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The redox imbalance induced by excessive reactive oxygen species (ROS) contributes to senescent phenotypes of chondrocytes in osteoarthritis (OA). However, there is limited evidence regarding the involvement of NADPH oxidase-4 (NOX4)/NFE2-related factor 2 (Nrf2) redox imbalance in OA. Isoquercetin (IQ), a quercetin derivative, exhibits promising antioxidative and anti-aging properties. Here, we found that IQ promoted redox homeostasis by inhibiting NOX4 and activating Nrf2-mediated antioxidant responses, thereby ameliorating OA. Specifically, IQ significantly suppressed the expression of senescence-associated secretory phenotypes (SASPs) in senescent chondrocytes. RNA sequencing analysis revealed that cellular senescence and oxidative stress were involved in the mechanism of IQ's effect on senescent chondrocytes. IQ effectively reversed redox imbalance, as evidenced by reduced levels of ROS and endogenous oxidants, and increased mitochondrial membrane potential and, elevated levels of endogenous antioxidants. Mechanistically, the elevated expression of NOX4 observed in patients with severe OA confirms its role in OA pathogenesis. Molecular docking and NOX4 knockdown experiments suggested that IQ may interact with NOX4 and inhibit its expression. This study identifies a potential therapeutic target and provides a promising candidate for OA treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in this work., (Copyright © 2025. Published by Elsevier B.V.)

Nitrate pollution in terrestrial and aquatic ecosystems in global agricultural areas poses an environmental concern. However, there is limited understanding of hydrogeological controls on the behavior of nitrogen compounds in unsaturated zones. Here, Self-Organizing Map and multiple isotopes approaches (δ 15 N-NO 3 - , δ 18 O-NO 3 - , and δ 15 N-NH 4 + ) were used to investigate the sources, transport and transformation of N-species in the unsaturated zone in an alluvial-lacustrine plain, southeast China. The results revealed significant spatial heterogeneity in soil texture and physicochemical properties with vertically four soil geochemical and N-species zones (high NO₃⁻, high Fe(Ⅲ) and Mn, low ionic, and high NH₄⁺ contents), dominated by agricultural input, soil minerals and redox conditions. Nitrate in the unsaturated zone primarily originated from fertilizers and soil nitrogen. Excess nitrogen fertilizers infiltrated into the soil, where mineralization, nitrification, and dissimilatory nitrate reduction to ammonium (DNRA) acted as key mechanisms for nitrogen transformation. The change in the depositional environment from the plain to the lakeshore area led to nitrification gradual decrease and DNRA significant increase. Consequently, a conceptual model of reactive transport of N-species, influenced by hydrogeologic conditions and biogeochemical processes, was proposed. This study provides a new insight into the nitrate behaviors in unsaturated zone and contributes to groundwater nitrogen management strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2025 Elsevier B.V. All rights reserved.)

This study aimed to clarify the antifungal activity and action mechanism of the lipopeptides from a marine Bacillus amyloliquefaciens HY2-1 against Penicillium digitatum both in vitro and in vivo. Results showed that HY2-1 lipopeptides exerted obvious inhibitions on spore germination and mycelium growth of P. digitatum. Furthermore, HY2-1 lipopeptides caused the aggravated lipid peroxidation, the decreased ergosterol biosynthesis, and the increased nucleic acid and protein leakage in P. digitatum, suggesting the damaged membrane integrity and permeability of P. digitatum. In addition, HY2-1 lipopeptides induced ROS burst and reduced the activities of antioxidant superoxide dismutase and peroxidase in P. digitatum, indicating that the intracellular redox homeostasis of P. digitatum was disturbed. In vivo biocontrol experiments showed that HY2-1 lipopeptides could effectively reduce the occurrence of green mold disease in citrus fruits artificially inoculated with P. digitatum spores. Most significantly, 4.8 mg/mL of HY2-1 lipopeptides achieved 100 % of biocontrol efficacy after 30 days of storage and increased significantly contents of total phenols and flavonoids in citrus peels, demonstrating that HY2-1 lipopeptides inhibited green mold disease by exerting their antifungal activities and triggering fruit defense responses. This study deepens the understanding of marine Bacillus lipopeptides in the biological control of postharvest diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, we developed a novel covalent organic framework (COF) material, termed RuCOFs, specifically designed and synthesized for electrochemiluminescence (ECL) sensor applications. RuCOFs are based on the classic ECL emitter Ru(dcbpy) 3 2+ , ingeniously integrating 4,4',4''-(1,3,5-triazine-2,4,6-triyl) triphenylamine (TAPT) with [2,2'-bipyridine]-5,5'-diamine (BPYDA), forming a structure with a high specific surface area. This configuration not only significantly enhances the stability of the ECL signal but also provides ideal N,N'-bipyridine chelating sites for efficient metal ion recognition. Utilizing Ru(dcbpy) 3 2+ -functionalized COF (RuCOFs), a novel dual-function ECL sensor was developed, achieving high sensitivity and selectivity in detecting mercury (Hg 2 ⁺) and zinc (Zn 2 ⁺) ions. Experimental results indicate that Hg 2 ⁺ significantly quenches the ECL signal, while Zn 2 ⁺ markedly enhances it, with detection limits of 4.71 nM for Hg 2 ⁺ and 6.57 nM for Zn 2 ⁺ across a wide linear response range from 1 μM to 1 nM. This research not only demonstrates the significant advantages of COF-based ECL sensing platforms in tracking environmental metal ions but also opens new possibilities for environmental monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Three-dimensional (3D) organoids derived from human pluripotent stem cells (hPSCs) have revolutionized in vitro tissue modeling, offering a unique opportunity to replicate physiological tissue organization and functionality. This study investigates the impact of radiation on skeletal muscle response using an innovative in vitro human 3D skeletal muscle organoids (hSMOs) model derived from hPSCs., Methods: The hSMOs model was established through a differentiation protocol faithfully recapitulating embryonic myogenesis and maturation via paraxial mesodermal differentiation of hPSCs. Key skeletal muscle characteristics were confirmed using immunofluorescent staining and RT-qPCR. Subsequently, the hSMOs were exposed to a clinically relevant dose of 2 Gy of radiation, and their response was analyzed using immunofluorescent staining and RNA-seq., Results: The hSMO model faithfully recapitulated embryonic myogenesis and maturation, maintaining key skeletal muscle characteristics. Following exposure to 2 Gy of radiation, histopathological analysis revealed deficits in hSMOs expansion, differentiation, and repair response across various cell types at early (30 min) and intermediate (18 h) time points post-radiation. Immunofluorescent staining targeting γH2AX and 53BP1 demonstrated elevated levels of foci per cell, particularly in PAX7 + cells, during early and intermediate time points, with a distinct kinetic pattern showing a decrease at 72 h. RNA-seq data provided comprehensive insights into the DNA damage response within the hSMOs., Conclusions: Our findings highlight deficits in expansion, differentiation, and repair response in hSMOs following radiation exposure, enhancing our understanding of radiation effects on skeletal muscle and contributing to strategies for mitigating radiation-induced damage in this context., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To explore the risk factors of Atrial Fibrillation (AF) with Cognitive Impairment (CI) and to analyze the relationship between cardiac function parameters and the degree of CI in patients., Methods: 120 AF patients were selected, and Montreal Cognitive Assessment (MoCA) was used to distinguish between AF patients with and without CI. Univariate analysis and multivariate Logistic regression analysis were used to evaluate the impact of sociodemographic data, disease-related data, and clinical data on risk factors for AF with CI. Pearson's method was used to analyze the correlation between cardiac function parameters and cognitive function scores in AF patients., Results: There were 89 patients with CI and 31 patients without CI, and the MoCA