Deficiency of IQCH causes male infertility in humans and mice.

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Core competencies among nurses engaged in pallative care: A scoping review.

AIM: To synthesize available evidence about core competencies for nurses engaged in palliative care. DESIGN: A scoping review conducted according to the framework from Joanna Briggs Institute. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist was adopted to report this scoping review. The PubMed, Web of Science, Embase, ScienceDriect, CNKI, WangFang, VIP and Sinomed databases were used to systematically search for published studies from their inception to December 2023. Two researchers independently screened and selected relevant studies and performed the data charting. RESULTS: Twenty-six studies were included in this scoping review. Among these, 14 studies identified core competency assessment instruments among nurses engaged in palliative care, with the Palliative Care Core Competence Questionnaire was used most frequently; 13 studies investigated the status of core competencies of nurses engaged in palliative care, the majority of included studies indicated that nurse's core competencies were at moderate levels; 11 studies explored the factors influencing the core competencies of the nurses engaged in palliative care, which were classified as sociodemographic-related factors, palliative care education-related factors, death attitude, palliative care practice-related experience and others. CONCLUSION: This scoping review offers a comprehensive overview of the current landscape of core competencies among nurses in palliative care. Findings suggested that the clinical nursing leaders need to develop tailored strategies and interventions to address specific factors and promote the continuous development of nurses' competencies in palliative care. RELEVANCE TO CLINICAL PRACTICE: Core competency assessment instruments equip nurses and healthcare organizations with a range of validated tools for evaluating their proficiency in palliative care. Targeted core competency enhancement programmes need to be developed to foster a nursing workforce better equipped to improve the quality of life of end-of-life patients and their families. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Decreased cobalamin sensitivity and biological aging acceleration in the general population.

BACKGROUND: The evidence on the association between cobalamin (Cbl) and aging or relevant outcomes is limited and controversial. We aimed to investigate the relationships between cobalamin intake- and function-related biomarkers and biological aging. METHODS: The study encompassed 22,812 participants aged 20 years and older from the National Health and Nutrition Examination Survey. A panel of biomarkers or algorithms was used to assess biological aging, including Klemera-Doubal Age Acceleration (KDMAccel), Phenotypic age acceleration (PhenoAgeAccel), telomere length, α-Klotho, and PhenoAge advancement. Weighted generalized linear regression analysis was used to assess the associations between cobalamin-intake biomarkers (serum cobalamin, cobalamin intake from food, cobalamin supplement use, serum methylmalonic acid [MMA], and homocysteine [Hcy]) and function-related biomarkers (functional cobalamin deficiency and cobalamin insensitivity index). RESULTS: Among the 22,812 individuals, the weighted mean (SE) age was 48.3 (0.2) years and 48.0% were males. Unexpectedly, serum and dietary cobalamin as well as serum MMA and Hcy levels were positively associated with most indicators of biological aging. Cobalamin sensitivity was assessed by the combination of binary Cbllow/high and MMAlow/high or Hcylow/high (cutoff values: 400 pg/mL for cobalamin, 250 nmol/L for MMA, and 12.1 µmol/l for Hcy) and a newly constructed cobalamin insensitivity index (based on the multiplicative term of serum cobalamin and serum MMA or Hcy). The multivariable-adjusted ß (95%CIs) of KDMAccel in the MMAlowCbllow, MMAlowCblhigh, MMAhighCbllow, and MMAhighCblhigh groups were reference, 0.27 (0.03 to 0.51), 0.85 (0.41 to 1.29), and 7.97 years (5.77 to 10.17) respectively, which were consistent for the combination of serum Hcy and cobalamin. Both cobalamin insensitivity indices were robustly associated with biological aging acceleration in a dose-response pattern (each p < 0.001). CONCLUSIONS: Decreased cobalamin sensitivity but not cobalamin insufficiency might be associated with biological aging acceleration. Further studies would improve understanding of the underlying mechanisms between decreased cobalamin sensitivity and biological aging acceleration.

Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor. AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Translation and validation of the Chinese version of Palliative Care Self-Efficacy Scale.

