Comparative Study on the Immunogenicity and Efficacy of Different Post-exposure Intramuscular Rabies Vaccination Regimens in China.

Objective: This study aimed to compare the current Essen rabies post-exposure immunization schedule (0-3-7-14-28) in China and the simple 4-dose schedule (0-3-7-14) newly recommended by the World Health Organization in terms of their safety, efficacy, and protection. Methods: Mice were vaccinated according to different immunization schedules, and blood was collected for detection of rabies virus neutralizing antibodies (RVNAs) on days 14, 21, 28, 35, and 120 after the first immunization. Additionally, different groups of mice were injected with lethal doses of the CVS-11 virus on day 0, subjected to different rabies immunization schedules, and assessed for morbidity and death status. In a clinical trial, 185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule, and blood was collected for RVNAs detection on days 28 and 42 after the first immunization. Results: A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day ( P < 0.05). The groups 0-3-7-14, 0-3-7-21, and 0-3-7-28 showed no statistically significant difference ( P > 0.05) in RVNAs levels at any time point. The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%, whereas that in the immunization groups was 40%. In the clinical trial, the RVNAs positive conversion rates on days 28 (14 days after 4 doses) and 42 (14 days after 5 doses) were both 100%, and no significant difference in RVNAs levels was observed ( P > 0.05). Conclusion: The simple 4-dose schedule can produce sufficient RVNAs levels, with no significant effect of a delayed fourth vaccine dose (14-28 d) on the immunization potential.

Smart Use of Skin Biopsy Punch in Treating Keloids: A Single-Center Retrospective Study.

BACKGROUND: Treatment of scarring has long been a problem due to high incidence and recurrence. Despite many existing treatment therapies, the efficacy remains unstable. OBJECTIVES: To determine the efficacy and safety of skin biopsy punch in combination with corticosteroid injection (BPCI) in treating keloids. APPROACH: This was a retrospective study. In total, 16 patients with keloids received BPCI. Changes in scar appearance, accompanied symptoms, and Vancouver Scar Scale (VSS) were analyzed. Patient satisfaction, VAS scores, and adverse effects were also evaluated. RESULTS: Scar appearance, accompanied symptoms, and VSS scores improved significantly after the treatment. The total effective rate was 93.75% at an 18-month follow-up on average. The mean reduction rate of VSS score was 58.44% (p < 0.0001), especially in height and pliability (84.44% and 78.19%, p < 0.0001). The recurrence rate in this study was 12.5% (n = 2) at an 18-month follow-up on average. Mild adverse effects of pain, pruritus, hypopigmentation, and telangiectasia were recorded. CONCLUSIONS: This study demonstrated BPCI might be an effective and safe therapy in keloids with a low long-time recurrence rate and well tolerance for patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Regulatory mechanisms of mitochondrial dynamics and its emerging role in renal pathophysiology].

Mitochondria are dynamically changing organelles that maintain stable mitochondrial morphology, number, and function through constant fusion and division, a process known as mitochondrial dynamics, which is an important mechanism for mitochondrial quality control. Excessive fusion and division of mitochondria can lead to a homeostatic imbalance in mitochondrial dynamics, causing mitochondrial dysfunction, leading to cellular damage, and even death. The physiological functions of the kidney are mainly powered by mitochondria, and homeostatic imbalance in mitochondrial dynamics affects mitochondrial function and is closely related to renal diseases such as acute kidney injury and diabetic nephropathy. This article reviews the regulation of mitochondrial kinetics, how imbalances in mitochondrial kinetic homeostasis affect mitochondrial injury, and the impact of mitochondrial injury on renal pathophysiology, in order to improve understanding and knowledge of the role of mitochondria in renal disease.

Short-term effectiveness and potential factors of ustekinumab based on real-world data in Chinese psoriasis patients.

