Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

NIGT1.4 maintains primary root elongation in response to salt stress through induction of ERF1 in Arabidopsis.

Plants employ various molecular mechanisms to maintain primary root elongation upon salt stress. Identification of key functional genes, therein, is important for improving crop salt tolerance. Through analyzing natural variation of the primary root length of Arabidopsis natural population under salt stress, we identified NIGT1.4, encoding an MYB transcription factor, as a novel contributor to maintained root growth under salt stress. Using both T-DNA knockout and functional complementation, NIGT1.4 was confirmed to have a role in promoting primary root growth in response to salt stress. The expression of NIGT1.4 in the root was shown induced by NaCl treatments in an ABA-dependent manner. SnRK2.2 and 2.3 were shown to interact with and phosphorylate NIGT1.4 individually. The growth of the primary root of snrk2.2/2.3/2.6 triple mutant was shown sensitive to salt stress, which was similar to nigt1.4 plants. Using DNA affinity purification sequencing, ERF1, a known positive regulator for primary root elongation and salt tolerance, was identified as a target gene for NIGT1.4. The transcriptional induction of ERF1 by salt stress was shown absent in nigt1.4 background. NIGT1.4 was also confirmed to bind to the promoter region of ERF1 by yeast one-hybrid experiment and to induce the expression of ERF1 by dual-luciferase analysis. All data support the notion that salt- and ABA-elicited NIGT1.4 induces the expression of ERF1 to regulate downstream functional genes that contribute to maintained primary root elongation. NIGT1.4-ERF1, therefore, acts as a signaling node linking regulators for stress resilience and root growth, providing new insights for breeding salt-tolerant crops.

High-Frequency Quartz Crystal Microbalance and Dual-Signaling Electrochemical Ratiometric Assays of PTP1B Activity Based on COF@Au@Fc Hybrids.

The abnormal expression of protein tyrosine phosphatase 1B (PTP1B) is highly related to several serious human diseases. Therefore, an accurate PTP1B activity assay is beneficial to the diagnosis and treatment of these diseases. In this study, a dual-mode biosensing platform that enabled the sensitive and accurate assay of PTP1B activity was constructed based on the high-frequency (100 MHz) quartz crystal microbalance (QCM) and dual-signaling electrochemical (EC) ratiometric strategy. Covalent-organic framework@gold nanoparticles@ferrocene@single-strand DNA (COF@Au@Fc-S0) was introduced onto the QCM Au chip via the chelation between Zr4+ and phosphate groups (phosphate group of the phosphopeptide (P-peptide) on the QCM Au chip and the phosphate group of thiol-labeled single-stranded DNA (S0) on COF@Au@Fc-S0) and used as a signal reporter. When PTP1B was present, the dephosphorylation of the P-peptide led to the release of COF@Au@Fc-S0 from the QCM Au chip, resulting in an increase in the frequency of the QCM. Meanwhile, the released COF@Au@Fc-S0 hybridized with thiol/methylene blue (MB)-labeled hairpin DNA (S1-MB) on the Au NPs-modified indium-tin oxide (ITO) electrode. This caused MB to be far away from the electrode surface and Fc to be close to the electrode, leading to a decrease in the oxidation peak current of MB and an increase in the oxidation peak current of Fc. Thus, PTP1B-induced dephosphorylation of the P-peptide was monitored in real time by QCM, and PTP1B activity was detected sensitively and reliably using this innovative QCM-EC dual-mode sensing platform with an ultralow detection limit. This platform is anticipated to serve as a robust tool for the analysis of protein phosphatase activity and the discovery of drugs targeting protein phosphatase.

The Contact Interface Electronic Coupling of Cobalt and Zirconia Enables Stable and Highly Efficient 4e- Oxygen Reduction Reaction Catalysis.

Cobalt (Co) is an efficient oxygen reduction reaction (ORR) catalyst but suffers from issues of easy deactivation and instability. Here, it shows that ZrO2 can stabilize Co through interface electron coupling and enables highly efficient 4e- ORR catalysis. Porous carbon nanofibers loaded with dispersed Co-nanodots (≈10 nm, 9.63 wt%) and ZrO2 nanoparticles are synthesized as the catalyst. The electron transfer from the metallic Co to ZrO2 causes interface-oriented electron enrichment that promotes the activation and conversion of O2, improving the efficiency of 4e- transfer. Moreover, the simulation results show that ZrO2 acts like an electron reservoir to store electrons from Co and slowly release them to the interface, solving the easy deactivation problem of Co. The catalyst exhibits a high half-wave potential (E1/2) of 0.84 V, which only decreases by 3.6 mV after 10 000 cycles, showing great stability. Particularly, the enhanced spin polarization of Co in a magnetic field reinforces the interface electron coupling that increases the E1/2 to 0.864 V and decreases the energy barrier of ORR from 0.81 to 0.63 eV, confirming that the proposed strategy is effective for constructing efficient and stable ORR catalysts.

