Ubiquitin-specific protease UBP14 stabilizes HY5 by deubiquitination to promote photomorphogenesis in Arabidopsis thaliana.

Transcription factor ELONGATED HYPOCOTYL5 (HY5) is the central hub for seedling photomorphogenesis. E3 ubiquitin (Ub) ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) inhibits HY5 protein accumulation through ubiquitination. However, the process of HY5 deubiquitination, which antagonizes E3 ligase-mediated ubiquitination to maintain HY5 homeostasis has never been studied. Here, we identified that Arabidopsis thaliana deubiquitinating enzyme, Ub-SPECIFIC PROTEASE 14 (UBP14) physically interacts with HY5 and enhances its protein stability by deubiquitination. The da3-1 mutant lacking UBP14 function exhibited a long hypocotyl phenotype, and UBP14 deficiency led to the failure of rapid accumulation of HY5 during dark to light. In addition, UBP14 preferred to stabilize nonphosphorylated form of HY5 which is more readily bound to downstream target genes. HY5 promoted the expression and protein accumulation of UBP14 for positive feedback to facilitate photomorphogenesis. Our findings thus established a mechanism by which UBP14 stabilizes HY5 protein by deubiquitination to promote photomorphogenesis in A. thaliana.

Genome-wide detection of human variants that disrupt intronic branchpoints.

Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found that BP and BP-2 (two nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which were validated experimentally. BPHunter is publicly available from https://hgidsoft.rockefeller.edu/BPHunter and https://github.com/casanova-lab/BPHunter.

Integrative Analyses Reveal the Correlation Between the Airway Microbiome and Host Metabolism in Severe Community-acquired Pneumonia.

Community-acquired pneumonia (CAP) is a significant global health concern, responsible for high mortality and morbidity. Recent research has revealed a potential link between disordered microbiome and metabolism in pneumonia, although the precise relationship between these factors and severe CAP remains unclear. To address this knowledge gap, we conducted a comprehensive analysis utilizing 16S sequencing and LC-MS/MS metabolomics data to characterize the microbial profile in sputum and metabolic profile in serum in patients with severe community-acquired pneumonia (sCAP). Our analysis identified 13 genera through LEfSe analysis and 15 metabolites meeting specific criteria (P < 0.05, VIP ≥ 2, and |Log2(FC)| ≥ 2). The findings of this study demonstrate the presence of altered coordination between the microbiome of the lower respiratory tract and host metabolism in patients with sCAP. The observed concentration trends of specific metabolites across different disease stages further support the potential involvement of the serum metabolism in the development of sCAP. These correlations between the airway microbiome and host metabolism in sCAP patients have important implications for optimizing early diagnosis and developing individualized therapeutic strategies.

Stiffness promotes cell migration, invasion, and invadopodia in nasopharyngeal carcinoma by regulating the WT-CTTN level.

Matrix stiffness potently promotes the malignant phenotype in various biological contexts. Therefore, identification of gene expression to participate in mechanical force signals transduced into downstream biochemical signaling will contribute substantially to the advances in nasopharyngeal carcinoma (NPC) treatment. In the present study, we detected that cortactin (CTTN) played an indispensable role in matrix stiffness-induced cell migration, invasion, and invadopodia formation. Advances in cancer research have highlighted that dysregulated alternative splicing contributes to cancer progression as an oncogenic driver. However, whether WT-CTTN or splice variants (SV1-CTTN or SV2-CTTN) regulate matrix stiffness-induced malignant phenotype is largely unknown. We proved that alteration of WT-CTTN expression modulated matrix stiffness-induced cell migration, invasion, and invadopodia formation. Considering that splicing factors might drive cancer progression through positive feedback loops, we analyzed and showed how the splicing factor PTBP2 and TIA1 modulated the production of WT-CTTN. Moreover, we determined that high stiffness activated PTBP2 expression. Taken together, our findings showed that the PTBP2-WT-CTTN level increases upon stiffening and then promotes cell migration, invasion, and invadopodia formation in NPC.

The Pathogenic Role of Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Nocardiosis with the Central Nervous System Involvement.

PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are implicated in the pathogenesis of Cryptococcus gattii (C. gattii) infection and pulmonary alveolar proteinosis (PAP). Their presence has also been noted in nocardiosis cases, particularly those with disseminated disease. This study delineates a case series characterizing clinical features and specificity of anti-GM-CSF Abs in nocardiosis patients. METHODS: In this study, eight patients were recruited to determine the presence or absence of anti-GM-CSF Abs. In addition to the detailed description of the clinical course, we thoroughly investigated the autoantibodies regarding the characteristics, isotypes, subclasses, titers, and neutralizing capacities by utilizing the plasma samples from patients. RESULTS: Of eight patients, five tested positive for anti-GM-CSF Abs, all with central nervous system (CNS) involvement; patients negative for these antibodies did not develop CNS nocardiosis. Distinct from previously documented cases, none of our patients with anti-GM-CSF Abs exhibited PAP symptoms. The titer and neutralizing activity of anti-GM-CSF Abs in our cohort did not significantly deviate from those found in C. gattii cryptococcosis and PAP patients. Uniquely, one individual (Patient 3) showed a minimal titer and neutralizing action of anti-GM-CSF Abs, with no relation to disease severity. Moreover, IgM autoantibodies were notably present in all CNS nocardiosis cases investigated. CONCLUSION: The presence of anti-GM-CSF Abs suggests an intrinsic immunodeficiency predisposing individuals toward CNS nocardiosis. The presence of anti-GM-CSF Abs helps to elucidate vulnerability to CNS nocardiosis, even with low titer of autoantibodies. Consequently, systematic screening for anti-GM-CSF Abs should be considered a crucial diagnostic step for nocardiosis patients.

Reliable Memristor Crossbar Array Based on 2D Layered Nickel Phosphorus Trisulfide for Energy-Efficient Neuromorphic Hardware.

Designing reliable and energy-efficient memristors for artificial synaptic arrays in neuromorphic computing beyond von Neumann architecture remains a challenge. Here, memristors based on emerging layered nickel phosphorus trisulfide (NiPS3 ) are reported that exhibit several favorable characteristics, including uniform bipolar nonvolatile switching with small operating voltage (<1 V), fast switching speed (< 20 ns), high On/Off ratio (>102 ), and the ability to achieve programmable multilevel resistance states. Through direct experimental evidence using transmission electron microscopy and energy dispersive X-ray spectroscopy, it is revealed that the resistive switching mechanism in the Ti/NiPS3 /Au device is related to the formation and dissolution of Ti conductive filaments. Intriguingly, further investigation into the microstructural and chemical properties of NiPS3 suggests that the penetration of Ti ions is accompanied by the drift of phosphorus-sulfur ions, leading to induced P/S vacancies that facilitate the formation of conductive filaments. Furthermore, it is demonstrated that the memristor, when operating in quasi-reset mode, effectively emulates long-term synaptic weight plasticity. By utilizing a crossbar array, multipattern memorization and multiply-and-accumulate (MAC) operations are successfully implemented. Moreover, owing to the highly linear and symmetric multiple conductance states, a high pattern recognition accuracy of ≈96.4% is demonstrated in artificial neural network simulation for neuromorphic systems.

Achieving Low-Dose Rate X-Ray Imaging Based on 2D/3D-Mixed Perovskite Films.

X-ray detection and imaging are widely used in medical diagnosis, product inspection, security monitoring, etc. Large-scale polycrystalline perovskite thick films possess high potential for direct X-ray imaging. However, the notorious problems of baseline drift and high detection limit caused by ions migration are still remained. Here, ion migration is reduced by incorporating 2D perovskite into 3D perovskite, thereby increasing the ion activation energy. This approach hinders ion migration within the perovskite film, consequently suppressing baseline drift and reducing the lowest detection limit(LOD) of the device. As a result, the baseline drifting declines by 20 times and the LOD reduces to 21.1 nGy s-1, while the device maintains a satisfactory sensitivity of 5.6 × 103 µC Gy-1 cm-2. This work provides a new strategy to achieve low ion migration in large-scale X-ray detectors and may provide new thoughts for the application of mixed-dimension perovskite.

Hyperuricemia: A key contributor to endothelial dysfunction in cardiovascular diseases.

