granules in the Treatment of Gouty Arthritis by Integrating Transcriptomics and Network Pharmacology.

Purpose: Yinhua Gout Granules (YGG) is a traditional Chinese medicine preparation with a variety of pharmacological effects, and its clinical efficacy in the treatment of gouty arthritis (GA) has been fully confirmed. However, the pharmacodynamic basis of YGG and its anti-inflammatory mechanism of action in GA are unknown. The objective of this study was to identify the active components and molecular mechanisms of YGG in the treatment of GA. Methods: Ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) and network pharmacology were used to identify and predict the potential active ingredients and related signaling pathways. Then, we revealed the anti-GA effects of YGG based on pharmacodynamic experiments in GA rats. Finally, we integrated transcriptomics and network pharmacology to elucidate the potential mechanism of action and verified the putative mechanism by molecular docking, immunohistochemical (IHC) and Western blot. Results: We have identified 10 major active components of YGG that may have anti-GA effects, such as ferulic acid, rutin, luteolin, etc. Using molecular docking, we found that 10 major compounds could bind well to TNF, PTGS2, IL-6, IL1ß, NOS2 and PTGS1, and the binding energies were all less than -5 kcal/mol. Animal studies have shown that YGG can improve joint inflammation and inflammatory cell infiltration, reduce serum UA, BUN and Cr levels (p<0.01), and decrease IL-1ß, IL-6, TNF-α, COX-2 and PGE2 levels in synovial tissue (p<0.01), which are associated with the pathogenesis of GA. IHC and Western blot results showed that YGG could regulate TLR4/MYD88/NF-κB pathway to inhibit the inflammatory response induced by GA. Conclusion: This study found that YGG could not only improve the disease of GA by inhibiting the production of UA in the body, but also target the regulation of TLR4/MYD88/NF-κB signaling pathway through a variety of active components to achieve effective therapeutic effects on GA.

Illness uncertainty and dysphagia in Chinese oral cancer patients: the mediation effect of catastrophic cognition.

PURPOSE: Dysphagia, a serious symptom of oral cancer, is also the most common. Further, patients who are more uncertain regarding their illness tend to catastrophize, which may affect their rehabilitation and long-term survival rate. Considering this relationship, this study aimed to investigate the occurrence of dysphagia in Chinese patients with oral cancer and explore the correlation between catastrophic cognition, illness uncertainty, and dysphagia. METHODS: Applying a cross-sectional design, convenience sampling was used to recruit 180 patients with oral cancer. Advanced statistical methods were employed to analyze the mediating effects of catastrophic cognition on illness uncertainty and dysphagia. RESULTS: Chinese patients with oral cancer had a mean dysphagia score of 52.88 ± 10.95. Catastrophic cognition and illness uncertainty in patients with oral cancer were significantly positively correlated (r = 0.447, P < 0.001). There was a significant negative correlation between dysphagia score and catastrophic cognition (r = -0.385, P < 0.001), and between dysphagia and illness uncertainty (r = -0.522, P < 0.001). Bootstrapping results indicated that the mediating effect of catastrophic cognition between illness uncertainty and dysphagia was -0.07 (95% CI: [-0.15, -0.03]) and significant, and the mediation effect accounted for 15.6% of the total effect. CONCLUSIONS: Chinese patients with oral cancer have poor swallowing function. Results suggest that catastrophic cognition partially mediated the relationship between illness uncertainty and dysphagia in patients with oral cancer. Medical staff can improve patients' swallowing function by reducing the level of catastrophic cognition via decreasing the level of illness uncertainty.

Comparison of femoral tunnel position and knee function in anterior cruciate ligament reconstruction: a retrospective cohort study using measuring-fluoroscopy method versus bony marker method.

