Light-induced insulator-metal transition in Sr2IrO4 reveals the nature of the insulating ground state.

Sr2IrO4 has attracted considerable attention due to its structural and electronic similarities to La2CuO4, the parent compound of high-Tc superconducting cuprates. It was proposed as a strong spin-orbit-coupled Jeff = 1/2 Mott insulator, but the Mott nature of its insulating ground state has not been conclusively established. Here, we use ultrafast laser pulses to realize an insulator-metal transition in Sr2IrO4 and probe the resulting dynamics using time- and angle-resolved photoemission spectroscopy. We observe a gap closure and the formation of weakly renormalized electronic bands in the gap region. Comparing these observations to the expected temperature and doping evolution of Mott gaps and Hubbard bands provides clear evidence that the insulating state does not originate from Mott correlations. We instead propose a correlated band insulator picture, where antiferromagnetic correlations play a key role in the gap opening. More broadly, our results demonstrate that energy-momentum-resolved nonequilibrium dynamics can be used to clarify the nature of equilibrium states in correlated materials.

Integration of background knowledge for automatic detection of inconsistencies in gene ontology annotation.

MOTIVATION: Biological background knowledge plays an important role in the manual quality assurance (QA) of biological database records. One such QA task is the detection of inconsistencies in literature-based Gene Ontology Annotation (GOA). This manual verification ensures the accuracy of the GO annotations based on a comprehensive review of the literature used as evidence, Gene Ontology (GO) terms, and annotated genes in GOA records. While automatic approaches for the detection of semantic inconsistencies in GOA have been developed, they operate within predetermined contexts, lacking the ability to leverage broader evidence, especially relevant domain-specific background knowledge. This paper investigates various types of background knowledge that could improve the detection of prevalent inconsistencies in GOA. In addition, the paper proposes several approaches to integrate background knowledge into the automatic GOA inconsistency detection process. RESULTS: We have extended a previously developed GOA inconsistency dataset with several kinds of GOA-related background knowledge, including GeneRIF statements, biological concepts mentioned within evidence texts, GO hierarchy and existing GO annotations of the specific gene. We have proposed several effective approaches to integrate background knowledge as part of the automatic GOA inconsistency detection process. The proposed approaches can improve automatic detection of self-consistency and several of the most prevalent types of inconsistencies.This is the first study to explore the advantages of utilizing background knowledge and to propose a practical approach to incorporate knowledge in automatic GOA inconsistency detection. We establish a new benchmark for performance on this task. Our methods may be applicable to various tasks that involve incorporating biological background knowledge. AVAILABILITY AND IMPLEMENTATION: https://github.com/jiyuc/de-inconsistency.

Global, regional, and national burden of ovarian cancer among young women during 1990-2019.

BACKGROUND: Ovarian cancer, the most devastating tumor in women globally, significantly impacts young women, compromising their daily lives and overall well-being. Ovarian cancer represents a significant public health concern due to its extensive physical and psychological consequences. MATERIAL AND METHODS: Data from the Global Burden of Disease were used to assess the global, regional, and national burden of ovarian cancer in young women aged 20-39 from 1990 to 2019. This analysis focused on trends measured by the estimated annual percentage change and explored the socioeconomic impacts via the socio-demographic index (SDI). RESULTS: During 1990-2019, the incidence and prevalence of ovarian cancer among young women increased globally, with annual rates of 0.74% and 0.89%, respectively. The mortality rate and disability-adjusted life years also rose annually by 0.20% and 0.23%, respectively. A significant burden shift was observed toward regions with lower SDI, with high fasting plasma glucose, BMI, and asbestos exposure identified as prominent risk factors, particularly in lower SDI regions. CONCLUSION: Our findings underscore ovarian cancer in young women as an escalating global health challenge, with the burden increasingly shifting toward lower socioeconomic areas. This underscores the necessity for targeted prevention and control strategies for ovarian cancer, focusing on reducing the identified risk factors and ensuring equitable health resource distribution.

The effect of multimorbidity patterns on physical and cognitive function in diabetes patients: a longitudinal cohort of middle-aged and older adults in China.

