Causal associations of BAFF-R on IgD+ CD24- B cell immune cell trait with hepatocellular carcinoma and the mediating role of phenylacetylglutamate levels: a Mendelian randomization study.

We conducted a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between immune cell traits and hepatocellular carcinoma (HCC) and identified the mediating factor of metabolites. The exposure factors were immune cell traits, the mediators were metabolites, and the outcome variable was HCC. Inverse-variance weighted method (IVW) was the main method. Weighted median, MR-Egger regression, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (MRPRESSO) methods were used as complementary methods. The results were tested by using the Bayesian weighted Mendelian randomization (BWMR) approach in our MR study. Subsequently, the potential mediating effect was investigated by conducting a two-step mediation analysis. We identified 26 traits with suggestive correlations between immune cell traits and HCC, with 4 immune cell traits among them having causal correlations with HCC. There were no causal correlations between HCC and immune cell traits in the reverse MR analysis. In the mediation analysis, we found a positive causal association between B cell-activating factor receptors (BAFF-R) on IgD+ CD24- B cell and HCC [IVW: odd ratio (OR), 0.845; 95% CI, 0.759-0.942; p = 0.002]. Phenylacetylglutamate (PAG) levels mediated 7.353% of the causal pathway from BAFF-R on IgD+ CD24- B cell and HCC. In conclusion, BAFF-R on IgD+ CD24- B cell lowers risk of HCC, with PAG levels playing a mediating role.

Kaempferol mitigates sepsis-induced acute lung injury by modulating the SphK1/S1P/S1PR1/MLC2 signaling pathway to restore the integrity of the pulmonary endothelial cell barrier.

Sepsis-induced acute lung injury (SALI) is the common complication of sepsis, resulting in high incidence and mortality rates. The primary pathogenesis of SALI is the interplay between acute inflammation and endothelial barrier damage. Studies have shown that kaempferol (KPF) has anti-sepsis properties. Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway's significance in acute lung damage and S1P receptor 1 (S1PR1) agonists potential in myosin light chain 2 (MLC2) phosphorylation are documented. Whether KPF can regulate the SphK1/S1P/S1PR1/MLC2 signaling pathway to protect the lung endothelial barrier remains unclear. This study investigates the KPF's therapeutic effects and molecular mechanisms in repairing endothelial cell barrier damage in both LPS-induced sepsis mice and human umbilical vein endothelial cells (HUVECs). KPF significantly reduced lung tissue damage and showed anti-inflammatory effects by decreasing IL-6 and TNF-α synthesis in the sepsis mice model. Further, KPF administration can reduce the high permeability of the LPS-induced endothelial cell barrier and alleviate lung endothelial cell barrier injury. Mechanistic studies showed that KPF pretreatment can suppress MLC2 hyperphosphorylation and decrease SphK1, S1P, and S1PR1 levels. The SphK1/S1P/S1PR1/MLC2 signaling pathway controls the downstream proteins linked to endothelial barrier damage, and the Western blot (WB) showed that KPF raised the protein levels. These proteins include zonula occludens (ZO)-1, vascular endothelial (VE)-cadherin and Occludin. The present work revealed that in mice exhibiting sepsis triggered by LPS, KPF strengthened the endothelial barrier and reduced the inflammatory response. The SphK1/S1P/S1PR1/MLC2 pathway's modulation is the mechanism underlying this impact.

Ser/Thr protein kinase Stk1 phosphorylates the key transcriptional regulator AlgR to modulate virulence and resistance in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the leading causes of nosocomial infections worldwide and has emerged as a serious public health threat, due in large part to its multiple virulence factors and remarkable resistance capabilities. Stk1, a eukaryotic-type Ser/Thr protein kinase, has been shown in our previous work to be involved in the regulation of several signalling pathways and biological processes. Here, we demonstrate that deletion of stk1 leads to alterations in several virulence- and resistance-related physiological functions, including reduced pyocyanin and pyoverdine production, attenuated twitching motility, and enhanced biofilm production, extracellular polysaccharide secretion, and antibiotic resistance. Moreover, we identified AlgR, an important transcriptional regulator, as a substrate for Stk1, with its phosphorylation at the Ser143 site catalysed by Stk1. Intriguingly, both the deletion of stk1 and the mutation of Ser143 of AlgR to Ala result in similar changes in the above-mentioned physiological functions. Furthermore, assays of algR expression in these strains suggest that changes in the phosphorylation state of AlgR, rather than its expression level, underlie changes in these physiological functions. These findings uncover Stk1-mediated phosphorylation of AlgR as an important mechanism for regulating virulence and resistance in P. aeruginosa.

