Cadonilimab (PD-1/CTLA-4) in combination with lenvatinib in unresectable hepatocellular carcinoma (uHCC): A retrospective real-world study.

Background: Previous research has shown that combining tyrosine kinase inhibitors (TKIs) with immunotherapy results in synergistic clinical efficacy. Cadonilimab, the first approved bi-specific antibody targeting PD-1 and CTLA-4, was studied to evaluate its efficacy and safety in combination with Lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). Methods: A retrospective study was conducted on 29 uHCC patients diagnosed at Nanfang Hospital, Southern Medical University, between July 7, 2022, and March 3, 2023. Patients received Cadonilimab (10 mg/kg, IV, every 3 weeks) combined with Lenvatinib (8 mg, orally, daily). The primary endpoint was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), median time to progression (mTTP), and safety. Results: By April 2023, 29 patients had been enrolled in the study. The ORR was 37.9 %, DCR was 82.8 %, mPFS was 8.1 months, mTTP was 8.2 months, and mOS was not reached. A total of 93.1 % of patients experienced at least one treatment-related adverse event (TRAE). The most common adverse events were weight loss (51.7 %), increased aspartate aminotransferase (48.3 %), leukocytopenia (48.3 %), and neutropenia (48.3 %). TRAEs of grade 3 or higher occurred in 51.7 % of patients, with no grade 4 TRAEs observed. Conclusion: This study demonstrated the efficacy and safety of this combination, potentially improving outcomes as a first-line therapy, and offering a novel therapeutic approach for advanced HCC.

Leveraging machine learning for sustainable cultivation of Zn-enriched crops in Cd-contaminated karst regions.

Karst soils often exhibit elevated zinc (Zn) levels, providing an opportunity to cultivate Zn-enriched crops. (meanwhile) However, these soils also frequently contain high background levels of toxic metals, particularly cadmium (Cd), posing potential health risks. Understanding the bioaccumulation of Cd and Zn and the related drivers in a high geochemical background area can provide important insights for the safe development of Zn-enriched crops. Traditional models often struggle to accurately predict metal levels in crop systems grown on soils with high geochemical background. This study employed machine learning models, including Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost), to explore effective strategies for sustainable cultivation of Zn-enriched crops in karst regions, focusing on bioaccumulation factors (BAF). A total of 10,986 topsoil samples and 181 paired rhizosphere soil-crop samples, including early rice, late rice, and maize, were collected from a karst region in Guangxi. The SVM and XGBoost models demonstrated superior performance, achieving R2 values of 0.84 and 0.60 for estimating the BAFs of Zn and Cd, respectively. Key determinants of the BAFs were identified, including soil iron and manganese contents, pH level, and the interaction between Zn and Cd. By integrating these soil properties with machine learning, a framework for the safe cultivation of Zn-enriched crops was developed. This research contributes to the development of strategies for mitigating Zn deficiency in crops grown on Cd-contaminated soils.

The role of imbalanced CD226/TIGIT on activated peripheral double-negative T cells in the pathogenesis of primary Sjögren's syndrome.

OBJECTIVES: To explore whether the balance of CD226 and TIGIT is disturbed in CD3+CD56-TCRαß+CD4-CD8- (DN) T cells and have a better understanding of the potential role of DN T cells in the pathogenesis of primary Sjögren's syndrome (pSS). METHODS: The percentage of DN T cells as well as the expression of CD226 and TIGIT was identified by flowmetry. After in vitro stimulation, we further detected the expression of activation and cytotoxic marker, as well as intracellular cytokines secreted by DN T cells. RESULTS: DN T cells were found to expand in the peripheral blood of pSS patients (1.77±0.66%) and correlate with IgG (r=0.451, p<0.05), C3 (r=-0.438, p<0.05) and C4 (r=-0.470, p<0.05). Imbalanced CD226/TIGIT was observed on peripheral DN T cells of pSS patients, especially the overexpression of inhibitory immunoreceptor TIGIT. The expression ratio of TIGIT and CD226 on DN T cells was elevated in pSS patients and correlated with ESSDAI scores≥5 (r=0.743, p<0.05). Besides, these DN T cells were found to be activated and show strong cytotoxicity. CONCLUSIONS: The balance between CD226 and TIGIT on DN T cells was disturbed and correlated with the disease activity in pSS patients, which may be implicated in the pathogenesis of pSS.

