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Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis. [Display omitted] • Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. • GAS6 overexpression overtly improved cardiac dysfunction in cecum ligation and puncture-challenged mice. • GAS6-elicited beneficial effects were removed by GAS6 knockout. • NLRP3 was involved in the role of GAS6 against septic myocardial injury. • Findings implicate an important potential of GAS6/Axl/NLRP3-based therapy in the treatment of septic myocardial injury. [ABSTRACT FROM AUTHOR]

[Display omitted] • S-nanoFe overtly inhibited the survival of bacteria and showed a significant protective effect on septic myocardial injury. • S-nanoFe treatment ameliorated several CLP-related pathological processes and signal pathways, in which AMPK plays a key role in the cardioprotection of S-nanoFe. • The RNA-seq detection further explored the comprehensive mechanisms of S-nanoFe in sepsis. • The surface passivation of nanoFe using sodium sulfide could effectively improve the stability of nanoFe without affecting the efficacy. • Our work provided an alternative strategy of nanoparticle for overcoming sepsis and septic myocardial injury. Myocardial injury is a serious complication in sepsis with high mortality. Zero-valent iron nanoparticles (nanoFe) displayed novel roles in cecal ligation and puncture (CLP)-induced septic mouse model. Nonetheless, its high reactivity makes it difficult for long-term storage. To overcome the obstacle and improve therapeutic efficiency, a surface passivation of nanoFe was designed using sodium sulfide. We prepared iron sulfide nanoclusters and constructed CLP mouse models. Then the effect of sulfide-modified nanoscale zero-valent iron (S-nanoFe) on the survival rate, blood routine parameters, blood biochemical parameters, cardiac function, and pathological indicators of myocardium was observed. RNA-seq was used to further explore the comprehensive protective mechanisms of S-nanoFe. Finally, the stability of S-nanoFe-1d and S-nanoFe-30 d, together with the therapeutic efficacy of sepsis between S-nanoFe and nanoFe was compared. The results revealed that S-nanoFe significantly inhibited the growth of bacteria and exerted a protective role against septic myocardial injury. S-nanoFe treatment activated AMPK signaling and ameliorated several CLP-induced pathological processes including myocardial inflammation, oxidative stress, mitochondrial dysfunction. RNA-seq analysis further clarified the comprehensive myocardial protective mechanisms of S-nanoFe against septic injury. Importantly, S-nanoFe had a good stability and a comparable protective efficacy to nanoFe. The surface vulcanization strategy for nanoFe has a significant protective role against sepsis and septic myocardial injury. This study provides an alternative strategy for overcoming sepsis and septic myocardial injury and opens up possibilities for the development of nanoparticle in infectious diseases. [ABSTRACT FROM AUTHOR]

Sepsis can cause various organ dysfunction, which heart failure may be associated with significant mortality. Recently, natural plant extracts have gradually attracted people's attention in the clinical treatment of cardiovascular diseases. Psoralidin (PSO) is one of the main bioactive compounds from the seeds of Psoralea corylifolia L and exhibits remarkable protective effects in diseases, including cancer, osteoporosis, and depression. Recently, NR1H3 is one of the emerging nuclear receptors targets for the various drugs. This study first reported the porotective role of PSO in septic myocardial injury, which was mainly attributed to the NR1H3-dependent manner. NR1H3 knockout mice subjected to cecal ligation and puncture (CLP) were used to investigate the involvement of NR1H3 in PSO protection. Our results showed that PSO prominently improved cardiac function, attenuated inflammation, inhibited oxidative stress, improved mitochondrial function, regulated ERS, suppressed apoptosis, and particularly increased NR1H3 and p-AMPK levels. However, NR1H3 knockout reversed the positive role of PSO in septic mice. Furthermore, activation of NR1H3 by T0901317 also increased the activity of AMPK and ACC in the HL-1 cardiomyocytes, indicating the regulatory relationship between NR1H3 and AMPK signaling. Together, this study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3/AMPK pathway. [Display omitted] • Psoralidin (PSO) treatment elevated the survival rate and improved cardiac function in CLP mice. • The protective mechanisms of PSO were contributed to the attenuated inflammation, oxidative stress, and apoptosis, improved mitochondrial function, and regulated ERS. • NR1H3 knockout nullified the protective roles of PSO against sepsis. • RNA-seq illustrated the comprehensive transcriptome regulated by PSO in CLP mice. • This study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3 pathway. [ABSTRACT FROM AUTHOR]