BACKGROUND: As one of the most effective biologic treatments for psoriasis, the short-term effectiveness of ustekinumab has yet to be studied extensively. OBJECTIVE: The purpose of this study was to evaluate the short-term effectiveness and potential factors within four weeks after the first-dose ustekinumab treatment based on real-world data. METHODS: The study enrolled 98 patients with moderate-to-severe psoriasis, given ustekinumab 45 mg at week 0, week 4, and then every 12 weeks. Based on clinical data collected at baseline and week 4, we investigated the short-term effectiveness of ustekinumab after the first dose and potential factors associated with the treatment. For evaluation, we collected demographic information, body data, medical history, laboratory examination results, Psoriasis Area and Severity Index (PASI), body surface area (BSA), and dermatology life quality index (DLQI). Response rates were calculated based on the number of patients that achieved a 75/90/100% reduction in PASI (PASI 75/90/100), and the primary treatment goal was to achieve PASI 75. RESULTS: The response rates for PASI 75/90/100 at week 4 were 30.5%, 18.9%, and 16.8%, respectively. For PASI 75, the response rate was higher in patients without metabolic syndrome (MS) (without MS vs. with MS: 36.9% vs. 5.9%, p = 0.013); the serum triglyceride (TG) level was significantly lower in patients achieving PASI 75 (expressed as mean ± standard deviation, achieved vs. unachieved: 1.82 ± 1.79 vs. 3.59 ± 8.89, p = 0.010). For PASI 100, the response rates were higher in female patients (female vs. male: 26.3% vs. 10.5%, p = 0.044) and patients with a family history of psoriasis (with family history vs. without family history: 44.4% vs. 13.9%, p = 0.042). In addition, the possibility of achieving PASI 75/90/100 went up along with the serum high-density lipoprotein cholesterol (HDL-C) level (expressed as adjusted odds ratio < 95% confidence interval>: PASI 75: 28.484 < 2.035-248.419>, p = 0.011; PASI 90: 28.226 < 2.828-281.729>, p = 0.004; PASI 100: 12.175 < 1.876-79.028>, p = 0.009). CONCLUSION: In this study, nearly one-third of patients achieved PASI 75 after only the first-dose ustekinumab treatment. Sex, family history of psoriasis, MS, serum TG level might affect the short-term effectiveness, and serum HDL-C level may be a potential factor. The possibility of achieving treatment goals (PASI 75/90/100) at week 4 increased along with serum HDL-C levels.

A Building Extraction Method for High-Resolution Remote Sensing Images with Multiple Attentions and Parallel Encoders Combining Enhanced Spectral Information.

Accurately extracting pixel-level buildings from high-resolution remote sensing images is significant for various geographical information applications. Influenced by different natural, cultural, and social development levels, buildings may vary in shape and distribution, making it difficult for the network to maintain a stable segmentation effect of buildings in different areas of the image. In addition, the complex spectra of features in remote sensing images can affect the extracted details of multi-scale buildings in different ways. To this end, this study selects parts of Xi'an City, Shaanxi Province, China, as the study area. A parallel encoded building extraction network (MARS-Net) incorporating multiple attention mechanisms is proposed. MARS-Net builds its parallel encoder through DCNN and transformer to take advantage of their extraction of local and global features. According to the different depth positions of the network, coordinate attention (CA) and convolutional block attention module (CBAM) are introduced to bridge the encoder and decoder to retain richer spatial and semantic information during the encoding process, and adding the dense atrous spatial pyramid pooling (DenseASPP) captures multi-scale contextual information during the upsampling of the layers of the decoder. In addition, a spectral information enhancement module (SIEM) is designed in this study. SIEM further enhances building segmentation by blending and enhancing multi-band building information with relationships between bands. The experimental results show that MARS-Net performs better extraction results and obtains more effective enhancement after adding SIEM. The IoU on the self-built Xi'an and WHU building datasets are 87.53% and 89.62%, respectively, while the respective F1 scores are 93.34% and 94.52%.

A BET inhibitor, NHWD-870, can downregulate dendritic cells maturation via the IRF7-mediated signaling pathway to ameliorate imiquimod-induced psoriasis-like murine skin inflammation.

Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of dendritic cells (DCs), which are primarily responsible for initiating an immune response. The bromodomain and extraterminal domain (BET) family plays a pivotal role in the transcriptional regulation of inflammation and its inhibitors can downregulate DCs maturation and activation. Here we investigated the effect of NHWD-870, a potent BET inhibitor, on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS) and IMQ. Application of NHWD-870 significantly ameliorated IMQ-triggered skin inflammation in mice, and markers associated with DC maturation (CD40, CD80 and CD86) were decreased in skin lesions, spleen and lymph nodes. Additionally, NHWD-870 reduced LPS or IMQ induced DCs maturation and activation in vitro, with lower expression of inflammatory cytokines [interleukin (IL)-12, IL-23, tumor necrosis factor-α, IL-6, IL-1ß, chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10]. In addition, we found that interferon regulatory factor 7 (IRF7) significantly increased during DCs maturation, and inhibition of IRF7 could impair BMDCs maturation and activation. What's more, IRF7 was highly expressed in both psoriatic patients and IMQ-induced psoriasis-like mice. Single-cell RNA sequencing of normal and psoriatic skin demonstrated that IRF7 expression was increased in DCs of psoriatic skin. While NHWD-870 could inhibit IRF7 and phosphorylated-IRF7 expression in vivo and in vitro. These results indicate that NHWD-870 suppresses the maturation and activation of DCs by decreasing IRF7 proteins which finally alleviates psoriasis-like skin lesions, and NHWD-870 may be a potent therapeutic drug for psoriasis.

Sonographic and clinicopathologic features of metaplastic breast carcinoma and infiltrating ductal carcinoma: a comparative single-center cohort study.

Background: The rarity of metaplastic breast carcinoma (MBC) has resulted in limited sonographic data. Given the inferior prognosis of MBC compared to invasive ductal carcinoma (IDC), accurate preoperative differentiation between the two is imperative for effective treatment planning and prognostic prediction. The objective of this study was to assess the diagnostic accuracy of MBC and differentiate it from IDC by analyzing sonographic and clinicopathologic features. Methods: In this retrospective cohort study, 197 women comprising 200 IDC lesions were enrolled between January 2012 and December 2021 and 20 women comprising 20 pure MBC lesions were enrolled between January 2019 and December 2019. A comparison was made between the sonographic and clinicopathologic characteristics of MBC and IDC. Results: The results indicated that patients with MBC had a higher proportion of tumor grade 3 (95.0% vs. 32.5%; P<0.001), high Ki-67 expression (100.0% vs. 75.0%; P<0.001), and the triple-negative subtype (90.0% vs. 13.0%; P<0.001) as compared to those with IDC. On ultrasound (US) findings, MBC lesions tended to have a larger size (≥5 cm: 45.0% vs. 1.5%; P<0.001), regular shape (45.0% vs. 1.5%, P<0.001), circumscribed margin (40.0% vs. 0.5%, P<0.001), a complex cystic and solid echo pattern (50.0% vs. 3.5%; P<0.001), and posterior acoustic enhancement (95.0% vs. 14.5%; P<0.001). Additionally, MBC was more likely to be misinterpreted as a benign lesion by sonographers than was IDC (30.0% vs. 4.5%; P<0.001). Multilayer perceptron analysis revealed posterior acoustic enhancement, circumscribed margins, and size as distinguishing factors between these two tumor types. The estimated rates of local recurrence, distant metastasis, and 5-year overall survival in 19 cases with MBC were found to be 10.5%, 31.6%, and 65.0%, respectively. Conclusions: MBC typically presents as a large breast mass with more benign US features in older women, findings which may facilitate its accurate diagnosis and differentiation from other breast masses.

Age at Natural Menopause, Reproductive Lifespan, and the Risk of Late-Onset Psoriasis and Psoriatic Arthritis in Women: A Prospective Cohort Study.