Efficacy of venoarterial extracorporeal membrane oxygenation with and without intra-aortic balloon pump in adult cardiogenic shock.

Introduction: Intra-aortic balloon pump (IABP) is sometimes coupled with Venoarterial extracorporeal membrane oxygenation (VA-ECMO) to treat patients with cardiogenic shock. In this study, we attempted to evaluate the association of the IABP approach on survival and vascular complication rates in adults with cardiogenic shock undergoing VA-ECMO. Methods: We performed a systematic search of original studies on VA-ECMO with and without IABP in PubMed, EMBASE, and the Cochrane Library. Results: A total of 42 studies with 8,759 patients were included. The pooled in-hospital deaths of patients on VA-ECMO with and without IABP were 2,962/4,807 (61.61%) versus 2,666/3,952 (67.45%). VA-ECMO with IABP presents lower in-hospital mortality (risk ratio, 0.88; 95% CI, 0.86-0.91; P < 0.00001). In addition, IABP was associated with lower in-hospital mortality of patients with postcardiotomy cardiogenic shock and ischaemic heart disease. (risk ratio, 0.93; 95% CI, 0.87-0.98; P = 0.01; risk ratio, 0.85; 95% CI, 0.82-0.89; P < 0.00001). There was no significant difference in in-hospital morbidity in neurological, gastrointestinal, limb-related, bleeding, and infection complications between patients on VA-ECMO with and without IABP. Discussion: In these observational studies, concomitant use of IABP and VA-ECMO in adult patients with cardiogenic shock was associated with reduced in-hospital mortality. Systematic Review Registration: PROSPERO [CRD42017069259].

A study on the mediating-moderate effect of the types of illicit drugs on mental health in China.

Background: In China, over 5 million people have been identified and registered by the public security institutions for using illicit drugs. The aim of this study is to compare the influence of different types of illicit drugs on the self-reported mental health of Chinese people. In particular, we want to assess the damage of Heroin, Methamphetamine and Ketamine to mental health in a social environment where drug use is strictly regulated. Methods: The study is based on survey with 6,906 people who use drugs in Guangdong province, China. Risk of mental health issue is measured using the Brief Symptoms Inventory 18 (BSI-18) Scale, and a higher BSI-18 score indicates more severe mental health problems. The data was analyzed through multilevel regression analysis, propensity score matching analysis and mediation analysis. Results: The three major types of illicit drugs have both moderating and mediating effects on the length of drug-use history, that Heroin use leads to longer drug-use duration, while Ketamine use causes more damage on mental health per unit time of drug-use duration. Average duration of Methamphetamine use is 0.7 year shorter than average duration of Heroin use, and average duration of Ketamine use is 1.7 year shorter than average duration of Heroin use. For each year of increase of drug-use duration, Ketamine use leads to 1.2 times more of BSI score increase than Heroin use, and 2.3 times more of BSI score increase than Methamphetamine use. Conclusion: These three drugs are associated with severe mental health issue in a society with strict drug regulation. Attention should be paid to the mental health of people regardless of the type of drugs they use.

Investigating immune dysregulation and hub genes in septic cardiomyopathy development.

