[Application of ion chromatographic fingerprint analysis for quality evaluation of tobacco flavors].

Tobacco flavor, an important tobacco additive, is an essential raw material in cigarette production that can effectively improve the quality of tobacco products, add aroma and taste, and increase the suction flavor. The quality consistency of tobacco flavors affects the quality stability of branded cigarettes. Therefore, the quality control of tobacco flavors is a major concern for cigarette and flavor manufacturers. Physical and chemical indices, odor similarity, and sensory efficacy are employed to evaluate the quality of tobacco flavors, and the analysis of chemical components in tobacco flavors is usually conducted using gas chromatography (GC) and high performance liquid chromatography (HPLC). However, because the composition of tobacco flavors is complex, their quality cannot be fully reflected using a single component or combination of components. Therefore, establishing an objective analytical method for the quality control of tobacco flavors is of extreme importance. Chromatographic fingerprint analysis is routinely used for the discriminative analysis of tobacco flavors. Chromatographic fingerprints refer to the general characteristics of the concentration profiles of different chemical compounds. In the daily procurement process, fingerprints established by GC and HPLC are effective for the evaluation and identification of tobacco flavors. However, given continuous improvements in aroma-imitation technology, some flavors with high similarity cannot be directly distinguished using existing methods. In this study, a method for the determination of organic acids and inorganic anions in tobacco flavors based on ion chromatography (IC) was developed to ensure the quality consistency of tobacco flavors. A 1.0 g sample of tobacco flavors and 10 mL of deionized water were mixed and vibrated for 30 min. The aqueous sample solution was passed through a 0.45 µm membrane filter and RP pretreatment column in succession to eliminate interferences and then subjected to IC. Standard solutions containing nine organic acids and seven inorganic anions were used to identify the anions in the tobacco flavors, and satisfactory reproducibility was obtained. The relative standard deviations (RSDs) for retention times and peak areas were <0.71% and <6.02%, respectively. The chromatographic fingerprints of four types of tobacco flavors (samples A-D) from five different batches were obtained. Nine tobacco flavor samples from different manufacturers (samples AY1-AY3, BY1-BY2, CY1-CY2, DY1-DY2) were also analyzed to obtain their chromatographic fingerprints. Hierarchical cluster and similarity analyses were used to evaluate the quality of tobacco flavors from different manufacturers. Hierarchical clustering refers to the process of subdividing a group of samples into clusters that exhibit a high degree of intracluster similarity and intercluster dissimilarity. The dendrograms obtained using SPSS 12.0 indicated good quality consistency among the samples in different batches. Samples AY3, BY2, CY2, and DY1 clustered with the batches of standard tobacco flavors. Therefore, hierarchical cluster analysis can effectively distinguish the quality of products from different manufacturers. The Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (version 2.0) was used to evaluate the similarity between the standard tobacco flavors and products from different manufacturers. Among the samples analyzed, samples AY3, BY2, CY2, and DY1 showed the highest similarity values (>97.7%), which was consistent with the results of the hierarchical cluster analysis. This finding indicates that IC combined with chromatographic fingerprint analysis could accurately determine the quality of tobacco flavors. GC combined with ultrasonic-assisted liquid-liquid extraction was also used to analyze the tobacco flavors and verify the accuracy of the proposed method. Compared with GC coupled with ultrasonic-assisted liquid-liquid extraction, IC demonstrated more significant quality differences among certain tobacco flavors.

Age-Related Conservation in Plant-Soil Feedback Accompanied by Ectomycorrhizal Domination in Temperate Forests in Northeast China.

