Endoplasmic Reticulum Stress Promotes Telomerase Reverse Transcriptase Expression Contributes to Development of Allergic Rhinitis.

BACKGROUND: The Th2 cell polarization is a crucial factor in the pathogenesis of allergic diseases. The underlying mechanism requires further investigation. Telomerase has an immune-regulating ability. The aim of this study is to elucidate the association between telomerase and Th2 cell polarization in patients with allergic rhinitis (AR). METHODS: CD4+ T cells were isolated from blood samples collected from AR patients and healthy control subjects. RNA sequencing was employed to analyze RNA samples extracted from CD4+ T cells. An AR mouse model was established using the ovalbumin-alum protocol. RESULTS: High telomerase gene activity and high endoplasmic reticulum (ER) stress status were observed in CD4+ T-cells in patients with AR. Positive correlation between the telomerase reverse transcriptase (TERT) gene expression in CD4+ T cells and AR response in patients with AR. TERT facilitated the degradation of Foxp3 proteins in CD4+ T cells, resulting in the polarization of Th2 cells. Sensitization with the ovalbumin-alum protocol enhanced the Tert expression in CD4+ T cells by exacerbating ER stress. Conditional inhibition of the Tert or eukaryotic translation initiation factor 2-α (Eif2a) expression in CD4+ T cells effectively attenuated experimental AR in mice. CONCLUSIONS: Elevated amounts of telomerase in CD4+ T cells were found in CD4+ T cells of subjects with AR. Telomerase promoted Th2 cell polarization by inducing Foxp3 protein degradation and promotes GATA3 activation. Inhibition of TERT or eIF2a alleviated experimental AR.

Diet affects inflammatory arthritis: a Mendelian randomization study of 30 dietary patterns causally associated with inflammatory arthritis.

Background: The causal associations between dietary intake and the risk and severity of Inflammatory Arthritis (IA) are currently unknown. Objective: In this study, we aimed to investigate the causal relationship between nine dietary categories (30 types of diet) and IA using Mendelian randomization (MR). Methods: We analyzed data from 30 diets and IA in a genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) that could influence the results of MR analyses were screened out through the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. SNPs were analyzed through two-sample bidirectional MR using inverse variance weighting, MR-Egger regression, and weighted median method. The multiplicity and heterogeneity of SNPs were assessed using MR-Egger intercept term tests and Cochran's Q tests. FDR correction was used to correct the p-values. Results: IVW results showed that Beef intake [Odds ratio (OR) = 2.862; 95% confidence interval (CI), 1.360-6.021, p = 0.006, p_fdr < 0.05] was positively associated with rheumatoid arthritis(RA); Dried fruit intake (OR = 0.522; 95% CI, 0.349-0.781, p = 0.002, p_fdr < 0.05), and Iron intake (OR = 0.864; 95%CI, 0.777-0.960, p = 0.007, p_fdr < 0.05) were negatively associated with RA, all of which were evidence of significance. Fresh fruit intake (OR = 2.528. 95% CI, 1.063-6.011, p = 0.036, p_fdr > 0.05) was positively associated with psoriatic arthritis (PsA); Cheese intake (OR = 0.579; 95% CI, 0.367-0.914, p = 0.019, p_fdr > 0.05) was negatively associated with PsA; both were suggestive evidence. Processed meat intake (OR = 0.238; 95% CI, 0.100-0.565, p = 0.001, p_fdr < 0.05) was negatively associated with reactive arthritis (ReA), a protective factor, and significant evidence. All exposure data passed the heterogeneity check (Cochrane's Q test p > 0.05) and no directional pleiotropy was detected. Leave-one-out analyses demonstrated the robustness of the causal relationship in the positive results. Conclusion: Our study presents genetic evidence supporting a causal relationship between diet and an increased risk of IA. It also identifies a causal relationship between various dietary modalities and different types of IA. These findings have significant implications for the prevention and management of IA through dietary modifications.

NCAPH, ubiquitinated by TRIM21, promotes cell proliferation by inhibiting autophagy of cervical cancer through AKT/mTOR dependent signaling.