Background: The prevalence of diabetes has increased rapidly, and comorbid chronic conditions are common among diabetes patients. However, little is known about the pattern of multimorbidity in diabetes patients and the effect on physical and cognitive function. This study aimed to assess the disease clusters and patterns of multimorbidity in diabetes patients using a novel latent class analysis (LCA) approach in middle-aged and older adults and explore the association between different clusters of multimorbidity in diabetes and the effect on physical and cognitive function. Methods: This national observational study included 1,985 diabetes patients from the four waves of the China Health and Retirement Longitudinal Study (CHARLS) in 2011 to 2018. Thirteen chronic diseases were used in latent class analysis to identify the patterns of multimorbidity in diabetes, which span the cardiovascular, physical, psychological, and metabolic systems. Cognitive function is assessed via a structured questionnaire in three domains: memory, executive function, and orientation. We combined activities of daily living (ADL) with instrumental activities of daily living (IADL) to measure physical function. Linear mixed models and negative binomial regression models were used to analyze the association between patterns of multimorbidity in diabetes and the effect on cognitive function and disability, respectively. Results: A sample of 1,985 diabetic patients was identified, of which 1,889 (95.2%) had multimorbidity; their average age was 60.6 years (standard deviation (SD) = 9.5), and 53.1% were women. Three clusters were identified: "cardio-metabolic" (n = 972, 51.5%), "mental-dyslipidemia-arthritis" (n = 584, 30.9%), and "multisystem morbidity" (n = 333, 17.6%). Compared with diabetes alone, the "multisystem morbidity" class had an increased association with global cognitive decline. All patterns of multimorbidity were associated with an increased risk of memory decline and disability; however, the "multisystem morbidity" group also had the strongest association and presented a higher ADL-IADL disability (ratio = 4.22, 95% CI = 2.52, 7.08) and decline in memory Z scores (ß = -0.322, 95% CI = -0.550, -0.095, p = 0.0058). Conclusion: Significant longitudinal associations between different patterns of multimorbidity in diabetes patients and memory decline and disability were observed in this study. Future studies are needed to understand the underlying mechanisms and common risk factors for multimorbidity in diabetes patients and to propose treatments that are more effective.

Metagenomic-based discovery and comparison of the lignin degrading potential of microbiomes in aquatic and terrestrial ecosystems via the LCdb database.

Lignin, as an abundant organic carbon, plays a vital role in the global carbon cycle. However, our understanding of the global lignin-degrading microbiome remains elusive. The greatest barrier has been absence of a comprehensive and accurate functional gene database. Here, we first developed a curated functional gene database (LCdb) for metagenomic profiling of lignin degrading microbial consortia. Via the LCdb, we draw a clear picture describing the global biogeography of communities with lignin-degrading potential. They exhibit clear niche differentiation at the levels of taxonomy and functional traits. The terrestrial microbiomes showed the highest diversity, yet the lowest correlations. In particular, there were few correlations between genes involved in aerobic and anaerobic degradation pathways, showing a clear functional redundancy property. In contrast, enhanced correlations, especially closer inter-connections between anaerobic and aerobic groups, were observed in aquatic consortia in response to the lower diversity. Specifically, dypB and dypA, are widespread on Earth, indicating their essential roles in lignin depolymerization. Estuarine and marine consortia featured the laccase and mnsod genes, respectively. Notably, the roles of archaea in lignin degradation were revealed in marine ecosystems. Environmental factors strongly influenced functional traits, but weakly shaped taxonomic groups. Null mode analysis further verified that composition of functional traits was deterministic, while taxonomic composition was highly stochastic, demonstrating that the environment selects functional genes rather than taxonomic groups. Our study not only develops a useful tool to study lignin degrading microbial communities via metagenome sequencing but also advances our understanding of ecological traits of these global microbiomes.

The mediating effect of eHealth literacy on the relationship between health personality and quality of life in community-dwelling older adults.

AIMS: To explore the relationship between health personality and quality of life among community-dwelling older adults and to examine the mediating effect of eHealth literacy on this relationship. METHODS: A total of 413 community-dwelling older adults from central China were recruited from September 2022 to January 2023. A cross-sectional investigation was conducted using the Chinese versions of the Health Personality Assessment (HPA), eHealth Literacy Scale (eHEALS), and 12-item Short Form Health Survey (SF-12). Correlations between the three variables were examined by Pearson analysis, and mediation analysis was conducted to explore the direct, indirect, and total effects of the health personality on quality of life vis-à-vis eHealth literacy. RESULTS: Health personality factors (including health neuroticism, health openness, and health conscientiousness), eHealth literacy, and quality of life are significantly correlated (P<0.05); eHealth literacy can play a significant mediating role in the relationship between health neuroticism (ß= -0.256, 95 %CI: [-0.405, -0.119]), health openness (ß = 0.488, 95 % CI: [0.343,0.652]), health conscientiousness (ß= 0.489, 95 % CI: [0.354, 0.634]) and quality of life. CONCLUSION: This study revealed that the effect of health personality factors (including health neuroticism, health openness, and health conscientiousness) on quality of life in older adults was mediated through eHealth literacy. IMPACT: Individual personality is essential to understanding eHealth literacy and quality of life among community-dwelling older adults. It may be helpful to identify the health personality traits of older adults first, then implement targeted interventions accordingly to enhance eHealth literacy and ultimately improve quality of life.