BACKGROUND: Previous studies have shown that surgical technique errors especially the wrong bone tunnel position are the primary reason for the failure of anterior cruciate ligament (ACL) reconstruction. In this study, we aimed to compare the femoral tunnel position and impact on knee function during the ACL reconstruction using measuring combined with fluoroscopy method and bony marker method for femoral tunnel localization. METHODS: A retrospective cohort study of patients undergoing ACL reconstruction using the bony marker method or measuring combined with fluoroscopy for femoral tunnel localization was conducted between January 2015 and January 2020. A second arthroscopic exploration was performed more than 1 year after surgery. Data regarding patient demographics, the femoral tunnel position, results of the Lysholm score, the International Knee Documentation Committee (IKDC) score, KT-1000 side-to-side difference, pivot shift grade, and Lachman grade of the knee were collected. RESULTS: A total of 119 patients were included in the final cohort. Of these, 42 cases were in the traditional method group, and 77 cases were in the measuring method group. The good tunnel position rate was 26.2% in the traditional method group and 81.8% in the measuring method group (p < 0.001). At the final follow-up, the Lysholm and IKDC scores were significantly greater in the measuring method group than the traditional method group (IKDC: 84.9 ± 8.4 vs. 79.6 ± 6.4, p = 0.0005; Lysholm: 88.8 ± 6.4 vs. 81.6 ± 6.4, p < 0.001). Lachman and pivot shift grades were significantly greater in the measuring method group (p = 0.01, p = 0008). The results of KT-1000 side-to-side differences were significantly better in the measuring method group compared with those in the traditional method group (p < 0.001). CONCLUSIONS: The combination of the measuring method and intraoperative fluoroscopy resulted in a concentrated tunnel position on the femoral side, a high rate of functional success, improved knee stability, and a low risk of tunnel deviation. This approach is particularly suitable for surgeons new to ACL reconstructive surgery.

Evidence of synergistic mechanisms of hepatoprotective botanical herbal preparation of Pueraria montana var. lobata and Schisandra sphenanthera.

Background: Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) and Schisandra sphenanthera Rehder & E.H. Wilson are traditional edible and medicinal hepatoprotective botanical drugs. Studies have shown that the combination of two botanical drugs enhanced the effects of treating acute liver injury (ALI), but the synergistic effect and its action mechanisms remain unclear. This study aimed to investigate the synergistic effect and its mechanism of the combination of Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) (PM) and Schisandra sphenanthera Rehder & E.H. Wilson (SS) in the treatment of ALI. Methods: High performance liquid chromatography (HPLC) were utilized to conduct the chemical interaction analysis. Then the synergistic effects of botanical hybrid preparation of PM-SS (BHP PM-SS) against ALI were comprehensively evaluated by the CCl4 induced ALI mice model. Afterwards, symptom-oriented network pharmacology, transcriptomics and metabolomics were applied to reveal the underlying mechanism of action. Finally, the key target genes were experimentally by RT-qPCR. Results: Chemical analysis and pharmacodynamic experiments revealed that BHP PM-SS was superior to the single botanical drug, especially at 2:3 ratio, with a better dissolution rate of active ingredients and synergistic anti-ALI effect. Integrated symptom-oriented network pharmacology combined with transcriptomics and metabolomics analyses showed that the active ingredients of BHP PM-SS could regulate Glutathione metabolism, Pyrimidine metabolism, Arginine biosynthesis and Amino acid sugar and nucleotide sugar metabolism, by acting on the targets of AKT1, TNF, EGFR, JUN, HSP90AA1 and STAT3, which could be responsible for the PI3K-AKT signaling pathway, MAPK signaling pathway and Pathway in cancer to against ALI. Conclusion: Our study has provided compelling evidence for the synergistic effect and its mechanism of the combination of BHP PM-SS, and has contributed to the development and utilization of BHP PM-SS dietary supplements.

Anti-hypertensive effect and potential mechanism of gastrodia-uncaria granules based on network pharmacology and experimental validation.