Autophagy is closely related to the occurrence and development of human malignancies; however, the detailed mechanisms underlying autophagy in cervical cancer require further investigation. Previously, we found that the ectopic expression of NCAPH, a regulatory subunit of condensed protein complexes, significantly enhanced the proliferation of tumor cells; however, the underlying mechanisms were unclear. Here, we revealed that NCAPH is a novel autophagy-associated protein in cervical cancer that promotes cell proliferation by inhibiting autophagosome formation and reducing autophagy, with no effect on the cell cycle, apoptosis, or aging. Tripartite motif-containing protein 21 (TRIM21) is well known to be involved in inflammation, autoimmunity and cancer, mainly via its E3 ubiquitin ligase activity. Mass spectrometry and immunoprecipitation assays showed that TRIM21 interacted with NCAPH and decreased the protein stability of NCAPH via ubiquitination at the K11 lysine residue. Structural domain mutation analysis revealed that TRIM21 combined with NCAPH through its PRY/SPRY and CC domains and accelerated the degradation of NCAPH through the RING domain. Furthermore, TRIM21 promoted autophagosome formation and reduced cell proliferation by inhibiting NCAPH expression and the downstream AKT/mTOR pathway in cervical cancer cells. Immunohistochemical staining revealed that the protein expression of TRIM21 was negatively correlated with that of NCAPH and positively correlated with that of beclin-1 in cervical cancer tissues. Therefore, we provide evidence for the role of the TRIM21-NCAPH axis in cervical cancer autophagy and proliferation and the involvement of the AKT/mTOR signaling pathway in this process. These results deepen our understanding of the carcinogenesis of cervical cancer, broaden the understanding of the molecular mechanisms of TRIM21 and NCAPH, and provide guidance for individualized treatment of cervical cancer in the future.

Time series prediction model using LSTM-Transformer neural network for mine water inflow.

Mine flooding accidents have occurred frequently in recent years, and the predicting of mine water inflow is one of the most crucial flood warning indicators. Further, the mine water inflow is characterized by non-linearity and instability, making it difficult to predict. Accordingly, we propose a time series prediction model based on the fusion of the Transformer algorithm, which relies on self-attention, and the LSTM algorithm, which captures long-term dependencies. In this paper, Baotailong mine water inflow in Heilongjiang Province is used as sample data, and the sample data is divided into different ratios of the training set and test set in order to obtain optimal prediction results. In this study, we demonstrate that the LSTM-Transformer model exhibits the highest training accuracy when the ratio is 7:3. To improve the efficiency of search, the combination of random search and Bayesian optimization is used to determine the network model parameters and regularization parameters. Finally, in order to verify the accuracy of the LSTM-Transformer model, the LSTM-Transformer model is compared with LSTM, CNN, Transformer and CNN-LSTM models. The results prove that LSTM-Transformer has the highest prediction accuracy, and all the indicators of its model are well improved.

Identification of K+-determined reaction pathway for facilitated kinetics of CO2 electroreduction.

Cations such as K+ play a key part in the CO2 electroreduction reaction, but their role in the reaction mechanism is still in debate. Here, we use a highly symmetric Ni-N4 structure to selectively probe the mechanistic influence of K+ and identify its interaction with chemisorbed CO2-. Our electrochemical kinetics study finds a shift in the rate-determining step in the presence of K+. Spectral evidence of chemisorbed CO2- from in-situ X-ray absorption spectroscopy and in-situ Raman spectroscopy pinpoints the origin of this rate-determining step shift. Grand canonical potential kinetics simulations - consistent with experimental results - further complement these findings. We thereby identify a long proposed non-covalent interaction between K+ and chemisorbed CO2-. This interaction stabilizes chemisorbed CO2- and thus switches the rate-determining step from concerted proton electron transfer to independent proton transfer. Consequently, this rate-determining step shift lowers the reaction barrier by eliminating the contribution of the electron transfer step. This K+-determined reaction pathway enables a lower energy barrier for CO2 electroreduction reaction than the competing hydrogen evolution reaction, leading to an exclusive selectivity for CO2 electroreduction reaction.