Adsorption of triblock copolymers confined between two plates: An analytical approach.

We present an approximate analytical approach to the adsorption problem of ABA triblock copolymers confined between two parallel plates in a θ solvent and give the expression of the propagator q(x, t) as a piece-wise function by solving the modified diffusion equation. In this way, the role of separation between the two plates, adsorption energy and block lengths on segment concentration profile, chain conformations, and interaction potential is then investigated, which agrees well with the numerical results. It is demonstrated that there are parallels between lengthening adsorbing A blocks and increasing surface affinity: strong adsorption and long adsorbing blocks favor the formation of loops and bridges, whereas more tails and free chains exist in the case of weak adsorption and short A blocks at large separations. For moderate and strong adsorptions, the bridging fraction begins to plummet at a separation larger than the end-to-end distance of non-adsorbing B block RB and becomes negligible at above 2RB owing to the entropy effect. The depth of the potential well in the interaction potential profile depends on the adsorption energy and A block length, while the location of the potential minimum corresponds to the onset of the sharp decrease in bridges.

Pharmacokinetic and Bioequivalence Study of Lisinopril/Hydrochlorothiazide Tablet Under Fasting and Postprandial Conditions in Healthy Chinese Subjects.

The objective of this research was to evaluate and compare the pharmacokinetic profiles and safety of lisinopril/hydrochlorothiazide (10 mg/12.5 mg) tablets in the test and reference formulations administered to participants in both fasting and postprandial states and to evaluate the bioequivalence of the 2 products in healthy Chinese volunteers. This study employed a single-center, randomized, open-label, single-dose dosing trial involving a cumulative 96 healthy adult participants (60 in the fasting group and 36 in the postprandial group). Each group comprised 2 sequence sets, and a 2-week washout period was implemented. There were no statistically significant differences in time to maximum concentration and terminal elimination half-life between the test and control groups under fasting and postprandial conditions (P > .05), and the 90% CIs for area under the plasma concentration-time curve and maximum plasma concentration were within the bioequivalence range of 80%-125%. Pharmacokinetic results indicate a large food effect for lisinopril, meaning that there is a loss of approximately 20%-25% of systemic exposure from fasting to postprandial administration for both preparations. The study demonstrated that a single oral dose of generic lisinopril/hydrochlorothiazide is bioequivalent to the reference product and well tolerated, with no significant adverse events observed, and that both products are similarly safe in a cohort of healthy Chinese male and female participants, following administration under fasting and postprandial conditions.

Protective effect of phosphorylated Athyrium multidentatum (Doll.) Ching polysaccharide on vascular endothelial cells in vitro and in vivo.

The purpose of this study was to prepare phosphorylated Athyrium multidentatum (Doll.) Ching polysaccharide (PPS) and investigate its protective effect on vascular endothelial cells (VECs) in vitro and in vivo and the underlying mechanisms. Sodium tripolyphosphate (STPP) and sodium trimetaphosphate (STMP) were used as phosphorylation reagents and PPS was characterized by Fourier transform infrared (FT-IR), 13 C nuclear magnetic resonance (13 C NMR) and 31 P nuclear magnetic resonance (31 P NMR) spectra. Chemical analysis demonstrated that PPS was composed of mannose, glucosamine, rhamnose, glucuronic acid, galacturonic acid, galactosamine, glucose, galactose, xylose, arabinose, and fucose with a molar ratio of 11.36:0.42:4.03:1.12:1.81:0.26:33.25:24.12:6.85:14.46:2.32 and a molecular weight of 28,837 Da. Results from in vitro and in vivo assays revealed that PPS protected human umbilical vein endothelial cells (HUVECs) against H2 O2 -induced oxidative injury and attenuated D-galactose-induced VECs damage in mice. RNA sequencing (RNA-seq) analysis identified 18 differentially expressed genes (DEGs) between D-galactose-treated and PPS-pretreated mice abdominal aorta. A deep analysis of these DEGs disclosed that PPS regulated the expression of genes involved in the functions of vascular endothelium repairment, cell growth and proliferation, cell survival and apoptosis, inflammation, angiogenesis and antioxidant, indicating that these biological processes might play crucial roles in the protective actions of PPS on VECs.