Secular Trends in Peak Bone Mineral Density: The National Health and Nutrition Examination Survey 1999-2018.

Peak bone mineral density (BMD) is one of the most important factors influencing the development of osteoporosis. It was predicted that a 10% increase in peak BMD will delay the onset of osteoporosis by 13 years. However, changes in peak BMD over time are unknown. This study aimed to investigate secular trends in peak BMD among young adults in the United States. Based on the National Health and Nutrition Examination Survey from 1999-2018, 3,975 males aged 19-28 years and 2370 females aged 31-40 years were our target population for estimating peak lumbar spine BMD. BMD was measured by dual-energy X-ray absorptiometry. Generalized linear models adjusted for multiple covariates were used to examine the secular trends in peak BMD in males and females, respectively. Secular trends for peak lumbar spine BMD from 1999-2000 to 2017-2018 were not statistically significant in males or females (all Plinear and Pquadratic > 0.05). Similar results were observed in race/ethnicity subgroups (all Plinear and Pquadratic > 0.05). However, in stratified analyses by obesity category, peak lumbar spine BMD in obese males and females increased from 1999-2000 to 2009-2010 and then decreased until 2017-2018, while peak lumbar spine BMD in non-obese females decreased from 1999-2000 to 2005-2006 and then increased until 2017-2018 (all Pquadratic < 0.05). Peak lumbar spine BMD was greater in obese males and females than in non-obese males and females up to 2009-2010, but not from 2011-2012 onwards. Overall, there were no significant secular trends in peak lumbar spine BMD. However, secular trends differed between obese and non-obese groups.

The Role of Endoscopic Ultrasound-guided Fine-needle Aspiration of Pelvic Lesions: A Meta-analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a potentially valuable tool for the diagnosis of pelvic lesions. The aim of this meta­analysis was to evaluate the efficacy and feasibility of EUS-FNA in the diagnosis of pelvic lesions. METHODS: We performed a computerized search of PubMed, EMBASE, Cochrane Library, and Science Citation Index, through March 2023. The main outcome measures examined in the meta-analysis were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. RESULTS: We evaluated 22 trials that used surgical pathology or imaging follow-up results as the reference standard. The studies comprised 844 patients. The cumulative sensitivity, specificity, PPV, NPV, and accuracy were 94%, 100%, 100%, 89%, and 96%, respectively. In the subgroup analysis, the prospective studies revealed the cumulative sensitivity, specificity, PPV, NPV, and accuracy were 91%, 100%, 100%, 85%, and 93%, respectively. CONCLUSIONS: In conclusion, we provide evidence that EUS-FNA is a qualitative diagnostic technique with high sensitivity, specificity, PPV, and accuracy. However, its NPV is slightly low, which does not exclude the risk of a missed diagnosis, and more randomized controlled trials or prospective studies are still needed in the future. EUS-FNA is effective and feasible for pelvic space-occupying lesions. This technique has high clinical application value for pelvic lesions.

Association Between Different Types of Physical Activity and Hepatic Steatosis and Liver Fibrosis: A Cross-Sectional Study Based on NHANES.

BACKGROUND AND AIMS: Many studies have shown a link between physical activity (PA) and nonalcoholic fatty liver disease (NAFLD). However, more research is needed to investigate the relationship between different types of PA and NAFLD. This study aimed to explore the potential link between different types of PA, hepatic steatosis, and liver fibrosis. STUDY: A cross-sectional study was conducted using the data set from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. A multiple linear regression model was used to examine the linear relationship between different types of PA, the controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). In addition, smoothing curve fitting and threshold effect analysis were used to depict their nonlinear relationship. RESULTS: This study involved 5933 adults. Multiple linear regression analysis revealed a significantly negative correlation between leisure-time PA and CAP, while the relationship between occupation-related PA, transportation-related PA, and CAP was not significant. Subgroup analysis further revealed that leisure-time PA was significantly negatively correlated with CAP in women and younger age groups (under 60 y old), while the relationship was not significant in men and older age groups. In addition, there was a significant negative correlation between leisure-time PA and liver fibrosis in men. CONCLUSIONS: Leisure-time PA can prevent hepatic steatosis, and women and young people benefit more. Occupation-related PA is not associated with hepatic steatosis and cannot replace leisure-time PA. In men, increasing leisure-time PA is more effective in preventing liver fibrosis.