Quantitative analysis of electroporation-mediated intracellular delivery via bioorthogonal luminescent reaction.

Efficient intracellular delivery is crucial for biotherapeutics, such as proteins, oligonucleotides, and CRISPR/Cas9 gene-editing systems, to achieve their efficacy. Despite the great efforts of developing new intracellular delivery carriers, the lack of straightforward methods for intracellular delivery quantification limits further development in this area. Herein, we designed a simple and versatile bioorthogonal luminescent reaction (BioLure assay) to analyze intracellular delivery. Our results suggest that BioLure can be used to estimate the amount of intracellularly delivered molecules after electroporation, and the estimation by BioLure is in good correlation with the results from complementary methods. Furthermore, we used BioLure assay to correlate the intracellularly-delivered RNase A amount with its tumoricidal activity. Overall, BioLure is a versatile tool for understanding the intracellular delivery process on live cells, and establishing the link between the cytosolic concentration of intracellularly-delivered biotherapeutics and their therapeutic efficacy.

Au@AuPd Core-Alloyed Shell Nanoparticles for Enhanced Electrocatalytic Activity and Selectivity under Visible Light Excitation.

Plasmonic catalysis has been employed to enhance molecular transformations under visible light excitation, leveraging the localized surface plasmon resonance (LSPR) in plasmonic nanoparticles. While plasmonic catalysis has been employed for accelerating reaction rates, achieving control over the reaction selectivity has remained a challenge. In addition, the incorporation of catalytic components into traditional plasmonic-catalytic antenna-reactor nanoparticles often leads to a decrease in optical absorption. To address these issues, this study focuses on the synthesis of bimetallic core@shell Au@AuPd nanoparticles (NPs) with ultralow loadings of palladium (Pd) into gold (Au) NPs. The goal is to achieve NPs with an Au core and a dilute alloyed shell containing both Au and Pd, with a low Pd content of around 10 atom %. By employing the (photo)electrocatalytic nitrite reduction reaction (NO2RR) as a model transformation, experimental and theoretical analyses show that this design enables enhanced catalytic activity and selectivity under visible light illumination. We found that the optimized Pd distribution in the alloyed shell allowed for stronger interaction with key adsorbed species, leading to improved catalytic activity and selectivity, both under no illumination and under visible light excitation conditions. The findings provide valuable insights for the rational design of antenna-reactor plasmonic-catalytic NPs with controlled activities and selectivity under visible light irradiation, addressing critical challenges to enable sustainable molecular transformations.

Study on co-amorphous emerging solubilization behavior after gelation during dissolution: The importance of complexation and anti-crystallization.

Co-amorphous (CM) is a promising technology for enhancing the aqueous solubility of insoluble drugs, but the gelation phenomenon has often occurred during the dissolution process and seriously threatened their solubility/dissolution performance. Therefore, it's quite important to design favorable CM systems to alleviate or even avoid the adverse effects of gelation phenomenon. In this study, CM systems of taxifolin (TAX) and oxymatrine (OMT) (TAX-OMT CMs) were constructed to improve the solubility and dissolution properties of TAX. Interestingly, TAX-OMT CMs gradually aggregated and obviously gelled during dissolution, but the solubility and dissolution of TAX in TAX-OMT CMs were significantly enhanced compared to crystalline TAX. Consequently, the underlying solubilization mechanisms of TAX-OMT CMs after gelation were systematically explored. For one thing, the complexation between the two components in TAX-OMT CMs was verified by phase solubility, fluorescence spectroscopy and isothermal titration calorimetry. For another, the residual solids of TAX-OMT CMs after dissolution evaluation were thoroughly characterized by means of powder X-ray diffraction, fourier transform infrared spectroscopy, scanning electron microscopy, which showed the anti-crystallization property of TAX-OMT CMs. Furthermore, molecular simulation demonstrated the intermolecular interactions of TAX-OMT CMs alone and TAX-OMT complexes in aqueous solution. Finally, pharmacokinetics study in rats suggested that the bioavailability of TAX in TAX-OMT CM (1:2) was approximately 5.5-fold higher than that of crystalline TAX after oral administration. Collectively, this study reveals the importance of complexation and anti-crystallization effects of CM systems on maintaining solubilization behavior after gelation, providing an effective strategy to improve the absorption performance of pharmaceutical CM systems.