Although a peak incidence of psoriasis in women aged around 60 years has been observed, the link between reproductive lifespan and late-onset psoriatic diseases is underexplored. This study aims to elucidate the association between reproductive lifespan and the risk of late-onset psoriasis and psoriatic arthritis (PsA). Utilizing the UK Biobank data, we conducted a prospective cohort study in postmenopausal women without baseline psoriatic diseases. The exposure variables included age at natural menopause (ANM) and duration from menarche to menopause, termed reproductive years. The outcome variables were incident psoriasis and PsA. We employed Cox regression analysis, factoring in polygenic risk scores for psoriatic diseases and recognized risk factors. We found that later ANM and longer reproductive years were significantly associated with decreased risks of late-onset psoriasis and PsA in a dose-dependent manner (P<.05). ANM after age 55 years led to a 34 and 46% risk reduction in late-onset psoriasis and PsA, respectively, compared with ANM before age 45 years (P<.001). The population-attributable risks of ANM were 17.4% for late-onset psoriasis and 21.6% for PsA. In conclusion, reproductive lifespan, with its inherent homeostasis, plays a pivotal yet overlooked role in late-onset psoriatic diseases. Investigations into estrogen-centric causes and sex-specific interventions are imperative.

Bardoxolone methyl inhibits the infection of rabies virus via Nrf2 pathway activation in vitro.

BACKGROUND: Rabies is a widespread, fatal, infectious disease. Several antivirals against rabies virus (RABV) infection have been reported, but no approved, RABV-specific antiviral drugs that inhibit RABV infection in the clinic after symptom onset are available. Therefore, more effective drugs to reduce rabies fatalities are urgently needed. Bardoxolone methyl (CDDO-Me), an FDA-approved compound that has long been known as an antioxidant inflammatory modulator and one of the most potent nuclear factor erythroid-derived 2-like 2 (Nrf2) activators, protects myelin, axons, and CNS neurons by Nrf2 activation. Therefore, we investigated the potency of its anti-RABV activity in vitro. METHODS: The mouse neuroblastoma cell line Neuro2a (N2a) and three RABV strains of different virulence were used; the cytotoxicity and anti-RABV activity of CDDO-Me in N2a cells were evaluated by CCK-8 assay and direct fluorescent antibody (DFA) assay. Pathway activation in N2a cells infected with the RABV strains SC16, CVS-11 or CTN upon CDDO-Me treatment was evaluated by western blotting (WB) and DFA assay. RESULTS: CDDO-Me significantly inhibited infection of the three RABV strains of differing virulence (SC16, CVS-11 and CTN) in N2a cells. We also examined whether CDDO-Me activates the Nrf2-associated pathway upon infection with RABV strains of differing virulence. Nrf2, phosphorylated sequestosome (SQSTM1), SQSTM1, hemoglobin oxygenase (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) expression in N2a cells increased to varying degrees with CDDO-Me treatment, accompanied by Kelch-like ECH-associated protein 1 (Keap1) dissociation, upon infection with SC16, CVS-11 or CTN. The activation of SQSTM1 phosphorylation was significantly associated with the degradation of Keap-1 in CDDO-Me-treated N2a cells upon RABV infection. Furthermore, N2a cells pretreated with the Nrf2-specific inhibitor ATRA showed a significant decrease in HO-1 and NQO1 expression and a decrease in the anti-RABV efficacy of CDDO-Me. These inhibitory effects were observed upon infection with three RABV strains of differing virulence. CONCLUSION: CDDO-Me inhibited RABV infection via Nrf2 activation, promoting a cytoprotective defense response in N2a cells. Our study provides a therapeutic strategy for RABV inhibition and neuroprotection during viral infection.

Novel Information-Driven Smoothing Spline Linearization Method for High-Precision Displacement Sensors Based on Information Criterions.