Layered Hydride LiH4 with a Pressure-Insensitive Superconductivity.

For hydride superconductors, each significant advance is built upon the discovery of novel H-based structural units, which in turn push the understanding of the superconducting mechanism to new heights. Based on first-principles calculations, we propose a metastable LiH4 with a wavy H layer composed of the edge-sharing pea-like H18 rings at high pressures. Unexpectedly, it exhibits pressure-insensitive superconductivity manifested by an extremely small pressure coefficient (dTc/dP) of 0.04 K/GPa. This feature is attributed to the slightly weakened electron-phonon coupling with pressure, caused by the reduced charge transfer from Li atoms to wavy H layers, significantly suppressing the substantial increase in the contribution of phonons to Tc. Its superconductivity originates from the strong coupling between the H 1s electrons and the high-frequency phonons associated with the H layer. Our study extends the list of H-based structural units and enhances the in-depth understanding of pressure-related superconductivity.

Relationship between glycated hemoglobin levels and three-month outcomes in acute ischemic stroke patients with or without diabetes: a prospective Korean cohort study.

OBJECTIVE: In patients experiencing acute ischemic stroke, there is ongoing debate surrounding the connection between chronic hyperglycemic status and their initial clinical outcomes. Our objective was to examine the connection between glycated hemoglobin (HbA1c) levels and adverse clinical outcomes at both 3-months adverse clinical outcomes in individuals with acute ischemic stroke (AIS) with and without diabetes. METHODS: The present prospective cohort study involved 896 AIS patients without diabetes and 628 with diabetes treated at a South Korean hospital from January 2010 to December 2016. The target independent variable is HbA1c. The outcome variable is a modified Rankin scale score ≥ 3. A binary logistic regression model was applied to assess the connection between HbA1c levels and 3-month poor clinical outcomes in AIS patients with and without diabetes. Additionally, a generalized additive model and smoothed curve fitting were utilized to explore potential nonlinear associations between HbA1c levels and 3-month adverse clinical outcomes in AIS patients with and without diabetes. RESULTS: The binary logistic regression model could not identify any statistically significant connection between HbA1c and 3-month adverse clinical outcomes in AIS patients, both those with and without diabetes, after correcting for various factors. However, a nonlinear relationship emerged between HbA1c and 3-month adverse clinical outcomes in AIS patients with diabetes. The inflection point for HbA1c was determined to be 6.1%. For HbA1c values ≤ 6.1%, an inverse association was observed between HbA1c and 3-month adverse clinical outcomes in diabetic AIS patients, and each 1% increase in HbA1c in AIS patients with DM was associated with an 87% reduction in 3-month adverse clinical outcomes (OR = 0.13, 95% CI: 0.02-0.81). Conversely, when HbA1c exceeded 6.1%, a positive association between HbA1c and 3-month adverse clinical outcomes became apparent in diabetic AIS patients, and each 1% increase in HbA1c in AIS patients with DM was associated with a 23% increase in 3-month adverse clinical outcomes (OR = 1.23, 95%CI: 1.03-1.47). However, it's important to note that no significant linear or nonlinear relationships were observed between HbA1c levels and 3-month adverse clinical outcomes in AIS patients without diabetes. CONCLUSION: Our findings suggest a nonlinear connection and threshold effect between HbA1c and 3-month adverse clinical outcomes in AIS patients with diabetes. AIS patients with diabetes had a lower risk of 3-month adverse clinical outcomes when their HbA1c control was close to 6.1%. Our findings may aid treatment decision-making and potentially guide interventions to optimize glycemic control in AIS patients.

Realizing the clinical utility of saliva for monitoring oral diseases.