This study investigates the effects of forest aging on ectomycorrhizal (EcM) fungal community and foraging behavior and their interactions with plant-soil attributes. We explored EcM fungal communities and hyphal exploration types via rDNA sequencing and investigated their associations with plant-soil traits by comparing younger (~120 years) and older (~250 years) temperate forest stands in Northeast China. The results revealed increases in the EcM fungal richness and abundance with forest aging, paralleled by plant-soil feedback shifting from explorative to conservative nutrient use strategies. In the younger stands, Tomentella species were prevalent and showed positive correlations with nutrient availability in both the soil and leaves, alongside rapid increases in woody productivity. However, the older stands were marked by the dominance of the genera Inocybe, Hymenogaster, and Otidea which were significantly and positively correlated with soil nutrient contents and plant structural attributes such as the community-weighted mean height and standing biomass. Notably, the ratios of longer-to-shorter distance EcM fungal exploration types tended to decrease along with forest aging. Our findings underscore the integral role of EcM fungi in the aging processes of temperate forests, highlighting the EcM symbiont-mediated mechanisms adapting to nutrient scarcity and promoting sustainability in plant-soil consortia.

Photothermal conditions and upwelling enhance very short-lived brominated halocarbons emissions in the western tropical Pacific Ocean.

Sea-to-air emissions of very short-lived brominated halocarbons (VSLBrHs) are known to contribute to 30 % of stratospheric and tropospheric ozone depletion. However, empirical data on their occurrence in open ocean are scarce, which makes it difficult to estimate the significant contribution of open ocean releases to the global budget of halocarbons. This study was conducted in 2022 to explore the spatial variations of VSLBrHs and their controlling factors in the western tropical Pacific Ocean (WTPO). The findings highlighted that high biological productivity and the resulting dissolved organic matter (DOM) as well as upwelling dynamics significantly influenced the distribution and production of VSLBrHs in seawater, with atmospheric levels primarily governed by oceanic emissions. Based on the simultaneous observation of seawater and atmospheric concentrations, the mean sea-to-air fluxes of CH2Br2, CHBr3, CHBrCl2, and CHBr2Cl were estimated to be 1.01, 6.65, 9.31, and 7.25 nmol m-2 d-1, respectively. Sea-to-air fluxes of these gases in the upwelling regions were 9.0, 4.6, 2.9, and 6.8 times those in the non-upwelling regions, respectively. Additionally, in-situ incubation experiments revealed that the enzymatic mediated biosynthesis pathways of VSLBrHs were enhanced under temperature and light-induced stress and in waters rich in humus-like substances. Therefore, we tentatively concluded that abundant photothermal conditions and the existence of upwelling in the WTPO made it a potential hotspot for the emission of VSLBrHs. This study offers critical insights into the environmental dynamics of VSLBrHs emissions and underscores the importance of regional oceanic conditions in influencing atmospheric greenhouse gas compositions.

Finite Element Analysis and Computational Fluid Dynamics Verification of Molten Pool Characteristics During Selective Laser Melting of Ti-6Al-4V Plates.

The finite element (FE) method is used to characterize the thermal gradient, solidification rate, and molten pool sizes of Ti-6Al-4V plates in the process of selective laser melting (SLM). The results are verified by using the computational fluid dynamics (CFD) simulation. The proposed FE model contains a series of toolpath information that is directly converted from a G-code file, including hatch spacing, laser power, layer thickness, dwell time, and scanning speed generated by using Slic3r software from a CAD file. A proposed multi-layer, multi-track FE model is used to investigate the influence of the laser power, scanning speed, and scanning path on the microstructure in the Ti-6Al-4V plate built via SLM. The processing window is also determined based on the proposed FE model. The FE results indicate that, with a decrease in the laser power and an increase in the scanning speed, the morphology of the crystal grains, showing fully columnar crystals, gradually deviates from the fully equiaxed region. The formed grains are dependent on the laser power, scanning speed, and deposition position, but they are not sensitive to the scanning path, and with the deposition from the bottom layer to the top layer, the size of the formed grains is gradually increasing, which shows a good agreement with the experimental results.

Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway.

Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.

Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.

Habitat suitability evaluation of invasive plant species Datura stramonium in Liaoning Province: Based on Biomod2 combination model.