Septic cardiomyopathy is a life-threatening heart dysfunction caused by severe infection. Considering the complexity of pathogenesis and high mortality, the identification of efficient biomarkers are needed to guide clinical practice. Based on multimicroarray analysis, this study aimed to explore the pathogenesis of septic cardiomyopathy and the related immune landscape. The results showed that septic cardiomyopathy resulted in organ dysfunction due to extreme pro- and anti-inflammatory effects. In this process, KLRG1, PRF1, BCL6, GAB2, MMP9, IL1R1, JAK3, IL6ST, and SERPINE1 were identified as the hub genes regulating the immune landscape of septic cardiomyopathy. Nine transcription factors regulated the expression of these genes: SRF, STAT1, SP1, RELA, PPARG, NFKB1, PPARA, SMAD3, and STAT3. The hub genes activated the Th17 cell differentiation pathway, JAK-STAT signaling pathway, and cytokine‒cytokine receptor interaction pathway. These pathways were mainly involved in regulating the inflammatory response, adaptive immune response, leukocyte-mediated immunity, cytokine-mediated immunity, immune effector processes, myeloid cell differentiation, and T-helper cell differentiation. These nine hub genes could be considered biomarkers for the early prediction of septic cardiomyopathy.

Synchronously Repairing Core/Surface Defects of Carbon Fibers by In Situ Growth of ZIF-8 and Uniquely Matched High-Energy Irradiation.

Currently, the actual mechanical properties of carbon fibers (CF) differ significantly from the theoretical values. This is primarily attributed to significant limitations imposed by structural defects, greatly hindering the widespread application of CF. To solve this problem, we used in situ growth of zeolitic imidazolate framework-8 (ZIF-8) and γ rays to modulate the core-shell of CF in this study. For the surface structure of CF during the process of γ irradiation, the organic structure within ZIF-8 gradually degrades and forms a cross-linking structure with the surface defects of the CF. This process significantly enhances the binding strength between inorganic material from the postdecomposition of ZIF-8 and the carbon layer on the surface of CF, repairing the surface defects. For the internal structure of CF, γ irradiation can improve the orientation of the internal micropores of CF and increase the degree of internal graphitization of CF. In this paper, an in-depth analysis of CF before and after repair was conducted by using characterization techniques such as nanoindentation and ultrasmall angle X-ray scattering (USAXS). Compared to unmodified CF, its mechanical properties improved by approximately 19.99%, which exceeds that in approximately 95% of similar works in the field.

Effects of Early Lactation Milking Frequency in an Automated Milking System on Cow Performance.

Automated milking systems (AMS) are increasingly adopted for dairy cow production, promoting individualized cow management dependent on factors like lactation stage, age, and productivity. The study objective was to investigate the effects of early lactation milking frequency on cows milked via AMS. Multiparous Holstein cows blocked by parity and due date were randomly assigned to treatments (n = 8 per treatment): three (3X) or six (6X) milkings per day (MPD). The experimental phase (EXP) was defined as 4 to 29 days in milk (DIM). The AMS settings were programed so 3X cows were limited to three MPD while 6X cows were allowed six MPD. Afterwards was the carry over phase (CO) ranging from 30 to 90 DIM; all cows were allowed up to six MPD. Measurements by the AMS included bodyweight, milk yield (MY), and pellet intake. Weekly composite milk samples were analyzed for macronutrient composition and fatty acid (FA) profile. Coccygeal blood was sampled at 3, 8 ± 1, and 13 ± 1 DIM; concentrations of blood plasma analytes were quantified. Greater MPD was achieved for 6X cows versus 3X cows during EXP, but similar during the CO. Daily MY was non-separable during the EXP while 6X cows in their third or greater lactation group (3 + LG) had greater MY than 3X cows of the same LG during the CO. Milk fat content and 4% fat-corrected MY were both greater for 6X, 3 + LG cows during the EXP compared to 3X, 3 + LG cows. Milk FA methyl esters (FAME) proportions were different between MPD groups, with 6X, 3 + LG cows having the lowest short, even-chain FA from de novo or post-absorptive origin. Differences in analytes indicated that 6X, 3 + LG cows experienced metabolic stress and incorporated greater FA from adipose tissue. Greater early lactation MPD in AMS may shift cow nutrient partitioning to support greater production in 3+ parity cows.

Fibronectin type III domain containing 4 alleviates myocardial ischemia/reperfusion injury via the Nrf2-dependent antioxidant pathway.

