Robust Temporal Link Prediction in Dynamic Complex Networks via Stable Gated Models With Reinforcement Learning.

Temporal link prediction is one of the most important tasks for predicting time-varying links by capturing dynamics within complex networks. However, it suffers from difficulties such as vulnerability to adversarial attacks and inadaptation to distinct evolutionary patterns. In this article, we propose a robust temporal link prediction architecture via stable gated models with reinforcement learning (SAGE-RL) consisting of a state encoding network (SEN) and a self-adaptive policy network (SPN). The former is utilized to capture network dynamics, while the latter helps the former adapt to distinct evolutionary patterns across various time periods. Within the SEN, a novel stable gate is introduced to ensure multiple spatiotemporal dependency paths and defend against adversarial attacks. An SPN is proposed to select different SEN instances by approximating the optimal action function, thereby adapting to various evolutionary patterns to learn the robust temporal and structural features from dynamic complex networks. It is proven that SAGE-LR with integral Lipschitz graph convolution is stable to relative perturbations in dynamic complex networks. With the aid of extensive experiments on five real-world graph benchmarks, SAGE-LR is shown to substantially outperform current state-of-the-art approaches in terms of precision and stability of temporal link prediction and ability to successfully defend against various attacks. We also implement the temporal link prediction in shipping transaction networks, which forecast effectively its potential transaction risks.

Predicting the potential mechanism of Radix Chimonanthi Pracecocis in treating osteoarthritis by network pharmacology analysis combined with experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Chimonanthi Pracecocis(RCP), also known as Tiekuaizi, widely used by the Miao community in Guizhou, exhibits diverse biological activities and holds promise for the treatment of osteoarthritis (OA). However, there is a lack of contemporary pharmacological research in this area. AIMS OF THE STUDY: This study aims to explore the potential of targets and mechanisms of RCP in the treatment of OA. MATERIALS AND METHODS: The chemical components of RCP were identified using UPLC-MS/MS, and active components were determined based on the Lipinski rule. RCP and OA-related targets were retrieved from public databases such as TCMSP and GeneCards. Network pharmacology approaches were employed to identify key genes. The limma package (version 3.40.2) in R 4.3.2 was used to screen for differentially expressed genes (DEGs) between OA and healthy individuals in GSE82107. DEGs were analyzed using an independent sample t-test and receiver operating characteristic analysis in GraphPad Prism 9.5.1. Additionally, molecular docking (SYBYL2.1.1) was used to analyze the binding interactions between the active components and target proteins. Finally, we established a papain-induced osteoarthritis (OA) rat model and treated it with RCP aqueous extract by gavage. We validated relevant indicators using real-time fluorescence quantitative polymerase chain reaction, western blot, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Seven active components and 53 targets were identified. The results of GO and KEGG enrichment analyses confirmed the significant role of RCP in the regulation of pyroptosis. Hypoxia-inducible factor-1α (HIF-1α) was identified as a key gene involved in the main biological functions. Molecular docking analysis revealed that Praecoxin, Isofraxidin, Esculin, and Naringenin can bind to the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) (T-Score > 5). Additionally, Praecoxin can bind to HIF-1α (T-Score > 5). In vivo experiments demonstrated that RCP significantly affects the NLRP3 inflammasome, which is regulated by the HIF-1α pathway. RCP inhibited pyroptosis and reduced synovial inflammation. CONCLUSIONS: This study confirmed the efficacy of RCP aqueous extract in the treatment of OA and identified seven active components (esculin, dihydrokaempferol, naringenin, praecoxin, carnosol, hydroxyvalerenic acid, isofraxidin) that may play an anti-pyroptosis role in the treatment of OA by downregulating the expression of HIF-1α and NLRP3 inflammasome.

In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.

The association between humidex and tuberculosis: a two-stage modelling nationwide study in China.

