Exceptional Early Jurassic fossils with leathery eggs shed light on dinosaur reproductive biology.

Our understanding of pre-Cretaceous dinosaur reproduction is hindered by a scarcity of evidence within fossil records. Here we report three adult skeletons and five clutches of embryo-containing eggs of a new sauropodomorph from the Lower Jurassic of southwestern China, displaying several significant reproductive features that are either unknown or unlike other early-diverging sauropodomorphs, such as relatively large eggs with a relatively thick calcareous shell formed by prominent mammillary cones, synchronous hatching and a transitional prehatching posture between the crocodilians and living birds. Most significantly, these Early Jurassic fossils provide strong evidence for the earliest known leathery eggs. Our comprehensive quantitative analyses demonstrate that the first dinosaur eggs were probably leathery, elliptical and relatively small, but with relatively long eggshell units, and that along the line to living birds, the most significant change in reptilian egg morphology occurred early in theropod evolution rather than near the origin of Aves.

Identification of SOCS3 and PTGS2 as new biomarkers for the diagnosis of gout by cross-species comprehensive analysis.

Background: Gout is the most common inflammatory arthritis in adults. Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue. Hyperuricemia is the main risk factor for MSU crystal deposition and gout. With the increasing burden of gout disease, the identification of potential biomarkers and novel targets for diagnosis is urgently needed. Methods: For the analysis of this subject paper, we downloaded the human gout data set GSE160170 and the gout mouse model data set GSE190138 from the GEO database. To obtain the differentially expressed genes (DEGs), we intersected the two data sets. Using the cytohubba algorithm, we identified the key genes and enriched them through GO and KEGG. The gene expression trends of three subgroups (normal control group, intermittent gout group and acute gout attack group) were analyzed by Series Test of Cluster (STC) analysis, and the key genes were screened out, and the diagnostic effect was verified by ROC curve. The expression of key genes in dorsal root nerve and spinal cord of gout mice was analyzed. Finally, the clinical samples of normal control group, hyperuricemia group, intermittent gout group and acute gout attack group were collected, and the expression of key genes at protein level was verified by ELISA. Result: We obtained 59 co-upregulated and 28 co-downregulated genes by comparing the DEGs between gout mouse model data set and human gout data set. 7 hub DEGs(IL1B, IL10, NLRP3, SOCS3, PTGS2) were screened out via Cytohubba algorithm. The results of both GO and KEGG enrichment analyses indicate that 7 hub genes play a significant role in regulating the inflammatory response, cytokine production in immune response, and the TNF signaling pathway. The most representative hub genes SOCS3 and PTGS2 were screened out by Series Test of Cluster, and ROC analysis results showed the AUC values were both up to 1.000. In addition, we found that PTGS2 expression was significantly elevated in the dorsal root ganglia and spinal cord in monosodium urate(MSU)-induced gout mouse model. The ELISA results revealed that the expression of SOCS3 and PTGS2 was notably higher in the acute gout attack and intermittent gout groups compared to the normal control group. This difference was statistically significant, indicating a clear distinction between the groups. Conclusion: Through cross-species comprehensive analysis and experimental verification, SOCS3 and PTGS2 were proved to be new biomarkers for diagnosing gout and predicting disease progression.

Defective Tungsten Oxides with Stacking Faults for Proton Exchange Membrane Green-Hydrogen Generation.

Defects can introduce atomic structural modulation and tailor performance of materials. Herein, it demonstrates that semiconductor WO3 with inert electrocatalytic behavior can be activated through defect-induced tensile strains. Structural characterizations reveal that when simply treated in Ar/H2 atmosphere, oxygen vacancies will generate in WO3 and cause defective structures. Stacking faults are found in defects, thus modulating electronic structure and transforming electrocatalytic-inert WO3 into highly active electrocatalysts. Density functional theory (DFT) calculations are performed to calculate *H adsorption energies on various WOx surfaces, revealing the oxygen vacancy composition and strain predicted to optimize the catalytic activity of hydrogen evolution reaction (HER). Such defective tungsten oxides can be integrated into commercial proton exchange membrane (PEM) electrolyser with comparable performance toward Pt-based PEM. This work demonstrates defective metal oxides as promising non-noble metal catalysts for commercial PEM green-hydrogen generation.