Fibronectin type III domain containing 4 (FNDC4) is highly homologous with FNDC5, which possesses various cardiometabolic protective functions. Emerging evidence suggests a noteworthy involvement of FNDC4 in fat metabolism and inflammatory processes. This study aimed to characterize the role of FNDC4 in myocardial ischemia/reperfusion (MI/R) injury and decrypt its underlying mechanisms. MI/R models of mice were established to investigate the alteration of FNDC4 in plasma and myocardium. We observed that plasma FNDC4 in MI/R-injury mice and patients experiencing acute myocardial infarction were both significantly reduced as opposed to their respective controls. Likewise, FNDC4 expression of myocardium decreased markedly in MI/R mice compared to the sham-operated group. Mice of FNDC4 knockout and myocardial overexpression were further introduced to elucidate the role of FNDC4 in MI/R injury by detecting cardiomyocyte apoptosis, myocardial infarct size, and cardiac function. Ablation of FNDC4 exacerbated cardiac dysfunction, increased myocardial infarction area and cardiomyocyte apoptosis when matched with wild-type mice post-MI/R. In contrast, FNDC4 overexpression through intramyocardial injection of rAAV9-Fndc4 significantly ameliorated cardiac function, reduced myocardial infarction area and cardiomyocyte apoptosis compared to sham group. Additionally, hypoxia-reoxygenation (H/R) was used to induce cardiomyocyte apoptosis, and to further elucidate the direct effects of FNDC4 on cardiomyocytes in vitro, and the results demonstrated that neonatal rat ventricular cardiomyocytes overexpressing FNDC4 showed less H/R-induced apoptosis, as evidenced by cleaved caspase 3 expression, TUNEL staining and flow cytometry. By performing RNA-seq analysis followed by cause-effect analysis, ERK1/2-Nrf2 pathway-mediated antioxidative effects were responsible for the protective roles of FNDC4 on cardiomyocytes. In summary, FNDC4 exerts cardioprotection against MI/R injury predominantly through mitigating oxidative stress responses and reducing cardiomyocyte apoptosis. These insights solidify the proposition of FNDC4 as a potential therapeutic aim for tackling MI/R damage.

Dietary supplementation with Macleaya cordata extract alleviates intestinal injury in broiler chickens challenged with lipopolysaccharide by regulating gut microbiota and plasma metabolites.

Introduction: The prevention and mitigation of intestinal immune challenge is crucial for poultry production. This study investigated the effects of dietary Macleaya cordata extract (MCE) supplementation on the prevention of intestinal injury in broiler chickens challenged with lipopolysaccharide (LPS). Methods: A total of 256 one-day-old male Arbor Acres broilers were randomly divided into 4 treatment groups using a 2×2 factorial design with 2 MCE supplemental levels (0 and 400 mg/kg) and 2 LPS challenge levels (0 and 1 mg/kg body weight). The experiment lasted for 21 d. Results and discussion: The results showed that MCE supplementation increased the average daily feed intake during days 0-14. MCE supplementation and LPS challenge have an interaction on the average daily gain during days 15-21. MCE supplementation significantly alleviated the decreased average daily gain of broiler chickens induced by LPS. MCE supplementation increased the total antioxidant capacity and the activity of catalase and reduced the level of malondialdehyde in jejunal mucosa. MCE addition elevated the villus height and the ratio of villus height to crypt depth of the ileum. MCE supplementation decreased the mRNA expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the jejunum. MCE addition mitigated LPS-induced mRNA up-expression of pro-inflammatory factors IL-1ß and IL-17 in the jejunum. MCE supplementation increased the abundance of probiotic bacteria (such as Lactobacillus and Blautia) and reduced the abundance of pathogenic bacteria (such as Actinobacteriota, Peptostretococcaceae, and Rhodococcus), leading to alterations in gut microbiota composition. MCE addition altered several metabolic pathways such as Amino acid metabolism, Nucleotide metabolism, Energy metabolism, Carbohydrate metabolism, and Lipid metabolism in broilers. In these pathways, MCE supplementation increased the levels of L-aspartic acid, L-Glutamate, L-serine, etc., and reduced the levels of phosphatidylcholine, phosphatidylethanolamine, thromboxane B2, 13-(S)-HODPE, etc. In conclusion, dietary supplementation of 400 mg/kg MCE effectively improved the growth performance and intestinal function in LPS-challenged broiler chickens, probably due to the modulation of gut microbiota and plasma metabolites.