Prevalence characteristics of cervical human papillomavirus infection in Chengdu and Aba District, Sichuan Province, China.

PURPOSE: The genotype distribution of human papillomavirus (HPV) infection varies greatly in different regions. This study aims to determine the prevalence and type-specific distribution of HPV among females from Chengdu and Aba in Sichuan Province, which differ in geographical location, economic status, and living habits. These can serve as evidence of epidemic patterns for future design and implementation of vaccination and screening programs. METHODS: A retrospective cross-sectional study was conducted on 144 113 women who underwent cervical screening at Chengdu Women's and Children's Central Hospital from January 2015 to September 2020. Meanwhile, 1799 samples from February 2018 to December 2021 were collected from Aba Maternal and Child Health Hospital. HPV DNA genotype testing was performed using real-time PCR. The overall prevalence, annual trend, age-specific prevalence, and type distribution were analyzed. RESULTS: The overall HPV prevalence was 22.51% in Chengdu. During 2015-2020, the highest prevalence rate was observed in 2018. Age-specific HPV distribution displayed a bimodal distribution among women aged ≤25 or ≥46 years old. The top three prevalent genotypes were HPV52, -16, and -58. Although the total prevalence of HPV in Aba was 14.23%, there was an upward trend from 2018 to 2021. However, no significant differences were identified in HPV infection rate across all age groups. HPV52, -53, and -16 were the major genotypes. Furthermore, single-type HPV infections and high-risk HPV infections were identified as the most common infection types in both regions. CONCLUSION: Our findings demonstrate the overall prevalence of HPV was still high in Chengdu and Aba. The age-specific prevalence distribution demonstrated different patterns. Non-vaccine-covered HR-HPV53, -51and LR-HPV81, -CP8304 were frequently detected, which was worth significant clinical attention. In summary, regional HPV screening provides valuable clinical guidance for cervical cancer prevention and vaccine selection in Western China.

Effect of Brick Aggregate Content on Performance of Recycled Construction-Solid-Waste Aggregate.

In road engineering, road construction requires a large amount of natural aggregate; its substitution with recycled construction-solid-waste aggregate not only saves resources but also reduces the burden on the environment. The main components of construction solid waste are concrete blocks and brick slag; the breakability of the latter can affect the performance of mixed recycled aggregate, which hinders the use of construction solid waste in road engineering applications. To analyze the applicability of recycled construction-solid-waste aggregate containing brick slag aggregate in the subgrade layer, the effect of brick aggregate content on the CBR (California bearing ratio) and crushing value of mixed recycled aggregates was evaluated based on laboratory tests, and the field compaction quality of the recycled aggregates was analyzed. The results show that the 9.5-19 mm mixed recycled aggregate samples were crushed to a higher degree during the compaction process. A brick aggregate content less than 40% had little effect on the performance of mixed recycled construction-solid-waste aggregate. It is recommended to use a 22 t road roller for five passes (two weak vibrations + two strong vibrations + one weak vibration) at a speed of 3 km/h in the main compaction stage of the subgrade filling.

Health Care Utilization by Patients With Chronic Pelvic Pain.