scores of patients with CI were lower than those in patients without CI. Age, occupational status, educational level, combined smoking history, drinking history, and heart failure, as well as systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, C-reactive protein, free thyroxine, free triiodothyronine, and D-dimer were risk factors for the patient with CI. Left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left atrial maximum volume in patients with CI were higher than those in patients without CI, and left ventricular ejection fraction and peak early diastolic velocity/peak late-diastolic mitral velocity ratio were lower., Conclusion: The cardiac function parameters of patients are closely related to attention, orientation, memory, visuospatial, and executive ability. Cardiac function parameters were closely related to cognitive functions., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Endogenous hydrogen sulfide (H 2 S) plays an important role in bone metabolism. However, the exact role of H 2 S in intestinal calcium and phosphorus absorption and its potential in preventing and treating primary osteoporosis remains unknown. Therefore, this study aimed to investigate the potential of H 2 S in promoting intestinal calcium and phosphorus absorption and alleviating primary osteoporosis. We measured the apparent absorptivity of calcium, femoral bone density, expression and sulfhydration of the duodenal endoplasmic reticulum protein of 57 kDa (ERp57), duodenal cystathionine γ-lyase (CSE) expression, and serum H 2 S content in adult and old CSE-knockout and wild-type mice. We also assessed intracellular reactive oxygen species (ROS) and Ca 2+ content in CSE-overexpressing or knockout intestinal epithelial cell (IEC)-6 cells. In senile mice, CSE knockout decreased endogenous H 2 S, ERp57 sulfhydration, and intestinal calcium absorption and worsened osteoporosis, which were partially reversed by GYY4137, an H 2 S donor. CSE overexpression in IEC-6 cells increased ERp57 sulfhydration, protein kinase A and C activity, and intracellular Ca 2+ , whereas CSE knockout exerted the opposite effects. Furthermore, hydrogen peroxide (H 2 O 2 ) stimulation had similar effects as in CSE knockout, which were reversed by pretreatment with sodium hydrosulfide before H 2 O 2 stimulation and restored by DL-dithiothreitol. These findings suggest that H 2 S attenuates primary osteoporosis by preventing ROS-induced ERp57 damage in intestinal epithelial cells by enhancing ERp57 activity and promoting intestinal calcium absorption, thereby aiding in developing therapeutic interventions to prevent osteoporosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

The synergism of host Paris polyphylla medium, the monoculture, and the coculture led to seventeen new metabolites, including eight sesquiterpenes, 1-7 having uncommon structural motifs compared to similar caryophyllene derivatives, 8 with an unprecedented bicyclic framework, and three xyloketals (13-15) with unprecedented frameworks from Nigrospora lacticolonia; one polyketide, 17 with novel bicyclo [2.2.2] undecane skeleton, and five polyketide-terpenoid hybrids, 20 (one novel sulfated), 21-24 from Penicillium rubens. The structures were determined mainly by the NMR, HRESIMS, ECD calculation, and single-crystal X-ray diffraction. Nine cryptic compounds (2-4, 5, 12-15, 17) were produced by the inductions of host medium and the coculture. The compounds 13 from N. lacticolonia, 24-26, 28, 29, and 31 from P. rubens indicated significant antiphytopathogenic activities against N. lacticolonia with MICs at 2-4 μg/mL. Moreover, compounds 22-26, 28, 29, and 31 from P. rubens showed antifungal activities against P. rubens with MICs at 2-4 μg/mL. The synergistic effects of host medium and the coculture can induce the structural diversity of metabolites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Methacrylic anhydride was added to 20 % gelatin solution to prepare gelatin methacryloyl (GelMA) but an unexpected gelation process was observed within several minutes. The experimental data revealed that the methacryloyl substitution can increase the hydrophobicity of gelatin and the micellar diameter in solution. Therefore, we speculated that the methacryloyl substitution caused the formation of micellar cross-links based on the hydrophobic residues of gelatin and the methacryloyl groups, thus obtaining the hydrophobic association hydrogels. The thixotropic and tensile experiments confirmed that GelMA hydrogel possessed the features of hydrophobic association hydrogels like self-healing and stretchable abilities. The rheological experiments revealed that the gelation rate and the mechanical strength of the GelMA hydrogels were in direct proportion to the concentration of GelMA and the degree of methacryloyl substitution. GelMA hydrogels possessed desirable thermal stability that it didn't melt after being heated to 90 °C. Furthermore, the MTT assays and calcein AM/PI staining revealed that GelMA hydrogel was biocompatible. These results collectively confirm that the hydrophobic association is a prospective and facile approach to prepare gelatin hydrogel with desirable properties for further application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The present study introduces a novel fluorescent sensor with an overtone peak reference designed for the detection of mercury (Ⅱ) ions (Hg 2+ ) and hydrogen sulfide (H 2 S). The study proposes two novel response mechanisms that hinges on the synergistic effect of cation exchange dissociation (CED) and photo-induced electron transfer (PET). This sensor exhibits a remarkable detection limit of 2.9 nM for Hg 2+ . Additionally, the sensor reacts with H 2 S to generate nickel sulfide (NiS) semiconductor nanoparticles, which amplify the fluorescence signal and enable a detection limit of 3.1 nM for H 2 S. The detection limit for H 2 S is further improved to 29.1 pM through the surface functionalization of the nanomaterial with pyridine groups (increasing reactivity) and chelation of gold nanoparticles (AuNPs), which enhances the sensor's specificity. This improvement is primarily due to the surface plasmon resonance (SPR) of AuNPs and their affinity for H 2 S. The single-emission strategy can yield skewed results due to environmental changes, whereas the overtone peak reference strategy enhances result accuracy and reliability by detecting environmental interference through reference emission peaks. In another observation, the low-toxicity dihydropyrene-bipyridine nanorods (TPP-BPY) has been successfully utilized for both endogenous and exogenous H 2 S detection in vivo using a mouse model. The successful development of TPP-BPY is expected to provide an effective tool for studying the role of H 2 S in biomedical systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Cancer stem cells (CSCs) are found in many solid tumors, which play decisive roles in the occurrence, recurrence and metastasis of tumors. However, drugs are difficult to kill CSCs due to their limited number and location in oxygen-deprived tissue far from the blood vessels. Meanwhile, the survival and stemness maintenance of CSCs strongly depend on the tumor microenvironment (TME). Herein, we developed a CD44 antibody modified iridium nanosheet with enzyme-like activity (defined as Ir Nts-Ab) that effectively eradicates CSCs for cancer therapy. We observe that Ir Nts-Ab can enrich tumor tissues to remove excessive reactive oxygen species and produce oxygen, thus alleviating hypoxia and the inflammatory TME to reduce the proportion of CSCs and inhibit metastasis. In addition, Ir Nts-Ab targets CSCs and normal cancer cells with near infrared II-region photothermal therapy (NIR-II PTT), and is easily taken up by CSCs due to recognition of the CD44 proteins. Moreover, photoacoustic imaging helps monitor drug accumulation and hypoxic TME improvement in tumor tissue. Importantly, Ir Nts-Ab has good biological safety, making it suitable for biomedical applications. This iridium nanozyme based on TME regulation as well as NIR-II PTT will be a promising strategy for the treatment of cancer. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs) are key factors that make tumors difficult to eradicate, and strongly depend on the hypoxic tumor microenvironment (TME), which plays a crucial role in the occurrence and metastasis of tumors. Herein, an antibody modified iridium nanosheet (definition as Ir Nts-Ab) was developed for targeted eradication of CSCs by photoacoustic imaging guided photothermal therapy (PTT) and TME regulation. Ir Nts-Ab with catalase-like activity could inhibit HIF-1α by producing oxygen, thus effectively reducing the proportion of CSCs and inhibiting tumor metastasis. Additionally, Ir Nts-Ab achieved the eradication of CSCs by PTT, and eliminated reactive oxygen species to decrease the inflammatory response, resulting in reduced tumor metastasis, which was promising for the cure of solid tumors in the clinics., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the risk factors for acute cerebral infarction(ACI) in patients with non-variceal upper gastrointestinal bleeding(NVUGIB), and construct a model for predicting ACI in NVUGIB patients., Methods: A model for predicting ACI induced by NVUGIB was established on the basis of a retrospective study that involved 1282 patients who were diagnosed with NVUGIB in the emergency department and Gastroenterology Department of Nanchang University Affiliated Ganzhou Hospital from January 2019 to December 2021. Receiver operating characteristic (ROC) curves were drawn to evaluate the sensitivity and specificity of the model and CHA 2 DS 2 -VASc score to predict ACI. Delong's test was used to compare AUCs of the present score and the CHA2DS2-VASc score., Results: There were 1282 patients enrolled in the study, including 69 in the ACI group and 1213 in the non-ACI group. Multivariate analysis revealed that hypertension, diabetes, red blood cell (RBC) transfusion, mechanical ventilation, D-dimer, rate pressure product (RPP), somatostatin and mean platelet volume (MPV) were factors associated with ACI induced by NVUGIB. A model based on the eight factors was established, Logit(P)= 0.265 + 1.382 × 1 + 1.120 × 2 + 1.769 × 3 + 0.839 × 4-1.549 × 5-0.361 × 6 + 0.045 × 7 + 1.158 × 8(or 1.069 ×9) (X1, hypertension=1; X2, diabetes=1; X3, RBC transfusion=1; X4, mechanical ventilation=1; X5, somatostatin=1; X6, MPV(fL); X7, D-dimer(ng/l); X8, low RPP= 1; X9, high RPP = 2). The area under ROC curve of the model was 0.873, the sensitivity and specificity were 0.768 and 0.887, respectively. The area under ROC curve of CHA 2 DS 2 -VASc score was 0.792, the sensitivity and specificity were 0.728 and 0.716, respectively. Delong's test showed the area under ROC curve of the present study was significantly larger than that of CHA2DS2-VASc score., Conclusions: Hypertension, diabetes, RBC transfusion, mechanical ventilation, D-dimer, RPP, somatostatin and MPV were factors associated with ACI induced by NVUGIB. A model constructed based on these factors showed excellent prediction of ACI, and was superior to CHA 2 DS 2 -VASc score. However, this needs to be further validated by multi-center study with a larger sample size., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest for this article., (Copyright © 2023. Published by Elsevier B.V.)

Ageratina adenophora (A. adenophora), one of the prominent invasive plants in the Asian continent has shown toxicity in animals. However, studies examining the gene expression and metabolic profiles of animals that ingest A. adenophora have not yet been reported in the literature. Therefore, considering the wide distribution of A. adenophora, it is necessary to elucidate the toxic mechanisms of A. adenophora via multiomics approach. In this study, we identified and evaluated the toxic mechanisms of action associated with bioactive compounds in A. adenophora by using network toxicology studies combined with metabolomics and transcriptomics and found that 2-deoxo-2-(acetyloxy)- 9-oxoageraphorone, 10Hβ-9-oxo-agerophorone, 10Hα-9-oxo-agerophorone, nerolidol, 9-oxo-10,11-dehydro-agerophorone were the main active toxic compounds in A. adenophora. In addition, using metabolomics approach we identified differential metabolites such as L-pyroglutamic acid, 1-methylhistidine, prostaglandin F2alpha and hydrocortisone from A. adenophora and these metabolites were involved in amino acid metabolism, lipid metabolism and signal conducting media regulation. Based on network toxicological analysis, we observed that, A. adenophora can affect the Ras signaling, Phospholipase D signaling and MAPK signaling pathways by regulating EGFR, PDGFRB, KIT and other targets. From the results of this study we concluded that A. adenophora induces liver inflammatory damage by activating the EGFR expression and Ras/Raf/MEK/ERK signaling pathways as well as affect nutrients metabolism and neuron conduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the lack of statistical methods, few studies have investigated the spatial autocorrelated distribution in the association between short-term exposure to PM 2.5 and mortality and used a statistical manner to explore the association-clustered regions, which play important roles in identifying high-sensitivity/susceptibility regions. The Sichuan Basin (SCB) is one of the most PM 2.5 -polluted areas, and the extreme economic imbalance may cause considerable spatial heterogeneity and clustering in PM 2.5 -mortality association. In this work, we used a recently proposed strategy by us to investigate the spatially autocorrelated and clustered association between daily PM 2.5 and cardiorespiratory mortality from 2015 to 2019 in 130 counties of the SCB. First, generalized additive models were independently constructed to obtain the county-level association estimations. Then, an estimation-error-based spatial scan statistic was used to detect the association-clustered regions. Third, multivariate conditional meta autoregression was used to obtain the spatially autocorrelated association distribution, based on which the attributable deaths were mapped and their inequality was evaluated using the Gini coefficient and Lorenz curve. Results showed that two significantly association-clustered regions were detected. One is mainly located in the megacity Chengdu where PM 2.5 presented a significantly stronger association with no threshold effect at low-level PM 2.5 but a threshold at high-level PM 2.5 . In the other cluster, a threshold effect at low-level PM 2.5 but no threshold at high-level PM 2.5 were found. The mortality risk at low/middle-level PM 2.5 decreased from Chengdu as the center to the surrounding areas. A total of 29,129 (2.0 %) deaths were attributable to the excess PM 2.5 exposure. The attributable deaths also decreased from Chengdu as the center to the surrounding areas with Gini coefficients of 0.43 and 0.3 for absolute and relative attributable deaths, respectively. This novel strategy provided a new epidemiological perspective regarding the association and implicated that Chengdu is significantly deserving of more attention regarding PM 2.5 -related health loss., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the risk factors for gastrointestinal bleeding in patients with cerebral infarction after dual antiplatelet therapy., Methods: Cerebral infarction patients who received dual antiplatelet therapy during January 2019 and December 2021 in Nanchang University Affiliated Ganzhou Hospital were included. Patients were divided into a bleeding group and a nonbleeding group. Propensity score matching was used to match the data between the two groups. The risk factors for cerebral infarction with gastrointestinal bleeding after receiving dual antiplatelet therapy were analyzed by conditional logistic regression., Results: There were 2370 cerebral infarction patients who received dual antiplatelet therapy included in the study. There were significant differences between the bleeding group and the nonbleeding group in terms of sex, age, smoking, drinking, hypertension, coronary heart disease, diabetes and peptic ulcer before matching. After matching, 85 patients were included in the bleeding group and nonbleeding group, and there was no significant difference between the two groups in terms of sex, age, smoking, drinking, previous cerebral infarction, hypertension, coronary heart disease, diabetes, gout or peptic ulcer. Conditional logistic regression analysis showed that long-term use of aspirin and severity of cerebral infarction were risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy, whereas the use of PPI was a protective factor against gastrointestinal bleeding., Conclusions: Long-term use of aspirin and severity of cerebral infarction are risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy. The use of PPIs could reduce the risk of gastrointestinal bleeding., Competing Interests: Declaration of Competing interest Authors declare no Conflict of Interests for this article., (Copyright © 2023. Published by Elsevier B.V.)