BACKGROUND: Under a changing climate, the joint effects of temperature and relative humidity on tuberculosis (TB) are poorly understood. To address this research gap, we conducted a time-series study to explore the joint effects of temperature and relative humidity on TB incidence in China, considering potential modifiers. METHODS: Weekly data on TB cases and meteorological factors in 22 cities across mainland China between 2011 and 2020 were collected. The proxy indicator for the combined exposure levels of temperature and relative humidity, Humidex, was calculated. First, a quasi-Poisson regression with the distributed lag non-linear model (DLNM) was constructed to examine the city-specific associations between humidex and TB incidence. Second, a multivariate meta-regression model was used to pool the city-specific effect estimates, and to explore the potential effect modifiers. RESULTS: A total of 849,676 TB cases occurred in the 22 cities between 2011 and 2020. Overall, a conspicuous J-shaped relationship between humidex and TB incidence was discerned. Specifically, a decrease in humidex was positively correlated with an increased risk of TB incidence, with a maximum relative risk (RR) of 1.40 (95% CI: 1.11-1.76). The elevated RR of TB incidence associated with low humidex (5th humidex) appeared on week 3 and could persist until week 13, with a peak at approximately week 5 (RR: 1.03, 95% CI: 1.01-1.05). The effects of low humidex on TB incidence vary by Natural Growth Rate (NGR) levels. CONCLUSION: A J-shaped exposure-response association existed between humidex and TB incidence in China. Humidex may act as a better predictor to forecast TB incidence compared to temperature and relative humidity alone, especially in regions with higher NGRs.

Intravenous immunoglobulin alleviates Japanese encephalitis virus-induced peripheral neuropathy by inhibiting the ASM/ceramide pathway.

Japanese encephalitis virus (JEV) infection is considered a global public health emergency. Severe peripheral neuropathy caused by JEV infection has increased disability and mortality rates in recent years. Because there are very few therapeutic options for JEV infection, prompt investigations of the ability of clinically safe, efficacious and globally available drugs to inhibit JEV infection and ameliorate peripheral neuropathy are urgently needed. In this study, we found that high doses of intravenous immunoglobulin, a function inhibitor of acid sphingomyelinase (FIASMA), inhibited acid sphingomyelinase (ASM) and ceramide activity in the serum and sciatic nerve of JEV-infected rats, reduced disease severity, reversed electrophysiological and histological abnormalities, significantly reduced circulating proinflammatory cytokine levels, inhibited Th1 and Th17 cell proliferation, and suppressed the infiltration of inflammatory CD4 + cells into the sciatic nerve. It also maintained the peripheral nerve-blood barrier without causing severe clinical side effects. In terms of the potential mechanisms, ASM was found to participate in immune cell differentiation and to activate immune cells, thereby exerting proinflammatory effects. Therefore, immunoglobulin is a FIASMA that reduces abnormal immune responses and thus targets the ASM/ceramide system to treat peripheral neuropathy caused by JEV infection.

Effect of visual impairment on subjective cognitive decline in older adults: a cross-sectional study in China.

OBJECTIVE: People with visual impairment have more functional limitations associated with subjective cognitive decline (SCD), and those with SCD are extremely susceptible to transitioning to irreversible cognitive impairment. This study aimed to explore if visual impairment is a significant predictor of SCD compared with other socioeconomic and health factors associated with SCD. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: The investigation aimed to assess the factors influencing SCD among 428 participants aged 60 and above in Zhaoyuan, China. PRIMARY OUTCOME MEASURES: The primary outcome variable was SCD, measured by the Chinese version of SCD questionnaire. Multiple logistic regression and propensity score matching (PSM) were used to analyse the influence of visual impairment on the subjective cognition of the elderly.32.2% of the elderly were experiencing SCD. Older adults with SCD showed a higher prevalence of visual impairment (72.5%) than the elderly without SCD (58.6%) (P=0.006). Multivariate logistic regression analysis showed that bad self-reported health status, lack of physical exercise and visual impairment were the risk factors for SCD in older adults, while more than 9 years of education was a protective factor. In addition, PSM model showed that after eliminating the dominant biases caused by the individual observable heterogeneity of older adults with and without visual impairment, the risk of SCD in the elderly with visual impairment was increased by 13.6%-14.5% and the difference was statistically significant (P<0.05). CONCLUSIONS: It was found that older adults experiencing visual impairments are at an elevated risk of developing SCD compared with their counterparts without such impairments. Additionally, visual impairment remains a significant risk factor for SCD in the elderly, even adjusting for potential biases arising from individual observable heterogeneity.

Biomass ash as soil fertilizers: Supercharging biomass accumulation by shifting auxin distribution.