As an end product of purine metabolism, uric acid (UA) is a major endogenous antioxidant in humans. However, impaired UA synthesis and excretion can lead to hyperuricemia (HUA), which may in turn induce endothelial dysfunction (ED) and contribute to the pathogenesis of cardiovascular diseases (CVDs; e.g., atherosclerosis and hypertension). In this review, we discuss recent advances and novel insights into the effects exerted by HUA conditions in ED and related underlying mechanisms focusing on impaired UA metabolism, reduction in the synthesis and bioavailability of nitric oxide, endothelial cell injury, the endothelial-to-mesenchymal transition, insulin resistance, procoagulant activity, and acquisition of an inflammatory phenotype. We additionally discuss intervention strategies for HUA-induced ED and the paradoxical roles of UA in endothelial function. We summarize major conclusions and perspectives: the deleterious effects of HUA contribute to the initiation and progression of CVD-related ED. However, the treatment strategies (in addition to urate-lowering therapy) for increasing endothelial function are limited because the majority of literature on pharmacological and pathophysiological mechanisms underlying HUA-induced ED solely describes in vitro models. Therefore, a better understanding of the mechanisms involved in HUA-induced ED is critical to the development of novel therapies for preventing and treating CVD-HUA comorbidities.

HO-1-induced autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to reduce gut permeability in cholestatic liver disease.

OBJECTIVES: The gut-liver axis disruption is a unified pathogenetic principle of cholestatic liver disease (CSLD). Increased gut permeability is the leading cause of gut-liver axis disruption. HO-1 is capable of protecting against gut-liver axis injury. However, it has rarely been reported whether autophagy is involved in HO-1 protecting gut-liver barrier integrity and the underlying mechanism. MATERIALS AND METHODS: Mice underwent bile duct ligation (BDL) was established as CSLD model in vivo. Caco-2 cells with LPS treatment was established as in vitro cell model. Immunofluorescence, western blot and transepithelial electrical resistance (TER) assay were used to observe epithelial tight junction (TJ) and autophagy. Liver injury and fibrosis were evaluated as well through H&E staining, masson staining, sirius red staining and ELISA. RESULTS AND CONCLUSIONS: Our study demonstrated that the epithelial TJ and TER were notably reduced both in BDL mice and in LPS treated intestinal epithelial cells. Increased HO-1 expression could significantly induce intestinal epithelial cell autophagy. Additionally, this increased autophagy level reversed the reduction effects of BDL or LPS on epithelial TJ and TER in vivo and in vitro, therefore decreased transaminase level in serum and relieved liver fibrosis in BDL mice. Besides, increased autophagy level in turn upregulated the expression of HO-1 by p62 degradation of Keap1 and subsequent activation of Nrf2 pathway. Collectively, these results indicate that HO-1 reduces gut permeability by enhancing autophagy level in CSLD, the increased autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to further improve gut-liver axis disruption. Therefore, our study confirms the critical role of autophagy in HO-1 ameliorating gut-liver axis injury during CSLD, highlighting HO-1 as a promising therapeutic target.

Rapid detection of pathogenic fungi from coastal population with respiratory infections using microfluidic chip technology.

BACKGROUND: Currently, culture methods are commonly used in clinical tests to detect pathogenic fungi including Candida spp. Nonetheless, these methods are cumbersome and time-consuming, thereby leading to considerable difficulties in diagnosis of pathogenic fungal infections, especially in situations that respiratory samples such as alveolar lavage fluid and pleural fluid contain extremely small amounts of microorganisms. The aim of this study was to elucidate the utility and practicality of microfluidic chip technology in quick detection of respiratory pathogenic fungi. METHODS: DNAs of clinical samples (mainly derived from sputa, alveolar lavage fluid, and pleural fluid) from 64 coastal patients were quickly detected using microfluidic chip technology with 20 species of fungal spectrum and then validated by Real-time qPCR, and their clinical baseline data were analyzed. RESULTS: Microfluidic chip results showed that 36 cases infected with Candida spp. and 27 cases tested negative for fungi, which was consistent with Real-time qPCR validation. In contrast, only 16 cases of fungal infections were detected by the culture method; however, one of the culture-positive samples tested negative by microfluidic chip and qPCR validation. Moreover, we found that the patients with Candida infections had significantly higher rates of platelet count reduction than fungi-negative controls. When compared with the patients infected with C. albicans alone, the proportion of males in the patients co-infected with multiple Candidas significantly increased, while their platelet counts significantly decreased. CONCLUSIONS: These findings suggest that constant temperature amplification-based microfluidic chip technology combined with routine blood tests can increase the detection speed and accuracy (including sensitivity and specificity) of identifying respiratory pathogenic fungi.