Knowledge of moisture sources is of great significance for the understanding of groundwater recharge and hydrological cycle. However, it is often difficult to identify the moisture sources and evolution especially in the areas with complex climate system. Isotopes in groundwater that acts as a climate archive provide a unique perspective on the moisture sources and evolution. In this study, the stable isotopes ( 2 H, 18 O) of precipitation and groundwater, radioactive isotope ( 14 C) of groundwater, water vapor trajectory modeling (HYSPLIT models) and d-excess based on mass balance model were employed to reveal the groundwater origin, moisture source and evolution in the northeastern Qaidam Basin, northeast Tibetan Plateau, China. The stable isotopic compositions indicate that the precipitation in the mountainous areas is the main origin of groundwater. The spatiotemporal variation of groundwater d-excess together with HYSPLIT modeling suggest that the moisture sources in the northeastern Qaidam Basin have been controlled by the Westerlies and did not alter obviously with time, whereas Delingha with relatively low elevation is influenced by both the Westerlies and local recycled moisture. More than 80 % water vapor derives from the northwest of study area for the plain and mountainous area, except for the mountainous area of Delingha, where approximately 23 % water vapor originates from the surface water evaporation in the plain area. The water vapor with high d-excess formed in the plain area is transported to the mountainous area and mixed with advected water vapor, resulting in the large d-excess of groundwater in Delingha. The moisture recycling fraction in precipitation for the mountainous area of Delingha is estimated to be about 2.0 % by using d-excess-based mass balance model. The results of the study could be helpful to the understanding of hydrological cycle of the area and elsewhere., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Groundwater nitrate (NO 3 - ) pollution has attracted widespread attention; however, accurately evaluating the sources of NO 3 - and their contribution patterns in regional groundwater is difficult in areas with multiple sources and complex hydrogeological conditions. In this study, 161 groundwater samples were collected from the Poyang Lake Basin for hydrochemical and dual NO 3 - isotope analyses to explore the sources of NO 3 - and their spatial contribution using the Positive Matrix Factorization (PMF) and Bayesian stable isotope mixing (MixSIAR) models. The results revealed that the enrichment of NO 3 - in groundwater was primarily attributed to sewage/manure (SM), which accounted for more than 50 %. The contributions of nitrogen fertilizer and soil organic nitrogen should also be considered. Groundwater NO 3 - sources showed obvious spatial differences in contributions. Regions with large contributions of SM (>90 %) were located in the southeastern part of the study area and downstream of Nanchang, which are areas with relatively high population density. Nitrogen fertilizer and soil organic nitrogen showed concentrated contributions in paddy soil in the lower reaches of the Gan and Rao Rivers, and these accumulations were mainly driven by the soil type, land use type, and topography. This study provides insight into groundwater NO 3 - contamination on a regional scale., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The source and evolution of sulfate (SO 4 2- ) in groundwater from abandoned mines are widely concerned environmental issues. Herein, major dissolved ions, multi-isotopes (δ 34 S, δ 18 O sulfate , δ 2 H and δ 18 O water ), machine learning (Self-organizing maps) and Bayesian isotope mixing model were used to identify the source and evolution of SO 4 2- in an abandoned mine (Fengfeng mine, northern China) with a multi-layer groundwater system. Groundwater in the study area was mainly divided into three clusters (Cluster I, Cluster II and Cluster III), dominated by Na-SO 4 , Ca-SO 4 and Ca-HCO 3 types, respectively. According to δ 2 H and δ 18 O water , groundwater in the study area mainly originated from atmospheric precipitation. δ 34 S, δ 18 O sulfate and SO 4 2- suggested that bacterial sulfate reduction did not affect the SO 4 2- isotopic composition. Dual SO 4 2- isotopes, and MixSIAR model revealed that the main source of SO 4 2- in the study area was pyrite oxidation/gypsum dissolution, accounting for an average of 57.4 % (gypsum), 71.24 % (pyrite oxidation) and 52.93 % (pyrite oxidation) of SO 4 2- in the samples of Clusters I-III, respectively. Combined with the hydrochemical diagrams, the evolution of SO 4 2- in different clusters of samples was derived. Cluster I was mainly gypsum dissolution; In contrast, Clusters II and III were mainly pyrite oxidation accompanied by carbonate dissolution, and Cluster II was also influenced by cation exchange. These findings will help in developing management strategies for protecting groundwater quality, which will provide a reference for the study of solute sources and S cycling in abandoned mines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

D-Psicose, a new-generation sugar substitute, has been enzymatically synthesized through D-fructose isomerization. However, isomerization often causes low yields due to unfavorable thermodynamic equilibria, which limited its further industrial application. In this study, we present a redox-driven multi-enzyme cascade, two-step biotransformation system to produce D-psicose from D-fructose. Compared to D-fructose isomerization, this method has a maximized theoretical conversion rate of 100%. D-Psicose-3-epimerase from Clostridiales (CBDPE), ribitol 2-dehydrogenase from Providencia alcalifaciens (PRDH), and formate dehydrogenase from Starkeya (SFDH) were co-expressed in Escherichia coli in the first step to produce D-allitol from D-fructose. Afterward, NADH oxidase from Streptococcus pyogenes (SPNOX), and ribitol 2-dehydrogenase from Rubrivivax sp. (RSRDH) were co-expressed in E. coli to oxidize D-allitol into D-psicose in the second step. The two-step biotransformation system was optimized to maximize the D-fructose-to-D-psicose conversion rate (up to 90%), corresponding to a concentration of 450 mM. This study suggests that this redox-driven multi-enzyme cascade strategy through a sugar-to-alcohol-to-sugar pathway has the advantage of great application for enhanced production of D-psicose and other rare sugars., Competing Interests: Conflict of Interest The authors confirm that there is no conflict of interest regarding this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

N6-methyladenosine (m6A) in RNAs is closely related to various biological progresses, but the specific regulatory mechanisms are still unclear. The existing m6A single-base resolution analysis techniques have problems of specificity and sensitivity to be improved, which can hardly meet the urgent needs of basic research and clinical applications. This work proposes a new strategy based on xeno nucleic acid (XNA) probe and CRISPR/Cas12a signal amplification for the sensitive detection of site-specific m6A modifications. According to the difference in the thermodynamic stability of hybridization between XNA probe with m6A-RNA and A-RNA, XNA was designed as a block probe to mediate m6A-RNA specific reverse transcription polymerase chain reaction (MsRT-PCR). Therefore, m6A can be specifically distinguished by converting difficult-to-test m6A modifications into easily detectable dsDNA fragments. Integration of CRISPR/Cas12a technology, skilfully designed sequences of crRNAs targeting m6A site-specific amplification dsDNA. The specificity was significantly improved through dual specific recognition of XNA probe and crRNA. Furthermore, the sensitivity of the assay was also greatly increased by the combined signal amplification of PCR and CRISPR/Cas12a. Additionally, we extend the application of CRISPR/Cas12a to flexible fluorescent and electrochemical biosensing system, which can accurately detect m6A modifications with different ranges of methylation fractions. The analysis results of m6A sites in MALAT1, ACTB and TPT1 further demonstrated the feasibility of the constructed biosensor for the accurate detection of hypomethylated samples in cells. The implementation of this work will provide strong technical support to promote the in-depth research on m6A in disease regulation mechanisms and in vitro molecular diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

The spatial distribution of mine water quality and geochemical controls must be investigated for water safety and ecosystem protection in Shaanxi-Inner Mongolian Coal Mine Base (SICMB). Based on 122 mine water samples collected from 14 mining areas, self-organizing maps (SOM) combining with principal component analysis (PCA) derived that the mine water samples were classified into seven clusters. Clusters 1 and 3 (C1 and C3) samples were dominant by HCO 3 -Ca and mixed types, which were distributed in the recharge area of the middle SICMB. In this area, the active groundwater circulation contributed to the good water quality. Cluster 2 (C2) samples were characterized by HCO 3 -Na type, mainly distributed in the discharge area of the middle SICMB. These samples were threatened by heavy fluorine contamination and high residual sodium carbonate (RSC) because of slow groundwater flow in this area. Clusters 4 and 5 (C4 and C5) samples, distributed in the northeast and middle SICMB, were characterized by high Cl - concentration and light fluorine contamination. They were influenced by anthropogenic input through faults or underground mining. In contrast, Clusters 6 and 7 (C6 and C7) samples with high salinity and sulfate were distributed in the southwest SICMB. The deep groundwater circulation enhanced water-rock interaction and contributed to poor water quality. These findings are beneficial to the management of mine water resources in the SICMB and provide an insight to investigate the mine water quality in large spatial scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

