Osmosensor-mediated control of Ca2+ spiking in pollen germination.

Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration1,2, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo3-5, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca2+ spiking is controlled directly by water through these hypo-osmosensors-that is, Ca2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins6. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca2+-permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.

BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation.

BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.

A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Identification of AURKA as a Biomarker Associated with Cuproptosis and Ferroptosis in HNSCC.

Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.

Expression and biochemical characterization of a Bacillus subtilis catalase in Pichia pastoris X-33.

Catalase, which catalyzes the decomposition of H2O2 to H2O and O2, is widely used to reduce H2O2 in industrial applications, such as in food processing, textile dyeing and wastewater treatment. In this study, the catalase (KatA) from Bacillus subtilis was cloned and expressed in the yeast Pichia pastoris X-33. The effect of the promoter in the expression plasmid on the activity level of the secreted KatA protein was also studied. First, the gene encoding KatA was cloned and inserted into a plasmid containing an inducible alcohol oxidase 1 promoter (pAOX1) or a constitutive glyceraldehyde-3-phosphate dehydrogenase promoter (pGAP). The recombinant plasmids were validated by colony PCR and sequencing and then linearized and transformed into the yeast P. pastoris X-33 for expression. With the promoter pAOX1, the maximum yield of KatA in the culture medium reached 338.8 ± 9.6 U/mL in 2 days of shake flask cultivation, which was approximately 2.1-fold greater than the maximum yield obtained with the promoter pGAP. The expressed KatA was then purified from the culture medium by anion exchange chromatography, and its specific activity was determined to be 14826.58 U/mg. Finally, the purified KatA exhibited optimum activity at 25 °C and pH 11.0. Its Km for hydrogen peroxide was 10.9 ± 0.5 mM, and its kcat/Km was 5788.1 ± 25.6 s-1 mM-1. Through the work presented in this article, we have therefore demonstrated efficient expression and purification of KatA in P. pastoris, which might be advantageous for scaling up the production of KatA for use in a variety of biotechnological applications.

Enhanced Electrical Conductivity of (001) Oriented Sr0.9La0.1TiO3 Microplatelets for Thermoelectric Applications.

Two-dimensional perovskite microplatelets have played an important role in various applications, especially acting as a template to guide grains' epitaxial growth in the preparation of textured ceramics. The (001) oriented Sr0.9La0.1TiO3 microplatelets with a high aspect ratio of ∼20 were synthesized and obtained from Aurivillius Bi4Ti3O12 precursors. To reveal the mechanism of topochemical microcrystal conversion of Bi4Ti3O12 to Sr0.9La0.1TiO3, the reaction interface, morphology development, and phase composition evolution of the (001) oriented Sr0.9La0.1TiO3 microplatelets were investigated. When the temperature of the molten salt is above 753 °C, multiple Sr0.9La0.1TiO3 topological nucleation events took place. At 950 °C, the polycrystalline aggregate of (001)-oriented Sr0.9La0.1TiO3 crystallites grew in place of the original single crystal Bi4Ti3O12 platelets. When the temperature reached 1150 °C, the Sr0.9La0.1TiO3 platelets preserved the shape of a high aspect ratio and exhibited not only enhanced electrical conductivity with a carrier concentration of 3.518 × 1020 cm-3 and carrier mobility of 8.460 cm2·V-1·s-1 but also significantly decreased thermal conductivity ranging from 5.65 W·m-1·K-1 at 300 K to 2.54 W·m-1·K-1 at 1073 K. It can be widely applied in the field of template grain growth methods for preparing textured thermoelectric ceramics to improve their thermoelectric properties.

Exercise rehabilitation to treat sarcopenia in pediatric transplant populations.