A noise-resistant linearization model that reveals the true nonlinearity of the sensor is essential for retrieving accurate physical displacement from the signals captured by sensing electronics. In this paper, we propose a novel information-driven smoothing spline linearization method, which innovatively integrates one new and three standard information criterions into a smoothing spline for the high-precision displacement sensors' linearization. Using theoretical analysis and Monte Carlo simulation, the proposed linearization method is demonstrated to outperform traditional polynomial and spline linearization methods for high-precision displacement sensors with a low noise to range ratio in the 10-5 level. Validation experiments were carried out on two different types of displacement sensors to benchmark the performance of the proposed method compared to the polynomial models and the the non-smoothing cubic spline. The results show that the proposed method with the new modified Akaike Information Criterion stands out compared to the other linearization methods and can improve the residual nonlinearity by over 50% compared to the standard polynomial model. After being linearized via the proposed method, the residual nonlinearities reach as low as ±0.0311% F.S. (Full Scale of Range), for the 1.5 mm range chromatic confocal displacement sensor, and ±0.0047% F.S., for the 100 mm range laser triangulation displacement sensor.

Multimodal Imaging Features and Prognosis of Metaplastic Breast Carcinoma.

RATIONALE AND OBJECTIVES: Metaplastic breast carcinoma (MBC) is an infrequent malignancy with an unfavorable prognosis, and there is a paucity of research on the multimodal imaging features of MBC. This study aimed to provide a comprehensive analysis of the multimodal imaging features, clinicopathological characteristics, and prognosis of MBC. MATERIALS AND METHODS: A total of 36 patients with histologically confirmed MBC from 2012 to 2021 were included in the study. We analyzed the pre-treatment multimodal imaging features, including mammography, ultrasonography (US), and magnetic resonance imaging (MRI), as well as clinicopathology and prognosis of MBC. Follow-up data included local recurrence, distant metastasis, and overall survival (OS) rate. RESULTS: MBC patients had a median age of 51 years at diagnosis. The most common histologic subtype was squamous cell carcinoma, with 86.1% of MBC being histological grade 3 and triple negative. The most common mammographic findings were irregular shape, non-calcification, and high density. The predominant US findings included irregular shape, parallel orientation, posterior acoustic enhancement, and hypoecho. On MRI, most masses exhibited irregular shape, spiculate margin, heterogeneous enhancement, Type II time intensity curve, and diffusion restriction on diffusion weighted images determined by apparent diffusion coefficient. According to breast imaging reporting and data system, mammography suggested malignancy in 50% of cases, US indicated a moderate to high suspicion of malignancy in 77.8% of cases, MRI revealed malignancy in all cases. At a median follow-up time of 48 months (range, 8-122 months) for 35 MBC patients, the local recurrence, distant metastasis, and OS rates were 11.4%, 28.6%, and 67.4%, respectively. CONCLUSION: The benign features of MBC on mammography and US may cause misinterpretation. However, the inclusion of malignant features observed on MRI can improve diagnostic accuracy.

Lactate dehydrogenase predicts disease progression outcome in COVID-19 patients treated with Azvudine.

Background: Azvudine has been approved in China for the treatment of COVID-19 patients. Previous studies have suggested a correlation between high levels of lactate dehydrogenase (LDH) and the severity of COVID-19. However, the impact of LDH levels in COVID-19 patients receiving Azvudine treatment remains unclear. Methods: In this retrospective cohort study, we analyzed the data of 351 hospitalized COVID-19 patients who were consecutively treated with Azvudine, with or without high LDH levels. The clinical features, treatment strategies and prognosis data were collected and analyzed. Results: Among the 351 hospitalized patients with COVID-19 treated with Azvudine (119 with high-LDH levels), the median age was 69 years (range 58-78), and 213 (60.7%) were male. Common symptoms included cough (86.0%), expectoration (73.5%), fever (69.8%), polypnea (47.6%) and poor appetite (46.4%). Patients with high LDH levels exhibited significantly elevated leucocyte and neutrophil counts, elevated level of myocardial enzymes, as well as higher levels of inflammatory markers such as interleukin-6, interleukin-10, procalcitonin, C reactive protein, ferritin, and prolonged erythrocyte sedimentation rate upon admission. COVID-19 patients with high-LDH levels had higher rates of corticosteroid therapy, non-invasive and invasive mechanical ventilation, worsened and death (2.5% vs. 0%). The Cox proportional hazard model demonstrated that high LDH levels (adjusted hazard ratio = 5.27; 95% confidence interval: 1.19, 14.50) were associated with a more unfavorable composite disease progression outcome among COVID-19 patients treated with Azvudine, after accounting for potential confounding variables. Conclusion: High-LDH levels predict a worse composite disease progression outcome in COVID-19 patients treated with Azvudine.

