Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.

Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.

Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency.

Recombinant adeno-associated virus (rAAV) vector gene delivery systems have demonstrated great promise in clinical trials but continue to face durability and dose-related challenges. Unlike rAAV gene therapy, integrating gene addition approaches can provide curative expression in mitotically active cells and pediatric populations. We explored a novel in vivo delivery approach based on an engineered transposase, Sleeping Beauty (SB100X), delivered as an mRNA within a lipid nanoparticle (LNP), in combination with an rAAV-delivered transposable transgene. This combinatorial approach achieved correction of ornithine transcarbamylase deficiency in the neonatal Spfash mouse model following a single delivery to dividing hepatocytes in the newborn liver. Correction remained stable into adulthood, while a conventional rAAV approach resulted in a return to the disease state. In non-human primates, integration by transposition, mediated by this technology, improved gene expression 10-fold over conventional rAAV-mediated gene transfer while requiring 5-fold less vector. Additionally, integration site analysis confirmed a random profile while specifically targeting TA dinucleotides across the genome. Together, these findings demonstrate that transposable elements can improve rAAV-delivered therapies by lowering the vector dose requirement and associated toxicity while expanding target cell types.

Evaluation of the antitumor effect of neoantigen peptide vaccines derived from the translatome of lung cancer.

Emerging evidence suggests that tumor-specific neoantigens are ideal targets for cancer immunotherapy. However, how to predict tumor neoantigens based on translatome data remains obscure. Through the extraction of ribosome-nascent chain complexes (RNCs) from LLC cells, followed by RNC-mRNA extraction, RNC-mRNA sequencing, and comprehensive bioinformatic analysis, we successfully identified proteins undergoing translatome and exhibiting mutations in the cells. Subsequently, novel antigens identification was analyzed by the interaction between their high affinity and the Major Histocompatibility Complex (MHC). Neoantigens immunogenicity was analyzed by enzyme-linked immunospot assay (ELISpot). Finally, in vivo experiments in mice were conducted to evaluate the antitumor effects of translatome-derived neoantigen peptides on lung cancer. The results showed that ten neoantigen peptides were identified and synthesized by translatome data from LLC cells; 8 out of the 10 neoantigens had strong immunogenicity. The neoantigen peptide vaccine group exhibited significant tumor growth inhibition effect. In conclusion, neoantigen peptide vaccine derived from the translatome of lung cancer exhibited significant tumor growth inhibition effect.

Absolute quantitation of human wild-type DNAI1 protein in lung tissue using a nanoLC-PRM-MS-based targeted proteomics approach coupled with immunoprecipitation.

BACKGROUND: Dynein axonemal intermediate chain 1 protein (DNAI1) plays an essential role in cilia structure and function, while its mutations lead to primary ciliary dyskinesia (PCD). Accurate quantitation of DNAI1 in lung tissue is crucial for comprehensive understanding of its involvement in PCD, as well as for developing the potential PCD therapies. However, the current protein quantitation method is not sensitive enough to detect the endogenous level of DNAI1 in complex biological matrix such as lung tissue. METHODS: In this study, a quantitative method combining immunoprecipitation with nanoLC-MS/MS was developed to measure the expression level of human wild-type (WT) DNAI1 protein in lung tissue. To our understanding, it is the first immunoprecipitation (IP)-MS based method for absolute quantitation of DNAI1 protein in lung tissue. The DNAI1 quantitation was achieved through constructing a standard curve with recombinant human WT DNAI1 protein spiked into lung tissue matrix. RESULTS: This method was qualified with high sensitivity and accuracy. The lower limit of quantitation of human DNAI1 was 4 pg/mg tissue. This assay was successfully applied to determine the endogenous level of WT DNAI1 in human lung tissue. CONCLUSIONS: The results clearly demonstrate that the developed assay can accurately quantitate low-abundance WT DNAI1 protein in human lung tissue with high sensitivity, indicating its high potential use in the drug development for DNAI1 mutation-caused PCD therapy.