The hydrogeochemical evolution of groundwater is related to and affected by long-term mining activities, which may deteriorate the quality of groundwater. The Fengfeng mine in Handan, North China has a 30-y history of coal mining with long-term mining activities and complex geological conditions, resulting in a complex hydrogeochemical environment in the mining region. In this study, the hydrogeochemical evolution mechanism of groundwater in a multi-aquifer system in the Fengfeng Mining Area was investigated using machine learning (self-organizing maps combined with K-means clustering) and sulfur and oxygen isotopes (δ 34 S SO4 and δ 18 O SO4 ). The hydrogeochemical characteristics of different aquifers in the mining area changed to different degrees after mining compared with the characteristics before mining. The spatiotemporal variations in groundwater components were found to be controlled by pyrite oxidation, gypsum dissolution, and carbonate dissolution, which are affected by mining activities. Pyrite oxidation primarily occurred in the Carboniferous thin-layer limestone aquifer (CLA) and Permian sandstone aquifer (PSA). The hydrogeochemical evolution in the Ordovician limestone aquifer (OLA), the main aquifer in the study area, was affected by leakage recharge from CLA and PSA caused by mining activities. The results showed that owing to the effects of long-term mining, the altered groundwater flow system affected the evolution of groundwater components in each aquifer, particularly the sulfate concentration. This study reveals a distinct hydrogeochemical evolution induced by mining activities, which can provide a basis for groundwater resource management in mining areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Numerous studies have studied the association between daily average temperature (DAT) and daily COVID-19 confirmed cases, which show considerable heterogeneity, even opposite results, among different regions. Such heterogeneity suggests that characterizing the association on a large area scale would ignore the local variation, even obtain false results in some local regions. So, characterizing the spatial distribution of heterogeneous DAT-COVID-19 associations and exploring the causes plays an important role on making temperature-related region-specific intervention measures and early-warning systems., Methods: Aiming to characterize the spatial distribution of associations between DAT and COVID-19 confirmed cases in the continental United States, we proposed a novel two-stage strategy. In the first stage, we used the common stratified distributed lag nonlinear model to obtain the rough state-specific associations. In the second stage, conditional autoregression was used to spatially smooth the rough estimations. Furtherly, based on the idea, two modified strategies were used to investigate the time-varying associations and the modification effects derived from the vaccination campaign., Results: Around one-third of states exhibit no significant association between DAT and daily confirmed COVID-19 cases. Most of the remaining states present a low risk at low DAT and a high risk at high DAT, but several states present opposite associations. The average association curve presents a 'S' shape with positive association between -8 - 18 °C and keeping flat out of the range. An increased vaccination coverage rate will increase the risk when DAT < 12 °C, but slightly affect the risk when DAT > 12 °C., Conclusion: A considerable spatial heterogeneity of DAT-COVID-19 associations exists in America and the average association curve presents a 'S' shape. The vaccination campaign significantly modifies the association when DAT is low, but only make a slight modification when DAT is high., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study evaluated the learning effects and examined the participants' perceptions of an interprofessional shared decision-making (IP-SDM) training program., Methods: This mixed-method study used a quasi-experimental pretest-posttest design in the quantitative phase and semi-structured interviews in the qualitative phase. The 6-week curriculum design, based on Kolb's experiential learning cycle, consisted of two simulated objective structured clinical examinations with standardized patients and blended teaching methods through various course modules., Results: A total of 39 multidisciplinary healthcare personnel completed the 6-week training program, and 32 of them participated in qualitative interviews. The IP-SDM training program effectively improved the SDM process competency of the participants from the perspectives of the participants, standardized patients, and clinical teachers. The interviews illustrated how the curriculum design enhanced learning; the effectiveness results indicated improvements in learners' attitude, knowledge, skills, and teamwork., Conclusion: This IP-SDM training program improved multidisciplinary healthcare personnel's competency, self-efficacy, and intention to engage in IP-SDM., Practice Implications: Applying Kolb's experiential learning cycle and blended teaching methods to develop and implement the IP-SDM training program can improve multidisciplinary healthcare personnel's knowledge, attitude, skills, and teamwork in IP-SDM., Competing Interests: Conflict of interest No other disclosures are reported., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Our previous study demonstrated that endothelial nitric oxide synthase (eNOS) gene serves as a candidate for modifiers of hypertrophic cardiomyopathy (HCM), which alters severity of HCM phenotypes. Herein, we sought to further elucidate the role of eNOS on cardiac myocyte hypertrophy and fibrosis, the major phenotypes of HCM., Methods: Male eNOS-deficient mice (eNOS-/-) and wild type control mice (eNOS+/+, C57B1/6 J) were used in this study. Myocyte size was analyzed in hematoxylin/eosin stained sections using an image analyzing system. Cardiac β-myosin heavy chain (β-MHC) and α-skeletal actin (α-SKA) levels, markers of myocyte hypertrophy were evaluated by Western blot. Cardiac collagen volume fraction (CVF) was examined in picrosirius red stained section using an image analyzing system. Cardiac expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and transforming growth factor beta 1 (TGF-β1), markers of fibrosis, were determined by Western blot., Results: Compared to eNOS+/+ mice, we found that; 1) myocyte size was significantly increased in eNOS-/- mice; 2) cardiac expression of β-MHC was markedly elevated, while α-SKA levels remained unchanged in eNOS-/- mice; 3) cardiac total and interstitial CVF levels were significantly higher in eNOS-/- mice; and 4) cardiac TIMP-1 levels were significantly greater in eNOS-/- mice, however, cardiac TGF-β1 was not differently expressed between the two groups., Conclusion: The current study revealed that eNOS plays a beneficial role in cardiac remodeling, preventing the heart from development of myocyte hypertrophy and cardiac fibrosis. These findings support our previous report that eNOS may modify the severity of HCM phenotypes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As an artificial nanomachine, a DNA walker demonstrates the potential for biosensing. In this study, a highly integrated, biostable, and autonomous electrochemical DNA walker sensor was rationally designed by a simple assembly of a Mn 2+ -dependent DNAzyme-powered DNA walker with nanoscale Mn 2+ @MOFs containing free carboxylic acid groups UiO-66(Zr)-(COOH) 2 . In this study, the release of Mn 2+ from Mn 2+ @MOFs was exploited to drive the autonomous and progressive operation of the DNA walker, and the DNAzyme-driven DNA walker was constructed by the co-modification of walking strands and track strands onto the gold electrode (GE) surface. The walking strand was a single-stranded DNA containing a DNAzyme sequence, which was pre-silenced by the locking strand. The track strand was a specially designed DNA sequence that the target can hybridize with the locking strand; hence, the walking strand is unlocked, and the liberated DNAzyme catalyzes the cleavage of track strands to drive the DNA walker operation, shifting tetraferrocene away from the electrode and producing a significant signal change. A detection limit of 38 fM was obtained with our new system, exhibiting a wide linear range from 1.5625 × 10 -9 M to 1 × 10 -13 M. The proposed approach provided a novel means for constructing an highly integrated, automated, and DNAzyme-driven DNA walker for bioanalysis., (Copyright © 2022. Published by Elsevier B.V.)