BmfR, a novel GntR family regulator, regulates biofilm formation in marine-derived, Bacillus methylotrophicus B-9987.

Biofilms are common living states for microorganisms, allowing them to adapt to environmental changes. Numerous Bacillus strains can form complex biofilms that play crucial roles in biocontrol processes. However, our current understanding of the molecular mechanisms of biofilm formation in Bacillus is mainly based on studies of Bacillus subtilis. Knowledge regarding the biofilm formation of other Bacillus species remains limited. In this study, we identified a novel transcriptional regulator, BmfR, belonging to the GntR family, that regulates biofilm formation in marine-derived Bacillus methylotrophicus B-9987. We demonstrated that BmfR induces biofilm formation by activating the extracellular polysaccharide structural genes epsA-O and negatively regulating the matrix gene repressor, SinR; of note it positively affects the expression of the master regulator of sporulation, Spo0A. Furthermore, database mining for BmfR homologs has revealed their widespread distribution among many bacterial species, mainly Firmicutes and Proteobacteria. This study advances our understanding of the biofilm regulatory network of Bacillus strains, and provides a new target for exploiting and manipulating biofilm formation.

Simulation and Experimental Investigation on Additive Manufacturing of Highly Dense Pure Tungsten by Laser Powder Bed Fusion.

Tungsten and its alloys have a high atomic number, high melting temperature, and high thermal conductivity, which make them fairly appropriate for use in nuclear applications in an extremely harsh radioactive environment. In recent years, there has been growing research interest in using additive manufacturing techniques to produce tungsten components with complex structures. However, the critical bottleneck for tungsten engineering manufacturing is the high melting temperature and high ductile-to-brittle transition temperature. In this study, laser powder bed fusion has been studied to produce bulk pure tungsten. And finite element analysis was used to simulate the temperature and stress field during laser irradiation. The as-printed surface as well as transverse sections were observed by optical microscopy and scanning electron microscopy to quantitatively study processing defects. The simulated temperature field suggests small-sized powder is beneficial for homogenous melting and provides guidelines for the selection of laser energy density. The experimental results show that ultra-dense tungsten bulk has been successfully obtained within a volumetric energy density of 200-391 J/mm3. The obtained relative density can be as high as 99.98%. By quantitative analysis of the pores and surface cracks, the relationships of cracks and pores with laser volumetric energy density have been phenomenologically established. The results are beneficial for controlling defects and surface quality in future engineering applications of tungsten components by additive manufacturing.

Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication.

BACKGROUND & AIMS: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication. METHODS: Serum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD. RESULTS: Serum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT. CONCLUSION: Inhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.

Machine learning-based prediction of cadmium pollution in topsoil and identification of critical driving factors in a mining area.

Mining activities have resulted in a substantial accumulation of cadmium (Cd) in agricultural soils, particularly in southern China. Long-term Cd exposure can cause plant growth inhibition and various diseases. Rapid identification of the extent of soil Cd pollution and its driving factors are essential for soil management and risk assessment. However, traditional geostatistical methods are difficult to simulate the complex nonlinear relationships between soil Cd and potential features. In this study, sequential extraction and hotspot analyses indicated that Cd accumulation increased significantly near mining sites and exhibited high mobility. The concentration of Cd was estimated using three machine learning models based on 3169 topsoil samples, seven quantitative variables (soil pH, Fe, Ca, Mn, TOC, Al/Si and ba value) and three quantitative variables (soil parent rock, terrain and soil type). The random forest model achieved marginally better performance than the other models, with an R2 of 0.78. Importance analysis revealed that soil pH and Ca and Mn contents were the most significant factors affecting Cd accumulation and migration. Conversely, due to the essence of controlling Cd migration being soil property, soil type, terrain, and soil parent materials had little impact on the spatial distribution of soil Cd under the influence of mining activities. Our results provide a better understanding of the geochemical behavior of soil Cd in mining areas, which could be helpful for environmental management departments in controlling the diffusion of Cd pollution and capturing key targets for soil remediation.