Growing quantities of biomass ashes (phyto-ashs) are currently produced worldwide due to the increasing biomass consumption in energy applications. Utilization of phyto-ash in agriculture is environmentally friendly solution. However, mechanisms involving the coordination of carbon metabolism and distribution in plants and soil amendment are not well known. In the present study, tobacco plants were chemically-fertilized with or without 2‰ phyto-ash addition. The control had sole chemical fertilizer; for two phyto-ash treatments, the one (T1) received comparable levels of nitrogen, phophorus, and potassium from phyto-ash and fertilizers as the control and another (T2) had 2‰ of phyto-ash and the same rates of fertilizers as the control. Compared with the control, phyto-ash addition improved the soil pH from 5.94 to about 6.35; T2 treatment enhanced soil available potassium by 30% but no difference of other elements was recorded among three treatments. Importantly, bacterial (but not fungal) communities were significantly enriched by phyto-ash addition, with the rank of richness as: T2 > T1 > control. Consistent with amelioration of soil properties, phyto-ash promoted plant growth through enlarged leaf area and photosynthesis and induced outgrowth of lateral roots (LRs). Interestingly, increased auxin content was recorded in 2nd and 3rd leaves and roots under phyto-ash application, also with the rank level as T2 > T1 > control, paralleling with higher transcripts of auxin synthetic genes in the topmost leaf and stronger [3H]IAA activity under phyto-ash addition. Furthermore, exogenous application of analog exogenous auxin (NAA) restored leaf area, photosynthesis and LR outgrowth to the similar level as T2 treatment; conversely, application of auxin transport inhibitor (NPA) under T2 treatment retarded leaf and root development. We demonstrated that phyto-ash addition improved soil properties and thus facilitated carbon balance within plants and biomass accumulation in which shifting auxin distribution plays an important role.

Penetration pathways, influencing factors and predictive models for dermal absorption of exobiotic molecules: A critical review.

This review provides a comprehensive summary of the skin penetration pathways of xenobiotics, including metals, organic pollutants, and nanoparticles (NPs), with a particular focus on the methodologies employed to elucidate these penetration routes. The impacts of the physicochemical properties of exogenous substances and the properties of solvent carriers on the penetration efficiencies were discussed. Furthermore, the review outlines the steady-state and transient models for predicting the skin permeability of xenobiotics, emphasizing the models which enable realistic visualization of pharmaco-kinetic phenomena via detailed geometric representations of the skin microstructure, such as stratum corneum (SC) (bricks and mortar) and skin appendages (hair follicles and sebaceous gland units). Limitations of published research, gaps in current knowledge, and recommendations for future research are highlighted, providing insight for a better understanding of the skin penetration behavior of xenobiotics and associated health risks in practical application contexts.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).

Association between mild depressive states in polycystic ovary syndrome and an unhealthy lifestyle.

Objective: Polycystic Ovary Syndrome (PCOS) is a prevalent and frequently encountered gynecological disorder. Its high variability and the complexities associated with its management often lead to psychological stress in affected women, manifesting in symptoms of depression. Embracing a healthy lifestyle is fundamental in PCOS treatment. Consistent adherence to a healthy lifestyle not only aids in improving PCOS symptoms but also plays a role in enhancing mental well-being. However, there is currently limited research examining the extent of depression, its prevalence, and its correlation with lifestyle among individuals with PCOS. Therefore, this study aims to explore the impact of lifestyle factors on the depressive state of individuals with PCOS. Methods: This cross-sectional study gathered data from 411 individuals with PCOS at a comprehensive hospital in Henan, China. Depression status was assessed using the Hamilton Depression Scale, and demographic information as well as lifestyle habits were simultaneously collected. Univariate and multivariate analyses using logistic regression were conducted to identify risk factors associated with the depressive state in PCOS. Results: Among the surveyed 411 individuals with PCOS, approximately 49.4% exhibited symptoms of depression, with 83.7% experiencing mild depressive symptoms. A disease duration of 1-3 years, the presence of acne, and unhealthy lifestyle factors such as high-fat diet, staying up late, lack of exercise, and mental stress emerged as significant risk factors for the onset of depressive symptoms. Conclusion: Depressive symptoms in individuals with PCOS are predominantly mild. The risk of comorbid depression in PCOS is associated with the presence of acne, frequent high-fat diet, regular staying up late, lack of exercise, and mental stress.

Adverse reactions of piperacillin: A literature review of case reports.