A radiomics model utilizing CT for the early detection and diagnosis of severe community-acquired pneumonia.

BACKGROUND: Community-Acquired Pneumonia (CAP) remains a significant global health concern, with a subset of cases progressing to Severe Community-Acquired Pneumonia (SCAP). This study aims to develop and validate a CT-based radiomics model for the early detection of SCAP to enable timely intervention and improve patient outcomes. METHODS: A retrospective study was conducted on 115 CAP and SCAP patients at Southern Medical University Shunde Hospital from January to December 2021. Using the Pyradiomics package, 107 radiomic features were extracted from CT scans, refined via intra-class and inter-class correlation coefficients, and narrowed down using the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. The predictive performance of the radiomics-based model was assessed through receiver operating characteristic (ROC) analysis, employing machine learning classifiers such as k-Nearest Neighbors (KNN), Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF), trained and validated on datasets split 7:3, with a training set (n = 80) and a validation set (n = 35). RESULTS: The radiomics model exhibited robust predictive performance, with the RF classifier achieving superior precision and accuracy compared to LR, SVM, and KNN classifiers. Specifically, the RF classifier demonstrated a precision of 0.977 (training set) and 0.833 (validation set), as well as an accuracy of 0.925 (training set) and 0.857 (validation set), suggesting its superior performance in both metrics. Decision Curve Analysis (DCA) was utilized to evaluate the clinical efficacy of the RF classifier, demonstrating a favorable net benefit within the threshold ranges of 0.1 to 0.8 for the training set and 0.2 to 0.7 for the validation set. CONCLUSIONS: The radiomics model developed in this study shows promise for early SCAP detection and can improve clinical decision-making.

The care needs of the elderly in China's elderly care institutions: a narrative synthesis.

China's population is ageing, affecting trends in social development and basic national conditions. More attention must be paid to the lack of care needs assessments for the elderly in China's pension institutions. This paper discusses a systematic evaluation of the care needs of the elderly in China's elderly care institutions. Literature was collected and synthesized after a search of the Web of Science, PubMed, and other databases for works published up to August 2021. Relevant content is proposed, including the name of the first author, publication date, study area, and sample size. Exactly 18 articles were included in the literature, documents that reported on a total of 7277 elderly people. The results showed a combined demand rate of primary care needs ≥50%. The top five needs included mental/psychological (76%), tranquillity/care (73%), living/environmental (71%), medical treatment (64%), and preventive healthcare (64%). The combined demand rate of secondary care needs was ≥50%. The top five needs included 79% for room/laundry/cleaning, 77% for psychological comfort and nursing, 73% for end-of-life care, 70% for disease diagnosis and treatment, and 69% for physical examination. The health needs of older people are diverse and focus mainly on mental/psychological, tranquility/care, living/environmental (71%), pharmacotherapy, and preventive healthcare.

Genome-wide DNA methylation changes in Oryzias melastigma embryos exposed to the water accommodated fraction of crude oil.

The water accommodated fraction (WAF) of crude oil exerts considerable impacts on marine fish during embryonic stage. Clarifying changes in epigenetic modifications is helpful for understanding the molecular mechanism underlying the toxicity of embryonic WAF exposure. The aim of this study was to explore genome-wide DNA methylation changes in Oryzias melastigma embryos after exposure to the nominal total petroleum hydrocarbon concentration of 500 µg/L in WAF for 7 days. Whole-genome bisulfite sequencing revealed that 8.47 % and 8.46 % of all the genomic C sites were methylated in the control and WAF-exposed groups, respectively. Among the three sequence contexts, methylated CG site had the largest number in both the two groups. The sequence preferences of nearby methylated cytosines were consistent between the two groups. A total of 4798 differentially methylated regions (DMRs) were identified in the promoter region. Furthermore, Gene Ontology analysis revealed that DMR-related genes were enriched mainly for functions related to development and nervous system. Additionally, the Kyoto Encyclopedia of Genes and Genomes pathways enriched in DMR-related genes were related to nervous system and endocrine system. These novel findings provide comprehensive insights into the genome-wide DNA methylation landscape of O. melastigma following embryonic WAF exposure, shedding light on the epigenetic regulatory mechanisms underlying WAF-induced toxicity.