Hypertension has become a major contributor to the morbidity and mortality of cardiovascular diseases worldwide. Despite the evidence of the anti-hypertensive effect of gastrodia-uncaria granules (GUG) in hypertensive patients, little is known about its potential therapeutic targets as well as the underlying mechanism. GUG components were sourced from TCMSP and HERB, with bioactive ingredients screened. Hypertension-related targets were gathered from DisGeNET, OMIM, GeneCards, CTD, and GEO. The STRING database constructed a protein-protein interaction network, visualized by Cytoscape 3.7.1. Core targets were analyzed via GO and KEGG using R package ClusterProfiler. Molecular docking with AutodockVina 1.2.2 revealed favorable binding affinities. In vivo studies on hypertensive mice and rats validated network pharmacology findings. GUG yielded 228 active ingredients and 1190 targets, intersecting with 373 hypertension-related genes. PPI network analysis identified five core genes: AKT1, TNF-α, GAPDH, IL-6, and ALB. Top enriched GO terms and KEGG pathways associated with the anti-hypertensive properties of GUG were documented. Molecular docking indicated stable binding of core components to targets. In vivo study showed that GUG could improve vascular relaxation, alleviate vascular remodeling, and lower blood pressure in hypertensive animal models possibly through inhibiting inflammatory factors such as AKT1, mTOR, and CCND1. Integrated network pharmacology and in vivo experiment showed that GUG may exert anti-hypertensive effects by inhibiting inflammation response, which provides some clues for understanding the effect and mechanisms of GUG in the treatment of hypertension.

Intercropping improves faba bean photosynthesis and reduces disease caused by Fusarium commune and cinnamic acid-induced stress.

Modern intensive cropping systems often contribute to the accumulation of phenolic acids in the soil, which promotes the development of soilborne diseases. This can be suppressed by intercropping. This study analyzed the effects of intercropping on Fusarium wilt based on its effect on photosynthesis under stress by the combination of Fusarium commune and cinnamic acid. The control was not inoculated with F. commune, while the faba bean plants (Vicia faba L.) were inoculated with this pathogen in the other treatments. The infected plants were also treated with cinnamic acid. This study examined the development of Fusarium wilt together with its effects on the leaves, absorption of nutrients, chlorophyll fluorescence parameters, contents of photosynthetic pigments, activities of photosynthetic enzymes, gas exchange parameters, and the photosynthetic assimilates of faba bean from monocropping and intercropping systems. Under monocropping conditions, the leaves of the plants inoculated with F. commune grew significantly less, and there was enhanced occurrence of the Fusarium wilt compared with the control. Compared with the plants solely inoculated with F. commune, the exogenous addition of cinnamic acid to the infected plants significantly further reduced the growth of faba bean leaves and increased the occurrence of Fusarium wilt. A comparison of the combination of F. commune and cinnamic acid in intercropped wheat and faba bean compared with monocropping showed that intercropping improved the absorption of nutrients, increased photosynthetic pigments and its contents, electron transport, photosynthetic enzymes, and photosynthetic assimilates. The combination of these factors reduced the occurrence of Fusarium wilt in faba bean and increased the growth of its leaves. These results showed that intercropping improved the photosynthesis, which promoted the growth of faba bean, thus, reducing the development of Fusarium wilt following the stress of infection by F. commune and cinnamic acid. This research should provide more information to enhance sustainable agriculture.

Metagenomic Next-Generation Sequencing as an Effective Diagnostic Tool for Talaromycosis in HIV-Negative Patients.