High efficiency of biosurfactants in stabilizing oil micro-droplets within the aging time scale of milliseconds: a microfluidic study.

Rapid adsorption of surfactants onto a freshly formed interface is vital for emulsification because emulsification is a competitive process occurring between the very short time span of interface formation and surfactant mass transport. The biosurfactant surfactin has been previously reported to reach adsorption equilibrium at the hydrophobic/hydrophilic interface within hundreds of milliseconds and rapidly reduce the interfacial tension compared to chemically synthesized surfactants. According to a prior study, surfactin is expected to exhibit good performance in stabilizing micro-droplets of oil within the aging time scale of milliseconds. Herein, the stabilities of micro-droplets of n-hexadecane in the presence of a biosurfactant, surfactin (C15-SFT), and a chemically synthesized surfactant, sodium cetyl benzene sulfonate (8-SCBS), were investigated using a microfluidic method. The coalescence frequency of micro-droplets, the evolution of micro-droplet size, and the coalescence time of micro-droplets were evaluated. The results indicated that C15-SFT exhibited superiority over 8-SCBS in stabilizing the micro-droplets of n-hexadecane. Biosurfactant C15-SFT effectively reduced the fusion probability between oil droplets and elongated the coalescence time compared to 8-SCBS, and these phenomena were obvious at a shorter aging time (150 ms) and lower surfactant concentration (0.1 × critical micelle concentration). The stabilities of micro-droplets increased with aging time and the bulk concentration of surfactants. Stable micro-droplets of n-hexadecane were formed in 1 × 10-4 mol L-1 C15-SFT solution at 600 ms aging time, and the bulk concentration was 1 × 10-3 mol L-1 in the case of 8-SCBS. The micro-droplets rarely coalesced in the presence of 1 × 10-4 mol L-1 C15-SFT after 600 ms aging time, but the micro-droplets in 1 × 10-4 mol L-1 8-SCBS coalesced frequently in the midstream and downstream of the coalescence chamber, and big droplets were dominant in the emulsion. The coalescence time of micro-droplets stabilized by C15-SFT was obviously longer than that of those stabilized by 8-SCBS under the same condition, indicating that the interfacial film formed by C15-SFT has much strength to resist coalescence during collisions. This work is helpful for understanding the activity of lipopeptides in the very short early stage of the emulsification process, laying the foundation for biosurfactant research in the fields of enhanced oil recovery, bioremediation of contaminated water or soil, etc.

Synthesis of C(3) SCF3-Substituted Pyrrolidinoindoline by PIII/PV Redox Catalysis Using CF3SO2Cl as Electrophilic CF3S Reagent.

This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.

Organophosphorus-Catalyzed Direct Dehydroxylative Thioetherification of Alcohols with Hypervalent Organosulfur Compounds.

A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PV═O redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.

Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Acute Myocardial Infarction With or Without Type 2 Diabetes: A Systematic Review and Meta-analysis.

ABSTRACT: Recent studies have revealed the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure patients. However, their effects on acute myocardial infarction (AMI) remain uncertain. Therefore, we conducted this meta-analysis to assess the effectiveness of SGLT2i in patients with AMI with or without diabetes. We conducted a comprehensive search of PubMed, Embase, and Cochrane Library encompassing data from inception until November 30, 2023. Relevant studies comparing SGLT2i with placebo or non-SGLT2i in patients with AMI were included. The mean difference and/or odds ratio (OR) with 95% confidence intervals were pooled using a fixed-effects model when the heterogeneity statistic (I2) was less than 50%; otherwise, a random-effects model was employed. Four randomized controlled trials and 4 observational studies involving 9397 patients with AMI were included in this meta-analysis. Patients treated with SGLT2i exhibited a significantly lower rate of hospitalization for heart failure (OR = 0.50, 95% CI: 0.32-0.80) and all-cause death (OR = 0.65, 95% CI: 0.44-0.95) compared with those treated with placebo or non-SGLT2i. Furthermore, the use of SGLT2i was associated with a significant increase in left ventricular ejection fraction (mean difference = 1.90, 95% CI: 1.62-2.17) and a greater reduction of N-terminal prohormone of brain natriuretic peptide (OR = 0.88, 95% CI 0.82-0.94). Subgroup analysis revealed that in patients with diabetes, SGLT2i exhibited similar effects. The present meta-analysis provided evidence indicating the effectiveness of SGLT2i in patients with AMI; SGLT2i may serve as an additional therapeutic option for patients with AMI, regardless of the presence or absence of diabetes.