In the era of personalized/precision health care, additional effort is being expended to understand the biology and molecular mechanisms of disease processes. How these mechanisms are affected by individual genetics, environmental exposures, and behavioral choices will encompass an expanding role in the future of optimally preventing and treating diseases. Considering saliva as an important biological fluid for analysis to inform oral disease detection/description continues to expand. This review provides an overview of saliva as a diagnostic fluid and the features of various biomarkers that have been reported. We emphasize the use of salivary biomarkers in periodontitis and transport the reader through extant literature, gaps in knowledge, and a structured approach toward validating and determine the utility of biomarkers in periodontitis. A summation of the findings support the likelihood that a panel of biomarkers including both host molecules and specific microorganisms will be required to most effectively identify risk for early transition to disease, ongoing disease activity, progression, and likelihood of response to standard periodontal therapy. The goals would be to develop predictive algorithms that serve as adjunctive diagnostic tools which provide the clinician and patient important information for making informed clinical decisions.

A Solar Evaporator Based on Polypyrrole Coated 3D Carbon Nanotube Materials for Efficient Solar-Driven Vapor Generation.

Highly porous light absorbers are fabricated based on polypyrrole (PPy)-coated carbon nanotube (CNT). Carbon nanotube sponge (CNTS) or carbon nanotube array (CNTA) with three-dimensional (3D) network structure is the framework of porous light absorbers. Both PPy@CNTS and PPy@CNTA composites exhibit excellent light absorption of the full solar spectrum. The CNTS and CNTA with porous structures have extremely large effective surface area for light absorption and for water evaporation that has great practical benefit to the solar-driven vapor generation. The PPy layer on CNT sidewalls significantly improves the hydrophilicity of porous CNTS and CNTA. The good wettability of water on CNT sidewalls makes water transport in porous CNT materials highly efficient. The PPy@CNTS and PPy@CNTA light absorbers achieve high water evaporation rates of 3.35 and 3.41 kg m-2 h-1, respectively, under 1-sun radiation. The orientation of nano channels in CNTA-based light absorbers also plays an important role in the solar-driven vapor generation. The water transport and vapor escape are more efficient in CNTA-based light absorbers as compared to the CNTS-based light absorbers due to the relatively short path for the water transport and the vapor escape in CNTA-based light absorbers.

Metallic Re3O2 with mixed-valence states.

Rhenium (Re) shows the richest valence states from +2 to +7 in compounds, but its mixed-valence states are still missing thus far. In this work, we have explored the Re-O phase diagram with a wide range of stoichiometric compositions under high pressure through first-principles structural search calculations. Besides identifying two novel high-pressure phases of ReO2 and ReO3, we reveal two hitherto unknown Re-rich Re3O2 and O-rich ReO4 compounds. Re atoms in Re3O2 show mixed-valence states due to their inequivalent coordination environments, the first example in Re-based compounds. Electronic structure calculations demonstrate that the four discovered Re-O phases exhibit metallicity contributed by Re 5d electrons. Among them, ReO3 has a predicted critical temperature of up to 12 K at 50 GPa, derived from the interaction between Re 5d electrons and Re-derived low-frequency phonons. Our study points to new opportunities to disclose novel transition metal compounds with mixed-valence states.

Photobacterium pectinilyticum sp. nov., a novel bacterium isolated from surface seawater of Qingdao offshore.

A Gram-staining-negative, facultative aerobic, motile strain, designated strain ZSDE20T, was isolated from the surface seawater of Qingdao offshore. Phylogenetic analysis of the 16S rRNA gene of strain ZSDE20T, affiliated it to the genus Photobacterium. It was closely related to Photobacterium lutimaris DF-42 T (98.92% 16S rRNA gene sequence similarity). Growth occurred at 4-28ºC (optimum 28ºC), pH 1.0-7.0 (optimum 7.0) and in the presence of 1-7% (w/v) NaCl (optimum 3%). The dominant fatty acids were summed feature 3 (C16:1 ω7c or/and C16:1 ω6c, 34.23%), summed feature 8 (C18:1 ω7c and C18:1 ω6c, 10.36%) and C16:0 (20.05%). The polar lipids of strain ZSDE20T comprised phosphatidylethanolamine, phosphatidylcholine, lyso-phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol dimannoside, phosphatidylinositol mannosides and two unknown lipids. The major respiratory quinone was ubiquinone-8 (Q-8). The DNA G + C content of strain ZSDE20T was 45.6 mol%. Average nucleotide identity (ANI) values between ZSDE20T and its reference species were lower than the threshold for species delineation (95-96%); in silico DNA-DNA hybridization further showed that strain ZSDE20T had less than 70% similarity to its relatives. Based on the polyphasic evidences, strain ZSDE20T is proposed as representing a novel species of the genus Photobacterium, for which the name Photobacterium pectinilyticum sp. nov. is proposed. The type strain is ZSDE20T (= MCCC 1K06283T = KCTC 82885 T).