The diagnosis of Talaromyces marneffei infection in HIV-negative patients remains challenging. There is an urgent need for rapid and convenient methods to diagnose this complicated disease. The aim of this study was to evaluate the diagnostic efficiency of metagenomic next-generation sequencing (mNGS) for talaromycosis in non-HIV-infected patients by comparing mNGS with traditional microbial culture. In total, 66 samples from 57 patients were analyzed via both mNGS and microbial culture. The ROC curve showed a sensitivity for mNGS of 97.22%, which was greater than that of microbial culture (61.11%). Samples from the respiratory tract, infectious skin lesions, and lymph nodes are recommended as routine samples for talaromycosis detection via mNGS. Furthermore, mNGS significantly reduced the diagnostic time compared to microbial culture. Overall, our study demonstrated that mNGS is a promising tool for rapid and accurate pathogenic detection in HIV-negative patients with talaromycosis.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3ß inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3ß/Nrf2 pathway.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3ß (GSK-3ß), a potential target of AD treatment. PURPOSE: To investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3ß pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. METHOD: The oxidative stress of PC12 cells was induced by H2O2 (600 µM) and the effects of TFGF-18 (2 and 8 µM) or ISO (12.5 and 50 µM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3ß (Ser9), GSK-3ß, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. RESULTS: TFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3ß (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3ß pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. CONCLUSIONS: TFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3ß/Nrf2 pathway.

Managing faba bean wilt disease through intercropping with wheat and reasonable nitrogen application: enhancing nutrient absorption and biochemical resistance in faba beans.

Faba bean wilt disease is a key factor limiting its production. Intercropping of faba bean with wheat has been adopted as a prevalent strategy to mitigate this disease. Nitrogen fertilizer improves faba bean yield, yet wilt disease imposes limitations. However, faba bean-wheat intercropping is effective in controlling wilt disease. To investigate the effect of intercropping under varying nitrogen levels on the incidence of faba bean wilt disease, nutrient uptake, and biochemical resistance in faba bean. Field and pot experiments were conducted in two cropping systems: faba bean monocropping (M) and faba bean-wheat intercropping (I). At four nitrogen levels, we assessed the incidence rate of wilt disease, quantified nutrient uptake, and evaluated biochemical resistance indices of plants. The application of N decreased the incidence rate of wilt disease, with the lowest reduction observed in intercropping at the N2 level. N application at levels N1, N2, and N3 enhanced the content of N, P, K, Fe, and Mn as well as superoxide dismutase (SOD), phenylalanine ammonia lyase (PAL), and polyphenol oxidase (PPO) activities and defense gene expression in monocultured plants. Additionally, these levels increased the contents of total phenols, flavonoids, soluble sugars, and soluble proteins, and all reached their maximum in intercropping at the N2 level. The application of intercropping and N effectively controlled the occurrence of faba bean wilt disease by promoting nutrient absorption, alleviating peroxidation stress, and enhancing resistance in plants. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01466-1.

Research progress of sorafenib drug delivery system in the treatment of hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the contemporary era, representing a significant global health concern. Early HCC patients have mild symptoms or are asymptomatic, which promotes the onset and progression of the disease. Moreover, advanced HCC is insensitive to chemotherapy, making traditional clinical treatment unable to block cancer development. Sorafenib (SFB) is a first-line targeted drug for advanced HCC patients with anti-angiogenesis and anti-tumor cell proliferation effects. However, the efficacy of SFB is constrained by its off-target distribution, rapid metabolism, and multi-drug resistance. In recent years, nanoparticles based on a variety of materials have been demonstrated to enhance the targeting and therapeutic efficacy of SFB against HCC. Concurrently, the advent of joint drug delivery systems has furnished crucial empirical evidence for reversing SFB resistance. This review will summarize the application of nanotechnology in the field of HCC treatment over the past five years. It will focus on the research progress of SFB delivery systems combined with multiple therapeutic modalities in HCC treatment.

Clinical cases series and pathogenesis of Lamb-Shaffer syndrome in China.

BACKGROUND: Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF. METHODS: This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF. RESULTS: Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein. CONCLUSIONS: Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus.

Gray matter morphometric biomarkers for distinguishing manganese-exposed welders from healthy adults revealed by source-based morphometry.