OBJECTIVE: To describe the patterns of health care utilization among patients with chronic pelvic pain. METHODS: Deidentified administrative claims data from the OptumLabs Data Warehouse were used. Adult female patients who had their first medical claim for chronic pelvic pain between January 1, 2016, and December 31, 2019, were included. Utilization was examined for 12 months after the index diagnosis. The greedy nearest neighbor matching method was used to identify a control group of individuals without chronic pelvic pain. Comparisons were made between those with and those without chronic pelvic pain using χ 2 tests for categorical data and Wilcoxon rank-sum tests for continuous data. RESULTS: In total, 18,400 patients were analyzed in the chronic pelvic pain cohort. Patients with chronic pelvic pain had a higher rate of chronic overlapping pain conditions. Patients with chronic pelvic pain had higher rates of health care utilization across all queried indices. They had more outpatient office visits; 55.5% had 10 or more office visits. Patients with chronic pelvic pain showed higher utilization of the emergency department (ED) (6.3 visits vs 1.9 visits; P <.001). Urine culture and pelvic ultrasonography were the most utilized tests. One-third of patients with chronic pelvic pain utilized physical therapy (PT), and 13% utilized psychological or behavioral therapy. Patients with chronic pelvic pain had higher rates of hysterectomy (8.9% vs 0.6%). The average total health care costs per patient with chronic pelvic pain per year was $12,254. CONCLUSION: Patients with chronic pelvic pain have higher rates of chronic overlapping pain conditions and undergo more ED visits, imaging tests, and hysterectomies than patients without chronic pelvic pain. Improving access to multidisciplinary care, increasing utilization of interventions such as PT and psychological or behavioral therapy, and reducing ED utilization may be possible targets to help reduce overall health care costs and improve patient care.

Structure-Based Design of Novel Thiazolone[3,2-a]pyrimidine Derivatives as Potent RNase H Inhibitors for HIV Therapy.

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 µM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.

Room-Temperature Phase Transition Material with Switchable Second-Order Nonlinear Optical Properties.

Phase transition materials with switchable second-order nonlinear optical (NLO) properties have attracted extensive attention because of their great application potential in photoelectric switches, sensors, and modulators, while metal-free organics with NLO switchability near room temperature remain scarce. Herein, we report a hydrogen-bonded metal-free organic crystal, 2-methylpropan-2-aminium 2,2-dimethylpropanoate (1), exhibiting a room-temperature phase transition and favorable NLO switchability. Through investigations on its thermal anomalies, dielectric properties, and crystal structures, we uncover that 1 holds a near-room-temperature phase transition at 303 K from noncentrosymmetric point group C2v to centrosymmetric one D2h, which is attributed to the order-disorder transformations of both tert-butylamine cations and dimethylpropionic acid anions. Accompanied by symmetry change during the phase transition, 1 exhibits reversible and repeatable NLO "on-off" switchability with a desirable switching contrast ratio of ca. 19 between high and low NLO states. This discovery demonstrates a metal-free organic crystal with NLO switching behavior near room temperature, serving as a promising candidate in smart and ecofriendly photoelectric functional materials and devices.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

A framework for longitudinal latent factor modelling of treatment response in clinical trials with applications to Psoriatic Arthritis and Rheumatoid Arthritis.

OBJECTIVE: Clinical trials involve the collection of a wealth of data, comprising multiple diverse measurements performed at baseline and follow-up visits over the course of a trial. The most common primary analysis is restricted to a single, potentially composite endpoint at one time point. While such an analytical focus promotes simple and replicable conclusions, it does not necessarily fully capture the multi-faceted effects of a drug in a complex disease setting. Therefore, to complement existing approaches, we set out here to design a longitudinal multivariate analytical framework that accepts as input an entire clinical trial database, comprising all measurements, patients, and time points across multiple trials. METHODS: Our framework composes probabilistic principal component analysis with a longitudinal linear mixed effects model, thereby enabling clinical interpretation of multivariate results, while handling data missing at random, and incorporating covariates and covariance structure in a computationally efficient and principled way. RESULTS: We illustrate our approach by applying it to four phase III clinical trials of secukinumab in Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA). We identify three clinically plausible latent factors that collectively explain 74.5% of empirical variation in the longitudinal patient database. We estimate longitudinal trajectories of these factors, thereby enabling joint characterisation of disease progression and drug effect. We perform benchmarking experiments demonstrating our method's competitive performance at estimating average treatment effects compared to existing statistical and machine learning methods, and showing that our modular approach leads to relatively computationally efficient model fitting. CONCLUSION: Our multivariate longitudinal framework has the potential to illuminate the properties of existing composite endpoint methods, and to enable the development of novel clinical endpoints that provide enhanced and complementary perspectives on treatment response.

Quantitative evaluation of disc degeneration using dual-energy CT: advantages of R-VH, D-VH values and the IVNCa + CT model.