A novel mRNA rabies vaccine as a promising candidate for rabies post-exposure prophylaxis protects animals from different rabies viruses.

Rabies, caused by the rabies virus (RABV), is the most fatal zoonotic disease. It is a neglected tropical disease which remains a major public health problem, causing approximately 59,000 deaths worldwide annually. Despite the existence of effective vaccines, the high incidence of human rabies is mainly linked to tedious vaccine immunisation procedures and the overall high cost of post-exposure prophylaxis. Therefore, it is necessary to develop an effective vaccine that has a simple procedure and is affordable to prevent rabies infection in humans. RABV belongs to the genus Lyssavirus and family Rhabdoviridae. Previous phylogenetic analyses have identified seven major clades of RABV in China (China I-VII), confirmed by analysing nucleotide sequences from both the G and N proteins. This study evaluated the immunogenicity and protective capacity of SYS6008, an mRNA rabies vaccine expressing rabies virus glycoprotein, in mice and cynomolgus macaques. We demonstrated that SYS6008 induced sufficient levels of rabies neutralising antibody (RVNA) in mice. In addition, SYS6008 elicited strong and durable RVNA responses in vaccinated cynomolgus macaques. In the pre-exposure prophylaxis murine model, one or two injections of SYS6008 at 1/10 or 1/30 of dosage provided protection against a challenge with a 30-fold LD50 of rabies virus (China I and II clades). We also demonstrated that in the post-exposure prophylaxis murine model, which was exposed to lethal rabies virus (China I-VII clades) before vaccination, one or two injections of SYS6008 at both 1/10 and 1/30 dosages provided better protection against rabies virus challenge than the immunization by five injections of commercial vaccines at the same dosage. In addition, we proved that SYS6008-induced RVNAs could neutralise RABV from the China I-VII clades. Finally, 1/10 of the dosage of SYS6008 was able to stimulate significant RABV-G specificity in the T cell response. Furthermore, we found that SYS6008 induced high cellular immunity, including RABV-G-specific T cell responses and memory B cells. Our results imply that the SYS6008 rabies vaccine, with a much simpler vaccination procedure, better immunogenicity, and enhanced protective capacity, could be a candidate vaccine for post-exposure prophylaxis of rabies infections.

Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a mendelian randomisation study in the UK Biobank.

OBJECTIVE: Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank(UKB). METHODS: To avoid immortal-time-biases in pharmacoepidemiologic studies, Mendelian randomisation was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with HbA1c, serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 407 159 participants were analyzed, including 9,126 EOP and 3,324 LOP. The AMPK-genetic-risk-score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS: AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.

Causal Associations Between Gut Microbiota and Psoriasis: A Mendelian Randomization Study.