Neuroimaging and clinical features of bilateral Wallerian degeneration of middle cerebellar peduncles subsequent to pontine infarction.

OBJECTIVE: Wallerian degeneration (WD) of the middle cerebellar peduncles (MCPs) following pontine infarction is a rare secondary degenerative neurological condition. Due to its infrequency, there is limited research on its characteristics. METHODS: This study aims to present three cases of WD of MCPs following pontine infarction and to analyze the prognosis, clinical manifestations, and neuroimaging features by amalgamating our cases with previously reported ones. RESULTS: The cohort consisted of 25 cases, comprising 18 men and 7 women aged 29 to 77 years (mean age: 66.2 years). The majority of patients (94%) exhibit risk factors for cerebrovascular disease, with hypertension being the primary risk factor. Magnetic resonance imaging (MRI) can detect WD of MCPs within a range of 21 days to 12 months following pontine infarction. This degeneration is characterized by bilateral symmetric hyperintensities on T2/FLAIR-weighted images (WI) lesions in the MCPs. Moreover, restricted diffusion, with hyperintensity on diffusion-weighted imaging (DWI) and low apparent diffusion coefficient (ADC) signal intensity may be observed as early as 21 days after the infarction. Upon detection of WD, it was observed that 20 patients (80%) remained asymptomatic during subsequent clinic visits, while four (16%) experienced a worsening of pre-existing symptoms. CONCLUSIONS: These findings underscore the importance of neurologists enhancing their understanding of this condition by gaining fresh insights into the neuroimaging characteristics, clinical manifestations, and prognosis of individuals with WD of bilateral MCPs.

The effects of CYP2B6 inactivators on the metabolism of ciprofol.

Ciprofol is a novel short-acting intravenous anaesthetic developed in China that is mainly metabolized by cytochrome P450 2B6 (CYP2B6) and uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). Currently, insufficient evidence is available to support drug‒drug interactions between ciprofol and CYP2B6 inactivators. Here, we established a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to assess the concentration of ciprofol and investigated the effects of psoralen and clopidogrel on the metabolism of ciprofol in liver microsomes and rats. In rat and human liver microsomes, the median inhibitory concentration (IC50) values of psoralen were 63.31 µmol·L-1 and 34.05 µmol·L-1, respectively, showing mild inhibitory effects on ciprofol metabolism, whereas the IC50 values of clopidogrel were 6.380 µmol·L-1 and 2.565 µmol·L-1, respectively, with moderate inhibitory effects. SD rats were randomly divided into three groups: psoralen (27 mg·kg-1), clopidogrel (7.5 mg·kg-1), and the same volume of 0.5% carboxy methyl cellulose. After 7 days, all rats were injected with 2.4 mg·kg-1 ciprofol. Compared with the control group, the AUC and MRT values of ciprofol in the psoralen and clopidogrel groups were significantly greater, whereas the CL values were significantly lower. In addition, the durations of loss of righting reflex (LORR) in the psoralen and clopidogrel groups were 16.1% and 23.0% longer than that in the control group, respectively. In conclusion, psoralen and clopidogrel inhibit ciprofol metabolism to different degrees and prolong the duration of LORR in rats.

Imbalance of mitochondrial quality control regulated by STING and PINK1 affects cyfluthrin-induced neuroinflammation.