BACKGROUND: In adult transplant (Tx) populations, exercise rehabilitation strategies may improve sarcopenia components (muscle mass [MM], strength [MS], and physical performance [PP]). Limited data are available regarding exercise rehabilitation therapy in pediatric Tx populations. METHODS: The purpose of this review is to critically evaluate the feasibility and impact of exercise programs (EP) that include resistance exercise (RE) on markers of sarcopenia in pediatric Tx populations. Literature searches in SCOPUS and WEB OF SCIENCE were conducted to identify studies applying EP with a RE component in pediatric populations in the Tx setting. RESULTS: Twelve articles (2008-2022) met inclusion criteria. The exercise interventions varied in length (3 weeks-12 months), intensity (low to moderate), time pre/post Tx (0 days-5 years post Tx), age of participants (3-18 years), adherence (63%-94%), and methodologies to measure components of sarcopenia. No studies measured all three components of sarcopenia concurrently. Approximately, 60% of studies found positive effects on MS and PP. Only one pediatric study measured body composition, therefore, the effect of exercise programs with RE components on MM is unknown. CONCLUSIONS: Exercise programs may be a beneficial treatment for sarcopenia in Tx populations, particularly in components of MS and PP. Studies measuring all three aspects of sarcopenia together in response to RE training in pediatrics remains an important gap. Studies that include body composition measurements in response to exercise are needed. Special considerations for the development of RE programs in pediatrics Tx populations are safety, supervision, engagement through family/peer involvement and incorporation of game/play-based elements.

Evaluating the expression level of genes related to autophagy in rheumatoid arthritis patients.

Rheumatoid arthritis or joint rheumatism is the most common systemic inflammatory disease of the joints and is considered one of the chronic autoimmune diseases. T cells and other immune cells are called to the synovial tissue and cause this disease to progress. Autophagy is a process that is associated with the breakdown of intracellular organelles. As a regulator of cell homeostasis, it can affect the activation of immune cells and participate in the pathogenesis of rheumatoid arthritis. This study aimed to evaluate the gene expression level of autophagy genes in two groups of rheumatoid arthritis patients and healthy individuals. For this purpose, peripheral blood was obtained from two groups of people, including 40 rheumatoid arthritis patients, and 40 healthy individuals. The expression of two genes related to autophagy, Atg5, and Beclin-1, was evaluated in peripheral blood cells using the real-time PCR method. The results showed that the expression of the Beclin-1 gene increased by 2.21 times in rheumatoid arthritis patients compared to healthy individuals (P = 0.024). The expression of the Atg5 gene in rheumatoid arthritis patients increased by 1.53 times compared to healthy subjects (P = 0.041). In general, this study showed that in rheumatoid arthritis patients, increased expression of autophagy genes could be involved in the pathogenesis of this disease. In other words, the findings showed that reducing autophagy can reduce the severity of the disease in people with rheumatoid arthritis.

Loss of DJ-1 function contributes to Parkinson's disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation.

Parkinson's disease (PD) is a common neurodegenerative motor disorder characterized by a dramatic reduction in pars compacta of substantia nigra dopaminergic neurons and striatal dopamine (DA) levels. Mutations or deletions in the PARK7/DJ-1 gene are associated with an early-onset familial form of PD. DJ-1 protein prevents neurodegeneration via its regulation of oxidative stress and mitochondrial function as well as its roles in transcription and signal transduction. In this study, we investigated how loss of DJ-1 function affected DA degradation, ROS generation and mitochondrial dysfunction in neuronal cells. We showed that loss of DJ-1 significantly increased the expression of monoamine oxidase (MAO)-B but not MAO-A in both neuronal cells and primary astrocytes. In DJ-1-knockout (KO) mice, MAO-B protein levels in the substantia nigra (SN) and striatal regions were significantly increased. We demonstrated that the induction of MAO-B expression by DJ-1 deficiency depended on early growth response 1 (EGR1) in N2a cells. By coimmunoprecipitation omics analysis, we found that DJ-1 interacted with receptor of activated protein C kinase 1 (RACK1), a scaffolding protein, and thus inhibited the activity of the PKC/JNK/AP-1/EGR1 cascade. The PKC inhibitor sotrastaurin or the JNK inhibitor SP600125 completely inhibited DJ-1 deficiency-induced EGR1 and MAO-B expression in N2a cells. Moreover, the MAO-B inhibitor rasagiline inhibited mitochondrial ROS generation and rescued neuronal cell death caused by DJ-1 deficiency, especially in response to MPTP stimulation in vitro and in vivo. These results suggest that DJ-1 exerts neuroprotective effects by inhibiting the expression of MAO-B distributed at the mitochondrial outer membrane, which mediates DA degradation, ROS generation and mitochondrial dysfunction. This study reveals a mechanistic link between DJ-1 and MAO-B expression and contributes to understanding the crosslinks among pathogenic factors, mitochondrial dysfunction and oxidative stress in PD pathogenesis.