Background: Distraction osteogenesis (DO) is a widely used bone regenerative technique. However, the DO process is slow, and the consolidation phase is long. Therefore, it is of great clinical significance to explore the mechanism of DO, and shorten its duration. Recent studies reported that stem cell exosomes may play an important role in promoting angiogenesis related to DO, but the mechanism remains unclear., Methods: Canine endothelial colony-forming cells (ECFCs) were isolated and cultured, and the expression of THBS1 in canine ECFCs were inhibited using a lentiviral vector. The exosomes secreted by canine ECFCs were isolated and extracted, and the effect of exosomes on the angiogenic activity of Human umbilical vein endothelial cells (HUVECs) was detected by proliferation, migration, and tube formation experiments. WB and qRT-PCR were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on HUVECs angiogenesis. Then, a mandibular distraction osteogenesis (MDO) model was established in adult male beagles, and exosomes were injected into the canine peripheral blood. Micro-CT, H&E, Masson, and IHC staining were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on angiogenesis and osteogenesis in the DO area., Results: ECFC-Exo accelerated HUVECs proliferation, migration and tube formation, and this ability was enhanced by inhibiting the expression of THBS1 in ECFC-Exo. Using Western blot-mediated detection, we demonstrated that inhibiting THBS1 expression in ECFCs-Exo activated PI3K, AKT, and ERK phosphorylation levels in HUVECs, which promoted VEGF and bFGF expressions. In the DO model of the canine mandible, ECFCs-Exo injected into the peripheral blood aggregated into the DO gap, thus promoting angiogenesis and bone formation in the DO tissue by reducing THBS1 expression in ECFC-Exo., Conclusion: Our findings suggested that ECFC-Exos markedly enhances angiogenesis of endothelial cells, and promotes bone healing in canine MDO. Thus, THBS1 plays a crucial role in the ECFC-Exos-mediated regulation of canine MDO angiogenesis and bone remodeling., The Translational Potential of This Article: This study reveals that the angiogenic promotion via THBS1 suppression in ECFC-Exos may be a promising strategy for shortening the DO duration., Competing Interests: None., (© 2022 The Authors.)

Of the 3 million older adults seeking fall-related emergency care each year, nearly one-third visited the Emergency Department (ED) in the previous 6 months. ED providers have a great opportunity to refer patients for fall prevention services at these initial visits, but lack feasible tools for identifying those at highest-risk. Existing fall screening tools have been poorly adopted due to ED staff/provider burden and lack of workflow integration. To address this, we developed an automated clinical decision support (CDS) system for identifying and referring older adult ED patients at risk of future falls. We engaged an interdisciplinary design team (ED providers, health services researchers, information technology/predictive analytics professionals, and outpatient Falls Clinic staff) to collaboratively develop a system that successfully met user requirements and integrated seamlessly into existing ED workflows. Our rapid-cycle development and evaluation process employed a novel combination of human-centered design, implementation science, and patient experience strategies, facilitating simultaneous design of the CDS tool and intervention implementation strategies. This included defining system requirements, systematically identifying and resolving usability problems, assessing barriers and facilitators to implementation (e.g., data accessibility, lack of time, high patient volumes, appointment availability) from multiple vantage points, and refining protocols for communicating with referred patients at discharge. ED physician, nurse, and patient stakeholders were also engaged through online surveys and user testing. Successful CDS design and implementation required integration of multiple new technologies and processes into existing workflows, necessitating interdisciplinary collaboration from the onset. By using this iterative approach, we were able to design and implement an intervention meeting all project goals. Processes used in this Clinical-IT-Research partnership can be applied to other use cases involving automated risk-stratification, CDS development, and EHR-facilitated care coordination., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel fluorescent probe (DSD) was reasonably designed and synthesized with dansyl-labeled dipeptide (Dan-Ser-Asp-NH 2 ). DSD featured remarkably large Stokes shift (230 nm) and perfect water solubility, and exhibited high selectivity and rapid recognition toward Cu 2+ via fluorescence quenching. The detection limit of DSD for Cu 2+ was 2.4 nM, indicated that DSD has excellent sensitivity. In addition, the stoichiometry between DSD and Cu 2+ were detected as 1:1 by fluorescence titration, Job's plot and ESI-HRMS data. As designed, DSD-Cu 2+ system was able to sequentially detect CN - according to the displacement approach with fluorescence "off-on" response, and the detection limit for CN - was calculated to be 41.9 nM. Specifically, the response time of DSD with Cu 2+ and CN - was less than 40 s, which rendered it suitable for real time detection in actual water samples. In addition, with the alternate addition of Cu 2+ and CN - , the reversible cycles could be repeated for at least 10 times, indicated that DSD was a promising reversibility probe. DSD showed low toxicity and good biocompatibility, and was successfully applied to detect Cu 2+ and CN - in living cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Fine particle pollution, specifically pollution by fine particulate matter (PM 2.5 ), remains a significant concern in developing countries and plays an important role in the development and progression of respiratory diseases. Increasing evidences have demonstrated that long non-coding RNAs (lncRNAs) may act as vital molecules by binding to specific RNA-binding protein (RBP); however, their relationship with PM 2.5 pollution is largely unexplored., Objective: We investigated the association between lncRNA and respiratory system inflammation caused by PM 2.5 ., Methods: PM 2.5 components were detected by gas chromatography-mass spectrometry (GC-MS), inductively coupled plasma-mass spectrometry (ICP-MS), and ionic chromatography. We established an inflammation model of PM 2.5 -induced toxicity in vivo (male and female SD rats, 0, 25, 50 and 100 mg/k PM 2.5 , 1, 7 and 14 days, single non-invasive tracheal instillation) and in vitro (rat alveolar macrophage cell line (NR8383), 0, 50, 100, 200, 400 μM PM 2.5 for 24, 48, and 72 h). lncRNA high-throughput sequencing (lncRNA-seq) was used to investigate lncRNA profiles in PM 2.5 -treated NR8383 cells, and RNA interference (RNAi) was applied to explore the function of the target lncRNA. The mechanisms associated with specific lncRNAs were explored using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and western blot., Results: PM 2.5 -treated NR8383 cells and SD rats exhibited respiratory inflammation. lncRNA AABR07005593.1 was a pro-inflammatory factor that regulated IL-6 levels. Mechanistically, ChIRP-MS and western blot analyses revealed that highly expressed lncRNA AABR07005593.1 interacted with MCCC1 to involve in the activation of NF-κB pathway, and ultimately promoted the expression of IL-6., Conclusion: This study demonstrated that PM 2.5 induced inflammation in vivo and in vitro. Furthermore, lncRNA AABR07005593.1 bound to MCCC1 to potentiated IL-6 expression. Therefore, lncRNA AABR07005593.1 may act as a potential biomarker for PM 2.5 inflammation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic myeloid leukemia (CML) is a hematologic malignancy originating from BCR-ABL oncogene-transformed hematopoietic stem cells (HSCs) known as leukemia stem cells (LSCs). Therefore, targeting LSCs is of primary importance to eradicate CML. The present study demonstrates that picropodophyllin (PPP) effectively induces apoptosis and inhibits colony formation in CML stem/progenitor cells as well as quiescent CML progenitors resistant to imatinib therapy, while sparing normal hematopoietic cells in vitro. Administration of PPP in vivo markedly diminishes CML stem/progenitor cells in a transgenic mouse model of CML by inhibition of cell proliferation and enhancement of apoptosis in LSK cells, and significantly improves survival of CML mice. Furthermore, PPP treatment preferentially leads to transcriptional activation of p53 in CML but not normal CD34 + cells, upregulation of p53 protein in LSCs-enriched Sca-1 + cells from CML mice, and increased phosphorylation of p53 and upregulation of Bax protein in Ku812 cells. These results suggest that the inhibitory effects of PPP on CML stem/progenitor