Targeting leucine-rich PPR motif-containing protein/LRPPRC by 5,7,4'-trimethoxyflavone suppresses esophageal squamous cell carcinoma progression.

JAK2/STAT3/MYC axis is dysregulated in nearly 70 % of human cancers, but targeting this pathway therapeutically remains a big challenge in cancer therapy. In this study, genes associated with JAK2, STAT3, and MYC were analyzed, and potential target genes were selected. Leucine-rich PPR motif-containing protein (LRPPRC) whose function and regulation are not fully understood, emerged as one of top 3 genes in terms of RNA epigenetic modification. Here, we demonstrate LRPPRC may be an independent prognostic indicator besides JAK2, STAT3, and MYC. Mechanistically, LRPPRC impairs N6-methyladenosine (m6A) modification of JAK2, STAT3, and MYC to facilitate nuclear mRNA export and expression. Meanwhile, excess LRPPRC act as a scaffold protein binding to JAK2 and STAT3 to enhance stability of JAK2-STAT3 complex, thereby facilitating JAK2/STAT3/MYC axis activation to promote esophageal squamous cell carcinoma (ESCC) progression. Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.

Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus.

Hydroxychloroquine (HCQ) has gained significant attention as a therapeutic option for systemic lupus erythematosus (SLE) because of its multifaceted mechanism of action. It is a lipophilic, lysosomotropic drug, that easily traverses cell membranes and accumulates in lysosomes. Once accumulated, HCQ alkalizes lysosomes within the cytoplasm, thereby disrupting their function and interfering with processes like antigen presentation. Additionally, HCQ has shown potential in modulating T-cell responses, inhibiting cytokine production, and influencing Toll-like receptor signaling. Its immunomodulatory effects have generated interest in its application for autoimmune disorders. Despite its established efficacy, uncertainties persist regarding the optimal therapeutic concentrations and their correlation with adverse effects such as retinal toxicity. Therefore, standardized dosing and monitoring guidelines are crucial. In this study, we provide a comprehensive review of the mechanisms, efficacy, dosing variations, and retinal toxicity profiles of HCQ, which are essential to optimize SLE treatment protocols and ensure patient safety.

Efficiency of bladder-sparing strategies for bladder cancer: an umbrella review.

Bladder preservation (BP) has emerged as a clinical alternative to radical cystectomy (RC) for alleviating the substantial physical and psychological burden imposed on localized bladder cancer patients. Nevertheless, disparities persist in the comparative evaluations of BP and RC. We aimed to address the disparities between BP and RC. An umbrella review and meta-analysis were conducted to explore these disparities. We extracted data from meta-analyses and randomized controlled trials (RCTs) selected after searching PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Review Manager 5.4.0 and R x64 4.1.3 were used to evaluate the collected data. Our study included 11 meta-analyses and 3 RCTs. In terms of progression-free survival, all the meta-analyses reported that patients with localized bladder cancer who underwent BP exhibited outcomes comparable to those who underwent RC. Meta-analyses regarding the outcomes of cancer-specific survival (CSS) and overall survival (OS) are controversial. To solve these issues, we conducted a pooled analysis of CSS data, which supported the similarity of CSS between BP and RC with no significant heterogeneity [odds ratio (OR): 1.2; 95% confidence interval (CI): 0.71-2.02; I2 = 26%]. Similarly, the pooled OS results extracted from three RCTs indicated the comparability of OS between BP and RC with no significant heterogeneity (OR: 1.12; 95% CI: 0.41-3.07; I2 = 33%). A combination of umbrella review and meta-analysis results suggested that BP had survival rates comparable to those of RC. We suggest that BP may be a more eligible therapy than RC for patients with localized muscle-invasive bladder cancer. This conclusion warrants further validation through randomized controlled trials.

EspP2 Regulates the Adhesion of Glaesserella parasuis via Rap1 Signaling Pathway.

Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate the effect of EspP2 on virulence, we used G. parasuis SC1401 in its wild-type form and SC1401, which was made EspP2-deficient. We demonstrated that EspP2 causes up-regulation of claudin-1 and occludin expression, thereby promoting the adhesion of G. parasuis to host cells; EspP2-deficiency resulted in significantly reduced adhesion of G. parasuis to cells. Transcriptome sequencing analysis of EspP2-treated PK15 cells revealed that the Rap1 signaling pathway is stimulated by EspP2. Blocking this pathway diminished occludin expression and adhesion. These results indicated that EspP2 regulates the adhesion of Glaesserella parasuis via Rap1 signaling pathway.

Effect of arsenic on the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is a complication of pregnancy associated with numerous adverse outcomes. There may be a potential link between GDM and arsenic (As) exposure, but this hypothesis remains controversial. This meta-analysis summarizes the latest studies evaluating the association between As and GDM. METHODS: A comprehensive search of the PubMed, Embase, and Scopus databases up to September 2023 was performed. The pooled estimates with 95% CIs were presented using forest plots. Estimates were calculated with random effects models, and subgroup and sensitivity analyses were conducted to address heterogeneity. RESULTS: A total of 13 eligible studies involving 2575 patients with GDM were included in this meta-analysis. The results showed that women exposed to As had a significantly increased risk of GDM (OR 1.47, 95% CI: 1.11 to 1.95, P = 0.007). Subgroup analyses suggested that the heterogeneity might be attributed to the years of publication. In addition, sensitivity analysis confirmed the robust and reliable results. CONCLUSIONS: This analysis suggested that women exposed to As have a greater risk of GDM. However, the significant heterogeneity across studies requires careful interpretation. REGISTRATION: The PROSPERO registration ID is CRD42023461820.

Sialic acids as attachment factors in mosquitoes mediating Japanese encephalitis virus infection.

The role of Culex mosquitoes in the transmission of Japanese encephalitis virus (JEV) is crucial, yet the mechanisms of JEV infection in these vectors remain unclear. Previous research has indicated that various host factors participate in JEV infection. Herein, we present evidence that mosquito sialic acids enhance JEV infection both in vivo and in vitro. By treating mosquitoes and C6/36 cells with neuraminidase or lectin, the function of sialic acids is effectively blocked, resulting in significant inhibition of JEV infection. Furthermore, knockdown of the sialic acid biosynthesis genes in Culex mosquitoes also leads to a reduction in JEV infection. Moreover, our research revealed that sialic acids play a role in the attachment of JEV to mosquito cells, but not in its internalization. To further explore the mechanisms underlying the promotion of JEV attachment by sialic acids, we conducted immunoprecipitation experiments to confirm the direct binding of sialic acids to the last α-helix in JEV envelope protein domain III. Overall, our study contributes to a molecular comprehension of the interaction between mosquitoes and JEV and offers potential strategies for preventing the dissemination of flavivirus in natural environments.IMPORTANCEIn this study, we aimed to investigate the impact of glycoconjugate sialic acids on mosquito infection with Japanese encephalitis virus (JEV). Our findings demonstrate that sialic acids play a crucial role in enhancing JEV infection by facilitating the attachment of the virus to the cell membrane. Furthermore, our investigation revealed that sialic acids directly bind to the final α-helix in the JEV envelope protein domain III, thereby accelerating virus adsorption. Collectively, our results highlight the significance of mosquito sialic acids in JEV infection within vectors, contributing to a better understanding of the interaction between mosquitoes and JEV.

Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic 18F-deoxyfluorination Probe.

Sigma-1 receptor (σ1R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ1R could provide a powerful tool for better understanding the underlying pathomechanism of σ1R in AD. In this study, we successfully developed a 18F-labeled σ1R radiotracer [18F]CNY-05 via an innovative ruthenium (Ru)-mediated 18F-deoxyfluorination method. [18F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [18F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [18F]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel 18F-radiolabeled σ1R PET probe, which enables visualizing brain σ1R in health and neurological diseases.

Cotyledonary somatic embryo is one kind of intermediate material similar to callus in the process of in vitro tissue culture from Rosa hybrida 'John F. Kennedy'.