Comprehensive insight into adsorption of chlortetracycline hydrochloride by room-temperature synthesized water-stable Zr-based metal-organic gel/sodium alginate beads.

Chlortetracycline hydrochloride (CTC) is one of the prevailing antibiotic pollutants that harm both environmental ecosystem and human health. Herein, Zr-based metal-organic gels (Zr-MOGs) with lower-coordinated active sites and hierarchically porous structures are fabricated via a facile straightforward room-temperature strategy for CTC treatment. More importantly, we incorporated the powder Zr-MOGs into low-cost sodium alginate (SA) matrix to achieve shaped Zr-based metal-organic gel/SA beads for enhancing the adsorption ability and ameliorating the recyclability. The Langmuir maximum adsorption capacities of Zr-MOGs and Zr-MOG/SA beads could reach 143.9 mg/g and 246.9 mg/g, respectively. What's more, in the manual syringe unit and continuous bead column experiments, Zr-MOG/SA beads could achieve an eluted CTC removal ratio as high as 96.3% and 95.5% in the river water sample, respectively. On top of that, the adsorption mechanisms were put forward as a combination of pore filling, electrostatic interaction, hydrophilic-lipophilic balance, coordination, π-π interaction as well as hydrogen bonding interaction. This study outlines a workable strategy for the facile preparation of candidate adsorbents for wastewater treatment.

Nomogram for predicting adhesive small bowel obstruction following emergency gastrointestinal surgery.

BACKGROUND: Postoperative adhesions are frequent and significant complications that typically arise following abdominal surgery. Currently, the existing evidence for predicting the risk of adhesive small bowel obstruction (ASBO) after emergency gastrointestinal surgery (EGS) remains inadequate. A reliable perioperative model that quantifies the risk of ASBO after EGS serves as a practical tool for guiding individually tailored surveillance. METHODS: A consecutive series of 1296 patients who underwent EGS for radiologically confirmed bowel/visceral inflammation or perforation between 2012 and 2022 at a tertiary academic medical center were included in this study to establish a best-fit nomogram. The nomogram was externally validated by assessing discrimination and calibration using an independent cohort from a separate medical center. RESULTS: A total of 116 patients (8.9%) developed at least one episode of ASBO after EGS during a median follow-up duration of 26 months. The results of multivariable logistic analysis indicated that male sex (P = 0.043), preoperative albumin level (P = 0.002), history of pelvic radiotherapy (P = 0.038), laparotomy (P = 0.044), and intensive care unit stay ≥ 72 h (P = 0.047) were identified as independent risk factors for developing ASBO. By incorporating these predictors, the developed nomogram exhibited good accuracy in risk estimation, as evidenced by a guide-corrected C-index score of 0.852 (95% CI 0.667-0.920) in the external validation cohort. Decision curve analysis and clinical impact curve demonstrated a clinically effective predictive model. CONCLUSION: By incorporating the nomogram as a supplemental tool in perioperative management, it becomes possible to accurately assess the individual's likelihood of developing ASBOs. This quantification enables surgeons to implement appropriate preventive measures, ultimately leading to improved outcomes.

Constructed Risk Prognosis Model Associated with Disulfidptosis lncRNAs in HCC.