INTRODUCTION: Previous studies have proposed a possible gut-skin axis, and linked gut microbiota to psoriasis risks. However, there is heterogeneity in existing evidence. Observational research is prone to bias, and it is hard to determine causality. Therefore, this study aims to evaluate possible causal associations between gut microbiota (GM) and psoriasis. METHODS: With published large-scale GWAS (genome-wide association study) summary datasets, two-sample Mendelian randomization (MR) was performed to sort out possible causal roles of GM in psoriasis and arthropathic psoriasis (PsA). The inverse variance weighted (IVW) method was taken as the primary evaluation of causal association. As complements to the IVW method, we also applied MR-Egger, weighted median. Sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept test, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global test, and leave-one-out analysis. RESULTS: By primary IVW analysis, we identified nominal protective roles of Bacteroidetes (odds ratio, OR 0.81, P = 0.033) and Prevotella9 (OR 0.87, P = 0.045) in psoriasis risks. Bacteroidia (OR 0.65, P = 0.03), Bacteroidales (OR 0.65, P = 0.03), and Ruminococcaceae UCG002 (OR 0.81, P = 0.038) are nominally associated with lower risks for PsA. On the other hand, Pasteurellales (OR 1.22, P = 0.033), Pasteurellaceae (OR 1.22, P = 0.033), Blautia (OR 1.46, P = 0.014), Methanobrevibacter (OR 1.27, P = 0.026), and Eubacterium fissicatena group (OR 1.21, P = 0.028) are nominal risk factors for PsA. Additionally, E. fissicatena group is a possible risk factor for psoriasis (OR 1.22, P = 0.00018). After false discovery rate (FDR) correction, E. fissicatena group remains a risk factor for psoriasis (PFDR = 0.03798). CONCLUSION: We comprehensively evaluated possible causal associations of GM with psoriasis and arthropathic psoriasis, and identified several nominal associations. E. fissicatena group remains a risk factor for psoriasis after FDR correction. Our results offer promising therapeutic targets for psoriasis clinical management.

Research on a Space-Time Continuous Sensing System for Overburden Deformation and Failure during Coal Mining.

Underground coal mining can cause the deformation, failure, and collapse of the overlying rock mass of a coal seam. If the mining design, monitoring, early warning, or emergency disposal are improper, in that case, it can often lead to mining disasters such as roof falls, water inrush, surface collapse, and ground fissures, seriously threatening the safety of mine engineering and the geological environment protection in mining areas. To ensure the intrinsic security of the entire coal mining process, aspace-time continuous sensing system of overburden deformation and failure was developed, which breaks through the limitations of traditional monitoring methods that characterize the evolution process of overlying rock deformation and ground subsidence. This paper summarizes the classification of typical overburden deformation and failure modes. It researches the space-time continuous sensing of rock-soil mass above the coal seam based on Distributed Fiber Optic Sensing (DFOS). A multi-range strain optical fiber sensing neural series from micron to meter was developed to achieve synchronous sensing of overburden separation, internal micro-cracks, and large rock mass deformation. The sensing cable-rock mass coupling test verified the reliability of the optical fiber monitoring data. The sensing neural network of overburden deformation was constructed using integrated optical fiber layout technology on the ground and underground. Different sensing nerves' performance and application effects in overburden deformation and failure monitoring were compared and analyzed with field monitoring examples. A physical model was used to carry out the experimental study on the overburden subsidence prediction during coal mining. The results showed that the optical fiber monitoring data were reliable and could be used to predict overburden subsidence. The reliability of the calculation model for overlying rock subsidence based on space-time continuous optical fiber sensing data was verified in the application of mining subsidence evaluation. A systematic review of the shortcomings of current overburden deformation observation technology during coal mining was conducted, and a space-time continuous sensing system for overburden deformation and failure was proposed. This system integrated sensing, transmission, processing, early warning, decision-making, and emergency response. Based on the fusion of multi-parameter sensing, multi-method transmission, multi-algorithm processing, and multi-threshold early warning, the system realized the real-time acquisition of space-time continuous information for the overburden above coal seams. This system utilizes long-term historical monitoring data from the research area for data mining and modeling, realizing the prediction and evaluation of the evolution process of overburden deformation as well as the potential for mining subsidence. This work provides a theoretical reference for the prevention and control of mining disasters and the environmental carrying capacity evaluation of coal development.

Exploring genetic associations between allergic diseases and indicators of COVID-19 using mendelian randomization.