OBJECTIVES: Accurately assessing the self-efficacy levels of palliative care professionals' is crucial, as low levels of self-efficacy may contribute to the suboptimal provision of palliative care. However, there is currently lacking a reliable and valid instrument for evaluating the self-efficacy of palliative care practitioners in China. Therefore, this study aimed to translate, adapt, and validate the Palliative Care Self-Efficacy Scale (PCSS) among Chinese palliative care professionals. METHODS: This study involved the translation and cross-cultural adaptation of the PCSS, and the evaluation of its psychometric properties through testing for homogeneity, content validity, construct validity, known-groups validity, and reliability. RESULTS: A total of 493 palliative care professionals participated in this study. The results showed the critical ratio value of each item was >3 (p < 0.01), and the corrected item-total correlation coefficients of all items ranged from 0.733 to 0.818, indicating a good homogeneity of the items with the scale. Additionally, the scale was shown to have good validity, with item-level content validity index ranged from 0.857 to 1.000, and scale-level content validity index/Ave was 0.956. The exploratory factor analysis and confirmatory factor analysis (CFA) confirmed the 2-factor structure of the Chinese version of PCSS (C-PCSS), explaining 74.19% of the variance. CFA verified that the 2-factor model had a satisfactory model fit, with χ2/df = 2.724, RMSEA = 0.084, GFI = 0.916, CFI = 0.967, and TLI = 0.952. The known-groups validity of C-PCSS was demonstrated good with its sensitive in differentiating levels of self-efficacy between professionals with less than 1 year of palliative care experience (p < 0.001) or without palliative care training (p = 0.014) and their counterparts. Furthermore, the C-PCSS also exhibited an excellent internal consistency, with the Cronbach's α for the total scale of 0.943. SIGNIFICANCE OF RESULTS: The findings from this study affirmed good validity and reliability of the C-PCSS. It can be emerged as a valuable and reliable instrument for assessing the self-efficacy levels of palliative care professionals in China.

An ultralight, pulverization-free integrated anode toward lithium-less lithium metal batteries.

The high-capacity advantage of lithium metal anode was compromised by common use of copper as the collector. Furthermore, lithium pulverization associated with "dead" Li accumulation and electrode cracking deteriorates the long-term cyclability of lithium metal batteries, especially under realistic test conditions. Here, we report an ultralight, integrated anode of polyimide-Ag/Li with dual anti-pulverization functionality. The silver layer was initially chemically bonded to the polyimide surface and then spontaneously diffused in Li solid solution and self-evolved into a fully lithiophilic Li-Ag phase, mitigating dendrites growth or dead Li. Further, the strong van der Waals interaction between the bottommost Li-Ag and polyimide affords electrode structural integrity and electrical continuity, thus circumventing electrode pulverization. Compared to the cutting-edge anode-free cells, the batteries pairing LiNi0.8Mn0.1Co0.1O2 with polyimide-Ag/Li afford a nearly 10% increase in specific energy, with safer characteristics and better cycling stability under realistic conditions of 1× excess Li and high areal-loading cathode (4 milliampere hour per square centimeter).

Nursing informatics competency and its associated factors among palliative care nurses: an online survey in mainland China.

BACKGROUND: Nursing informatics (NI) competency is a required core competency for high-quality care in digitally enabled healthcare environments. Given the increasing reliance on digital health in palliative care settings, it becomes crucial to evaluate the NI competency of nurses to ensure the seamless integration and effective utilization of digital health in their clinical practice. This study aimed to investigate the level of NI competency and explore its associated factors among palliative care nurses in mainland China. METHODS: A cross-sectional design was conducted for this study, involving a total of 409 palliative care nurses from 302 hospitals in mainland China. Anonymous data were collected through a self-designed sociodemographic questionnaire, the Nursing Informatics Competency Scale (NICS) and the Innovative Self-Efficacy Scale. RESULTS: The total score of the NICS was 129.19 ± 22.02, which indicated that Chinese palliative care nurses had a moderate level of NI competency. There was a positive correlation between innovative self-efficacy and NI competency (r = 0.602, P < 0.01). The hospital level and innovative self-efficacy were identified as statistically significant factors influencing nurses' NI competency based on multiple linear regression analysis results. These associated factors could explain 35.1% of the difference in NI competency. CONCLUSIONS: This study found that palliative care nurses in mainland China exhibited moderate levels of NI competency and identified the hospital level and innovative self-efficacy as associated factors of nurses' NI competency. Measures such as developing supported strategies, including targeted NI training programs by nursing education managers of primary-level hospitals and creating a positive culture of innovation by healthcare institutions can be considered to improve the level of NI competency among Chinese palliative care nurses.