cells are associated with selective activation of p53 pathway and propose that PPP is a potent agent that selectively targets CML LSCs, and may be of value in the CML therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H 2 S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H 2 S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor., Main Methods: The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH) 2 D 3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H 2 S donor GYY4137 or H 2 S generating enzyme inhibitors aminooxyacetic acid and propargylglycine., Key Findings: Serum H 2 S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H 2 S generation showed opposite effects., Significance: Our findings suggest that H 2 S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aortic dissection (AD) is a life-threatening cardiovascular disease with a high mortality rate. The accurate and generalized 3-D reconstruction of AD from CT-angiography can effectively assist clinical procedures and surgery plans, however, is clinically unavaliable due to the lacking of efficient tools. In this study, we presented a novel multi-stage segmentation framework for type B AD to extract true lumen (TL), false lumen (FL) and all branches (BR) as different classes. Two cascaded neural networks were used to segment the aortic trunk and branches and to separate the dual lumen, respectively. An aortic straightening method was designed based on the prior vascular anatomy of AD, simplifying the curved aortic shape before the second network. The straightening-based method achieved the mean Dice scores of 0.96, 0.95 and 0.89 for TL, FL, and BR on a multi-center dataset involving 120 patients, outperforming the end-to-end multi-class methods and the multi-stage methods without straightening on the dual-lumen segmentation, even using different network architectures. Both the global volumetric features of the aorta and the local characteristics of the primary tear could be better identified and quantified based on the straightening. Comparing to previous deep learning methods dealing with AD segmentations, the proposed framework presented advantages in segmentation accuracy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

As a multifunctional nuclear protein, the human positive cofactor 4 (PC4) is highly expressed in various tumors including breast cancer and has potential roles in cancer development and progression. However, the functional signatures and molecular mechanisms of PC4 in triple negative breast cancer (TNBC) progression and chemotherapeutic response are still unknown. In this study, we found that PC4 is significantly upregulated in TNBC cells compared with non-TNBC cells, implying its potential role in TNBC. Then, in vivo and in vitro studies revealed that knockdown of PC4 increased chemosensitivity of Oxaliplation (Oxa) in TNBC by suppressing mTOR pathway. Therefore, our findings demonstrated the signatures and molecular mechanisms of PC4 in TNBC chemotherapeutic response, and indicated that PC4 might be a promising therapeutic target for TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Malaria remains a widespread life-threatening infectious disease, leading to an estimated 219 million cases and around 435,000 deaths. After an unprecedented success, the antimalarial progress is at a standstill. Therefore, new methods are urgently needed to decrease drug resistant and enhance antimalarial efficacy. According to the alteration of erythrocyte biomechanical properties and the immune evasion mechanism of parasites, drugs, which can improve blood circulation, can be chosen to combine with antimalarial drugs for malaria treatment. Ginkgo biloba extract (GBE), one of drug for vascular disease, was used to combine with artemisinin for Plasmodium yoelii therapy. Artemisinin-GBE combination therapy (AGCT) demonstrated remarkable antimalarial efficacy by decreasing infection rate, improving blood microcirculation and modulating immune system. Besides, the expression of invasion related genes, such as AMA1, MSP1 and Py01365, can be suppressed by AGCT, hindering invasion process of merozoites. This new antimalarial strategy, combining antimalarial drugs with drugs that improve blood circulation, may enhance the antimalarial efficacy and ameliorate restoration ability, proving a potential method for finding ideal compatible drugs to improve malaria therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) often causes neuronal death and axonal degeneration. In this study, we report a new strategy for preparing injectable and conductive polysaccharides-based hydrogels that could sustainably deliver brain-derived neurotrophic factor (BDNF) for SCI repair. We used poly(lactic-co-glycolic acid) (PLGA) as a carrier to encapsulate BDNF. The resulting microspheres were then modified with tannic acid (TA). The polysaccharides-based hydrogel composed of oxidized dextran (Dex) and hyaluronic acid-hydrazide (HA) was mixed with TA-modified microspheres to form the ultimate BDNF@TA-PLGA/Dex-HA hydrogel. Our results showed that the hydrogel had properties similar to natural spinal cords. Specifically, the hydrogel had soft mechanical properties and high electrical conductivity. The cross-sectional morphology of the hydrogel exhibited a continuous and porous structure. The swelling and degradation behaviors of the Dex-HA hydrogel in vitro indicated the incorporation of TA into hydrogel matrix could improve the stability of the hydrogel matrix as well as extend the release time of BDNF from the matrix. Furthermore, results from immunostaining and real-time PCR demonstrated that BDNF@TA-PLGA/Dex-HA hydrogel could promote the differentiation of neural stem cells (NSCs) into neurons and inhibit astrocyte differentiation in vitro. These results show the great potential of this hydrogel as a biomimetic material in SCI regeneration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

In this study, based on the extensive discussion of the phase transformation process of metal-organic frameworks (MOFs)--MIL-88A(Fe) under thermal treatment, the catalytic performance of MIL-88A-derived iron/carbon (FexC) composites on persulfate (PS) activation for phenol degradation was investigated. FexC-600 (γ-Fe 2 O 3 /C) exhibited a superior catalytic activity on PS activation for phenol degradation due to higher carbon content, more sp 2 -hybridized structure, carbonyl group and defective sites in composites, in which 98.23% of phenol (20 mg/L) was degraded after 60 min with 0.3 g/L catalyst and 0.3 g/L PS at ambient pH (6.1). The phenol degradation experiments and mechanism studies revealed that there was a catalytic synergism between iron oxides and carbon component in FexC 400-600 composites. Moreover, sulfate radicals (SO 4 - ), hydroxyl radical (•OH), singlet oxygen ( 1 O 2 ) and interfacial electron transfer process all involved in the degradation of phenol by FexC 400-600 composites, but the 1 O 2 -mediated non-radical oxidation was the dominant pathway rather than reactive radicals. Finally, the possible mechanism of PS activation on FexC 400-600 composites was proposed. This work discusses the synergistic catalytic mechanism of FexC composites on PS activation, and favors to provide a better understanding of the metal species and carbon component interaction in iron/carbon-based materials., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Knowledge of groundwater discharge (location and sources) into Poyang Lake is needed for water resources management and ecological security. In this study, hydrochemical and stable (δD and δ 18 O) and radium ( 223 Ra, 224 Ra, 226 Ra, and 228 Ra) isotopic approaches were employed to study the hydrochemical and isotopic characteristics of groundwater and surface water (river water and lake water) to identify the places where groundwater discharged into Poyang Lake and the groundwater discharge sources. The results showed that the groundwater discharge area was extensive during the dry season. The locations of predominant groundwater discharge were indicated by the evolution of radium and stable isotopes in lake water along two water flow profiles. At the confluence of Ganjiang and Xiushui rivers, groundwater with more negative δ 18 O value than that of the lake water discharged into this area, and the estimated groundwater discharge proportion in this area was close to that of the river water input. The main sources of groundwater input for Poyang Lake were inferred to originate from clastic rock pore-fissure aquifer and bedrock fissured aquifer around this lake. This study also found that groundwater affected by the anthropogenic activities may have discharged into Poyang Lake. Future studies are required to focus on groundwater discharge into Poyang Lake for its management and protection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Lithium