OBJECTIVE: To evaluate the correlation between dual-energy CT (DECT) virtual calcium free (VNCA), CT attenuation, the ratio and difference of VNCA to CT attenuation, and Pfirrmann grading of lumbar disc degeneration. METHODS: A retrospective analysis on 135 intervertebral discs from 30 patients who underwent DECT and MR. Discs was graded using the Pfirrmann system. ROIs on the sagittal plane assessed HU value, VNCA value, Rho value, Z value, R-VH value, and D-VH value. Correlation, grade differences, and multivariate regression models were assessed. Diagnostic performance and cut-off values were determined using AUC. RESULTS: VNCA (r = 0.589, P < 0.001), R-VH (r = 0.622, P < 0.001), and D-VH (r = 0.613, P < 0.001) moderately correlated with Pfirrmann grading. HU (r = 0.388, P < 0.001), Rho (r = 0.142, P = 0.102), and Z (r = -0.125, P = 0.153) showed a weak correlation. R-VH, D-VH, and VNCA had significantly higher correlation than HU. Statistically significant differences were observed in P values of VNCA, HU, R-VH, and D-VH in relative groups (P < 0.05), but not in Rho and Z values (P > 0.05). R-VH and D-VH had significant differences between Pfirrmann grades 1 and 2, and grades 2 and 3 (early stage) (P < 0.05). AUC readings of R-VH and D-VH (≥2, ≥3, ≥4) were higher. The multivariate model IVNCa + CT had the highest AUC. CONCLUSION: The new quantitative indices R-VH value and D-VH value of DECT have advantages over VNCA value and HU value in evaluating early-stage disc degeneration (≥2 grades, ≥3 grades). The multivariate model IVNCa + CT has the best AUC values for evaluating disc degeneration at all stages.

Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Characterising the distribution of mangroves along the southern coast of Vietnam using multi-spectral indices and a deep learning model.

Mangroves are an ecologically and economically valuable ecosystem that provides a range of ecological services, including habitat for a diverse range of plant and animal species, protection of coastlines from erosion and storms, carbon sequestration, and improvement of water quality. Despite their significant ecological role, in many areas, including in Vietnam, large scale losses have occurred, although restoration efforts have been underway. Understanding the scale of the loss and the efficacy of restoration requires high resolution temporal monitoring of mangrove cover on large scales. We have produced a time series of 10-m-resolution mangrove cover maps using the Multispectral Instrument on the Sentinel 2 satellites and with this tool measured the changes in mangrove distribution on the Vietnamese Southern Coast (VSC). We extracted the annual mangrove cover ranging from 2016 to 2023 using a deep learning model with a U-Net architecture based on 17 spectral indices. Additionally, a comparison of misclassification by the model with global products was conducted, indicating that the U-Net architecture demonstrated superior performance when compared to experiments including multispectral bands of Sentinel-2 and time-series of Sentinel-1 data, as shown by the highest performing spectral indices. The generated performance metrics, including overall accuracy, precision, recall, and F1-score were above 90 % for entire years. Water indices were investigated as the most important variables for mangrove extraction. Our study revealed some misclassifications by global products such as World Cover and Global Mangrove Watch and highlighted the significance of our study for local analysis. While we did observe a loss of 34,778 ha (42.2 %) of mangrove area in the region, 47,688 ha (57.8 %) of new mangrove area appeared, resulting in a net gain of 12,910 ha (15.65 %) over the eight-year period of the study. The majority of new mangrove areas were concentrated in Ca Mau peninsulas and within estuaries undergoing recovery programs and natural recovery processes. Mangrove loss occurred in regions where industrial development, wind farm projects, reclaimed land, and shrimp pond expansion is occurring. Our study provides a theoretical framework as well as up-to-date data for mapping and monitoring mangrove cover change that can be readily applied at other sites.

CXCL9 mediating the effect of thyroid disorders on oral and oropharyngeal cancer risk: A mediation Mendelian randomization study.