Cardiac dysfunction is a common complication in patients with sepsis triggering high morbidity and mortality. Lycorine (LYC), the main effective monomer component extracted from Lycoris bulbs, possesses antiviral, anti-inflammatory, analgesic, liver protection properties. In this study, the effect of LYC pre- and post-treatment as well as the underlying mechanism were evaluated in the cecal ligation and puncture (CLP) model of Balb/c mice. The survival rate, anal temperature, sepsis score, blood biochemical/routine indicators, cardiac function, sepsis-related pathophysiological processes, and AMPK signaling in septic mice were observed by echocardiography, histological staining, western blot, qPCR, and etc. LYC pretreatment attenuated myocardial injury in septic mice by improving survival rate, sepsis score, blood biochemical/routine indicators, cardiac function and structure, inhibiting inflammation and oxidative stress, improving mitochondrial function, modulating endoplasmic reticulum stress, and activating AMPK pathway. In particular, AMPK deficiency and AMPK inhibitor (Compound C) partially reversed the protective effects of LYC in septic mice. In addition, LYC posttreatment also has slight protective phenotypes on septic myocardial injury, but the effect is not as ideal as pretreatment. Taken together, these findings suggest that LYC may be a potential drug for the treatment of sepsis. Graphical abstract Schematic diagram depicting the protective role of LYC in sepsis and septic myocardial injury. LYC pretreatment attenuated myocardial injury in septic mice by activating AMPK pathway, accompanied by reducing inflammation, inhibiting oxidative stress, improving mitochondrial function, and modulating ER stress. [Display omitted] • Cardiac dysfunction is a common complication in patients with sepsis triggering high morbidity and mortality. • LYC pretreatment attenuated myocardial injury in septic mice by reducing inflammation, inhibiting oxidative stress, improving mitochondrial function, modulating endoplasmic reticulum stress (ERS), and activating AMPK pathway. • AMPK deficiency and AMPK inhibitor Compound C partially reversed the protective effects of LYC in septic mice. • LYC posttreatment also has slight protective phenotypes on septic myocardial injury, but the effect is not as ideal as pretreatment. [ABSTRACT FROM AUTHOR]

• High-performance flexible strain sensors based on scorpion-leg-inspired gradient crack arrays are achieved. • Gradient crack arrays controllably form in periodic thickness-gradient metal films on flexible substrates. • The cracks are progressively open under mechanical strain, behaving a unique sensing mechanism. • Applications for human activity monitoring and information encryption are demonstrated. Wearable flexible strain sensors based on conductive films have shown great application potential in many high-tech fields. They have high requirements for synergistic performances of sensitivity, flexibility, stability and durability. However, overcoming the trade-off between high sensitivity and high stretchability is still a great challenge in this research. Here we develop a facile strategy to prepare high-performance flexible strain sensors based on gradient crack arrays inspired by the gradient slits on scorpion legs. The gradient crack arrays with branched or hierarchical features controllably form in a periodic thickness-gradient metal film prepared by one-step masking technique on a flexible substrate. The cracks are progressively open from the thickest film region to the thinnest one under mechanical strain, behaving a unique sensing mechanism. As a result, the gradient crack-based strain sensors possess excellent comprehensive performances including high sensitivity (up to 21000), wide sensing range (∼70 %), low detection limit (0.02 %), quick response speed (below to 80 ms), excellent stability and durability (up to 15,000 cycles at 5 % strain). As demonstration of applications, the sensors are used to monitor various human activities and to express and encrypt information by bending bidirectionally. This work provides a novel way to fabricate highly sensitive, stretchable, robust, multifunctional, crack-based flexible strain sensors, which would greatly expand the applications in flexible electronics and wearable devices. [ABSTRACT FROM AUTHOR]