FIB-4 index is associated with mortality in critically ill patients with alcohol use disorder: Analysis from the MIMIC-IV database.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and all-cause mortality in critically ill patients with alcohol use disorder (AUD) is unclear. The present study aimed to investigate the predictive ability of FIB-4 for all-cause mortality in critically ill AUD patients and the association between them. METHODS: A total of 2528 AUD patients were included using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. FIB-4 was calculated for each patient using the existing formula. The patients were equally divided into four groups based on the quartiles of FIB-4. Multivariate logistic regression and Cox proportional hazard model were used to evaluate the association of FIB-4 with in-hospital mortality, 28-day mortality and 1-year mortality. Kaplan-Meier curves were used to analyse the incidence of 28-day mortality among four groups. RESULTS: FIB-4 was positively associated with 28-day mortality of AUD patients with hazard ratio (HR) of 1.354 [95% confidence interval (CI) 1.192-1.538]. There were similar trends in the in-hospital mortality [odds ratio (OR): 1.440, 95% CI (1.239-1.674)] and 1-year mortality [HR: 1.325, 95% CI (1.178-1.490)]. CONCLUSION: Increased FIB-4 is associated with greater in-hospital mortality, 28-day mortality and 1-year mortality in critically ill AUD patients.

Optimization of Hospital Drug Management Model under the Supervision of Internet Plus Medical Health.

Objective: This study aims to investigate the use of proton pump inhibitors (PPIs) among inpatients in a hospital and analyze the rationality of their use. Methods: We analyzed the medication records of 1986 inpatients from January 2023 to June 2023, focusing on patients using PPIs under the "Internet + medical service" model. Additionally, we compared and analyzed the drug use patterns, including dosage form, dosage, medication frequency, average daily cost, and sales amount, between two groups: those treated before and after the implementation of the "Internet + medical service" model. The control group comprised 1962 inpatients treated with PPIs from July 2022 to December 2022. We also compared drug inventory time, account coincidence rate, error rate, and nursing satisfaction between the two periods. Results: Among the hospitalized patients using PPIs, 892 cases were male (44.91%) and 1094 cases were female (55.09%). Regarding age distribution, 456 cases were aged 18-45 (22.96%), 845 cases were aged 46-65 (42.55%), and 685 cases were over 65 years old (34.49%). The top 10 departments with the highest frequency of PPI use included gastroenterology (8.36%), oncology, hematology, trauma orthopedics (6.95% each), cardiovascular medicine, neurology (6.39% each), general surgery (6.29%), respiratory, critical care (5.84%), renal rheumatology, immunology (5.79%), and spine surgery (5.59%). Omeprazole enteric-coated capsules accounted for the highest proportion (25.08%), followed by rabeprazole enteric-coated tablets (22.96%) and pantoprazole sodium enteric-coated tablets (20.04%). After implementing the "Internet + medical service" model, there was a reduction in irrational PPI use, medication error rates, and inventory time. Moreover, the account coincidence rate and satisfaction rate increased significantly (P < .05). Conclusion: The utilization of PPIs in hospitals is notably high. Implementing the "Internet + medical service" model can effectively improve the rationality of PPI use. Clinicians should adhere to relevant indications when prescribing PPIs and conduct drug interventions to prevent overuse.

Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau.

BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

The Characterization of G-Quadruplexes in Tobacco Genome and Their Function under Abiotic Stress.

Tobacco is an ideal model plant in scientific research. G-quadruplex is a guanine-rich DNA structure, which regulates transcription and translation. In this study, the prevalence and potential function of G-quadruplexes in tobacco were systematically analyzed. In tobacco genomes, there were 2,924,271,002 G-quadruplexes in the nuclear genome, 430,597 in the mitochondrial genome, and 155,943 in the chloroplast genome. The density of the G-quadruplex in the organelle genome was higher than that in the nuclear genome. G-quadruplexes were abundant in the transcription regulatory region of the genome, and a difference in G-quadruplex density in two DNA strands was also observed. The promoter of 60.4% genes contained at least one G-quadruplex. Compared with up-regulated differentially expressed genes (DEGs), the G-quadruplex density in down-regulated DEGs was generally higher under drought stress and salt stress. The G-quadruplex formed by simple sequence repeat (SSR) and its flanking sequence in the promoter region of the NtBBX (Nitab4.5_0002943g0010) gene might enhance the drought tolerance of tobacco. This study lays a solid foundation for further research on G-quadruplex function in tobacco and other plants.