Natural products for Gut-X axis: pharmacology, toxicology and microbiology in mycotoxin-caused diseases.

Introduction: The gastrointestinal tract is integral to defending against external contaminants, featuring a complex array of immunological, physical, chemical, and microbial barriers. Mycotoxins, which are toxic metabolites from fungi, are pervasive in both animal feed and human food, presenting substantial health risks. Methods: This review examines the pharmacological, toxicological, and microbiological impacts of natural products on mycotoxicosis, with a particular focus on the gut-x axis. The analysis synthesizes current understanding and explores the role of natural products rich in polysaccharides, polyphenols, flavonoids, and saponins. Results: The review highlights that mycotoxins can disrupt intestinal integrity, alter inflammatory responses, damage the mucus layer, and disturb the bacterial balance. The toxins' effects are extensive, potentially harming the immune system, liver, kidneys, and skin, and are associated with serious conditions such as cancer, hormonal changes, genetic mutations, bleeding, birth defects, and neurological issues. Natural products have shown potential anticancer, anti-tumor, antioxidant, immunomodulatory, and antitoxic properties. Discussion: The review underscores the emerging therapeutic strategy of targeting gut microbial modulation. It identifies knowledge gaps and suggests future research directions to deepen our understanding of natural products' role in gut-x axis health and to mitigate the global health impact of mycotoxin-induced diseases.

Postbiotics in inflammatory bowel disease: efficacy, mechanism, and therapeutic implications.

Inflammatory bowel disease (IBD) is one of the most challenging diseases in the 21st century, and more than 10 million people around the world suffer from IBD. Because of the limitations and adverse effects associated with conventional IBD therapies, there has been increased scientific interest in microbial-derived biomolecules, known as postbiotics. Postbiotics are defined as the preparation of inanimate microorganisms and/or their components that confer a health benefit on the host, comprising inactivated microbial cells, cell fractions, metabolites, etc. Postbiotics have shown potential in enhancing IBD treatment by reducing inflammation, modulating the immune system, stabilizing intestinal flora and maintaining the integrity of intestinal barriers. Consequently, they are considered promising adjunctive therapies for IBD. Recent studies indicate that postbiotics offer distinctive advantages, including spanning clinical (safe origin), technological (easy for storage and transportation) and economic (reduced production costs) dimensions, rendering them suitable for widespread applications in functional food/pharmaceutical. This review offers a comprehensive overview of the definition, classification and applications of postbiotics, with an emphasis on their biological activity in both the prevention and treatment of IBD. © 2024 Society of Chemical Industry.

Toward quantitative characterization of simulated earthquake-cycle complexities.

Earthquake cycle simulations based on the rate-and-state friction formulation are evolutions of nonlinear dynamical systems (NDS). The term "cycle" implies an overall stable structure that is a phase-space attractor naturally traced out by trajectories of NDS as it evolves. Quantitatively characterizing these attractors should be a basis for measuring complexities of the simulated earthquake cycles, i.e. to determine if and how regular or chaotic they are. I first revisit the textbook-standard quasi-dynamic spring-slider system from an NDS perspective, explicitly showing the attractors, their relationship with the parameters of the NDS, and how they can be characterized taken advantage of their low-dimensionality while aiming to extend the analysis to high-dimensionality. I evaluate two approaches, computing the Lyapunov exponents (LEs) and measuring correlation dimensions, with the simple spring-slider and earthquake-cycle examples whose phase-space attractors can be visually verified. I conclude LEs are too inconvenient and computationally expensive to use whereas measuring correlation dimensions is an easy and effective approach even with highly non-uniform time sampling present in all simulations. For earthquake-cycle simulations, an attractor reconstruction is performed based on Taken's theorem to corroborate my correlation-dimension results. The current method is limited in its ability to detect chaos in a dichotomous manner, which illuminates the direction for future study. An improving ability to quantitatively characterize earthquake-cycle simulations as an overall stable structure offers new opportunities to understand exotic seismic observations such as slow-slip events and enables more informative comparison with real data, particularly from paleoseismology, which could have far-reaching implications in earthquake forecasting.