Proposed scheme depicting the mechanisms by which PSO protects against ADR-induced cardiotoxicity by activating the SIRT1/PPARγ signaling pathway. [Display omitted] • The beneficial effect of PSO on Adriamycin (ADR)-induced cardiotoxicity, which is manifested in amelioration of mitochondrial dysfunction, myocardial fibrosis, oxidative stress, and apoptosis • PSO protects ADR-induced cardiotoxicity via regulating SIRT1/PPARγ signaling pathway • PSO is proved to be a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in clinical and amplify the application of ADR in oncotherapy. Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy. [ABSTRACT FROM AUTHOR]

Background: The implication of mutational variant allelic frequency (VAF) has been increasingly considered in the prognostic interpretation of molecular data in myeloid malignancies. However, the impact of VAF on outcomes of myelodysplastic syndromes (MDS) has not been extensively explored. Methods: Targeted next-generation sequencing was performed in 350 newly diagnosed MDS cases. The associations of mutational VAF of each gene with overall survival (OS) and leukemia-free survival (LFS) were examined by multivariate Cox regression after univariate analysis. Results: Shorter OS was independently associated with DNMT3A VAF (HR 1.020 per 1% VAF increase; 95% CI 1.005–1.035; p = 0.011) and TP53 VAF (HR 1.014 per 1% VAF increase; 95% CI 1.006–1.022; p = 0.001). LFS analyses revealed that TET2 VAF (HR 1.013 per 1% VAF increase; 95% CI 1.005–1.022; p = 0.003) and TP53 VAF (HR 1.012 per 1% VAF increase; 95% CI 1.004–1.021; p = 0.005) were independently associated with faster leukemic transformation. Furthermore, we established nomograms to predict OS and LFS, respectively, by integrating independent mutational predictors into the revised International Prognostic Scoring System. Conclusion: Our study highlights that VAF of certain genes should be incorporated into routine clinical prognostication of survival and leukemic transformation of MDS. [ABSTRACT FROM AUTHOR]

[Display omitted] In a previous study, we used metabolomic techniques to identify a new metabolite of Danshen Dripping Pills called isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP), which has potential as a drug candidate for cardiovascular diseases. This study aimed to explore the protective effects of IDHP against septic myocardial injury, as well as its molecular mechanism. Wild type or GAS6 knockout mice injured by cecal ligation and puncture (CLP) were used to observe the effect of IDHP. Here, we found that a specific concentration of IDHP (60 mg/kg) significantly increased the survival rate of septic mice to about 75 % at 72 h post CLP, and showed improvements in sepsis score, blood biochemistry parameters, cardiac function, and myocardial tissue damage. Furthermore, IDHP inhibited myocardial oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. Molecularly, we discovered that IDHP treatment reversed the CLP-induced downregulation of GAS6, Axl, and p-AMPK/AMPK expression. In addition, GAS6 knockout reversed the positive effect of IDHP in septic mice, indicated by more severe myocardial tissue damage, oxidative stress, inflammatory response, and mitochondrial dysfunction. GAS6 knockout also resulted in decreased levels of GAS6, Axl, and p-AMPK/AMPK. Taken together, our study provides evidence that IDHP has significant cardioprotective effects against sepsis by regulating the GAS6/Axl-AMPK signaling pathway. This finding has important therapeutic potential for treating sepsis. [ABSTRACT FROM AUTHOR]

Claudin-5 has recently attracted increasing attention by its potential as a novel treatment target in the early stage of heart failure. However, whether Claudin-5 produces beneficial effects on myocardial ischemia and reperfusion (IR) injury has not been elucidated yet. In this study, we identified reduced levels of Claudin-5 in the hearts of mice subjected to acute myocardial IR injury and murine HL-1 cardiomyocytes subjected to hypoxia and reoxygenation (HR). We then constructed cardiac-specific Cldn5 -overexpressing mice using an adeno-associated virus (AAV9) vector and demonstrated that Cldn5 overexpression ameliorated cardiac dysfunction and myocardial damage in mice subjected to myocardial IR injury. Moreover, Cldn5 overexpression attenuated myocardial oxidative stress (DHE and protein levels of Nrf2, HO-1, and NQO1), inflammatory response (levels of MPO, F4/80, Ly6C, and circulating inflammatory cells), mitochondrial dysfunction (protein levels of PGC-1α, NRF1, and TFAM), endoplasmic reticulum stress (protein levels of