BACKGROUND: Chronic overexposure to manganese (Mn) may result in neurotoxicity, which is characterized by motor and cognitive dysfunctions. This study aimed to utilize multivariate source-based morphometry (SBM) to explore the biomarkers for distinguishing Mn-exposed welders from healthy controls (HCs). METHODS: High-quality 3D T1-weighted MRI scans were obtained from 45 Mn-exposed full-time welders and 33 age-matched HCs in this study. After extracting gray matter structural covariation networks by SBM, multiple classic interaction linear models were applied to investigate distinct patterns in welders compared to HCs, and Z-transformed loading coefficients were compared between the two groups. A receiver operating characteristic (ROC) curve was used to identify potential biomarkers for distinguishing Mn-exposed welders from HCs. Additionally, we assessed the relationships between clinical features and gray matter volumes in the welders group. RESULTS: A total of 78 subjects (45 welders, mean age 46.23±4.93 years; 33 HCs, mean age 45.55±3.40 years) were evaluated. SBM identified five components that differed between the groups. These components displayed lower loading weights in the basal ganglia, thalamus, default mode network (including the lingual gyrus and precuneus), and temporal lobe network (including the temporal pole and parahippocampus), as well as higher loading weights in the sensorimotor network (including the supplementary motor cortex). ROC analysis identified the highest classification power in the thalamic network. CONCLUSIONS: Altered brain structures might be implicated in Mn overexposure-related disturbances in motivative modulation, cognitive control and information integration. These results encourage further studies that focus on the interaction mechanisms, including the basal ganglia network, thalamic network and default mode network. Our study identified potential neurobiological markers in Mn-exposed welders and illustrated the utility of a multivariate method of gray matter analysis.

Spotlight on necroptosis: Role in pathogenesis and therapeutic potential of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which is one of the major factors leading to disability and severe economic burden. Necroptosis is an important form of programmed cell death (PCD), a highly regulated caspase-independent type of cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL)-mediated, play a key role in the pathophysiology of various inflammatory, infectious and degenerative diseases. Recent studies have shown that necroptosis plays an important role in the occurrence and development of IDD. In this review, we provide an overview of the initiation and execution of necroptosis and explore in depth its potential mechanisms of action in IDD. The analysis focuses on the connection between NP cell necroptosis and mitochondrial dysfunction-oxidative stress pathway, inflammation, endoplasmic reticulum stress, apoptosis, and autophagy. Finally, we evaluated the possibility of treating IDD by inhibiting necroptosis, and believed that targeting necroptosis may be a new strategy to alleviate the symptoms of IDD.

In vitro evaluation of the impact of a bioceramic root canal sealer on the mechanical properties of tooth roots.

Bacground/purpose: Endodontically treated teeth are more prone to vertical root fracture with the mechanical property changes to some extent during root canal treatment. This study aimed to investigate the effects of a bioceramic sealer on the mechanical properties of tooth roots. Materials and methods: Dentin discs were dried by two different methods (ethanol drying and paper points drying) and then filled with a BC sealer named iRoot SP. SEM and EDS were used to analyze the newly formed minerals in dentin tubules. Elastic modulus and hardness of the secondary dentin in areas proximal to the primary dentin (PD-SD) and areas proximal to canal or iRoot SP (SD-C/SD-iRoot SP) were measured using nanoindentation technique. The compressive strength of roots filled with iRoot SP were tested by compressive loading test. Results: (1) Penetration and mineralization: Paper points drying was more conducive to iRoot SP adhesion, spreading and penetration into the dentin tubules than 95% ethanol drying. (2) Micromechanical properties: After filling root canal with iRoot SP, the elastic modulus and hardness of SD-iRoot SP were higher than those of PD-SD (P = 0.001 and P = 0.000). (3) Fracture resistance: The compressive strength of the roots filled with iRoot SP was not significantly different from that of the roots unprepared and unfilled (P = 0.957), but was higher than that of the roots prepared and unfilled (P = 0.009). Conclusion: Excessive drying (95% ethanol drying method) is not conducive to the penetration and mineralization of the BC sealer iRoot SP into dentin tubules. The good bioactivity of iRoot SP was responsible for increasing the elastic modulus and hardness of dentin, which strengthened the prepared roots.