Disulfidptosis is a novel cell death mode in which the accumulation of disulfide bonds in tumor cells leads to cell disintegration and death. Long-stranded noncoding RNAs (LncRNAs) are aberrantly expressed in hepatocellular carcinoma (HCC) and have been reported to carry significant potential as a biomarker for HCC prognosis. However, lncRNA studies with disulfidptosis in hepatocellular carcinoma have rarely been reported. Therefore, this study aimed to construct a risk prognostic model based on the disulfidptosis-related lncRNA and investigate the mechanisms associated with disulfidptosis in hepatocellular carcinoma. The clinical and transcriptional information of 424 HCC patients was downloaded from The Cancer Genome Atlas (TCGA) and divided into test and validation sets. Furthermore, 1668 lncRNAs associated with disulfidptosis were identified using Pearson correlation. Six lncRNA constructs were finally identified for the risk prognostic model using one-way Cox proportional hazards (COX), multifactorial COX, and lasso regression. Kaplan-Meier (KM) analysis, principal component analysis, receiver operating characteristic curve (ROC), C-index, and column-line plot results confirmed that the constructed model was an independent prognostic factor. Based on the disulfidptosis risk score, risk groups were identified as potential predictors of immune cell infiltration, drug sensitivity, and immunotherapy responsiveness. Finally, we confirmed that phospholipase B domain containing 1 antisense RNA 1 (PLBD1-AS1) and muskelin 1 antisense RNA (MKLN1-AS) were highly expressed in hepatocellular carcinoma and might be potential biomarkers in HCC by KM analysis and quantitative real-time PCR (RT-qPCR). This study demonstrated that lncRNA related to disulfidptosis could serve as a biomarker to predict prognosis and treatment targets for HCC.

Characteristics, secondary transformation and odor activity evaluation of VOCs emitted from municipal solid waste incineration power plant.

Volatile organic compounds (VOCs) emitted from municipal solid waste incineration power plant (MSWIPP) plays a significant role in the formation of O3 and PM2.5 and odor pollution. Field test was performed on four MSWIPPs in an area of the North China Plain. Nonmethane hydrocarbons (NMHCs) and 102 VOCs were identified and quantified. Ozone formation potential (OFP), secondary organic aerosol formation potential (SOAFP), and odor activity of the detected VOCs were evaluated. Results showed that the average concentration of NMHCs and VOCs were 1648.6 ± 1290.4 µg/m3 and 635.3 ± 588.8 µg/m3, respectively. Aromatics (62.1%), O-VOCs (16.0%), and halo hydrocarbons (10.0%) were the main VOCs groups in the MSWIPP exhaust gas. VOCs emission factor of MSWIPP was 2.43 × 103 ± 2.27 × 103 ng/g-waste. The OFP and SOAFP of MSWIPP were 960.18 ± 2158.17 µg/m3 and 1.57 ± 3.38 µg/m3, respectively. Acrolein as the dominant VOC species was the major odor contributor with a percentage of odor contribution of 65.9%. Benzene and 1,2,4-trimethylbenzene as the dominant VOC species were the main contributors of O3 formation potentials, in which 1,2,4-trimethylbenzene was also the main contributors of SOA formation potential.

Highly Selective Electrocatalytic Oxidation of Amines to Nitriles Assisted by Water Oxidation on Metal-Doped α-Ni(OH)2.

Selective oxidation to synthesize nitriles is critical for feedstock manufacturing in the chemical industry. Current strategies typically involve substitutions of alkyl halides with toxic cyanides or the use of strong oxidation reagents (oxygen or peroxide) under ammoxidation/oxidation conditions, setting considerable challenges in energy efficiency, sustainability, and production safety. Herein, we demonstrate a facile, green, and safe electrocatalytic route for selective oxidation of amines to nitriles under ambient conditions, assisted by the anodic water oxidation on metal-doped α-Ni(OH)2 (a typical oxygen evolution reaction catalyst). By controlling the balance between co-adsorption of the amine molecule and hydroxyls on the catalyst surface, we demonstrate that Mn doping significantly promotes the subsequent chemical oxidation of amines, resulting in Faradaic efficiencies of 96% for nitriles under ≥99% conversion. This anodic oxidation is further coupled with cathodic hydrogen evolution for overall atomic economy and additional green energy production.