BACKGROUND: Rose is recognized as an important ornamental plant worldwide, and it is also one of the most widely used flowers in gardens. At present, the improvement of rose traits is still difficult and uncertain, and molecular breeding can provide new ideas for the improvement of modern rose varieties. Somatic embryos are quite good receptors for genetic transformation. However, little is known about the molecular mechanisms underlying during the regeneration process of rose somatic embryos. To elucidate the molecular regulation mechanism of somatic embryo plantlet regeneration, the relationship between the differences in traits of the two different regenerated materials and the significantly differentially expressed genes (DEGs) related to phytohormone pathways in the process of regeneration were be investigated. RESULTS: These representative two regenerated samples from single-piece cotyledonary somatic embryo (SPC) culture of Rosa hybrida 'John F. Kennedy', were harvested for transcriptome analysis, with the SPC explants at the initial culture (Day 0) as the control. The differentially expressed genes (DEGs) in the materials from two different types for regeneration approach (SBF type: the regeneration approach type of single bud formed from SPC explants; MBF type: the regeneration approach type of multiple buds formed from SPC explants) were be screened by means of the transcriptome sequencing technology. In this study, a total of about 396.24 million clean reads were obtained, of which 78.95-82.92% were localized to the reference genome, compared with the initial material (CK sample), there were 5594 specific genes in the material of SBF type and 6142 specific genes in the MBF type. The DEGs from the SBF type material were mainly concentrated in the biological processes of GO terms such as phytohormones, substance transport, cell differentiation, and redox reaction. The KEGG enrichment analysis revealed these DEGs were more active in ubiquinone and other terpenoid-quinone biosynthesis, fatty acid elongation, steroid biosynthesis, and glycosphingolipid biosynthesis-globo and isoglobo series. In contrast, the DEGs induced by the MBF type material were mainly associated with the biological processes such as phytohormones, phosphorylation, photosynthesis and signal transduction. According to KEGG analysis, these DEGs of MBF type were significantly enriched in the porphyrin and chlorophyll metabolism, brassinosteroid biosynthesis, carotenoid biosynthesis, and peroxisome. Furthermore, the results from the phytohormone pathways analysis showed that the auxin-responsive factor SAUR and the cell wall modifying enzyme gene XTH were upregulated for expression but the protein phosphatase gene PP2C was downregulated for expression in SBF type; the higher expression of the ethylene receptor ETR, the ethylene transduction genes EBF1/2, the transcription factor EIN3, and the ethylene-responsive transcription factor ERF1/2 were induced by MBF type. CONCLUSIONS: According to the GO and KEGG analysis, it indicated the DEGs between two different regenerated materials from somatic embryos were significantly different which might be causing morphological differences. That was somatic embryos from Rosa hybrida 'John F. Kennedy' could regenerate plantlet via both classic somatic embryogenesis (seed-like germination) and organogenesis, cotyledonary somatic embryos should be considered as one kind of intermediate materials similiar to callus, rather than the indicator materials for somatic embryogenesis.

An endothelial-related prognostic index for bladder cancer patients.

BACKGROUND: Within the tumor microenvironment, endothelial cells hold substantial sway over bladder cancer (BC) prognosis. Herein, we aim to elucidate the impact of endothelial cells on BC patient outcomes by employing an integration of single-cell and bulk RNA sequencing data. METHODS: All data utilized in this study were procured from online databases. R version 3.6.3 and relevant packages were harnessed for the development and validation of an endothelial-associated prognostic index (EPI). RESULTS: EPI was formulated, incorporating six genes (CYTL1, FAM43A, GSN, HSPG2, RBP7, and SLC2A3). EPI demonstrated significant prognostic value in both The Cancer Genome Atlas (TCGA) and externally validated dataset. Functional results revealed a profound association between EPI and endothelial cell functionality, as well as immune-related processes. Our findings suggest that patients with low-risk EPI scores are more likely to respond positively to immunotherapy, as indicated by immune checkpoint activity, immune infiltration, tumor mutational burden, stemness index, TIDE, and IMvigor210 analyses. Conversely, individuals with high-risk EPI scores exhibited heightened sensitivity to cisplatin, docetaxel, and gemcitabine treatment regimens. CONCLUSION: We have effectively discerned pivotal genes from the endothelial cell perspective and constructed an EPI for BC patients, thereby offering promising prospects for precision medicine.