Unraveling the roles of coastal bacterial consortia in degradation of various lignocellulosic substrates.

Lignocellulose, as the most abundant natural organic carbon on earth, plays a key role in regulating the global carbon cycle, but there have been only few studies in marine ecosystems. Little information is available about the extant lignin-degrading bacteria in coastal wetlands, limiting our understanding of their ecological roles and traits in lignocellulose degradation. We utilized in situ lignocellulose enrichment experiments coupled with 16S rRNA amplicon and shotgun metagenomics sequencing to identify and characterize bacterial consortia attributed to different lignin/lignocellulosic substrates in the southern-east intertidal zone of East China Sea. We found the consortia enriched on woody lignocellulose showed higher diversity than those on herbaceous substrate. This also revealed substrate-dependent taxonomic groups. A time-dissimilarity pattern with increased alpha diversity over time was observed. Additionally, this study identified a comprehensive set of genes associated with lignin degradation potential, containing 23 gene families involved in lignin depolymerization, and 371 gene families involved in aerobic/anaerobic lignin-derived aromatic compound pathways, challenging the traditional view of lignin recalcitrance within marine ecosystems. In contrast to similar cellulase genes among the lignocellulose substrates, significantly different ligninolytic gene groups were observed between consortia under woody and herbaceous substrates. Importantly, we not only observed synergistic degradation of lignin and hemi-/cellulose, but also pinpointed the potential biological actors at the levels of taxa and functional genes, which indicated that the alternation of aerobic and anaerobic catabolism could facilitate lignocellulose degradation. Our study advances the understanding of coastal bacterial community assembly and metabolic potential for lignocellulose substrates. IMPORTANCE It is essential for the global carbon cycle that microorganisms drive lignocellulose transformation, due to its high abundance. Previous studies were primarily constrained to terrestrial ecosystems, with limited information about the role of microbes in marine ecosystems. Through in situ lignocellulose enrichment experiment coupled with high-throughput sequencing, this study demonstrated different impacts that substrates and exposure times had on long-term bacterial community assembly and pinpointed comprehensive, yet versatile, potential decomposers at the levels of taxa and functional genes in response to different lignocellulose substrates. Moreover, the links between ligninolytic functional traits and taxonomic groups of substrate-specific populations were revealed. It showed that the synergistic effect of lignin and hemi-/cellulose degradation could enhance lignocellulose degradation under alternation of aerobic and anaerobic conditions. This study provides valuable taxonomic and genomic insights into coastal bacterial consortia for lignocellulose degradation.

Culture conditions of mouse ESCs impact the tumor appearance in vivo.

Various culture conditions by small molecules have been explored to extend pluripotency of stem cells, but their impacts on cell fate in vivo remain elusive. We systematically compared the effects of various culture conditions on the pluripotency and cell fate in vivo of mouse embryonic stem cells (ESCs) by tetraploid embryo complementation assay. Conventional ESC cultures in serum/LIF-based condition produced complete ESC mice and also the survival to adulthood at the highest rates of all other chemical-based cultures. Moreover, long-term examination of the survived ESC mice demonstrated that conventional ESC cultures did not lead to visible abnormality for up to 1.5-2 years, whereas the prolonged chemical-based cultures developed retroperitoneal atypical teratomas or leiomyomas. The chemical-based cultures exhibited transcriptomes and epigenomes that typically differed from those of conventional ESC cultures. Our results warrant further refinement of culture conditions in promoting the pluripotency and safety of ESCs in future applications.

Cross-cultural adaptation and psychometric evaluation of the Health Personality Assessment for Chinese older adults.

INTRODUCTION: The Health Personality Assessment (HPA) is a reliable and brief instrument to evaluating personality in the health domain, but it has not been used in China. OBJECTIVES: To cross-culturally adapt and evaluate the psychometric property of HPA among Chinese older adults. METHODS: The Chinese version of HPA was generated following Beaton's guidelines. The psychometric evaluation of the HPA was conducted on 482 community-dwelling older adults. RESULTS: The Chinese version of HPA showed good internal consistency, item-total correlations, criterion validity, and test-retest reliability within a 2-week interval. Results of confirmatory factor analysis indicated a satisfactory model fit, convergent validity and discriminant validity were also in the acceptable range. CONCLUSIONS: HPA showed good reliability and validity among the Chinese population. The generalization of the HPA may provide a new tool for health practitioners from the personality perspective.