GRP78, ATF6, and CHOP and p-PERK), energy metabolism disorder (p-AMPK and ACC), and apoptosis (TUNEL assay and protein levels of Bax and Bcl2) in mice subjected to myocardial IR. Next, we generated Cldn5 knockdown cells by lentiviral shRNA and observed that Cldn5 knockdown inhibited cell viability and affected the expression or activation of these IR-related signalings in HL-1 cardiomyocytes subjected to HR. Mechanistically, SIRT1 was proved to be involved in regulating the expression of Claudin-5 by co-immunoprecipitation analysis and Sirt1 knockdown experiments. Our data demonstrated that targeting Claudin-5 may represent a promising approach for preventing and treating acute myocardial IR injury. • Claudin-5 is reduced during myocardial ischemia and reperfusion (IR) and cardiomyocyte hypoxia and reoxygenation (HR). • Cldn5 overexpression mitigates IR-induced cardiac injury and dysfunction. • Cldn5 overexpression ameliorates several IR-related pathophysiological alterations. • Cldn5 knockdown aggravates HR-induced cell injury and disruption of essential signaling pathways in HL-1 cardiomyocytes. • SIRT1 is partly involved in regulating Claudin-5 in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Sub-event detection for social media is getting increasingly important because social media platforms have played key roles in disseminating vital information to the public. However, conventional methods fail to achieve high-quality analysis of events evolution due to the severe sparseness and noise of tweets data. In this paper, we propose an unsupervised sub-event detection model which learns rich information from hashtags with a Text-CNN model. Furthermore, a two steps training method leveraged by KL divergence is introduced to further reduce the negative influence of incoherent semantics. The experiments show that our method achieves very good performance on datasets of different languages. On the Chinese dataset, in terms of NMI, and BCubed F1 precision, our method has a significant increase of 5.1%, and 11.9%, respectively, over the baseline methods. In most cases, our method significantly improves the performance of sub-event detection compared with state-of-the-art methods. [Display omitted] • A hashtag-based sub-event detection framework enhances semantic information utilization. • An unsupervised sub-event representation with a Text-CNN model learns sub-event representation from tweets. • A two-step training method reduces the influence of inconsistent information from tweets. [ABSTRACT FROM AUTHOR]

For the first time, we present that the heterogeneous microstructure of Ce/Y/La-based multi-main-phase (MMP) magnets, the origin of intergrain and intragrain Volta potential discrepancy (a), initiates peculiar corrosion mechanisms: (b) preferential corrosion of RE-rich intergranular phase yields an abnormal increase in the corrosion resistance, which is ascribed to high surface integration of stable REFe 2 and RE 2 Fe 14 B phases; (c) local Ce-rich region with lower Volta potential, including Ce-rich shell (type I, upper red rectangle) and Ce-rich core (type II, bottom blue rectangle), evolves as crucial proceeding source of pit corrosion within 2:14:1 grain. • Whole-process corrosion behavior of multi-main-phase magnet was firstly investigated. • Heterogeneous microstructure is the origin of intergrain/intragrain potential discrepancy. • Abnormally increased anti-corrosion is closely correlated to intergranular heterogeneity. • Local Ce-rich shell/core with lower potential evolves as preferential sites for pit corrosion. Heterogeneous microstructure of multi-main-phase (MMP) Nd-Ce-Y-Fe-B sintered magnet is unraveled to generate local electrode potential discrepancy of intergranular multi-phases and intragrain core-shells, being the origin of peculiar corrosion behaviors relative to conventional Nd-Fe-B. i) For intergranular heterogeneity, the preferential corrosion of active RE-rich phase yields an abnormal enhancement of anti-corrosion performance. ii) For intragrain heterogeneity, local Ce-rich shell and Ce-rich core with lower Volta potentials evolve as preferential sites for pit corrosion, resulting in large cavities and apparent Ce-oxide accumulation. Above findings unlock the close correlation between heterogeneous microstructure and whole-process corrosion behavior of MMP magnets for the first time. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of interests JSJ reports grants and non-financial support from WHO, outside the submitted work. MW reports grants from the Wellcome Trust during the conduct of the study. All other authors declare no competing interests.