Efficacy and safety of generic cefoperazone/sulbactam versus branded cefoperazone/sulbactam in the treatment of bacterial infections: a systematic review and meta-analysis.

This study aim to assess the clinical efficacy and safety of generic cefoperazone/sulbactam compared to the branded cefoperazone/sulbactam (Sulperazon) in treating bacterial infections through a meta-analysis. Searches were conducted across PubMed, Embase, Cochrane Library, CNKI, WanFang, VIP databases, and Clinical Trials database, resulting in the inclusion of 11 studies comprising 7 randomized controlled trials (RCTs) and 4 retrospective cohort studies (RCSs). Meta-analysis of the RCTs indicated no statistical differences in clinical success rates, clinical cure rates, microbiological eradication rates, and incidence of adverse reactions between the generic cefoperazone/sulbactam and the branded version. Findings from the RCSs aligned with those from the RCTs, demonstrating that generic versions of cefoperazone/sulbactam are equivalent in efficacy and safety to their branded counterparts in treating bacterial infections.

A generalizable and easy-to-use COVID-19 stratification model for the next pandemic via immune-phenotyping and machine learning.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has affected billions of people worldwide, and the lessons learned need to be concluded to get better prepared for the next pandemic. Early identification of high-risk patients is important for appropriate treatment and distribution of medical resources. A generalizable and easy-to-use COVID-19 severity stratification model is vital and may provide references for clinicians. Methods: Three COVID-19 cohorts (one discovery cohort and two validation cohorts) were included. Longitudinal peripheral blood mononuclear cells were collected from the discovery cohort (n = 39, mild = 15, critical = 24). The immune characteristics of COVID-19 and critical COVID-19 were analyzed by comparison with those of healthy volunteers (n = 16) and patients with mild COVID-19 using mass cytometry by time of flight (CyTOF). Subsequently, machine learning models were developed based on immune signatures and the most valuable laboratory parameters that performed well in distinguishing mild from critical cases. Finally, single-cell RNA sequencing data from a published study (n = 43) and electronic health records from a prospective cohort study (n = 840) were used to verify the role of crucial clinical laboratory and immune signature parameters in the stratification of COVID-19 severity. Results: Patients with COVID-19 were determined with disturbed glucose and tryptophan metabolism in two major innate immune clusters. Critical patients were further characterized by significant depletion of classical dendritic cells (cDCs), regulatory T cells (Tregs), and CD4+ central memory T cells (Tcm), along with increased systemic interleukin-6 (IL-6), interleukin-12 (IL-12), and lactate dehydrogenase (LDH). The machine learning models based on the level of cDCs and LDH showed great potential for predicting critical cases. The model performances in severity stratification were validated in two cohorts (AUC = 0.77 and 0.88, respectively) infected with different strains in different periods. The reference limits of cDCs and LDH as biomarkers for predicting critical COVID-19 were 1.2% and 270.5 U/L, respectively. Conclusion: Overall, we developed and validated a generalizable and easy-to-use COVID-19 severity stratification model using machine learning algorithms. The level of cDCs and LDH will assist clinicians in making quick decisions during future pandemics.

Quality of life improvements in women with uterine fibroids treated with relugolix combination therapy during the LIBERTY long-term extension study: A descriptive subgroup analysis in women with anemia at baseline.

OBJECTIVE: To investigate the effects of 52 weeks of treatment with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) and quality of life (QoL) in women with heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline. METHODS: This post hoc analysis included women from the LIBERTY long-term extension study with anemia (hemoglobin concentration ≤10.5 g/dL) at pivotal study baseline and documented hemoglobin values at week 52 (anemia-evaluable population). Treatment responders: women achieving a menstrual blood loss volume of <80 mL and a ≥50% reduction over the last 35 days of treatment. Anemia responders were women achieving a hemoglobin increase of >2 g/dL from baseline to week 52. Least squares (LS) mean changes from baseline in uterine fibroid symptom (UFS)-QoL symptom severity, fatigue, and health-related QoL total (HR-QoL) and (sub)scale scores were calculated. RESULTS: In total, 115 women were included in the anemia-evaluable population. Of 39 anemia-evaluable women who received continuous treatment with relugolix combination therapy for 52 weeks, 34 (87.2%) met treatment responder criteria and 23 (59.0%) were anemia responders. LS mean hemoglobin concentration increased by 29.4% at week 52. LS mean UFS-QoL symptom severity and fatigue scores decreased by 38.5 and 31.9 points, respectively, and HR-QoL total score increased by 41.6 points. CONCLUSION: In women with UF and a high disease burden due to anemia, relugolix combination therapy substantially improved hemoglobin levels, decreased distress due to symptoms, especially fatigue, over 52 weeks.