[Effects of Biochar-loaded Ammonia Nitrogen on Soil Carbon Emissions, Enzyme Activity, and Microbial Communities].

The form of soil nitrogen input significantly affects soil CO2 emission. As a new form of nitrogen input, biochar-loaded ammonia nitrogen not only reduces the input of chemical nitrogen fertilizer in farmland but also reduces the cost of environmental treatment. It is of great significance to promote the zero growth of national chemical fertilizer, the prevention and control of farmland non-point source pollution, and the realization of the national goal of "carbon peak" and "carbon neutralization." Through an indoor culture experiment, the effects of different nitrogen input forms on soil carbon emission, enzyme activity, and microbial community were studied through four treatments:no fertilization (CK), single application of chemical nitrogen fertilizer (CF), biochar combined application of chemical nitrogen fertilizer (BF), and biochar-loaded ammonia nitrogen (BN). The results showed that compared with that in CF, BF significantly increased cumulative carbon emissions (66.24 %), whereas BN had no significant difference. It is worth noting that the cumulative carbon emissions were significantly reduced by 35.28 % compared with that in BF and BN. Compared with those in CF and BF, the activities of ß-glucosidase, peroxidase, and polyphenol oxidase treated with BN significantly increased by 20.25 % and 5.20 %, respectively. Compared with that in CF, the BF treatment increased microbial community richness and community diversity, whereas the BN treatment decreased microbial community richness. Compared with that in BF, the relative abundance of Proteobacteria decreased by 11.16 %, and the relative abundance of Actinobacteria and Bacteroidota increased by 8.12 % and 5.83 %, respectively, in which xylosidase activity was the most important soil factor affecting microbial community structure. The relative abundance of Chloroflexi was significantly correlated with cellobiose hydrolase activity, and the relative abundance of Gemmatimonadetes was significantly correlated with ß-glucosidase activity. There was a very significant correlation between the relative abundance of Proteobacteria and cumulative carbon emissions. To summarize, compared with those under biochar combined with chemical nitrogen fertilizer, biochar loaded with ammonia nitrogen significantly reduced cumulative carbon emissions, and its emission reduction effect was better. The results of this study will be beneficial to the landing of the national "double carbon strategy," the healthy development of the biological natural gas industry, the construction of the national green cultivation circular agriculture system, and the realization of the national zero growth strategy of chemical fertilizer.

Improving bio-conditioning dewatering performance of food waste anaerobic digestate at low ambient temperatures by heating treatment.

Food waste anaerobic digestate (FWAD) containing high concentrations of contaminants must be purified or recycled. Bio-conditioning dewatering followed by activated sludge process (BDAS) has emerged as a promising technology for treating FWAD. However, the bio-conditioning dewatering as a pivotal step of BDAS is often negatively affected by low ambient temperatures often occurred in winter. This study investigated the role of heating FWAD in improving the bio-conditioning dewatering performance of FWAD. Batch experiments demonstrated that the bio-conditioning dewatering efficiency increased with temperature rise. Notably, due to the low energy consumption, 50°C was considered to be the most appropriate heating treatment temperature, realizing a drastic reduction of specific resistance to filtration (SRF) of bio-conditioned FWAD from initial 1.24 × 1012 m/kg in the control at a ambient temperature of 10°C to 5.42 × 1011 m/kg and a saving of 25% in bio-conditioning reagents cost. The results of the pilot-scale and large-scale experiments revealed that heating treatment made the bio-conditioning dewatering more stable regardless of the fluctuation of ambient temperature in practical engineering. The decrease in the viscosity of bio-conditioned FWAD and the enhancement in microbial fermentation liquor flocculation capacity through heating treatment played pivotal roles in improving the bio-conditioning dewatering performance of FWAD. This work provides a cost-effective strategy to achieve efficient bio-conditioning dewatering at a relatively low ambient temperature, which was helpful in the engineering application of the novel BDAS process in wastewater treatment.