Short telomeres impede germ cell specification by upregulating MAPK and TGFß signaling.

Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFß and MAPK/ERK signaling for somatic cell differentiation. Notably, elevated Fst expression in TGFß pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Re-elongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFß and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFß and MAPK signaling.

Pharmacokinetic and Bioequivalent Study of Potassium Chloride Sustained-Release Tablet Under Different Dietary Conditions in Healthy Chinese Subjects.

Potassium (K+ ) is an endogenous substance that is an essential dietary component. However, the interaction between dietary arrangements and specific effects of dietary K+ intake in bioequivalence studies remains unclear. To investigate the influence of dietary arrangement on the bioequivalence of potassium chloride (KCl) sustained-release tablets in healthy Chinese volunteers, the pharmacokinetics of KCl were compared in two open-label, single-center, randomized, two-period crossover studies with different dietary conditions. All volunteers received an oral dose of 6 g of KCl sustained-release tablets under fasting conditions, with different dietary arrangements. Urine samples were collected on baseline days and 48 hours after tablet consumption. Inductively coupled plasma-optical emission spectrometry was used to measure the concentration of K+ in the urine samples. Pharmacokinetic parameters were analyzed using Phoenix WinNonlin software in a noncompartmental model. In either clinical trial, no significant differences were observed in the maximal rate of urinary excretion and cumulative urinary excretion from 0 to 24 hours of K+ between the reference and test drugs. The bioequivalence studies of both KCl sustained-release tablet formulations were successfully conducted under different dietary conditions.

[Cell metabolomics study of ginkgo flavone aglycone combined with doxorubicin against liver cancer in synergy].

Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 µg·mL~(-1) GA and 0.5 µmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, ß-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.

HD-Zip III Gene Family: Identification and Expression Profiles during Leaf Vein Development in Soybean.

Leaf veins constitute the transport network for water and photosynthetic assimilates in vascular plants. The class III homeodomain-leucine zipper (HD-Zip III) gene family is central to the regulation of vascular development. In this research, we performed an overall analysis of the HD-Zip III genes in soybean (Glycine max L. Merr.). Our analysis included the phylogeny, conservation domains and cis-elements in the promoters of these genes. We used the quantitative reverse transcription-polymerase chain reaction to characterize the expression patterns of HD-Zip III genes in leaf vein development and analyze the effects of exogenous hormone treatments. In this study, twelve HD-Zip III genes were identified from the soybean genome and named. All soybean HD-Zip III proteins contained four highly conserved domains. GmHB15-L-1 transcripts showed steadily increasing accumulation during all stages of leaf vein development and were highly expressed in cambium cells. GmREV-L-1 and GmHB14-L-2 had nearly identical expression patterns in soybean leaf vein tissues. GmREV-L-1 and GmHB14-L-2 transcripts remained at stable high levels at all xylem developmental stages. GmREV-L-1 and GmHB14-L-2 were expressed at high levels in the vascular cambium and xylem cells. Overall, GmHB15-L-1 may be an essential regulator that is responsible for the formation or maintenance of soybean vein cambial cells. GmREV-L-1 and GmHB14-L-2 were correlated with xylem differentiation in soybean leaf veins. This study will pave the way for identifying the molecular mechanism of leaf vein development.

Exploring automatic inconsistency detection for literature-based gene ontology annotation.

MOTIVATION: Literature-based gene ontology annotations (GOA) are biological database records that use controlled vocabulary to uniformly represent gene function information that is described in the primary literature. Assurance of the quality of GOA is crucial for supporting biological research. However, a range of different kinds of inconsistencies in between literature as evidence and annotated GO terms can be identified; these have not been systematically studied at record level. The existing manual-curation approach to GOA consistency assurance is inefficient and is unable to keep pace with the rate of updates to gene function knowledge. Automatic tools are therefore needed to assist with GOA consistency assurance. This article presents an exploration of different GOA inconsistencies and an early feasibility study of automatic inconsistency detection. RESULTS: We have created a reliable synthetic dataset to simulate four realistic types of GOA inconsistency in biological databases. Three automatic approaches are proposed. They provide reasonable performance on the task of distinguishing the four types of inconsistency and are directly applicable to detect inconsistencies in real-world GOA database records. Major challenges resulting from such inconsistencies in the context of several specific application settings are reported. This is the first study to introduce automatic approaches that are designed to address the challenges in current GOA quality assurance workflows. The data underlying this article are available in Github at https://github.com/jiyuc/AutoGOAConsistency.