Demethylases in tumors and the tumor microenvironment: Key modifiers of N6-methyladenosine methylation.

RNA methylation modifications are widespread in eukaryotes and prokaryotes, with N6-methyladenosine (m6A) the most common among them. Demethylases, including Fat mass and obesity associated gene (FTO) and AlkB homolog 5 (ALKBH5), are important in maintaining the balance between RNA methylation and demethylation. Recent studies have clearly shown that demethylases affect the biological functions of tumors by regulating their m6A levels. However, their effects are complicated, and even opposite results have appeared in different articles. Here, we summarize the complex regulatory networks of demethylases, including the most important and common pathways, to clarify the role of demethylases in tumors. In addition, we describe the relationships between demethylases and the tumor microenvironment, and introduce their regulatory mechanisms. Finally, we discuss evaluation of demethylases for tumor diagnosis and prognosis, as well as the clinical application of demethylase inhibitors, providing a strong basis for their large-scale clinical application in the future.

Perspectives of telemedicine-based services among family caregivers of patients with end-of-life cancer: a qualitative study in mainland China.

BACKGROUND: Despite being driven by a strong sense of duty and familial obligation, providing care for patients nearing the end of life poses challenges for family caregivers. Telemedicine has rapidly gained traction as a transformative approach to healthcare delivery, offering an array of benefits that could be particularly valuable in end-of-life care. However, research on the perspectives of telemedicine-based services among family caregivers of patients with end-of-life cancer is limited. Therefore, this study aims to explore the perspectives and preferences of telemedicine-based services among family caregivers of patients with end-of-life cancer and provide a framework for developing and executing a tailored telemedicine-based end-of-life care program that addresses the unique needs of family caregivers in mainland China. METHOD: A descriptive phenomenological approach was used. Family caregivers were selected using purposive sampling at a tertiary cancer hospital. One-on-one semi-structured interviews were conducted with the participants from November to December 2022. Colaizz's method was used to analyze the interviews. RESULTS: Fourteen participants participated in interviews. Three themes and ten subthemes were identified: motivation to receive telemedicine services (relief from the burden of home care; access to professional health care services), supportive care needs for telemedicine services (support for symptom management; negative emotional adjustment; death education; daily life care guidance), and functional expectations of telemedicine service platforms (ease of use; real-time online guidance and response; personalized automatic reminder; targeted matching push of health knowledge). CONCLUSION: Family caregivers expressed interest in telemedicine-based services and identified various care needs before receiving telemedicine services. The findings of this study can help policymakers and healthcare providers develop more effective and culturally appropriate telemedicine-based service programs that can better support family caregivers of end-of-life cancer patients.

Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis.

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

A Fully Amorphous, Dynamic Cross-Linked Polymer Electrolyte for Lithium-Sulfur Batteries Operating at Subzero-Temperatures.