Keloid scarring is a complex fibroproliferative disorder characterised by excessive fibroblast proliferation. Inhibition of cellular glycolysis effectively suppresses the proliferation of keloid fibroblasts (KFs). Neural precursor cell-expressed developmentally downregulated gene 4-like (NEDD4L), a ubiquitin ligase, regulates cell proliferation in different diseases. This study investigated the effects of NEDD4L on glucose metabolism, proliferation and migration in KFs. Primary KFs were isolated from keloid skin tissues obtained from patients with active-stage keloids. Cell transfection was used to upregulate or downregulate NEDD4L and Yin Yang 1 (YY1) in KFs. Protein expression was assessed by immunohistochemistry and western blotting. The viability, proliferative capacity and migration ability of KFs were evaluated using the MTT method and the EdU and wound healing assays, respectively. The regulatory effect of NEDD4L on YY1 ubiquitination was examined by coimmunoprecipitation. The interaction between YY1 and hexokinase 2 (HK2) was confirmed by a dual-luciferase reporter assay. NEDD4L was downregulated, whereas YY1 and HK2 were highly expressed in keloid tissues compared with normal skin. Overexpression of NEDD4L inhibited the proliferation and migration of KFs. NEDD4L promoted YY1 degradation in KFs by inducing its ubiquitination. Upregulation of YY1 induced glucose consumption and lactate production in KFs via the transcriptional regulation of HK2. Increased expression of YY1 reversed the reduced viability, proliferation, and migration of KFs overexpressing NEDD4L. YY1 also reversed the NEDD4L-induced inhibition of glucose consumption and lactate production in KFs. Additionally, an in vivo study confirmed the inhibitory roles of NEDD4L overexpression and YY1 knockdown in keloid formation. NEDD4L suppressed the viability, proliferation and migration of KFs by regulating YY1 ubiquitination-mediated glycolysis through HK2. These findings suggest a novel regulatory axis, NEDD4L/YY1/HK2, that mediates glucose metabolism in keloid formation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Adriamycin (ADR)-induced cardiomyopathy is a common problem in many cancer survivors. Recently, specific chemokine receptors have garnered interest as therapeutic targets in cardiovascular diseases., Objectives: This study aim to report the role of C-C chemokine receptor 9 (CCR9)/C-C chemokine ligand 25 (CCL25) and its therapeutic potential in ADR-induced cardiomyopathy., Methods: Functional gene knockout and overexpression mouse models were utilized to investigate the role of CCR9 against ADR-induced cardiomyopathy. Transcriptome sequencing was also performed to identify the downstream molecular mechanisms of CCR9., Results: This study revealed that CCR9 and CCL25 levels were increased in mice and HL-1 cells injured by ADR, consistent with the results of patients with heart failure. Both in vivo and in vitro, CCR9 overexpression overtly aggravated cardiac dysfunction, accompanied by decreased AMPK activity and increased mitochondrial dysfunction, fibrosis, oxidative stress, and apoptosis. However, the cardiac harmful effects of ADR were reserved by CCR9 knockdown, as well as CCR9 overexpression aggravated cardiotoxicity were reserved by AMPK agonist GSK621. By constructing different domain-missing CCR9 mutants, we suspected that the △4 region of CCR9 is important for AMPK activity. Furthermore, transcriptome sequencing  further illustrated the mechanism of CCR9 overexpression aggravated ADR-induced cardiotoxicity, which was associated with CYP1A1. Finally, lithospermic acid (LA) was screened and alleviated ADR-induced cardiotoxicity through regulation of CCR9/CCL25-AMPK signaling, bolstering CCR9-targeted potential clinical application., Conclusion: These findings present a promising target and drug for treating chemotherapy-induced cardiotoxicity., 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. Production and hosting by Elsevier B.V.)