Berberine Ameliorates Inflammation in Acute Lung Injury via NF-κB/Nlrp3 Signaling Pathway.

The inflammatory response is the key pathophysiological character of acute lung injury (ALI). Berberine (BBR), a natural quaternary ammonium alkaloid, plays a functional role in anti-inflammation both in vitro and in vivo. However, the underlying mechanism between BBR and ALI has not been expounded. Here, we found that BBR improved the permeability of pulmonary and repressed the inflammatory factors in the lipopolysaccharides (LPSs)-induced ALI model. We demonstrated that BBR could suppress the expression of phosphorylated nuclear factor-kappa B (NF-κB) and further restrain the downstream gene nucleotide-binding domain and leucine-rich repeat protein-3 (Nlrp3). Moreover, we also revealed that BBR could directly interact with Nlrp3 protein. After knocked down of Nlrp3 by using siRNA, the protective role of BBR was abrogated in vitro. The expression of IL-1ß and IL-18 was downregulated by BBR via the two signaling pathways. Notably, in Nlrp3 deficient mice, the protective effect of BBR was abolished. These findings demonstrate that BBR has a depressant effect on inflammatory response caused by LPS via regulating NF-κB/Nlrp3 signaling pathway, providing a potential therapeutic strategy in ALI.

S-nitrosylation of c-Jun N-terminal kinase mediates pressure overload-induced cardiac dysfunction and fibrosis.

Cardiac fibrosis (CF) is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases. Phosphorylation-dependent activation of c-Jun N-terminal kinase (JNK) induces cardiac fibrosis. However, whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question. A biotin-switch assay confirmed that S-nitrosylation of JNK (SNO-JNK) increased significantly in the heart tissues of hypertrophic patients, transverse aortic constriction (TAC) mice, spontaneously hypertensive rats (SHRs), and neonatal rat cardiac fibroblasts (NRCFs) stimulated with angiotensin II (Ang II). Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site. S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163 (C116/163A) inhibited Ang II-induced myofibroblast transformation. We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase (iNOS). 1400 W, an inhibitor of iNOS, abrogated the profibrotic effects of Ang II in NRCFs. Mechanistically, SNO-JNK facilitated the nuclear translocation of JNK, increased the phosphorylation of c-Jun, and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA. Finally, WT and iNOS-/- mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis. Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis. Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis.

LncRNA NEAT1 controls the lineage fates of BMSCs during skeletal aging by impairing mitochondrial function and pluripotency maintenance.

Aged bone marrow mesenchymal stem cells (BMSCs) exhibit aberrant self-renewal and lineage specification, which contribute to imbalanced bone-fat and progressive bone loss. In addition to known master regulators of lineage commitment, it is crucial to identify pivotal switches governing the specific differentiation fate of aged BMSCs. Here, we profiled differences in epigenetic regulation between adipogenesis and osteogenesis and identified super-enhancer associated lncRNA nuclear-enriched abundant transcript 1 (NEAT1) as a key bone-fat switch in aged BMSCs. We validated that NEAT1 with high enhancer activity was transcriptionally activated by ATF2 and directed aged BMSCs to a greater propensity to differentiate toward adipocytes than osteoblasts by mediating mitochondrial function. Furthermore, we confirmed NEAT1 as a protein-binding scaffold in which phosphorylation modification of SOX2 Ser249/250 by CDK2 impaired SOX2/OCT4 complex stability and dysregulated downstream transcription networks of pluripotency maintenance. In addition, by sponging miR-27b-3p, NEAT1 upregulated BNIP3L, BMP2K, and PPARG expression to shape mitochondrial function and osteogenic/adipogenic differentiation commitment, respectively. In extracellular communication, NEAT1 promoted CSF1 secretion from aged BMSCs and then strengthened osteoclastic differentiation by extracellular vesicle delivery. Notably, Neat1 small interfering RNA delivery induced increased bone mass in aged mice and decreased fat accumulation in the bone marrow. These findings suggest that NEAT1 regulates the lineage fates of BMSCs by orchestrating mitochondrial function and pluripotency maintenance, and might be a potential therapeutic target for skeletal aging.