The role and mechanism of miR-425-3p regulating neuronal pyroptosis -mediated inorganic arsenic-induced generalized anxiety disorder.

Pyroptosis plays a critical role in the pathogenesis of mental disorders. However, its specific role and mechanism in arsenic (As)-induced generalized anxiety disorder (GAD) remain elusive. We utilized the data from CtdBbase, Phenopedia and DisGeNet to analyze genes that interact with arsenic poisoning and GAD. Subsequently KEGG and GO enrichment analysis were conducted to preliminatively predict the mechanism of inorganic arsenic-induced GAD. Male Wistar rats were administered water containing NaAsO2 (50, 100 µg/L) to evaluate GAD-like behavior through open field test and elevated plus maze. The expression of differential miRNAs including miR-425-3p, and pyroptosis in the prefrontal cortex of rats were detected. Furthermore, SKNSH cells were stimulated with NaAsO2 to examine the molecular changes, and then miR-425-3p mimic was transfected into SKNSH cells to detect pyroptosis in order to verify the function of miR-425-3p. Inorganic arsenic was confirmed to induce GAD-like behavior in rats, characterized by decreased locomotor activity and exploratory activities. Rats with inorganic arsenic-induced GAD exhibited reduced miR-425-3p expression levels in the prefrontal cortex and increased expression of pyroptosis-related proteins, including NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Treating with different concentrations of NaAsO2 showed that inorganic arsenic exposure downregulates miR-425-3p expression in SKNSH cells and upregulates the expression levels of pyroptosis-related proteins. Dual-luciferase reporter gene experiments demonstrated that miR-425-3p targets the NFKB1. Overexpressing miR-425-3p reversed the inorganic arsenic-induced pyroptosis in SKNSH cells by inhibiting the expression of NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Our findings suggest that inorganic arsenic exposure may induce GAD-like behavior in rats by downregulating miR-425-3p in prefrontal cortex, which targets NF-κB and regulates pyroptosis in neuronal cells.

Perspectives on dementia care self-learning platform: A focus group study of family and professional caregivers.

OBJECTIVE: To compare perspectives of family and professional caregivers regarding an online self-learning platform. METHODS: Family and professional caregivers were interviewed separately. A thematic analysis was conducted with 12 family caregivers and 13 professional caregivers of people living with dementia in Macao using six semi-structured focus group interviews. RESULTS: Family and professional caregivers had different perspectives regarding the application of online learning program Four main themes emerged from the focus groups, including similarities and differences, namely 1) Need for services; 2) Accessibility to services; 3) Barriers to online learning; 4) Adjustments to the platform. CONCLUSIONS: The psychological assurance offered by an online learning program is imperative to the well-being of family caregivers. By identifying the gap between the needs and abilities of family caregivers and those imagined by professional caregivers, it allows for the development of support programs and interventions tailored to meet the specific needs of family caregivers.

[Identification of novel genetic loci associated with major depressive disorder and the hippocampus in a European population using the condFDR method].

OBJECTIVE: To identify additional loci associated with depression and the hippocampus (HIP) through genome-wide association study. METHODS: The depression-related genome-wide association study (GWAS) meta summary data was downloaded from the official website of the Psychiatric Genomics Consortium, which had involved 170 756 cases and 329 443 controls. The left and right hippocampal volume GWAS data sets were downloaded from the UK Biobank, which involved 33 224 participants. The conditional false discovery rate (condFDR) was used to identify novel genetic loci for depression and left and right hippocampal volumes, and a conjunctional false discovery rate (conjFDR) was used to evaluate the enrichment of pleiotropic loci between depression and left and right hippocampal volumes. RESULTS: Respectively, 7, 13, and 12 new loci have been associated with depression, left hippocampal volume and right hippocampal volume, with a significant threshold of condFDR < 0.01. A site of rs1267073 locus was found to be shared by the depression and right hippocampal volume with a threshold of conjFDR < 0.01. CONCLUSION: Above findings have provided more insights into the genetic mechanisms underlying the volume of hippocampus and the risk for depression. The results may also provide evidence for future clinical trials for treating depression.