Solid-state lithium-sulfur batteries have shown prospects as safe, high-energy electrochemical storage technology for powering regional electrified transportation. Owing to limited ion mobility in crystalline polymer electrolytes, the battery is incapable of operating at subzero temperature. Addition of liquid plasticizer into the polymer electrolyte improves the Li-ion conductivity yet sacrifices the mechanical strength and interfacial stability with both electrodes. In this work, we showed that by introducing a spherical hyperbranched solid polymer plasticizer into a Li+ -conductive linear polymer matrix, an integrated dynamic cross-linked polymer network was built to maintain fully amorphous in a wide temperature range down to subzero. A quasi-solid polymer electrolyte with a solid mass content >90 % was prepared from the cross-linked polymer network, and demonstrated fast Li+ conduction at a low temperature, high mechanical strength, and stable interfacial chemistry. As a result, solid-state lithium-sulfur batteries employing the new electrolyte delivered high reversible capacity and long cycle life at 25 °C, 0 °C and -10 °C to serve energy storage at complex environmental conditions.

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study.

BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Exploring the telehealth readiness and its related factors among palliative care specialist nurses: a cross-sectional study in China.

BACKGROUNDS: The majority of Chinese people who are nearing the end of their lives prefer to receive home-based palliative care. Telehealth, as a new service model, has the potential to meet the increasing demand for this service, especially in remote areas with limited resources. However, nurse-led telehealth-based palliative care services are still in the pilot implementation phase. Assessing the telehealth readiness among palliative care specialist nurses and identifying associated factors is crucial to facilitate the successful implementation of telehealth services. Therefore, this study aimed to examine TH readiness and its related factors among Chinese palliative care specialist nurses. METHODS: Four hundred nine Chinese palliative care specialist nurses from 28 provinces or municipalities participated in this study between July and August 2022. The Chinese version of Telehealth Readiness Assessment Tools (TRAT-C), and Innovative Self-Efficacy Scale (ISES-C) were used to assess the degree of TH readiness and the levels of innovative self-efficacy. RESULTS: The total score of the TRAT-C was 65.31 ± 9.09, and the total score of ISES was 29.27 ± 5.78. The statistically significant factors that influenced telehealth readiness were the experience of using telehealth platforms or services, the willingness to provide telehealth to patients, and the level of nurses' innovative self-efficacy. The innovative self-efficacy is positively correlated to telehealth readiness (r = 0.482, P < 0.01). These related factors could explain 27.3% of the difference in telehealth readiness. CONCLUSION: The telehealth readiness of Chinese palliative care specialist nurses are at a moderate level. Measures such as providing incentives to promote nurses' innovation self-efficacy by nurse managers, and establishing a comprehensive telehealth training system for palliative care specialist nurses should be taken to facilitate the implementation of telehealth services in the field of palliative care.

Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study.

BACKGROUND: Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes. METHODS: This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999-2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015. RESULTS: During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95%CIs) per doubling of MMA for all-cause mortality were 1.19 (1.04-1.37) in females with diagnosed diabetes versus 1.58 (1.36-1.86) in male counterparts. In addition, MMA levels had an insignificant or weak correlation with sex hormone profiles at baseline, regardless of diabetes status and sex. CONCLUSIONS: Sex difference in mortality risk was especially significant in diagnosed type 2 diabetes. Increasing equivalent exposure to mitochondrial metabolite MMA was associated with a greater excess risk of future mortality in males with diabetes than in females.

Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy.

BACKGROUND: Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy. METHODS: Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16-20 h after inducing fatal sepsis. RESULTS: We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague-Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation. CONCLUSIONS: These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

A Self-Reconfigured, Dual-Layered Artificial Interphase Toward High-Current-Density Quasi-Solid-State Lithium Metal Batteries.

The uncontrollable dendrite growth and unstable solid electrolyte interphase have long plagued the practical application of Li metal batteries. Herein, a dual-layered artificial interphase LiF/LiBO-Ag is demonstrated that is simultaneously reconfigured via an electrochemical process to stabilize the lithium anode. This dual-layered interphase consists of a heterogeneous LiF/LiBO glassy top layer with ultrafast Li-ion conductivity and lithiophilic Li-Ag alloy bottom layer, which synergistically regulates the dendrite-free Li deposition, even at high current densities. As a result, Li||Li symmetric cells with LiF/LiBO-Ag interphase achieve an ultralong lifespan (4500 h) at an ultrahigh current density and area capacity (20 mA cm-2 , 20 mAh cm-2 ). LiF/LiBO-Ag@Li anodes are successfully applied in quasi-solid-state batteries, showing excellent cycling performances in symmetric cells (8 mA cm-2 , 8 mAh cm-2 , 5000 h) and full cells. Furthermore, a practical quasi-solid-state pouch cell coupling with a high-nickel cathode exhibits stable cycling with a capacity retention of over 91% after 60 cycles at 0.5 C, which is comparable or even better than that in liquid-state pouch cells. Additionally, a high-energy-density quasi-solid-state pouch cell (10.75 Ah, 448.7 Wh kg-1 ) is successfully accomplished. This well-orchestrated interphase design provides new guidance in engineering highly stable interphase toward practical high-energy-density lithium metal batteries.