INTRODUCTION: The established association between thyroid disorders (TD) and its two main subtypes-hyperthyroidism and hypothyroidism-and the incidence of oral and oropharyngeal cancer (OCPC) has been substantiated. However, the direct causal relationship and potential intermediary mechanisms linking these conditions have not been clearly defined in prior studies. MATERIAL & METHODS: This study employed univariate Mendelian randomization (MR) analysis to explore those relationship. Instrumental variables from genome-wide association study (GWAS) datasets for TD (n = 218,792), hyperthyroidism (n = 460,499), hypothyroidism (n = 213,990), and OCPC (n = 12,619), along with 41 intermediary inflammatory cytokines (n = 8293), were analyzed. Inverse variance weighting (IVW) method assessed the causal relationships, while summary MR analysis with pQTL datasets from decode and 91 inflammatory cytokines explored the cytokines' roles as biomarkers and therapeutic targets for OCPC. Multivariable MR (MVMR) analysis quantified the mediation effect of these cytokines in the TD-OCPC relationship. RESULTS: UVMR analysis provided strong evidence for a causal relationship between TD (OR = 1.376, 95 % CI = 1.142-1.656, p = 0.001), hyperthyroidism (OR = 1.319, 95 % CI=1.129-1.541, p = 0.001), hypothyroidism (OR = 1.224, 95 % CI = 1.071-1.400, p = 0.003), and the risk of OCPC. CXCL9 was identified as a significant intermediary in mediating the risk of OCPC from TD and its two subtypes (OR = 1.218, 95 % CI = 1.016-1.461, P = 0.033), suggesting its potential as a predictive biomarker for OCPC. MVMR analysis further revealed that CXCL9 mediated 7.94 %, 14.4 %, and 18 % of the effects of TD, hyperthyroidism, and hypothyroidism on OCPC risk, respectively. DISCUSSION: This study not only elucidated the potential causal relationships between TD including its two subtypes and OCPC risk, but also highlighted CXCL9 as a pivotal mediator in this association.

Inflammatory cytokines mediating the effect of oral lichen planus on oral cavity cancer risk: a univariable and multivariable mendelian randomization study.

BACKGROUND: While observational studies and experimental data suggest a link between oral lichen planus (OLP) and oral cavity cancer (OCC), the causal relationship and the role of inflammatory cytokines remain unclear. METHODS: This study employed a univariable and multivariable Mendelian Randomization (MR) analysis to investigate the causal relationship between OLP and the risk of OCC. Additionally, the potential role of inflammatory cytokines in modulating this association was explored. Instrumental variables were derived from genetic variants associated with OLP (n = 377,277) identified in Finngen R9 datasets, with 41 inflammatory cytokines as potential mediators, and OCC (n = 4,151) as the outcome variable. Analytical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO were utilized to assess the causal links among OLP, inflammatory cytokines, and OCC risk. Multivariable MR (MVMR) was then applied to quantify the mediating effects of these cytokines in the relationship between OLP and increased OCC risk. RESULTS: MR analysis provided strong evidence of a causal relationship between OLP (OR = 1.417, 95% CI = 1.167-1.721, p < 0.001) and the risk of OCC. Furthermore, two inflammatory cytokines significantly influenced by OLP, IL-13 (OR = 1.088, 95% CI: 1.007-1.175, P = 0.032) and IL-9 (OR = 1.085, 95% CI: 1.005-1.171, P = 0.037), were identified. Subsequent analysis revealed a significant causal association only between IL-13 (OR = 1.408, 95% CI: 1.147-1.727, P = 0.001) and higher OCC risk, establishing it as a potential mediator. Further, MVMR analysis indicated that IL-13 (OR = 1.437, 95% CI = 1.139-1.815, P = 0.002) mediated the relationship between OLP and OCC, accounting for 8.13% of the mediation. CONCLUSION: This study not only elucidates the potential causal relationship between OLP and the risk of OCC but also highlights the pivotal mediating role of IL-13 in this association.

shinyTempSignal: an R shiny application for exploring temporal and other phylogenetic signals.