Aim: This study aimed to summarize case reports of adverse drug reactions (ADRs) caused by piperacillin and explore their effects on human organs in real-world settings. Method: Case reports of piperacillin ADRs were collected by searching databases such as PubMed, Embase, Web of Science, CNKI, WanFang, and VIP from inception to December 2022. Results: A total of 170 patients were ultimately included. The results revealed that ADRs caused by piperacillin were primarily associated with the entire body, followed by the blood system, skin and soft tissues, and the nervous system. The most frequently reported cases included anaphylactic shock, drug fever, rash, and thrombocytopenia. The most severe ADRs were identified as anaphylactic shock and bullous epidermal necrolysis. Furthermore, a comparison was made between systemic adverse reactions caused by piperacillin as a single drug and two composite preparations of piperacillin/ß-lactamase inhibitor. ADRs not mentioned in the instructions included convulsions or hallucinations and Kounis syndrome (KS). Conclusion: This review suggests that the most severe ADRs associated with piperacillin are toxic epidermal necrolysis and anaphylactic shock. Rare ADRs caused by piperacillin, such as myoclonic jerks, hallucinations, and KS, were identified. The most common symptom with domestic preparations of piperacillin/sulbactam and piperacillin sodium was dyspnea.

In vivo evidence of sea buckthorn relieving oxidative stress and improving immune performance of common carp (Cyprinus carpio L.).

BACKGROUND: Sea buckthorn has the functions of antioxidation, antitumor, anti-inflammation and regulating energy metabolism. In order to investigate the effects of sea buckthorn powder and sea buckthorn flavonoids on the antioxidant properties, immune function and muscle fatty acid composition of common carp, an oral feeding experiment was carried out. RESULTS: The administration of glucose significantly reduced the levels of glutathione and the activity of total antioxidant capacity enzyme in serum and hepatopancreas, while concurrently upregulating the level of malondialdehyde (MDA)(P < 0.05). Conversely, oral intake of sea buckthorn powder and flavonoids increased antioxidant enzyme activity and decreased MDA levels. In terms of antioxidant molecular indicators, sea buckthorn powder and sea buckthorn flavonoids significantly increased the mRNA levels of nuclear factor NF-E2-related factor (nrf2) in the hepatopancreas and muscle. Meanwhile, mRNA expression levels of downstream antioxidant-related genes (gr, cat, gpx, and sod) regulated by Nrf2 were also upregulated. In the immune aspects, the mRNA expression levels of proinflammatory cytokines, such as interleukin-6 (il-6), interleukin-1ß (il-1ß) and nuclear factor-κB (nf-κb), were reduced but the expressions of anti-inflammatory cytokines, such as growth factor-ß (tgf-ß) and interleukin-10 (il-10), were enhanced in the head kidney and spleen tissues after oral administration with sea buckthorn. In terms of muscle fatty acid composition, the ratio of n-3 polyunsaturated fatty acid (PUFA)/n-6 PUFA was notably higher after administering sea buckthorn flavonoids than that of the glucose group (P < 0.05). CONCLUSION: This study demonstrated that oral administration of sea buckthorn powder and sea buckthorn flavonoids significantly enhanced the antioxidant capacity and immune response and improved the muscle fatty acid compositions in common carp, and also mitigated the adverse effects of glucose treatment to a certain extent. © 2024 Society of Chemical Industry.

PET Imaging of Fibroblast Activation Protein in Various Cancers Using [18F]AlF­NOTA­FAPI­04: Comparison with 18F-FDG in a Single-Center, Prospective Study.

RATIONALE AND OBJECTIVES: Targeting fibroblast-activation protein is a newer diagnostic approach for the visualization of tumor stroma, and a novel aluminum-[18F] fluoride (Al18F)-labeled fibroblast-activation protein inhibitor-4 (FAPI-04), hereafter [18F] AlF-NOTA-FAPI-04, presents a promising alternative to gallium 68 (68Ga)-labeled FAPI owing to its relatively longer half-life. This study sought to evaluate the clinical usefulness of [18F] AlF-NOTA-FAPI-04 PET/CT for the diagnosis of various types of cancer, compared to [18F] FDG PET/CT. MATERIALS AND METHODS: In this prospective study conducted from October 2021 to January 2024, a total of 148 patients with 16 different tumor entities underwent contemporaneous 18F-FDG and 18F-FAPI-04 PET/CT either for an initial assessment or for recurrence detection. Uptake of 18F-FDG and 18F-FAPI-04 was quantified by the maximum standard uptake value (SUV max). Diagnostic sensitivity, specificity, and accuracy were compared by using the McNemar test between these two imaging agents. RESULTS: 18F-FAPI-04 PET/CT could clearly depict 16 different types of cancer with excellent image contrast, thereby leading to a higher detection rate of primary tumors than did 18F-FDG PET/CT (98.06% vs. 81.55%, P＜0.001). In per-lymph node analysis, the sensitivity, specificity, and accuracy in the diagnosis of metastatic lymph nodes were 92.44%, 90.44%, and 91.56%, respectively, which was much higher than that 18F-FDG PET/CT (80.23%, 79.41%, and 79.87%, respectively). Meanwhile, 18F-FAPI-04 PET/CT outperformed 18F-FDG PET/CT in identifying more suspected distant metastases (86.57% vs. 74.13%, P＜0.001). Furthermore, 18F-FAPI-04 PET/CT upgraded tumor staging in 36/101 patients (35.6%), and detected tumor recurrence or metastases in 43/47 patients (91.49%). CONCLUSION: Our findings demonstrated that primary and metastatic lesions in patients with various types of malignant tumors are well-visualized on 18F-FAPI-04 PET/CT, which exhibited a superior diagnostic performance than 18F-FDG PET/CT. Moreover, 18F-FAPI-04 PET/CT is a promising tool for tumor staging and follow-up of various malignancies.