Disparities and effectiveness of COVID-19 vaccine policies in three representative European countries.

OBJECTIVE: The aim of this study was to examine the Coronavirus disease 2019(COVID-19) vaccine policies disparities and effectiveness in Germany, Denmark and Bulgaria, with a view to providing lessons for global vaccination and response to possible outbreak risks. METHODS: This study analyzed big data through public information on the official websites of the Ministries of Health of the European Union, Germany, Denmark and Bulgaria and the official websites of the World Health Organization. We systematically summarized the COVID-19 vaccine policies of the three countries, and selected the following six indicators for cross-cutting vaccination comparisons: COVID-19 vaccine doses administered per 100 people, COVID-19 vaccination rate, the share of people with fully vaccinated, the share of people only partly vaccinated, cumulative confirmed COVID-19 cases per million, cumulative confirmed COVID-19 deaths per million. Meanwhile, we selected the following four indicators for measuring the effectiveness of COVID-19 vaccine policy implementation: daily cases per million, daily deaths per million, the effective reproduction rate (Rt), the moving-average case fatality rate (CFR). RESULTS: Although these three EU countries had the same start time for vaccination, and the COVID-19 vaccine supply was coordinated by the EU, there are still differences in vaccination priorities, vaccination types, and vaccine appointment methods. Compared to Germany and Denmark, Bulgaria had the least efficient vaccination efforts and the worst vaccination coverage, with a vaccination rate of just over 30% as of June 2023, and the maximum daily deaths per million since vaccination began in the country was more than three times that of the other two countries. From the perspective of implementation effect, vaccination has a certain effect on reducing infection rate and death rate, but the spread of new mutant strains obviously aggravates the severity of the epidemic and reduces the effectiveness of the vaccine. Among them, the spread of the Omicron mutant strain had the most serious impact on the three countries, showing an obvious epidemic peak. CONCLUSIONS: Expanding vaccination coverage has played a positive role in reducing COVID-19 infection and mortality rates and stabilizing Rt. Priority vaccination strategies targeting older people and at-risk groups have been shown to be effective in reducing COVID-19 case severity and mortality in the population. However, the emergence and spread of new variant strains, and the relaxation of epidemic prevention policies, still led to multiple outbreaks peaking. In addition, vaccine hesitancy, mistrust in government and ill-prepared health systems are hampering vaccination efforts. Among the notable ones are divergent types of responses to vaccine safety issue could fuel mistrust and hesitancy around vaccination. At this stage, it is also necessary to continue to include COVID-19 vaccination in priority vaccination plans and promote booster vaccination to prevent severe illness and death. Improving the fairness of vaccine distribution and reducing the degree of vaccine hesitancy are the focus of future vaccination work.

Composition and influencing factors of hospitalization expenses for epilepsy patients based on path analysis.

OBJECTIVE: This study aimed to understand the composition and influencing factors of epilepsy patients' hospitalization expenses, thus providing a reference for reducing the disease burden of epilepsy patients in low- and middle-income developing countries. METHODS: A total of 4206 hospitalized cases of epilepsy from 2018 to 2020 were collected. Descriptive statistics were used to understand the patient cost composition, path analysis was used to understand the direct and indirect factors of hospitalization expenses. RESULTS: From 2018 to 2020, the average hospitalization expenses for epilepsy patients was 4,299.93 RMB yuan, and the average length of stay was 2.47 days. The highest proportion of hospitalization expenses was diagnosis costs (> 50%), followed by comprehensive medical service costs and drug costs. In terms of the total effect coefficient, the major factors affecting the hospitalization expenses were length of stay (0.880), emergency admission(0.463), and the comorbidities and complications(> 0.250). Hospital length of stay, discharge mode(death) and number of hospitalizations(2 times) affect hospitalization expenses through direct effect. Long-term hospitalization (> 30 days), admission routes(emergency), the comorbidities and complications, presence of drug allergy, and age also affect hospitalization expenses through indirect effects. CONCLUSION: Diagnosis costs and length of stay are important factors affecting the medical expenses of epilepsy inpatients. In general, the quality control of the hospital is good, but it still needs to standardize the diagnosis and treatment behavior of medical staff through the clinical path.