Bacillus subtilis ameliorates Escherichia coli-induced endometritis in mice via maintaining endometrial barrier and inhibiting inflammatory response.

Endometritis is a common obstetric disease that occurs most frequently after parturition in a variety of animals. Animal infertility due to endometritis severely hinders animal husbandry and often causes serious economic losses to the dairy farming industry. According to reports, Bacillus subtilis (B. subtilis) can prevent pathogenic colonization of epithelial cells and exert immunostimulatory effects. The present study aimed to reveal the protective effect of B. subtilis on endometritis induced by Escherichia coli (E. coli) in mice. The experimental model required in this experiment was established by injecting E. coli intrauterinely, and different concentrations of B. subtilis H28 were administered 10 days before E. coli injection. The pathological changes in the uterine tissue of mice were assessed by haematoxylin-eosin (H&E) staining. Myeloperoxidase (MPO) activity measurements and enzyme-linked immunosorbent assay (ELISA) based measurement of pro-inflammatory cytokines levels were performed. Activation of NF-κB signaling pathway were detected by Western blot, and the changes in the levels of tight junction proteins (TJPs) was analyzed using Western blot detection and quantitative real-time polymerase chain reaction (qRT-PCR). As seen from the results, B. subtilis H28 pretreatment decreased uterine neutrophil infiltration, IL-1ß and TNF-α production, and the NF-κB activation during endometritis induced by E. coli. In addition, B. subtilis H28 significantly increased the expression of the tight junction proteins ZO-1, claudin-3 and occludin in uterine infected with E. coli. In conclusion, in the present study, we found that B. subtilis H28 ameliorated E. coli-induced endometritis by maintaining the endometrial barrier and inhibiting the inflammatory response.

Chronic acrylamide exposure resulted in dopaminergic neuron loss, neuroinflammation and motor impairment in rats.

Acrylamide (ACR) as a by-product of Maillard reaction is widely present in food. Although ACR is known to exhibit neurotoxicity, most studies about ACR neurotoxicity are currently short-term high-dose providing limited reference value for human exposure. The present study aims to determine the effects of chronic ACR exposure on dopaminergic neurons in rat nigra and the potential mechanism from the perspective of NLRP3 inflammasome-mediated neuroinflammation. The SD rats were maintained on treated drinking water providing dosages of 0, 0.5, or 5 mg/kg/day ACR for 12 months. ACR exposure caused motor dysfunction in rats, which was associated with dopaminergic neuron loss, α-Synuclein (α-Syn) accumulation and decreased brain-derived neurotrophic factor (BDNF) in nigra. ACR activated microglia by increasing Iba-1+, Iba-1+CD68+ positive cells and the percentage of ameboid-shaped ones in rat nigra. ACR markedly upregulated the protein levels of NLRP3 inflammasome constituents NLRP3 and caspase-1 and inflammatory cytokine IL-1ß. ACR chronic exposure increased the risk of Parkinson's disease (PD) like dopaminergic neuron depletion in nigra potentially through NLRP3 inflammasome-mediated neuroinflammtion.

Altered coordination in a blue copper protein upon association with redox partner revealed by carbon-deuterium vibrational probes.

Proteins tune the reactivity of metal sites; less understood is the impact of association with a redox partner. We demonstrate the utility of carbon-deuterium labels for selective analysis of delicate metal sites. Introduced into plastocyanin, they reveal substantial strengthening of the key Cu-Cys89 bond upon association with cytochrome f.

Elevated troponin I levels on admission predict long-term mortality in patients with acute cerebral infarction following thrombolysis.