Breaking the burnout cycle: Association of dispositional mindfulness with production line workers' job burnout and the mediating role of social support and psychological empowerment.

Burnout among production line workers has become an issue for their physical and mental health and for the productive efficiency of companies. However, this large group of workers has received insufficient attention, particularly in exploring how employees' dispositional factors are associated with burnout. Therefore, this study aimed to examine the association between dispositional mindfulness and job burnout and the potential mediating roles played by perceived social support and psychological empowerment. Participants in the study included 780 production line workers recruited from a foreign company in China. Participants completed measures related to dispositional mindfulness, perceived social support, psychological empowerment, and job burnout. The results showed that (a) dispositional mindfulness was significantly related to lower burnout (ß = -0.446, 95% CI [-0.552, -0.340]); (b) perceived social support (ß = -0.073, 95% CI [-0.126, -0.025]) and psychological empowerment (ß = -0.106, 95% CI [-0.171, -0.058]) mediated this association individually; and (c) perceived social support and psychological empowerment had a serial mediating effect in this context (ß = -0.055, 95% CI [-0.095, -0.028]). This study revealed the association between dispositional mindfulness and job burnout, with an additional focus on how dispositional mindfulness correlates with other resources, such as perceived social support and psychological empowerment.

Unveiling behaviors of 8:2 fluorotelomer sulfonic acid (8:2 FTSA) in Arabidopsis thaliana: Bioaccumulation, biotransformation and molecular mechanisms of phytotoxicity.

8:2 fluorotelomer sulfonic acid (8:2 FTSA) has been commonly detected in the environment, but its behaviors in plants are not sufficiently known. Here, the regular and multi-omics analyses were used to comprehensively investigate the bioaccumulation, biotransformation, and toxicity of 8:2 FTSA in Arabidopsis thaliana. Our results demonstrated that 8:2 FTSA was taken up by A. thaliana roots and translocated to leaves, stems, flowers, and seeds. 8:2 FTSA could be successfully biotransformed to several intermediates and stable perfluorocarboxylic acids (PFCAs) catalyzed by plant enzymes. The plant revealed significant growth inhibition and oxidative damage under 8:2 FTSA exposure. Metabolomics analysis showed that 8:2 FTSA affected the porphyrin and secondary metabolisms, resulting in the promotion of plant photosynthesis and antioxidant capacity. Transcriptomic analysis indicated that differentially expressed genes (DEGs) were related to transformation and transport processes. Integrative transcriptomic and metabolomic analysis revealed that DEGs and differentially expressed metabolites (DEMs) in plants were predominantly enriched in the carbohydrate metabolism, amino acid metabolism, and lipid metabolism pathways, resulting in greater energy consumption, generation of more nonenzymatic antioxidants, alteration of the cellular membrane composition, and inhibition of plant development. This study provides the first insights into the molecular mechanisms of 8:2 FTSA stress response in plants.

HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development.

Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no-ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A-modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon-stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination-mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A-tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness-related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A-tagged mRNA associated with stemness maintenance, which suppresses BCSCs self-renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A-modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A-tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.

Association between educational attainment and thyroid cancer: evidence from a univariable and multivariable Mendelian randomization study.