Coupling coordination degree of healthcare resource supply, demand and elderly population change in China.

OBJECT: To analyze the trend of the coupling and coordination of the supply and demand of healthcare resources between the elderly population and healthcare resources in China during the period of 2012-2022, to reveal the impact of the growth of the elderly population on the relationship between the supply and demand of healthcare resources, and to put forward suggestions to improve the coupling and coordination between the supply and demand of healthcare resources and the elderly population, in order to cope with the challenges of an aging society. METHODS: By obtaining relevant data from authoritative data sources such as China Statistical Yearbook, Health and Health Statistics Yearbook, and the Chinese government website from 2012 to 2022, we constructed a comprehensive measurement index for the three systems of elderly population, healthcare resource supply, and healthcare resource demand; Using the entropy value method to assign weights to the indicators, combined with the coupling coordination degree model, to reveal the changes of the elderly population change and the supply and demand of medical and health resources; using ArcGIS technology, to study the spatial characteristics of the elderly population change and the supply and demand of medical and health resources. RESULTS: From 2012 to 2022, the supply and demand of healthcare resources and the variation of the elderly population in China show a continuous growth trend, and the comprehensive development level of the system gradually climbs from a low level to a high level. The fluctuation of coupling degree and coordination degree rises, although the coordination degree has always been lower than the coupling degree, but the distance between the coordination degree and the coupling degree gradually narrows with the passage of time. The coordination degree between population aging and medical and health resources development shows spatial heterogeneity in China, with the eastern region significantly higher than the western region/. CONCLUSIONS: The coupling degree between population aging and healthcare resource supply and demand in China from 2012 to 2022 shows a general upward trend from low coupling to medium-high coupling, but it is worth noting that even though the degree of coupling increases, the degree of coordination is still relatively lagging behind, suggesting that the government and relevant departments need to pay more attention to coordinated allocation and management of healthcare resources. At the same time, the spatial differences in the degree of coordination among provinces suggest that future policymakers should take regional differences into full consideration in policymaking and sustainable development.

Passive hyperthermia alters the resting-state functional connectivity of mouse brain.

PURPOSE: To investigate how passive hyperthermia affect the resting-state functional brain activity based on an acute mouse model after heat stress exposure. MATERIALS AND METHODS: Twenty-eight rs-fMRI data of C57BL/6J male mice which weighing about 24 ∼ 29 g and aged 12 ∼ 16 weeks were collected. The mice in the hyperthermia group (HT, 40 °C ± 0.5 °C, 40 min) were subjected to passive hyperthermia before the anesthesia preparation for scanning. While the normal control group (NC) was subjected to normothermia condition (NC, 20 °C ± 2 °C, 40 min). After data preprocessing, we performed independent component analysis (ICA) and region of interested (ROI)-ROI functional connectivity (FC) analyses on the data of both HT (n = 13) and NC (n = 15). RESULTS: The group ICA analysis showed that the HT and the NC both included 11 intrinsic connectivity networks (ICNs), and can be divided into four types of networks: the cortical network (CN), the subcortical network (SN), the default mode network (DMN), and cerebellar networks. CN and SN belongs to sensorimotor network. Compared with NC, the functional network organization of ICNs in the HT was altered and the overall functional intensity was decreased. Furthermore, 13 ROIs were selected in CN, SN, and DMN for further ROI-ROI FC analysis. The ROI-ROI FC analysis showed that passive hyperthermia exposure significantly reduced the FC strength in the overall brain represented by CN, SN, DMN of mice. CONCLUSION: Prolonged exposure to high temperature has a greater impact on the overall perception and cognitive level of mice, which might help understand the relationship between neuronal activities and physiological thermal sensation and regulation as well as behavioral changes.