BACKGROUND/OBJECTIVE: Cardiac diseases are frequently accompanied by elevated levels of biomarkers, among which, troponin is commonly investigated. The levels of plasma cardiac troponin I (cTnI), which has been shown to predict short-term mortality, are elevated in patients with acute cerebral infarction (ACI). However, few studies have assessed the association between cTnI concentration and long-term mortality in patients with ACI following thrombolysis. METHODS: Patients with ACI admitted between January 1, 2014, and December 31, 2016, were registered. Data on demographics and outcomes with elevated cTnI levels were also collected. RESULTS: A total of 145 patients with ACI were recruited; 97 (66%), 30 (20%), and 18 (12%) patients had cTnI concentrations < 0.030 (group 1), 0.030-0.10 (group 2), and > 0.10 µg/L (group 3), respectively. cTnI elevation was associated with older age, atrial fibrillation, congestive heart failure, renal insufficiency, coronary artery disease, stroke severity (National Institutes of Health Stroke Scale score), and prior smoking history at admission. After adjusting for comorbidities and severity at 3 months after ACI, cTnI elevation on admission was significantly associated with ascending 5-year mortality (hazard ratio, 1.80; 95% confidence interval, 1.22-2.65). CONCLUSIONS: Even after adjusting for several possible confounders, cTnI elevation in patients with ACI treated with rt-PA was associated with a 1.80-fold increased risk of 5-year mortality.

Therapeutic effects of cationic liposomes on lupus-prone MRL/lpr mice are mediated via inhibition of TLR4-triggered B-cell activation.

We previously reported that co-delivery of dihydroartemisinin and high mobility group box 1 (HMGB1) siRNAs, using cell penetrating peptide (TAT)-modified cationic liposomes (TAT-CLs-DHA/siRNA), resulted in promising activity for the treatment of inflammatory disease through TLR4 signaling pathway. In the current study, we further investigated the therapeutic effects of TAT-CLs-DHA/siRNA on lupus-prone MRL/lpr mice and explored its effects on B cell responses. In vitro, we found that TAT-CLs-DHA/siRNA suppressed the proliferation and activation of B cells through the TLR4 signaling pathway. Following parenteral administration every 4 days, TAT-CLs-DHA/siRNA significantly reduced proteinuria, glomerulonephritis, serum anti-dsDNA antibody and secretion of interleukin (IL)-6, IL-10, IL-17 and IL-21. Moreover, Western blotting showed that TAT-CLs-DHA/siRNA modulated the B-cell intrinsic pathway by downregulating expression of HMGB1, TLR4, MyD88 and NF-κB. This co-delivery system thus represents a promising treatment option for lupus nephritis, and also highlights a novel target of lupus treatment through B cell TLR4 signal pathway.

Cadmium induces liver dysfunction and ferroptosis through the endoplasmic stress-ferritinophagy axis.

Cadmium (Cd) is a type of high-risk heavy metal that can damage organs such as the liver, but its mechanism is not yet clear. Ferroptosis is a newly discovered mode of regulatory cell death. We explored whether ferroptosis is involved in Cd-induced liver damage and the underlying mechanism. Our research showed that Cd induced liver damage by inducing ferroptosis, and the use of ferroptosis inhibitors reduced the degree of liver damage. Moreover, the occurrence of ferroptosis was accompanied by the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway, and inhibiting endoplasmic reticulum (ER) stress reduced ferroptosis demonstrating that ferroptosis induced by Cd is dependent on ER stress. In addition, chloroquine, a common autophagy inhibitor, mitigated ferroptosis caused by Cd exposure. Then, the iron chelator deferoxamine reduced Cd-induced lipid peroxidation and cell death, demonstrating that the iron regulation disorder caused by ferritin phagocytosis contributes to the Cd-induced ferroptosis. In conclusion, our results show that Cd-induced liver toxicity is accompanied by ferroptosis, which contributes to Cd inducing oxidative stress to trigger autophagy and ER stress to promote the process of ferroptosis.