Datura stramonium, as a major invasive plant in Liaoning Province, is difficult to be removed after its successful invasion, and is a great threat to ecological environment and biodiversity. To evaluate the habitat suitabi-lity of D. stramonium, we collected its geographic distribution data in Liaoning Province through field investigation and database query, and using the Biomod2 combination model, and investigated its potential and suitable distribution areas and main influencing environmental variables at present and under future climate change scenarios, respectively. The results showed that the combined model which composed of GLM (generalized linear model), GBM (generalized boosting regression model), RF (random forest model), and MaxEnt (maximum entropy model) had a good performance. By classifying the habitat suitability of D. stramonium into four categories: high-, medium-, low- and un-suitable habitats, we found that the high-suitable habitats were generally distributed in the northwest and south of Liaoning Province, with an area of about 3.81×104 km2, accounting for 25.8% of the total area. The medium-suitable habitats were mostly distributed in the northwest and central parts of Liaoning Province, with an area of about 4.19×104 km2, accounting for 28.3% of the total area. Slope and clay content of topsoil (0-30 cm) were the two main variables explaining the habitat suitability of D. stramonium, and the total suitability of D. stramonium first increased and then decreased with the increasing slope and clay content of topsoil in this region. Under future climate change scenarios, the total suitability of D. stramonium showed an expanding trend, and its suitability would be obviously increased in Jinzhou, Panjin, Huludao, and Dandong.

Breaking the Size Limitation of Directly-Synthesized PbS Quantum Dot Inks Toward Efficient Short-wavelength Infrared Optoelectronic Applications.

PbS quantum dots (QDs) are promising building blocks for solution-processed short-wavelength infrared (SWIR) devices. The recently developed direct synthesis of semi-conductive PbS QD inks has substantially simplified the preparation processing and reduced the material cost, while facing the challenge to synthesize large-size QDs with absorption covering the SWIR region. Herein, we for the first time realize a low-cost, scalable synthesis of SWIR PbS QD inks after an extensive investigation of the reaction kinetics. Finally, based on these PbS SWIR QD inks, the solar cell demonstrates a record-high power conversion efficiency (PCE) of 1.44 % through an 1100 nm cutoff silicon filter and the photodetector device shows a low dark current density of 2×10-6  A cm-2 at -0.8 V reverse bias with a high external quantum efficiency (EQE) of 70 % at ≈1300 nm. Our results realize the direct synthesis of low-cost and scalable SWIR QD inks and may accelerate the industrialization of consumer SWIR technologies.

Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury.

Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.

[Community structure of phyllosphere fungi associated with dominant tree species in a broad-leaved Korean pine forest of Changbai Mountain, Northeast China]. / é•¿ç™½å±±é˜”å¶çº¢æ¾æž—ä¼˜åŠ¿æ ‘ç§å¶é™ çœŸèŒç¾¤è½ç»“æž„.

Forest is the main component of terrestrial ecosystems that harbors about 40% of the existing species on the earth. As a vital component of biodiversity, phyllosphere microbes in the canopy play a critical and unique role in maintaining plant health, improving host resistance, and influencing global biogeochemical cycle. However, the studies on the community structure of phyllosphere fungi in natural forests are scarce as compared to that on rhizosphere microbes. Consequently, we know litter about how phyllosphere fungi associates with leaf traits. In this study, we analyzed fungal community composition of canopy leaves of six dominant tree species (i.e., Pinus koraiensis, Tilia amurensis, Quercus mongolica, Acer mono, Fraxinus mandshurica, and Ulmus japonica), in a broad-leaved Korean pine forest of Changbai Mountain Nature Reserve in Jilin Province, using high-throughput sequencing. We compared the differences of phyllosphere fungal community structure and functional groups of different dominant tree species. Moreover, 14 key leaf functional traits of their host trees were measured to investigate the relationships between fungal community composition and leaf functional traits. We found that the dominant phyla and class of phyllosphere fungi were Ascomycota and Basidiomycota, and Dothideomycetes and Taphrinomycetes, respectively. Results of LEfSe analysis indicated that all the tree species except Ulmus japonica had significant biomarkers, such as the Eurotiomycetes of Pinus koraiensis and the Ascomycetes of Quercus mongolica. The main functional groups of phyllosphere fungi were pathotroph. The results of redundancy and envfit analysis showed that functional traits related to plant nutrient acquisition as well as resistance to diseases and pests were the main factors influencing the community structure of phyllosphere fungi.

ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer.

DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m6A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m6A modification in PDAC cells. The m6A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m6A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m6A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

Cost-effectiveness analysis of durvalumab plus etoposide: platinum in the first-line therapy of extensive stage small-cell lung cancer from the Chinese payers' perspective.

INTRODUCTION: Results from the CASPIAN trial (Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer) trial demonstrated the clinical benefit of durvalumab plus etoposide-platinum (EP) chemotherapy as first-line treatment for patients with extensive stage small-cell lung cancer (ES-SCLC). However, considering the high price of durvalumab, it is unclear whether addition of durvalumab to EP chemotherapy has economic value compared with EP alone. In this study, we aimed to evaluate the cost-effectiveness of durvalumab plus EP chemotherapy as a first-line treatment for patients with ES-SCLC. METHODS: A Markov model comprising three health states (stable, progressive, and dead) was developed to simulate the process of small-cell lung cancer. Utility and costs were obtained from published resources. Health outcomes were derived from the CASPIAN trial. Costs were calculated based on the standard medical fees in Zhejiang Province from Chinese patients' perspective. Utility values were obtained from published data. One-way and probabilistic sensitivity analyses were applied to verify model robustness. RESULTS: The addition of durvalumab to EP chemotherapy costs more than $32,220, with a gain of 0.14 quality-adjusted life years (QALYs) compared with EP alone. The incremental cost-effective ratio was $230,142.9 per QALY, which exceeds the willingness to pay threshold of $28,527 per QALY. In the sensitivity analysis, the utility values for the progressive state, costs of durvalumab and EP chemotherapy, and costs for the progressive state were considered to be the three most sensitive factors in the model. CONCLUSION: The addition of durvalumab to EP chemotherapy is not a cost-effective strategy in the first-line therapy of ES-SCLC from the Chinese payers' perspective.

Mortality and Readmission Rates After Heart Failure: A Systematic Review and Meta-Analysis.

OBJECTIVE: The current work aimed to examine the rates of and risk factors for mortality and readmission after heart failure (HF). SETTING: A systematic search was carried out in PubMed, the Cochrane Library, and EMBASE to identify eligible reports. The random-effects model was utilized to evaluate the pooled results. PARTICIPANTS: A total of 27 studies with 515,238 participants were finally meta-analysed. The HF patients had an average age of 76.3 years, with 51% of the sample being male, in the pooled analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measures were 30-day and 1-year readmission rates, mortality, and risk factors for readmission and mortality. RESULTS: The effect sizes for readmission and mortality were estimated as the mean and 95% confidence interval (CI). The estimated 30-day and 1-year all-cause readmission rates were 0.19 (95% CI 0.14-0.23) and 0.53 (95% CI 0.46-0.59), respectively, while the all-cause mortality rates were 0.14 (95% CI 0.10-0.18) and 0.29 (95% CI 0.25-0.33), respectively. Comorbidities were highly prevalent in individuals with HF. CONCLUSION: Heart failure hospitalization is followed by high readmission and mortality rates.

H2S alleviates aortic aneurysm and dissection: Crosstalk between transforming growth factor 1 signaling and NLRP3 inflammasome.