The use of non-vitamin K antagonist oral anticoagulants in chronic thromboembolic pulmonary hypertension: an updated meta-analysis.

Studies have demonstrated the beneficial effects of non-vitamin K antagonist oral anticoagulants (NOACs) for the treatment of atrial fibrillation and venous thromboembolism (VTE). The impact of NOACs on chronic thromboembolic pulmonary hypertension (CTEPH) remains controversial. This meta-analysis was conducted to investigate the effectiveness and safety of NOACs compared with vitamin K antagonists (VKAs) in patients with CTEPH. A comprehensive search of PubMed, Embase, and Cochrane Library was conducted for relevant studies, encompassing data from inception until November 2023. The data were pooled using a fixed-effects model if the I2 value was less than 50%; otherwise, a random-effects model was employed. Overall, two randomized controlled trials (RCTs) and eight observational studies involving 4556 patients with CTEPH were included. Patients receiving NOACs exhibited a significantly lower incidence of all-cause mortality (odds ratio [OR] = 0.52, 95% confidence interval [CI]: 0.36-0.76) and major bleeding (OR = 0.58, 95% CI: 0.36-0.92) compared to those with VKAs. There were no significant differences in the rate of VTE recurrence (OR = 1.07, 95% CI: 0.72-1.59), total bleeding (OR = 0.78, 95% CI: 0.60-1.01), and minor bleeding (OR = 1.11, 95% CI: 0.73-1.69) between the two studied groups. Similar results were found in the subgroup analysis and sensitivity analysis.This meta-analysis provided evidence that NOACs could be superior to VKAs for the treatment of CTEPH. NOACs might be safe and a convenient alternative to VKAs for thromboprophylaxis in patients with CTEPH.

Unraveling thermodynamic anomalies of water: A molecular simulation approach to probe the two-state theory with atomistic and coarse-grained water models.

Thermodynamic and dynamic anomalies of water play a crucial role in supporting life on our planet. The two-state theory attributes these anomalies to a dynamic equilibrium between locally favored tetrahedral structures (LFTSs) and disordered normal liquid structures. This theory provides a straightforward, phenomenological explanation for water's unique thermodynamic and dynamic characteristics. To validate this two-state feature, it is critical to unequivocally identify these structural motifs in a dynamically fluctuating disordered liquid. In this study, we employ a recently introduced structural parameter (θavg) that characterizes the local angular order within the first coordination shell to identify these LFTSs through molecular dynamics simulations. We employ both realistic water models with a liquid-liquid critical point (LLCP) and a coarse-grained water model without an LLCP to study water's anomalies in low-pressure regions below 2 kbar. The two-state theory consistently describes water's thermodynamic anomalies in these models, both with and without an LLCP. This suggests that the anomalies predominantly result from the two-state features rather than criticality, particularly within experimentally accessible temperature-pressure regions.

Associations between cooking fuel use, its transitions, and worsening sensory impairments among Chinese middle-aged and older adults: a cohort study.