IRGM/Irgm1 deficiency inhibits neutrophil-platelet interactions and thrombosis in experimental atherosclerosis and arterial injury.

BACKGROUND: Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools. METHODS: The thrombi images, platelet activation makers and NETs makers were detected in the serum of STEMI patients and controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherothrombosis in vivo, ApoE-/-Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK-cPLA2 signals inhibitors were used. RESULTS: Serum IRGM was positively correlated with PF4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production. CONCLUSIONS: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis.

Noncoordinating Flame-Retardant Functional Electrolyte Solvents for Rechargeable Lithium-Ion Batteries.

In Li-ion batteries, functional cosolvents could significantly improve the specific performance of the electrolyte, for example, the flame retardancy. In case the cosolvent shows strong Li+-coordinating ability, it could adversely influence the electrochemical Li+-intercalation reaction of the electrode. In this work, a noncoordinating functional cosolvent was proposed to enrich the functionality of the electrolyte while avoiding interference with the Li storage process. Hexafluorocyclotriphosphazene, an efficient flame-retardant agent with proper physicochemical properties, was chosen as a cosolvent for preparing functional electrolytes. The nonpolar phosphazene molecules with low electron-donating ability do not coordinate with Li+ and thus are excluded from the primary solvation sheath. In graphite-anode-based Li-ion batteries, the phosphazene molecules do not cointercalate with Li+ into the graphite lattice during the charging process, which helps to maintain integral anode structure and interface and contributes to stable cycling. The noncoordinating cosolvent was also applied to other types of electrode materials and batteries, paving a new way for high-performance electrochemical energy storage systems with customizable functions.

Renin-angiotensin system antagonists and mortality due to pneumonia, influenza, and chronic lower respiratory disease in patients with hypertension.

BACKGROUND: It is controversial whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) have a potentially beneficial role in the respiratory system. This study investigated the association between ACEI/ARB medications and respiratory-related mortality in hypertensive patients in a real-world nationally representative cohort. METHODS: This was a retrospective analysis based on a prospective cohort study. A total of 10,530 patients with hypertension aged ≥ 20 years were included. The data was extracted from the US National Health and Nutrition Examination Survey during 1988-1994 and 1999-2006. The study was approved by the Institutional Review Boards. Moreover, inform concent was taken form all the participants. RESULTS: Overall, 27.7% (n = 2920) patients took ACEI/ARB agents. During a median follow-up of 12.4 years, 278 individuals died of respiratory disease, including chronic lower respiratory disease (n = 155) and influenza or pneumonia (n = 123). Compared with the patients without ACEI/ARB use, those taking ACEI/ARB were not associated with respiratory-specific mortality in a multivariable-adjusted Cox model. After 1: 1 matching, taking ACEI/ARB was also not related to respiratory mortality (Hazard ratio (HR) = 1.07, 95% CI: 0.79-1.43), influenza- or pneumonia-related (HR = 1.00, 95% CI: 0.65-1.54) and chronic pulmonary mortality (HR = 1.13, 95% CI: 0.75-1.69). After separating ACEI and ARB from anti-hypertensive medications, those associations remained unchanged. CONCLUSIONS: We discovered no significant link between ACEI or ARB medication and pulmonary-related mortality in hypertensive patients. In hypertensive patients, standard ACEI/ARB administration may have little effect on the respiratory system.