Omnidirectional image super-resolution via position attention network.

For convenient transmission, omnidirectional images (ODIs) usually follow the equirectangular projection (ERP) format and are low-resolution. To provide better immersive experience, omnidirectional image super resolution (ODISR) is essential. However, ERP ODIs suffer from serious geometric distortion and pixel stretching across latitudes, generating massive redundant information at high latitudes. This characteristic poses a huge challenge for the traditional SR methods, which can only obtain the suboptimal ODISR performance. To address this issue, we propose a novel position attention network (PAN) for ODISR in this paper. Specifically, a two-branch structure is introduced, in which the basic enhancement branch (BE) serves to achieve coarse deep feature enhancement for extracted shallow features. Meanwhile, the position attention enhancement branch (PAE) builds a positional attention mechanism to dynamically adjust the contribution of features at different latitudes in the ERP representation according to their positions and stretching degrees, which achieves the enhancement for the differentiated information, suppresses the redundant information, and modulate the deep features with spatial distortion. Subsequently, the features of two branches are fused effectively to achieve the further refinement and adapt the distortion characteristic of ODIs. After that, we exploit a long-term memory module (LM), promoting information interactions and fusions between the branches to enhance the perception of the distortion, aggregating the prior hierarchical features to keep the long-term memory and boosting the ODISR performance. Extensive results demonstrate the state-of-the-art performance and the high efficiency of our PAN in ODISR.

Genetically Predicted Peripheral Immune Cells Mediate the Effect of Gut Microbiota on Influenza Susceptibility.

The communication mechanism of the gut-lung axis has received increasing attention in recent years, particularly in acute respiratory infectious diseases such as influenza. The peripheral immune system serves as a crucial bridge between the gut and the lungs, two organs that are not in close proximity to each other. However, the specific communication mechanism involving gut microbiota, immune cells, and their anti-influenza effects in the lung remains to be further elucidated. In this study, the effects of 731 species of peripheral immune cells and 211 different gut microbiota on influenza outcomes were analyzed using a two-sample Mendelian randomization analysis. After identifying specific species of gut microbiota and peripheral immune cells associated with influenza outcomes, mediation analyses were conducted to determine the mediating effects of specific immune cells in the protective or injurious effects of influenza mediated by gut microbiota. 19 species of gut microbiota and 75 types of peripheral immune cells were identified as being associated with influenza susceptibility. After rigorous screening, 12 combinations were analyzed for mediated effects. Notably, the down-regulation of CD64 on CD14- CD16- cells mediated 21.10% and 18.55% of the protective effect of Alcaligenaceae and Dorea against influenza, respectively. In conclusion, focusing on influenza, this study genetically inferred different types of gut microbiota and peripheral immune cells to determine their protective or risk factors. Furthermore, mediation analysis was used to determine the proportion of mediating effects of peripheral immune cells in gut microbiota-mediated susceptibility to influenza. This helps elucidate the gut-lung axis mechanism by which gut microbiota affects influenza susceptibility from the perspective of regulation of peripheral immune cells.

Effectiveness and safety of segmentectomy vs. wedge resection for the treatment of patients with operable non­small cell lung cancer: A meta­analysis and systematic review.