BACKGROUND: Vascular remodeling and inflammation are involved in aortic aneurysm (AA) and aortic dissection (AD). TGF-ß1 signaling is involved in tissue fibrosis, extracellular matrix remodeling and inflammation, which are linked with AA and AD. The inhibition of NLRP3 inflammasome suppresses AA and AD. Hydrogen sulfide (H2S) exerts anti-vascular remodeling and anti-inflammatory properties, but little is known about its action on AA and AD progression. METHODS: The effect of H2S on AA and AD formation was investigated in Sprague-Dawley (SD) rat fed a normal diet supplemented with 0.25% ß-aminopropionitrile (BAPN). HE staining, Masson's trichrome staining, Picrosirius red staining and EVG staining were to evaluate vascular remodeling in the aortic wall. Western blotting and IHC were to detect the expression of TGF-ß1 and matrix metalloproteinases (MMPs) and NLRP3 inflammasome-associated proteins. The interaction between TGF-ß1 signaling and NLRP3 inflammasome was explored in Human aortic vascular smooth muscle cells (HA-VSMCs). RESULTS: H2S alleviated AA and AD progression. Specifically, it improved irregular tissue arrangement and vascular fibrosis, increased the expression of elastin fibers, decreased collagen deposition and the expression of TGF-ß1 and matrix metalloproteinases (MMP-2/9). In addition, H2S inhibited the expression of proteins involved in NLRP3 inflammasome. Furthermore, H2S down-regulated TGF-ß1 signaling and then ameliorated vascular fibrosis by preventing NLRP3 inflammasome activation. Finally, H2S inhibited NLRP3 inflammasome activation and decreased the level of IL-1ß by disrupting TGF-ß1 signaling. CONCLUSIONS: These data support a crosstalk between TGF-ß1 signaling and NLRP3 inflammasome. H2S inhibits AA and AD progression via blocking the crosstalk.

Environmental enrichment combined with fasudil promotes motor function recovery and axonal regeneration after stroke.

Fasudil, a Rho-associated protein kinase (ROCK) inhibitor, has a protective effect on the central nervous system. In addition, environmental enrichment is a promising technique for inducing the recovery of motor impairments in ischemic stroke models. The present study aimed to explore whether environmental enrichment combined with fasudil can facilitate motor function recovery and induce cortical axonal regeneration after stroke. First, a mouse model of ischemic cerebral stroke was established by photochemical embolization of the left sensorimotor cortex. Fasudil solution (10 mg/kg per day) was injected intraperitoneally for 21 days after the photothrombotic stroke. An environmental enrichment intervention was performed on days 7-21 after the photothrombotic stroke. The results revealed that environmental enrichment combined with fasudil improved motor function, increased growth-associated protein 43 expression in the infarcted cerebral cortex, promoted axonal regeneration on the contralateral side, and downregulated ROCK, p-LIM domain kinase (LIMK)1, and p-cofilin expression. The combined intervention was superior to monotherapy. These findings suggest that environmental enrichment combined with fasudil treatment promotes motor recovery after stroke, at least partly by stimulating axonal regeneration. The underlying mechanism might involve ROCK/LIMK1/cofilin pathway regulation. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 20160858A232) on February 24, 2016.

Environmental enrichment combined with fasudil treatment inhibits neuronal death in the hippocampal CA1 region and ameliorates memory deficits.

Currently, no specific treatment exists to promote recovery from cognitive impairment after a stroke. Dysfunction of the actin cytoskeleton correlates well with poststroke cognitive declines, and its reorganization requires proper regulation of Rho-associated kinase (ROCK) proteins. Fasudil downregulates ROCK activation and protects neurons against cytoskeleton collapse in the acute phase after stroke. An enriched environment can reduce poststroke cognitive impairment. However, the efficacy of environmental enrichment combined with fasudil treatment remains poorly understood. A photothrombotic stroke model was established in 6-week-old male C57BL/6 mice. Twenty-four hours after modeling, these animals were intraperitoneally administered fasudil (10 mg/kg) once daily for 14 successive days and/or provided with environmental enrichment for 21 successive days. After exposure to environmental enrichment combined with fasudil treatment, the number of neurons in the hippocampal CA1 region increased significantly, the expression and proportion of p-cofilin in the hippocampus decreased, and the distribution of F-actin in the hippocampal CA1 region increased significantly. Furthermore, the performance of mouse stroke models in the tail suspension test and step-through passive avoidance test improved significantly. These findings suggest that environmental enrichment combined with fasudil treatment can ameliorate memory dysfunction through inhibition of the hippocampal ROCK/cofilin pathway, alteration of the dynamic distribution of F-actin, and inhibition of neuronal death in the hippocampal CA1 region. The efficacy of environmental enrichment combined with fasudil treatment was superior to that of fasudil treatment alone. This study was approved by the Animal Ethics Committee of Fudan University of China (approval No. 2019-Huashan Hospital JS-139) on February 20, 2019.