Nervous system diseases are a global health problem, and with the increase in the elderly population around the world, their incidence will also increase. Harmful substances in the environment are closely related to the occurrence of nervous system diseases. China is a large agricultural country, and thus the insecticide cyfluthrin has been widely used. Cyfluthrin is neurotoxic, but the mechanism of this injury is not clear. Inflammation is an important mechanism for the occurrence of nervous system diseases. Mitochondria are the main regulators of the inflammatory response, and various cellular responses, including autophagy, directly affect the regulation of inflammatory processes. Mitochondrial damage is related to mitochondrial quality control (MQC) and PTEN-induced kinase 1 (PINK1). As an anti-inflammatory factor, stimulator of interferon genes (STING) participates in the regulation of inflammation. However, the relationship between STING and mitochondria in the process of cyfluthrin-induced nerve injury is unclear. This study established in vivo and in vitro models of cyfluthrin exposure to explore the role of MQC and to clarify the mechanism of action of STING and PINK1. Our results showed that cyfluthrin can increase the reactive oxygen species (ROS) level, resulting in mitochondrial damage and inflammation. In this process, an imbalance in MQC leads to the aggravation of mitochondrial damage, and high STING expression drives the occurrence of inflammation. We established a differential expression model of STING and PINK1 to further determine the underlying mechanism and found that the interaction between STING and PINK1 regulates MQC to affect the levels of mitochondrial damage and inflammation. When STING and PINK1 expression are downregulated, mitochondrial damage and STING-induced inflammation are significantly alleviated. In summary, a synergistic effect between STING and PINK1 on cyfluthrin-induced neuroinflammation may exist, which leads to an imbalance in MQC by inhibiting mitochondrial biogenesis and division/fusion, and PINK1 can reduce STING-driven inflammation.

Constructing Stiff ß-Sheet for Self-Reinforced Alginate Fibers.

The application of alginate fibers is limited by relatively low mechanical properties. Herein, a self-reinforcing strategy inspired by nature is proposed to fabricate alginate fibers with minimal changes in the wet-spinning process. By adapting a coagulation bath composing of CaCl2 and ethanol, the secondary structure of sodium alginate (SA) was regulated during the fibrous formation. Ethanol mainly increased the content of ß-sheet in SA. Rheological analysis revealed a reinforcing mechanism of stiff ß-sheet for enhanced modulus and strength. In combination with Ca2+ crosslinking, the self-reinforced alginate fibers exhibited an increment of 39.0% in tensile strength and 71.9% in toughness. This work provides fundamental understanding for ß-sheet structures in polysaccharides and a subsequent self-reinforcing mechanism. It is significant for synthesizing strong and tough materials. The self-reinforcing strategy involved no extra additives and preserved the degradability of the alginate. The reinforced alginate fibers exhibited promising potentials for biological applications.

Distinct phenotype and prognosis of immune-mediated necrotizing myopathy based on clinical-serological-pathological classification.

OBJECTIVE: The aim of the study was to investigate the characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM) based on clinical, serological and pathological classification. METHODS: A total of 138 patients with IMNM who met the 2018 European Neuromuscular Center criteria for IMNM including 62 anti-SRP, 32 anti-HMGCR-positive and 44 myositis specific antibody-negative were involved in the study. All patients were followed up and evaluated remission and relapse. Clustering analysis based on clinical, serological, and pathological parameters was used to define subgroups. RESULTS: Clustering analysis classified IMNM into three clusters. Cluster 1 patients (n = 35) had the highest CK levels, the shortest disease course, severe muscle weakness, and more inflammation infiltration in muscle biopsy. Cluster 2 patients (n = 79) had the lowest CK level and moderate inflammation infiltrate. Cluster 3 patients (n = 24) had the youngest age of onset, the longest disease course and the least frequency of inflammatory infiltration. Patients in cluster 3 had the longest time-to-remission (median survival time: 61[18.3, 103.7] vs 20.5[16.2, 24.9] and 27[19.6, 34.3] months) and shortest relapse-free time than those in cluster 1 and 2 (median remission time 95%CI: 34[19.9, 48.0] vs 73[49.0, 68.7] and 73[48.4, 97.6] months). Patients with age of onset >55 years, more regeneration of muscle fibers, more CD4+T infiltration, and MAC deposition had more favorable outcomes regarding time to achieving remission. CONCLUSIONS: Stratification combining clinical, serological, and pathological features could distinguish phenotypes and prognosis of IMNM. The pathological characteristics may impact the long-term prognosis of patients with IMNM.