The present study compared the differences in effectiveness and safety between segmentectomy (ST) and wedge resection (WR) in patients with operable non-small cell lung cancer (NSCLC). The PubMed, EMBASE, Cochrane Library and Web of Science databases were searched for papers published from inception until July 2023. The inclusion criteria were based on the population, intervention, comparator, outcomes and study designs. ROBINS-I was selected to assess the risk of bias and quality of evidence in the included non-randomised studies. Appropriate effect sizes were selected, and subgroup analyses, heterogeneity tests, sensitivity analyses and publication bias were applied. A total of 18 retrospective studies were included, involving 19,381 patients with operable NSCLC. The 5-year overall survival rate [hazard ratio (HR), 0.19; 95% confidence interval (CI), 0.04, 0.34; P=0.014; I2=76.3%], lung cancer-specific survival rate (HR, 0.3; 95% CI, 0.21, 0.38; P<0.01; I2=13.8%) and metastasis rate [odds ratio (OR), 1.56; 95% CI, 1.03, 2.38; P=0.037] in patients with operable NSCLC treated with WR were worse than those in patients treated with ST. The incidence of postoperative complications (OR, 0.44; 95% CI, 0.23, 0.82) in the WR group was lower than in the ST treatment group. There was no difference in postoperative recurrence (OR, 2.15; 95% CI, 0.97, 4.74; P=0.058) and mortality (risk difference, 0.04; 95% CI, -0.03, 0.11; P=0.287) between groups. Based on current evidence, patients with NSCLC treated with ST surgery have better postoperative survival but more complications than those patients treated with WT, while the effect of WR and ST on the recurrence rate and distant metastasis rate remains controversial.

The trunk replaces the longer mandible as the main feeding organ in elephant evolution.

The long-trunked elephantids underwent a significant evolutionary stage characterized by an exceptionally elongated mandible. The initial elongation and subsequent regression of the long mandible, along with its co-evolution with the trunk, present an intriguing issue that remains incompletely understood. Through comparative functional and eco-morphological investigations, as well as feeding preference analysis, we reconstructed the feeding behavior of major groups of longirostrine elephantiforms. In the Platybelodon clade, the rapid evolutionary changes observed in the narial region, strongly correlated with mandible and tusk characteristics, suggest a crucial evolutionary transition where feeding function shifted from the mandible to the trunk, allowing proboscideans to expand their niches to more open regions. This functional shift further resulted in elephantids relying solely on their trunks for feeding. Our research provides insights into how unique environmental pressures shape the extreme evolution of organs, particularly in large mammals that developed various peculiar adaptations during the late Cenozoic global cooling trends.

The elephant's trunk is one of the most efficient food-gathering organs in the animal kingdom. From large branches to thin blades of grass, it can coil around and bring many types of vegetation to the animals' strong, short mandibles. This versatility allows elephants to thrive in a range of environments, including grasslands. Trunks are not the only spectacular feature to emerge in Proboscideans, the family of which elephants are the only surviving group. During the early and middle Miocene (between 23 to 11.6 million years ago), many of these species had dramatically elongated lower jaws; how and why this trait emerged then disappeared is poorly understood. The role that lengthened mandibles and trunks played during feeding also remains unclear. To address these questions, Li et al. focused on Platybelodon, Choerolophodon and Gomphotherium, which belong to three Proboscidean families that roamed Northern China between 17 and 15 million years ago. Each had elongated lower jaws, but with strikingly distinct lengths and morphologies. Chemical analyses on enamel samples helped determine which habitat the families occupied, while mathematical modelling revealed how their mandibles tackled different types of plants. Trunk shape was assessed via analyses of the nasal region. The results suggest that Choerolophodon had mandibles better suited for processing branches and a short, 'primitive' trunk. Gomphotherium sported a versatile jaw that could handle both grass and trees, as well as a rather 'elephant-like' trunk. The jaw of Platybelodon seemed well-adapted to cut grass, and remarkable bone structures point towards a long, strong and flexible trunk. While modern elephants fully depend on their trunks to eat, morphological constraints suggest that, in these species, the appendage only served to assist feeding (e.g., by pressing down on branches). All families shared an environment that included grasslands and forests, but analyses suggest that, for a period, Choerolophodon favored relatively closed habitats while Platybelodon spread into grasslands and Gomphotherium navigated both landscapes. This suggests that the evolution of long, strong and flexible trunks is tightly associated with grazing. About 14 million years ago, a global cooling event led to grasslands expanding worldwide. The fossil record shows the mandibles of Proboscideans starting to shorten after this period, including in the descendants of Gomphotherium that would give rise to modern elephants. The work by Li et al. sheds light onto these evolutionary processes, and the environmental pressures which helped shape the trunk.