BACKGROUND: This study aimed to explore the associations between household air pollution (HAP), measured by cooking fuel use, sensory impairments (SI), and their transitions in Chinese middle-aged and older adults. METHODS: Participants were recruited from the 2011 China Health and Retirement Longitudinal Study (CHARLS) and were subsequently followed up until 2018. Data on SI were collected by self-reported hearing and vision impairments, which were divided into three categories: non-SI, single SI (hearing or vision impairment), and dual SI (DSI). Cooking fuels, including solid and clean fuels, are proxies for HAP. The transitions of cooking fuels and SI refer to the switching of the fuel type or SI status from baseline to follow-up. Cox proportional hazard regression models were used to explore associations, and hazard ratios (HRs) and 95% confidence intervals (CI) were used to evaluate the strength of the association. RESULTS: The prevalence of non-SI, single SI, and DSI was 59.6%, 31.8%, and 8.6%, respectively, among the 15,643 participants at baseline in this study. Over a median follow-up of 7.0 years, 5,223 worsening SI transitions were observed. In the fully adjusted model, solid fuel use for cooking was associated with a higher risk of worsening SI transitions, including from non-SI to single SI (HR = 1.08, 95% CI = 1.01-1.16) and from non-SI to DSI (HR = 1.26, 95% CI = 1.09-1.47), but not from single SI to DSI. In addition, compared to those who always used solid fuels, participants who switched from solid to clean fuel for cooking appeared to have attenuated the risk of worsening SI transitions. The statistical significance of the associations remained in the set of sensitivity analyses. CONCLUSION: Solid fuel use was associated with higher risks of worsening SI transitions, while converting the type of cooking fuel from solid to clean fuels may reduce the risk of worsening SI transitions. Our study suggests that tailored clean fuel interventions, especially in developing countries, should be implemented to prevent sensory impairments and hence reduce the burden of sensory impairment-related disability.

Solvation Structure and Derived Interphase Tuning for High-Voltage Ni-Rich Lithium Metal Batteries with High Safety Using Gem-Difluorinated Ionic Liquid Based Dual-Salt Electrolytes.

Stabilizing electrolytes for high-voltage lithium metal batteries (LMBs) is crucial yet challenging, as they need to ensure stability against both Li anodes and high-voltage cathodes (above 4.5 V versus Li/Li+ ), addressing issues like poor cycling and thermal runaway. Herein, a novel gem-difluorinated skeleton of ionic liquid (IL) is designed and synthesized, and its non-flammable electrolytes successfully overcome aforementioned challenges. By creatively using dual salts, fluorinated ionic liquid and dimethyl carbonate as a co-solvent, the solvation structure of Li+ ions is efficiently controlled through electrostatic and weak interactions that are well unveiled and illuminated via nuclear magnetic resonance spectra. The as-prepared electrolytes exhibit high security avoiding thermal runaway and show excellent compatibility with high-voltage cathodes. Besides, the solvation structure derives a robust and stable F-rich interphase, resulting in high reversibility and Li-dendrite prevention. LiNi0.6 Co0.2 Mn0.2 O2 /Li LMBs (4.5 V) demonstrate excellent long-term stability with a high average Coulombic efficiency (CE) of at least 99.99 % and a good capacity retention of 90.4 % over 300 cycles, even can work at a higher voltage of 4.7 V. Furthermore, the ultrahigh Ni-rich LiNi0.88 Co0.09 Mn0.03 O2 /Li system also delivers excellent electrochemical performance, highlighting the significance of fluorinated IL-based electrolyte design and enhanced interphasial chemistry in improving battery performance.

A natural butter glyceride as a plasticizer for improving thermal, mechanical, and biodegradable properties of poly(lactide acid).

Polylactic acid (PLA) is a biobased and biodegradable thermoplastic polyester with great potential to replace petroleum-based plastics. However, its poor toughness and slow biodegradation rate affect broad applications of PLA in many areas. In this study, a glycerol triester existing in natural butter, glycerol tributyrate, was creatively explored and compared with previously investigated triacetin and tributyl citrate, as potential plasticizers of PLA for achieving improved mechanical and biodegradation performances. The compatibilities of these agents with PLA were assessed quantitively via the Hansen solubility parameter (HSP) and measured by using different testing methods. The incorporation of these compounds with varied contents ranging from 1 to 30 % in PLA altered thermal, mechanical, and biodegradation properties consistently, and the relationship and impacts of chemical structures and properties of these agents were systematically investigated. The results demonstrated that glycerol tributyrate is a novel excellent plasticizer for PLA and the addition of this triester not only effectively reduced the glass transition, cold crystallization, and melting temperatures and Young's modulus, but also led to a significant improvement in the enzymatic degradation rate of the plasticized PLA. This study paves a way for the development of sustainable and eco-friendly food grade plasticized PLA products.