Fibrosis, an aberrant reparative response to tissue injury, involves a disruption in the equilibrium between the synthesis and degradation of the extracellular matrix, leading to its excessive accumulation within normal tissues, and culminating in organ dysfunction. Manifesting in the terminal stages of nearly all chronic ailments, fibrosis carries a high mortality rate and poses a significant threat to human health. Heme oxygenase-1 (HO-1) emerges as an endogenous protective agent, mitigating tissue damage through its antioxidant, anti-inflammatory, and antiapoptotic properties. Numerous studies have corroborated HO-1's potential as a therapeutic target in anti-fibrosis treatment. This review delves into the structural and functional attributes, and the upstream and downstream pathways of HO-1. Additionally, the regulatory networks and mechanisms of HO-1 in cells associated with fibrosis are elucidated. The role of HO-1 in various fibrosis-related diseases is also explored. Collectively, this comprehensive information serves as a foundation for future research and augments the viability of HO-1 as a therapeutic target for fibrosis., (© 2024 Wiley Periodicals LLC.)

With the widespread use of tetracycline antibiotics (TCs) and the application of manure fertilizer in farmland, TCs and their metabolites especially 4-epimers have been heavily detected in agricultural soil. However, existing studies have focused on the residual and environmental behavior of maternal TCs, and few studies have looked at the ecotoxicity of their 4-epimers in soil. In this study, the degradation and interconversion of tetracycline (TC), oxytetracycline (OTC) and their 4-epimers (4-epitetracycline, ETC; 4-epioxytetracycline, OTC) were revealed. Their effects on antibiotic resistance genes (ARGs), mobile genetic elements (MGEs) and bacterial community in soil were also investigated in comparison. The results showed that the 4-epimers could be substantially transformed to their parents and degraded as a whole. The degradation rates of four selected pollutants are followed: TC > OTC > ETC > EOTC. This indicated that when TCs entered the soil, part of TCs transformed into slower-degraded 4-epimers, and these 4-epimers could also be converted back to their antibiotic parents, causing the long-term residue of TCs in soil. When added to the soil alone, TC and OTC significantly promoted the proliferation of most ARGs and MGEs, among them, trb-C, IS1247 and IS1111 were the top three genes in abundance. ETC and EOTC had little effect at the beginning. However, as the 4-epimers continuously converted into their parents after one month of cultivation, ETC and EOTC treatments showed similar promoting effect on ARGs and MGEs, indicating that the effect of ETC and EOTC on soil resistome was lagged and mainly caused by their transformed parents. Nocardioides, unclassified_Rhizobiaceae, norank_Sericytochromatia, Microlunatus, Solirubrobacter and norank_67-14 were the most frequent hosts of ARGs, Most of which belong to the phylum Actinobacteria. Due to their large transformation to TCs, slow degradation rate and potential effects on soil microbes and ARGs, the harm of TCs' 4-epimers on soil ecosystem cannot be ignored., 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 Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lymphocyte activation gene 3 (LAG-3) has been considered as the next generation of immune checkpoint and a promising prognostic biomarker of immunotherapy. As with programmed cell death protein-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen-4 inhibitors, positron emission tomography (PET) imaging strategies could benefit the development of clinical decision-making of LAG-3-related therapy. In this study, we developed and validated 68 Ga-labeled cyclic peptides tracers for PET imaging of LAG-3 expression in bench-to-bedside studies., Methods: A series of LAG-3-targeted cyclic peptides were modified and radiolabeled with 68 GaCl 3 and evaluated their affinity and specificity, biodistribution, pharmacokinetics, and radiation dosimetry in vitro and in vivo. Furthermore, hu-PBL-SCID (PBL) mice