Triptycene Branched Poly(aryl-co-aryl piperidinium) Electrolytes for Alkaline Anion Exchange Membrane Fuel Cells and Water Electrolyzers.

Alkaline polymer electrolytes (APEs) are essential materials for alkaline energy conversion devices such as anion exchange membrane fuel cells (AEMFCs) and water electrolyzers (AEMWEs). Here, we report a series of branched poly(aryl-co-aryl piperidinium) with different branching agents (triptycene: highly-rigid, three-dimensional structure; triphenylbenzene: planar, two-dimensional structure) for high-performance APEs. Among them, triptycene branched APEs showed excellent hydroxide conductivity (193.5 mS cm-1 @80 °C), alkaline stability, mechanical properties, and dimensional stability due to the formation of branched network structures, and increased free volume. AEMFCs based on triptycene-branched APEs reached promising peak power densities of 2.503 and 1.705 W cm-2 at 75/100 % and 30/30 % (anode/cathode) relative humidity, respectively. In addition, the fuel cells can run stably at a current density of 0.6 A cm-2 for 500 h with a low voltage decay rate of 46 µV h-1 . Importantly, the related AEMWE achieved unprecedented current densities of 16 A cm-2 and 14.17 A cm-2 (@2 V, 80 °C, 1 M NaOH) using precious and non-precious metal catalysts, respectively. Moreover, the AEMWE can be stably operated under 1.5 A cm-2 at 60 °C for 2000 h. The excellent results suggest that the triptycene-branched APEs are promising candidates for future AEMFC and AEMWE applications.

RNA N6-methyladenosine demethylase FTO inhibits glucocorticoid-induced osteoblast differentiation and function in bone marrow mesenchymal stem cells.

Excess glucocorticoids (GCs) have been reported as key factors that impair osteoblast (OB) differentiation and function. However, the role of RNA N6-methyladenosine (m6 A) in this process has not yet been elucidated. In this study, we report that both the mRNA and protein expression of fat mass and obesity-associated gene (FTO), a key m6 A demethylase, were dose-dependently downregulated during OB differentiation by dexamethasone (DEX) in bone marrow mesenchymal stem cells (BMSCs), and FTO was gradually increased during OB differentiation. Meanwhile, FTO knockdown suppressed OB differentiation and mineralization, whereas overexpression of wide-type FTO, but not mutant FTO (mutated m6 A demethylase active site), reversed DEX-induced osteogenesis impairment. Interfering with FTO inhibited proliferation and the expression of Ki67 and Pcna in BMSCs during OB differentiation, whereas forced expression of wide-type FTO improved DEX-induced inhibition of BMSCs proliferation. Moreover, FTO knockdown reduced the mRNA stability of the OB marker genes Alpl and Col1a1, and FTO-modulated OB differentiation via YTHDF1 and YTHDF2. In conclusion, our results suggest that FTO inhibits the GCs-induced OB differentiation and function of BMSCs.

PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection.

Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-ß induction in vivo and in vitro. In the early phase of infection, PCV2 promotes the phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling, which directly silences the catalytic activity of cGAS. Subsequently, phosphorylation of cGAS at S278 can facilitate the K48-linked poly-ubiquitination of cGAS at K389, which can been served as a signal for recognizing by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), to promote the translocation of K48-ubiquitinated-cGAS from cytosol to autolysosome depending on the deacetylase activity of HDAC6, thereby eventually resulting in a markedly increased cGAS degradation in PCV2 infection-induced autophagic cells relative to Earle's Balanced Salt Solution (EBSS)-induced autophagic cells (a typical starving autophagy). Importantly, we found that PCV2 Cap and its binding protein gC1qR act as predominant regulators to promote porcine cGAS phosphorylation and HDAC6 activation through mediating PI3K/AKT signaling and PKCδ signaling activation. Based on this finding, gC1qR-binding activity deficient PCV2 mutant (PCV2RmA) indeed shows a weakened inhibitory effect on IFN-ß induction and a weaker boost effect for other DNA viruses infection compared to wild-type PCV2. Collectively, our findings illuminate a systematic regulation mechanism by which porcine circovirus counteracts the cGAS-STING signaling pathway to inhibit the type I interferon induction and promote DNA virus infection, and identify gC1qR as an important regulator for the immunosuppression induced by PCV2.