Surface-induced water crystallisation driven by precursors formed in negative pressure regions.

Ice nucleation is a crucial process in nature and industries; however, the role of the free surface of water in this process remains unclear. To address this, we investigate the microscopic freezing process using brute-force molecular dynamics simulations. We discover that the free surface assists ice nucleation through an unexpected mechanism. The surface-induced negative pressure enhances the formation of local structures with a ring topology characteristic of Ice 0-like symmetry, promoting ice nucleation despite the symmetry differing from ordinary ice crystals. Unlike substrate-induced nucleation via water-solid interactions that occurs directly on the surface, this negative-pressure-induced mechanism promotes ice nucleation slightly inward the surface. Our findings provide a molecular-level understanding of the mechanism and pathway behind free-surface-induced ice formation, resolving the longstanding debate. The implications of our discoveries are of substantial importance in areas such as cloud formation, food technology, and other fields where ice nucleation plays a pivotal role.

RAB5A in triple-negative breast cancer: a critical role in macrophage reshaping in an exosomal miR-21-dependent manner.

Breast cancer is the leading cause of cancer-related deaths in females, and triple-negative breast cancer (TNBC) is characterized as one of the main subtypes of breast cancer, with poor prognosis and limited treatments. Investigating the molecular basis or discovering relevant oncogenes will greatly help in developing effective targeted therapies. In this study, we ascertained that RAB5A depletion in TNBC cells suppresses the secretion of exosomes and blocks the polarization of macrophages toward an M2 phenotype. By scanning miRNAs associated with macrophage polarization, we identified that miR-21 was the pivotal component in tumor cell-derived exosomes and played a key role in RAB5A-mediated macrophage polarization. The enhanced expression of miR-21 in macrophages is able to potentiate the M2 polarization of macrophages in the presence of tumor cells. Pellino-1 (PELI1) was subsequently identified as the target of miR-21, and forced PELI1 expression partially abrogated the M2 polarization of macrophages induced by miR-21 overexpression. Macrophages stimulated with RAB5A-depleted TNBC cells (coculture, conditioned medium or exosomes) impaired their capability to promote the proliferation, migration, and invasion of tumor cells. In vivo xenograft experiments further confirmed that RAB5A knockdown TNBC cells exhibited reduced tumor formation and impaired tumor-associated macrophage recruitment. These studies shed light on the potential underlying mechanism of RAB5A-mediated macrophage polarization in an exosomal miR-21-dependent manner and provide an experimental basis for the development of RAB5A- or exosome-based tumor therapeutic strategies.

Chitosan as a promising materials for the construction of nanocarriers for diabetic retinopathy: an updated review.

Diabetic retinopathy (DR) is a condition that causes swelling of the blood vessels of the retina and leaks blood and fluids. It is the most severe form of diabetic eye disease. It causes vision loss in its advanced stage. Diabetic retinopathy is responsible for causing 26% of blindness. Very insufficient therapies are accessible for the treatment of DR. As compared to the conventional therapies, there should be enhanced research on the controlled release, shorter duration, and cost-effective therapy of diabetic retinopathy. The expansion of advanced nanocarriers-based drug delivery systems has been now employed to exploit as well as regulate the transport of many therapeutic agents to target sites via the increase in penetration or the extension of the duration of contact employing production by enclosing as well as distributing tiny molecules in nanostructured formulation. Various polymers have been utilized for the manufacturing of these nanostructured formulations. Chitosan possesses incredible biological and chemical properties, that have led to its extensive use in pharmaceutical and biomedical applications. Chitosan has been used in many studies because of its enhanced mucoadhesiveness and non-toxicity. Multiple studies have used chitosan as the best candidate for manufacturing nanocarriers and treating diabetic retinopathy. Numerous nanocarriers have been formulated by using chitosan such as nanostructured lipid carriers, solid lipid nanoparticles, liposomes, and dendrimers for treating diabetic retinopathy. This current review elaborates on the recent advancements of chitosan as a promising approach for the manufacturing of nanocarriers that can be used for treating diabetic retinopathy.