Cost-effectiveness analysis of metformin versus insulin in the treatment of gestational diabetes mellitus.

OBJECTIVE: Although there have been many studies on gestational diabetes mellitus (GDM) treatment, there is still a knowledge gap regarding the comparative cost-effectiveness of metformin and insulin in the treatment phase. Existing studies have focused on treatment efficacy and drug safety, but relatively little has been explored regarding cost-effectiveness analysis. In particular, no comprehensive study has evaluated the cost-effectiveness of metformin and insulin for GDM treatment. Therefore, this study aimed to fill this knowledge gap by conducting a cost-effectiveness analysis of these two treatments for GDM. METHODS: A decision-analytic model was used to compare the cost-effectiveness of metformin and insulin in China. Probabilities, costs, and utilities were derived from the literature. The cost and quality-adjusted life years (QALYs) were calculated using the roll-back method. The strategy was considered cost-effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay (WTP) threshold of ¥242,938 per QALY. Sensitivity analyses were also conducted to assess the robustness of the results. RESULTS: The roll-back analysis indicated that insulin was not cost-effective compared to metformin, resulting in increased costs and decreased QALYs, with a negative ICER. These findings suggested that metformin is a cost-effective option than insulin. Furthermore, the sensitivity analysis showed that the model was robust. CONCLUSIONS: Compared with insulin, metformin is a cost-effective treatment option for GDM.

Effect of hydroxychloroquine blood concentration on the efficacy and ocular toxicity of systemic lupus erythematosus.

In the absence of evidence-based guidance on the impact of hydroxychloroquine (HCQ) blood concentration on efficacy and ocular toxicity in systemic lupus erythematosus (SLE), the clinical monitoring of HCQ blood concentration is not yet widely performed, which raised concerns about the necessity of conducting HCQ blood concentration monitoring. In this retrospective study, we consecutively enrolled 135 patients with SLE who received HCQ treatment for more than 6 months from July 2022 to December 2022. Ocular toxicity was evaluated by collecting relevant retinal parameters using optical coherence tomography angiography (OCTA). Therapeutic efficacy was evaluated using the SLE disease activity index (SLEDAI) and relevant clinical parameters. HCQ blood concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Spearman correlation analysis revealed that the cumulative dose of HCQ was positively correlated with the foveal avascular zone (FAZ) perimeter and FAZ area (r = 0.734, P < 0.001; r = 0.784, P < 0.001). Meanwhile, the treatment duration of HCQ was positively correlated with FAZ perimeter and FAZ area (r = 0.761, P < 0.001; r = 0.882, P < 0.001). The univariate and multivariate logistic regression analyses indicated that HCQ blood concentration was associated with the disease activity of patients with SLE (odds ratio 0.994, 95% CI 0.990-0.999). HCQ blood concentration may be an important factor in assessing the therapeutic effectiveness of SLE patients. The HCQ-related ocular toxicity was a long-term effect related to long term exposure, rather than the blood concentration of HCQ at the time of testing. More importantly, when addressing HCQ-related ocular toxicity, it may be crucial to pay attention to the cumulative dose and treatment duration of HCQ.

Influence of different factors on coseismic deformation of the 2015 Mw7.8 earthquake in Nepal.