is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youths is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether lithium vs other mood-stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality., Method: COBY is a naturalistic, longitudinal study of 413 youths, 7 to 17.11 years old at intake, with BD. At each visit, medication exposure, psychiatric symptoms, and psychosocial function over the preceding follow-up period were assessed using the Adolescent Longitudinal Interval Follow-Up Evaluation. Using mixed models, we determined whether participants taking lithium vs OMS (but not lithium) differed regarding mood symptoms, suicidality, psychosocial function, hospitalization, aggression, and substance use., Results: A total of 340 participants contributed 2,638 six-month follow-up periods (886 lithium, 1,752 OMS), over a mean follow-up of 10 years. During lithium (vs OMS) follow-up periods, participants were older, less likely to have lifetime anxiety, and less likely to be on antidepressants (p values<.005). After covariate adjustment, the lithium group (vs OMS) had half as many suicide attempts (p = .03), fewer depressive symptoms (p = .004), less psychosocial impairment (p = .003), and less aggression (p = .0004). Similar findings were observed in the subgroup of follow-up periods in which participants were <18 years old., Conclusion: Findings are consistent with adult studies, showing that lithium is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youths with BD., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The development of sensitive and convenient detection methods to monitor thrombin without the use of enzymes or complex nanomaterials is highly desirable for the diagnosis of cardiovascular diseases. In this article, tetraferrocene was first synthesized and then a sensitive and homogeneous electrochemical aptasensor was developed for thrombin detection based on host-guest recognition between tetraferrocene and β-cyclodextrin (β-CD). In the absence of thrombin, the double stem-loop of thrombin aptamer (TBA) prevented tetraferrocenes labeled at both ends from entering the cavity of β-CD deposited on gold electrode surface. After binding with thrombin, the stem-loop structure of TBA opened and transformed into special G-quarter structure, forcing tetraferrocene into the cavity of β-CD. As a result, thrombin allowed eight ferrocene molecules to reach the gold electrode surface, greatly amplifying the response signal. The obtained aptasensors showed dynamic detection range from 4 pM to 12.5 nM with detection limit around 1.2 pM. Overall, the results indicate that the proposed aptasensors are promising for future rapid clinical detection of thrombin and development of signal amplification strategies for detection of various proteins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Several studies have demonstrated that PM 2.5 inhalation is associated with an increased risk of cerebrovascular disease (CVD), in which inflammation plays an important role. The mechanisms of this disease are not fully understood to date. Long non-coding RNAs (lncRNAs) are involved in many pathophysiological processes, such as immune responses; however, their functions associated with inflammation are largely unexplored. High-throughput sequencing assay and obtained numerous lncRNAs that altered the expression in response to PM 2.5 treatment in HUVECs. NONHSAT247851.1 was also identified, which was significantly up-regulated to control the expression of immune response genes. Mechanistically, the results indicated that NONHSAT247851.1 knockdown reduced the expression of IL1β. In study, we investigated NONHSAT247851.1 as a promoter in regulating immune response genes via binding with raf-1 to regulate the phosphorylation level of p65 protein in HUVECs. The data collected suggests that NONHSAT247851.1 regulates inflammation via interaction with raf-1 to control the inflammatory expression in PM 2.5 exposure., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this work, a novel homogeneous electrochemical aptasensor based on electrically assisted bond and tetraferrocene signal amplification was constructed for thrombin detection. Importantly, modification of the electrode is not necessary for this sensor, requiring only the construction of a simple and efficient probe. In addition, a brand new signal marker-tetraferrocene, containing four ferrocene molecules, was employed as a label to the terminal position of the probe. Compared with a single ferrocene moiety, tetraferrocene possesses a larger amplification signal for rapid detection of thrombin. In the detection of thrombin, the selected aptamer probe with a stem-loop structure was labeled with tetraferrocene at the 3' terminal and thiol at the 5' terminal, respectively. Confinement of the thiol to the stem-loop structure of the probe, the ability of thiol to reach the surface of electrode lossed even with the aid of the applied potential. However, upon treatment with the target protein of thrombin the stem-loop structure opened, promoting rapid attachment of the thiol group to the electrode interface generating Au-S self-assembly with the action of potential-assistance. The electrochemical signal of tetraferrocene could be measured by differential pulse voltammetry (DPV), which was subsequently used for target quantitative detection. This strategy displayed a detection limit as low as 0.126 pM, and an inherently high specificity for the detection of a single mismatch. Moreover, it exhibited advanced specificity against common interfering proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The worldwide expansion of shale gas production and increased use of hydraulic fracturing have raised public concerns about safety and risks of groundwater resources in shale gas extraction areas. China has the largest shale gas resources in the world, most of which are located in the Sichuan Basin. Shale gas extraction in the Sichuan Basin has been increasing rapidly in recent years. However, the potential impact on shallow groundwater quality has not yet been systematically investigated. In order to evaluate the possible impact of shale gas extraction on groundwater quality, we present, for the first time, the hydrochemistry and Sr isotopic data of shallow groundwater, as well as flowback and produced water (FP water) in the Changning shale gas field in Sichuan Basin, one of the major shale gas fields in China. The Changning FP water is characterized by high salinity (TDS of 13,100-53,500 mg/L), Br/Cl (2.76 × 10 -3 ) and 87 Sr/ 86 Sr (0.71849), which are distinguished from the produced waters from nearby conventional gas fields with higher Br/Cl (4.5 × 10 -3 ) and lower 87 Sr/ 86 Sr (0.70830-0.71235). The shallow groundwater samples were collected from a Triassic karst aquifer in both active and nonactive shale gas extraction areas. They are dominated by low salinity (TDS of 145-1100 mg/L), Ca-HCO 3 and Ca-Mg-HCO 3 types water, which are common in carbonate karst aquifers. No statistical difference of the groundwater quality was observed between samples collected in active versus nonactive shale gas extraction areas. Out of 66 analyzed groundwater, three groundwater samples showed relatively higher salinity above the background level, with low 87 Sr/ 86 Sr (0.70824-0.7110) and Br/Cl (0.5-1.8 × 10 -3 ) ratios relatively to FP water, excluding the possibility of contamination from FP water. None of the groundwater samples had detected volatile organic compounds (VOCs). The integration of geochemical and statistical analysis shows no direct evidence of groundwater contamination caused by shale gas development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Long-term exposure to fine particulate matter (PM 2.5 ) may cause or exacerbate many diseases, including respiratory inflammation. However, the full mechanism is not yet fully understood. The newly discovered long chain non-coding RNA, though unable to encode proteins, regulates multiple life activities and participates in the development of inflammation. In this study, we set up a cell inflammation model by using normal bronchial 16HBE cells exposed to PM 2.5 . High-throughput sequencing, as well as real-time fluorescent quantitative PCR detection and validation, was performed on the inflamed cells to evaluate the expression level of long chain noncoding RNA that helped us to identify the LncRNA LOC101927514. Inhibiting LncRNA LOC101927514 expression by RNAi, reflected in a reduction in inflammation, is driven by PM 2.5 . In addition, we identify LncRNA LOC101927514 to be located within the nucleus and binds to STAT3, altering the inflammatory state of the cells and IL6 and IL8 release. This study identifies that LncRNA LOC101927514 is a new potential target for future treatment of the inflammatory response activated by PM 2.5 in the respiratory system., (Copyright © 2019. Published by Elsevier B.V.)