The molecular clock model is fundamental for inferring species divergence times from molecular sequences. However, its direct application may introduce significant biases due to sequencing errors, recombination events, and inaccurately labeled sampling times. Improving accuracy necessitates rigorous quality control measures to identify and remove potentially erroneous sequences. Furthermore, while not all branches of a phylogenetic tree may exhibit a clear temporal signal, specific branches may still adhere to the assumptions, with varying evolutionary rates. Supporting a relaxed molecular clock model better aligns with the complexities of evolution. The root-to-tip regression method has been widely used to analyze the temporal signal in phylogenetic studies and can be generalized for detecting other phylogenetic signals. Despite its utility, there remains a lack of corresponding software implementations for broader applications. To address this gap, we present shinyTempSignal, an interactive web application implemented with the shiny framework, available as an R package and publicly accessible at https://github.com/YuLab-SMU/shinyTempSignal. This tool facilitates the analysis of temporal and other phylogenetic signals under both strict and relaxed models. By extending the root-to-tip regression method to diverse signals, shinyTempSignal helps in the detection of evolving features or traits, thereby laying the foundation for deeper insights and subsequent analyses.

Toxic effects of microplastics and nitrite exposure on intestinal histology, digestion, immunity, and microbial community of shrimp Litopenaeus vannamei.

Nitrite and microplastics (MPs) are environmental pollutants that threaten intestinal integrity and affect immune function of shrimp. In this study, the shrimp Litopenaeus vannamei were exposed to the individual and combined stress of nitrite and microplastics for 14 days, and the changes of intestinal histology and physiological functions were investigated. After single and combined stress, affectations occurred in intestinal tissue; the antioxidant enzyme activities (MDA, H2O2, CAT increased) and gene expression levels (CAT, SOD, GPx, HSP70 up-regulated) changed. The expression levels of detoxification genes (CYP450, UGT down-regulated, GST up-regulated), apoptosis genes (CASP-3 up-regulated) and endoplasmic reticulum stress genes (Bip, GRP94 down-regulated) changed. Furthermore, the stress also increased intestinal microbial diversity, causing bacterial composition variation, especially beneficial bacteria and pathogenic bacteria. These results suggested that nitrite and microplastics stress had adverse effects on the intestinal health of L. vannamei by affecting intestinal tissue morphology, immune response and microbial community.

Silkworm pupae protein co-degradation by magnetic nanoparticles immobilized proteinase K and Mucor circinelloides aspartic protease for further utilization of sericulture by-products.

Silkworm pupae, by-product of sericulture industry, is massively discarded. The degradation rate of silkworm pupae protein is critical to further employment, which reduces the impact of waste on the environment. Herein, magnetic Janus mesoporous silica nanoparticles immobilized proteinase K mutant T206M and Mucor circinelloides aspartic protease were employed in the co-degradation. The thermostability of T206M improved by enhancing structural rigidity (t1/2 by 30 min and T50 by 5 °C), prompting the degradation efficiency. At 65 °C and pH 7, degradation rate reached the highest of 61.7%, which improved by 26% compared with single free protease degradation. Besides, the immobilized protease is easy to separate and reuse, which maintains 50% activity after 10 recycles. Therefore, immobilized protease co-degradation was first applied to the development and utilization of silkworm pupae resulting in the release of promising antioxidant properties and reduces the environmental impact by utilizing a natural and renewable resource.

A Sn-Based Hybrid Ferroelastic Semiconductor with High-Temperature Dielectric Switching.

Organic-inorganic halide hybrids have been extensively developed and used in optoelectronic devices because of their superior performance such as ease of assembly, flexible structural tunability, and excellent optoelectronic properties. Ferroelastic strain might be used to modulate and control photoelectric properties such as photovoltaic voltage, while organic-inorganic hybrid ferroelastic semiconductors remain relatively unexplored. Herein, we successfully design a new Sn-base, lead-free hybrid ferroelastic semiconductor, [TPMA]2[SnCl6] (TPMA = benzyl trimethylammonium). It undergoes a high-temperature -3mF-1-type ferroelastic phase transition at 408 K, and intriguingly, its ferroelastic domains can be simultaneously switched under the stimulation of external heat and stress. The ferroelastic phase transition might be derived from the order-disorder transition of organic cations during heating and cooling. Moreover, [TPMA]2[SnCl6] also demonstrates a high-temperature dielectric switching property around 408 K, which has good stability and reproducibility. With those benefits, [TPMA]2[SnCl6] shows great potential in applications such as energy storage devices, optoelectronic devices, shape memory, intelligent switches, and so on.