[Application of Deep Learning to Diagnose and Classify Adolescent Idiopathic Scoliosis].

A deep learning-based model for automatic diagnosis and classification of adolescent idiopathic scoliosis has been constructed. This model mainly included key points detection and Cobb angle measurement. 748 full-length standing spinal X-ray images were retrospectively collected, of which 602 images were used to train and validate the model, and 146 images were used to test the model performance. The results showed that the model had good diagnostic and classification performance, with an accuracy of 94.5%. Compared with experts' measurement, 94.9% of its Cobb angle measurement results were within the clinically acceptable range. The average absolute difference was 2.1°, and the consistency was also excellent (r2≥0.9552, P<0.001). In the future, this model could be applied clinically to improve doctors' diagnostic efficiency.

[Development and Application of Deep Learning-Based Model for Quality Control of Children Pelvic X-Ray Images].

Objective: A deep learning-based method for evaluating the quality of pediatric pelvic X-ray images is proposed to construct a diagnostic model and verify its clinical feasibility. Methods: Three thousand two hundred and forty-seven children with anteroposteric pelvic radiographs are retrospectively collected and randomly divided into training datasets, validation datasets and test datasets. Artificial intelligence model is conducted to evaluate the reliability of quality control model. Results: The diagnostic accuracy, area under ROC curve, sensitivity and specificity of the model are 99.4%, 0.993, 98.6% and 100.0%, respectively. The 95% consistency limit of the pelvic tilt index of the model is -0.052-0.072. The 95% consistency threshold of pelvic rotation index is -0.088-0.055. Conclusion: This is the first attempt to apply AI algorithm to the quality assessment of children's pelvic radiographs, and has significantly improved the diagnosis and treatment status of DDH in children.

Eradicating Helicobacter pylori via 13C-urea breath screening to prevent gastric cancer in indigenous communities: a population-based study and development of a family index-case method.

OBJECTIVE: Screening and eradication of Helicobacter pylori help reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme. DESIGN: We enrolled residents aged 20-60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the 13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases. RESULTS: Between 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence of H. pylori than those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%). CONCLUSION: A high participation rate, a high eradication rate of H. pylori and an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities. TRIAL REGISTRATION NUMBER: NCT03900910.

Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice.

Osteoporosis is caused by enhanced bone resorption and relatively reduced bone formation. There is an unmet need to develop new agents with both antiresorptive and anabolic effects to treat osteoporosis, although drugs with either effect alone are available. A small molecular compound, plumbagin, was reported to inhibit receptor activator of nuclear factor kappa-B ligand-induced osteoclast (OC) differentiation by inhibiting IκBα phosphorylation-mediated canonical NF-κB activation. However, the key transcriptional factor RelA/p65 in canonical NF-κB pathway functions to promote OC precursor survival but not terminal OC differentiation. Here, we found that plumbagin inhibited the activity of NF-κB inducing kinase, the key molecule that controls noncanonical NF-κB signaling, in an ATP/ADP-based kinase assay. Consistent with this, plumbagin inhibited processing of NF-κB2 p100 to p52 in the progenitor cells of both OCs and osteoblasts (OBs). Interestingly, plumbagin not only inhibited OC but also stimulated OB differentiation in vitro. Importantly, plumbagin prevented trabecular bone loss in ovariectomized mice. This was associated with decreased OC surfaces on trabecular surface and increased parameters of OBs, including OB surface on trabecular surface, bone formation rate, and level of serum osteocalcin, compared to vehicle-treated mice. In summary, we conclude that plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects on bone and could represent a new class of agent for the prevention and treatment of osteoporosis.