In Geophysics, topographic factors are observations that can be directly measured, but they are often ignored to simplify the model. Studying the coseismic deformation caused by earthquakes helps accurately determine the epicenter's parameterization. It provides a reference for the reasonable layout of coseismic observation stations and GNSS observation stations. After the Mw7.8 earthquake in Nepal in 2015, GCMT, USGS, GFZ, CPPT, and other institutions released their epicenter parameter. However, according to their parameters, the coseismic displacements simulated by the spectral-element method are quite different from the GNSS observations. Firstly, this paper inverts the geometric parameters of the seismogenic fault with Nepal's coseismic GNSS displacement. The spectral-element method determines the source's location and depth under the heterogeneous terrain and outputs the source parameters. Among the results of many studies, the surface source is more consistent with the generation mechanism of large earthquakes. Secondly, this paper calculates the fault slip distribution of this earthquake using SDM (Steepest Descent Method) based on GNSS and InSAR data, which is divided into 1500 subfaults, and the moment tensor of each subfault is calculated. This paper investigates the distribution characteristics of the coseismic deformation field of the 2015 Mw 7.8 earthquake in Nepal under three different models. The results show that the influence of topographic factors is ~ 20%, and the influence of heterogeneous factors is ~ 10%. This paper concludes that the influence of topographic factors is much more significant than that of heterogeneous factors, and the influence of both should be addressed in coseismic deformation calculations.

A Novel Four-Gene Signature Based on Nonsense-Mediated RNA Decay for Predicting Prognosis in Hepatocellular Carcinoma: Bioinformatics Analysis and Functional Validation.

Purpose: Nonsense-mediated RNA decay (NMD), a surveillance pathway for selective degradation of aberrant mRNAs, is associated with cancer progression. Its potential as a predictor for aggressive hepatocellular carcinoma (HCC) is unclear. Here, we present an innovative NMD risk model for predicting HCC prognosis. Methods: The Cancer Genome Atlas (TCGA) data of 374 liver HCC (LIHC) and 50 normal liver samples were extracted. A risk model based on NMD-related genes was developed through least absolute shrinkage and selection operator Cox (LASSO-Cox) regression of the LIHC-TCGA data. Prognostic validation was done using GSE54236, GSE116174, and GSE76427 data. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model. We also constructed nomograms for survival prediction. Tumor immune infiltration was evaluated using the CIBERSORT algorithm, and the tumor cell phenotype was assessed. Finally, mouse experiments verified UPF3B knockdown effects on HCC tumor characteristics. Results: We developed a risk model based on four NMD-related genes (PABPC1, RPL8, SMG5, and UPF3B) and validated it using GSE54236, GSE116174, and GSE76427 data. The model effectively distinguished high- and low-risk groups corresponding to unfavorable and favorable HCC outcomes. Its prognostic prediction accuracy was confirmed through time-dependent ROC analysis, and clinical-use nomograms with calibration curves were developed. Single-cell RNA sequencing results indicated significantly higher expression of SMG5 and UPF3B in tumor cells. Knockdown of SMG5 and UPF3B inhibited HCC cell proliferation, invasion, and migration, while affecting cell-cycle progression and apoptosis. In vivo, UPF3B knockdown delayed tumor growth and increased immune cell infiltration. Conclusion: Our NMD-related gene-based risk model can help identify therapeutic targets and biomarkers for HCC. Additionally, it assists clinicians in predicting the prognosis of HCC patients.

Why step in? Shifting justifications for bystander behaviors through interventions with youth in the Middle East.

Research shows positive bystander intervention effectively mitigates bullying experiences. Yet, more evidence regarding bystander responses to bias-based social exclusion (BSE) is needed in intergroup contexts, especially in the majority world and in areas of intractable conflict. This study assessed the effectiveness of skills and skills + contact-based interventions for BSE among 148 Palestinian Citizens of Israel (Mage = 10.55) and 154 Jewish-Israeli (Mage = 10.54) early adolescents (Girls = 52.32%) in Tel Aviv-Yafo. Bystander responses were assessed by participants' reactions to hypothetical BSE scenarios over three time points. Repeated measures ANOVAs revealed both interventions significantly increased positive and decreased negative bystander responses, with changes maintained at the follow-up. The opposite result pattern emerged for the control group. Findings suggest that both interventions can effectively encourage youth to publicly challenge BSE, even amidst intractable conflict.