Generalization Beyond Feature Alignment: Concept Activation-Guided Contrastive Learning.

Learning invariant representations via contrastive learning has seen state-of-the-art performance in domain generalization (DG). Despite such success, in this paper, we find that its core learning strategy - feature alignment - could heavily hinder model generalization. Drawing insights in neuron interpretability, we characterize this problem from a neuron activation view. Specifically, by treating feature elements as neuron activation states, we show that conventional alignment methods tend to deteriorate the diversity of learned invariant features, as they indiscriminately minimize all neuron activation differences. This instead ignores rich relations among neurons - many of them often identify the same visual concepts despite differing activation patterns. With this finding, we present a simple yet effective approach, Concept Contrast (CoCo), which relaxes element-wise feature alignments by contrasting high-level concepts encoded in neurons. Our CoCo performs in a plug-and-play fashion, thus it can be integrated into any contrastive method in DG. We evaluate CoCo over four canonical contrastive methods, showing that CoCo promotes the diversity of feature representations and consistently improves model generalization capability. By decoupling this success through neuron coverage analysis, we further find that CoCo potentially invokes more meaningful neurons during training, thereby improving model learning.

The Role of TPM3 in Protecting Cardiomyocyte from Hypoxia-Induced Injury via Cytoskeleton Stabilization.

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein-protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies.

Recent Progress in Glucose-Responsive Insulin.

Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application. By integrating GRI with glucose-sensitive elements, GRI is capable of releasing or activating insulin in response to plasma or interstitial glucose levels without external monitoring, thereby improving glycemic control and reducing hypoglycemic risk. In this Perspective, we first introduce the history of GRI development and then review major glucose-responsive components that can be leveraged to control insulin delivery. Subsequently, we highlight the recent advances in GRI delivery carriers and insulin analogs. Finally, we provide a look to the future and the challenges of clinical application of GRI.

Application of rhizobium inoculation in regulating heavy metals in legumes: A meta-analysis.

Rhizobium inoculation has been widely applied to alleviate heavy metal (HM) stress in legumes grown in contaminated soils, but it has generated inconsistent results with regard to HM accumulation in plant tissues. Here, we conducted a meta-analysis to assess the performance of Rhizobium inoculation for regulating HM in legumes and reveal the general influencing factors and processes. The meta-analysis showed that Rhizobium inoculation in legumes primarily increased the total HM uptake by stimulating plant biomass growth rather than HM phytoavailability. Inoculation had no significant effect on the average shoot HM concentration (p > 0.05); however, it significantly increased root HM uptake by 61 % and root HM concentration by 7 % (p < 0.05), indicating safe agricultural production while facilitating HM phytostabilisation. Inoculation decreased shoot HM concentrations and increased root HM uptake in Vicia, Medicago and Glycine, whereas it increased shoot HM concentrations in Sulla, Cicer and Vigna. The effects of inoculation on shoot biomass were suppressed by nitrogen fertiliser and native microorganisms, and the effect on shoot HM concentration was enhanced by high soil pH, organic matter content, and phosphorous content. Inoculation-boosted shoot nutrient concentration was positively correlated with increased shoot biomass, whereas the changes in pH and organic matter content were insufficient to significantly affect accumulation outcomes. Nitrogen content changes in the soil were positively correlated with changes in root HM concentration and uptake, whereas nitrogen translocation changes in the tissues were positively correlated with changes in HM translocation. Phosphorus solubilisation could improve HM phytoavailability at the expense of slight biomass promotion. These results suggest that the diverse growth-promoting characteristics of Rhizobia influence the trade-off between biomass-HM phytoavailability and HM translocation, impacting HM accumulation outcomes. Our findings can assist in optimising the utilisation of legume-Rhizobium systems in HM-contaminated soils.

Discrimination of polysorbate 20 by high-performance liquid chromatography-charged aerosol detection and characterization for components by expanding compound database and library.

Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.