Epidural electrical stimulation effectively restores locomotion function in rats with complete spinal cord injury.

Epidural electrical stimulation can restore limb motor function after spinal cord injury by reactivating the surviving neural circuits. In previous epidural electrical stimulation studies, single electrode sites and continuous tetanic stimulation have often been used. With this stimulation, the body is prone to declines in tolerance and locomotion coordination. In the present study, rat models of complete spinal cord injury were established by vertically cutting the spinal cord at the T8 level to eliminate disturbance from residual nerve fibers, and were then subjected to epidural electrical stimulation. The flexible extradural electrode had good anatomical topology and matched the shape of the spinal canal of the implanted segment. Simultaneously, the electrode stimulation site was able to be accurately applied to the L2-3 and S1 segments of the spinal cord. To evaluate the biocompatibility of the implanted epidural electrical stimulation electrodes, GFAP/Iba-1 double-labeled immunofluorescence staining was performed on the spinal cord below the electrodes at 7 days after the electrode implantation. Immunofluorescence results revealed no significant differences in the numbers or morphologies of microglia and astrocytes in the spinal cord after electrode implantation, and there was no activated Iba-1+ cell aggregation, indicating that the implant did not cause an inflammatory response in the spinal cord. Rat gait analysis showed that, at 3 days after surgery, gait became coordinated in rats with spinal cord injury under burst stimulation. The regained locomotion could clearly distinguish the support phase and the swing phase and dynamically adjust with the frequency of stimulus distribution. To evaluate the matching degree between the flexible epidural electrode (including three stimulation contacts), vertebral morphology, and the level of the epidural site of the stimulation electrode, micro-CT was used to scan the thoracolumbar vertebrae of rats before and after electrode implantation. Based on the experimental results of gait recovery using three-site stimulation electrodes at L2-3 and S1 combined with burst stimulation in a rat model of spinal cord injury, epidural electrical stimulation is a promising protocol that needs to be further explored. This study was approved by the Animal Ethics Committee of Chinese PLA General Hospital (approval No. 2019-X15-39) on April 19, 2019.

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

Strong influence of strain gradient on lithium diffusion: flexo-diffusion effect.

Lithium ion batteries (LIBs) work under a sophisticated external force field and the electrochemical properties could be modulated by strain. Owing to electro-mechanical coupling, the change of micro local structures can greatly affect the lithium (Li) diffusion rate in solid state electrolytes and the electrode materials of LIBs. In this study, we found, through first-principles calculations, that the strain gradient in bilayer graphene (BLG) significantly affects the Li diffusion barrier, which is termed as the flexo-diffusion effect. The Li diffusion barrier substantially decreases/increases under a positive/negative strain gradient, leading to a change of Li diffusion coefficient of several orders of magnitude at 300 K. Interestingly, the regulation effect of strain gradient is much more significant than that of a uniform strain field, which can have a remarkable effect on the rate performance of batteries, with a considerable increase in the ionic conductivity and a slight change of the original material structure. Moreover, our ab initio molecular dynamics simulations (AIMD) show that the asymmetric distorted lattice structure provides a driving force for Li diffusion, resulting in oriented diffusion along the positive strain gradient direction. We predict the new phenomenon of a flexo-diffusion effect from a theoretical calculation aspect, these findings could extend present LIB technologies by introducing a novel strain gradient engineering.