BACKGROUND: Thyroid cancer and educational attainment have been related in observational studies. It is unclear if these correlations indicate causative relationships. METHODS: Using large-scale genome-wide association studies (GWAS) datasets, we conducted an univariable and multivariable Mendelian randomization (MR) study to assess a potential connection between educational attainment and thyroid cancer. The inverse-variance weighted (IVW) analysis method is used as our primary outcome. Additionally, we carry out several sensitivity analyses to evaluate the pleiotropy and robustness of the causal estimates. RESULTS: Univariate MR study shows 4.2 years of additional education is associated with a 41.4% reduction in thyroid cancer risk (OR = 0.586; 95% CI: 0.378-0.909; P = 0.017). Further multivariable MR analysis revealed that body mass index (BMI) acted as a partial mediating factor in the protective impact of higher educational attainment against thyroid cancer. CONCLUSION: This MR study provided genetic evidence that longer education attainment is related to a lower risk of thyroid cancer. Strategies of expanding education may reduce the burden of thyroid cancer in the world.

Social disabling: A qualitative study of interpersonal interaction patterns of shiduers in China.

The experience of shidu (i.e., losing one's only child) completely changes the lives and social interaction patterns of people. However, current research findings on interpersonal interactions of individuals who are experiencing shidu (referred to as "shiduers") are inconsistent, reducing the effectiveness of support programs. Therefore, a qualitative analysis was conducted on the interpersonal interaction process of shiduers using the classic grounded theory. The results showed that "shidu" as an interpersonal information has two contradictory attributes, "family shame" and "family routine," which create a social disabling dilemma for shiduers. Shiduers can reset their interpersonal relationships by establishing a clear inner and outer circle of relationships (centralizing) and by sequencing and typing relationships (differentiating). The interpersonal interactions of shiduers are complex and depend on the type of relationship. The current results can help community workers target individual support, family empowerment, and community building for people experiencing shidu.

Automated detection of small bowel lesions based on capsule endoscopy using deep learning algorithm.

BACKGROUND: In order to overcome the challenges of lesion detection in capsule endoscopy (CE), we improved the YOLOv5-based deep learning algorithm and established the CE-YOLOv5 algorithm to identify small bowel lesions captured by CE. METHODS: A total of 124,678 typical abnormal images from 1,452 patients were enrolled to train the CE-YOLOv5 model. Then 298 patients with suspected small bowel lesions detected by CE were prospectively enrolled in the testing phase of the study. Small bowel images and videos from the above 298 patients were interpreted by the experts, non-experts and CE-YOLOv5, respectively. RESULTS: The sensitivity of CE-YOLOv5 in diagnosing vascular lesions, ulcerated/erosive lesions, protruding lesions, parasite, diverticulum, active bleeding and villous lesions based on CE videos was 91.9 %, 92.2 %, 91.4 %, 93.1 %, 93.3 %, 95.1 %, and 100 % respectively. Furthermore, CE-YOLOv5 achieved specificity and accuracy of more than 90 % for all lesions. Compared with experts, the CE-YOLOv5 showed comparable overall sensitivity, specificity and accuracy (all P > 0.05). Compared with non-experts, the CE-YOLOv5 showed significantly higher overall sensitivity (P < 0.0001) and overall accuracy (P < 0.0001), and a moderately higher overall specificity (P = 0.0351). Furthermore, the time for AI-reading (5.62 ± 2.81 min) was significantly shorter than that for the other two groups (both P < 0.0001). CONCLUSIONS: CE-YOLOv5 diagnosed small bowel lesions in CE videos with high sensitivity, specificity and accuracy, providing a reliable approach for automated lesion detection in real-world clinical practice.

Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21.

Interferon (IFN) contributes to the host's antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and the mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with and degrades the TRPV2 channel in myeloid cells, reducing its expression and providing host protection against viral infections. Moreover, viral infection upregulates TRIM21 in paracrine and autocrine manners, downregulating TRPV2 in neighboring cells to prevent viral spread to uninfected cells. Consistently, the Trim21-/- mice are more susceptible to HSV-1 and VSV infection than the Trim21+/+ littermates, in which viral susceptibility is rescued by inhibition or deletion of TRPV2. Mechanistically, TRIM21 catalyzes the K48-linked ubiquitination of TRPV2 at Lys295. TRPV2K295R is resistant to viral-infection-induced TRIM21-dependent ubiquitination and degradation, promoting viral infection more profoundly than wild-type TRPV2 when reconstituted into Lyz2-Cre;Trpv2fl/fl myeloid cells. These findings characterize targeting the TRIM21-TRPV2 axis as a conducive strategy to control viral spread to bystander cells.