We carried out a bidirectional Mendelian randomization (MR) including cases of eczema (N = 218,792), asthma (N = 462,933), and allergic rhinitis (N = 112,583). COVID-19 susceptibility (N = 1,683,768), COVID-19 hospitalization (N = 1,887,658), and COVID-19 severe respiratory symptom (N = 1,388,342) were sampled from GWAS database. The MR analysis was primarily based on inverse variance weighted (IVW), supplemented by several other algorithms. In the bidirectional MR analysis, eczema was negatively associated with COVID-19 susceptibility (odds ratio (OR) IVW = 0.92; p = 0.031) and COVID-19 hospitalization (ORIVW = 0.81, p = 0.010); asthma was negatively associated with COVID-19 susceptibility (ORIVW = 0.65, p = 0.005) and COVID-19 severe respiratory symptom (ORIVW = 0.20, p = 0.001). No significant association was found between allergic rhinitis and COVID-19 susceptibility (ORIVW = 0.80, p = 0.174), COVID-19 hospitalization (ORIVW = 0.71, p = 0.207), or COVID-19 severe respiratory symptom (ORIVW = 0.56; p = 0.167). The reverse MR analysis showed no potential reverse causal association. Our findings provided new evidence that allergic diseases might be associated with different risks of COVID-19 susceptibility, hospitalization, and severe respiratory symptom.

BCX4430 inhibits the replication of rabies virus by suppressing mTOR-dependent autophagy invitro.

Rabies is a fatal neurological infectious disease caused by rabies virus (RABV). However, no effective anti-RABV drugs for treatment during the symptomatic phase are available. The novel adenosine nucleoside analog galidesivir (BCX4430) has broad-spectrum activity against a wide variety of highly pathogenic RNA viruses. In this study, we observed no apparent cytotoxicity of BCX4430 at the highest concentration of 250 µΜ, and which was displayed stronger antiviral activity against different virulent RABV in N2a or BHK-21 cells until 72 hpi. Meanwhile, BCX4430 showed greater anti-RABV activity than T-705 and anti-RABV activity similar to that of ribavirin in N2a cells. Furthermore, BCX4430 dose- and time-dependently inhibited RABV replication via mTOR-dependent autophagy inhibition in N2a cells with increased phospho-mTOR and phospho-SQSTM1 and decreased LC3-II levels. Taken together, these findings suggest that BCX4430 has potent anti-RABV activity in vitro and might provide a basis for the development of novel drug therapies against RABV.

CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes.

Psoriasis is a chronic inflammatory skin disease featuring rapid proliferation of epidermal cells. Although elevated glycolysis flux has been reported in psoriasis, the molecular mechanisms underlying its pathogenesis remain unclear. We investigated the role of the integral membrane protein CD147 in psoriasis pathogenesis, observing its high expression in psoriatic skin lesions of humans and imiquimod (IMQ)-induced mouse models. In mouse models, genomic deletion of epidermal CD147 markedly attenuated IMQ-induced psoriatic inflammation. We found that CD147 interacted with glucose transporter 1 (Glut1). Depletion of CD147 in the epidermis blocked glucose uptake and glycolysis in vitro and in vivo. In CD147-knockout mice and keratinocytes, oxidative phosphorylation was increased in the epidermis, indicating CD147's pivotal role in glycolysis reprogramming during pathogenesis of psoriasis. Using non-targeted and targeted metabolic techniques, we found that epidermal deletion of CD147 significantly increased the production of carnitine and α-ketoglutaric acid (α-KG). Depletion of CD147 also increased transcriptional expression and activity of γ-butyrobetaine hydroxylase (γ-BBD/BBOX1), a crucial molecule for carnitine metabolism, by inhibiting histone trimethylations of H3K9. Our findings demonstrate that CD147 is critical in metabolic reprogramming through the α-KG-H3K9me3-BBOX1 axis in the pathogenesis of psoriasis, indicating that epidermal CD147 is a promising target for psoriasis treatment.