models were constructed to validate the capacity of [ 68 Ga]Ga-CC09-1 for mapping of LAG-3 + lymphocytes infiltrates using longitudinal PET imaging. Lastly, [ 68 Ga]Ga-CC09-1 was translated into the first-in-human studies to assess its safety, biodistribution and potential for imaging of LAG-3 expression., Results: A series of cyclic peptides targeting LAG-3 were employed as lead compounds to design and develop 68 Ga-labeled PET tracers. In vitro binding assays showed higher affinity and specificity of [ 68 Ga]Ga-CC09-1 in Chinese hamster ovary-human LAG-3 cells and peripheral blood mononuclear cells. In vivo PET imaging demonstrated better imaging capacity of [ 68 Ga]Ga-CC09-1 with a higher tumor uptake of 1.35±0.33 per cent injected dose per gram and tumor-to-muscle ratio of 17.18±3.20 at 60 min post-injection. Furthermore, [ 68 Ga]Ga-CC09-1 could detect the LAG-3 + lymphocyte infiltrates in spleen, lung and salivary gland of PBL mice. In patients with melanoma and non-small cell lung cancer, primary lesions with modest tumor uptake were observed in [ 68 Ga]Ga-CC09-1 PET, as compared with that of [ 18 F]FDG PET. More importantly, [ 68 Ga]Ga-CC09-1 delineated the heterogeneity of LAG-3 expression within large tumors., Conclusion: These findings consolidated that [ 68 Ga]Ga-CC09-1 is a promising PET tracer for quantifying the LAG-3 expression in tumor microenvironment, indicating its potential as a companion diagnostic for patients stratification and therapeutic response monitoring in anti-LAG-3 therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Myocardial ischemia-reperfusion (IR) injury is a common medical issue contributing to the onset and progression of ischemic heart diseases (IHD). Growth arrest-specific gene 6 (GAS6), a vitamin K-dependent secretory protein, promotes cell proliferation and inhibits inflammation and apoptosis through binding with Tyro3, Axl, and Mertk (TAM) receptors., Objectives: Our study aimed to examine the effect of GAS6 pathways activation as a potential new treatment in myocardial IR injury., Methods: Gain- and loss-of-function experiments were utilized to determine the roles of GAS6 in the pathological processes of myocardial IR injury., Results: Our results revealed down-regulated levels of GAS6, Axl, and SIRT1 in murine hearts subjected to IR injury, and cardiomyocytes challenged with hypoxia reoxygenation (HR) injury. GAS6 overexpression significantly improved cardiac dysfunction in mice subjected to myocardial IR injury, accompanied by reconciled mitochondrial dysfunction, oxidative stress, and apoptosis. In vitro experiments also observed a protective effect of GAS6 in cardiomyocytes. SIRT1 was found to function as a downstream regulator for GAS6/Axl signaling axis. Through screening a natural product library, a polyphenol natural compound catechin was identified to exhibit a protective effect by turning on GAS6/Axl-SIRT1 cascade., Conclusions: Together, our findings indicate that GAS6 emerges as a potential novel target in the management of myocardial IR injury and other related anomalies., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Background and Objectives: Cognitive impairments are common in idiopathic REM sleep behavior disorder (iRBD), in which the cholinergic degeneration of nucleus basalis of Meynert (NBM) may play an important role. However, the progressive changes of NBM, the relationship between progressive NBM degeneration and progression of cognitive impairments, and whether degeneration of the NBM can predict cognitive decline in patients with iRBD remain unclear. This study aimed to investigate the cross-sectional and longitudinal microstructural alterations in the NBM of patients with iRBD using free-water imaging and whether free water in the NBM is related to cognitive, mood, and autonomic function., Methods: We compared the baseline free-water values in the NBM between 59 healthy controls (HCs), 57 patients with iRBD, 57 patients with Parkinson disease (PD) with normal cognition (PD-NC), and 64 patients with PD with cognitive impairment (PD-CI). Thirty patients with iRBD and 40 HCs had one longitudinal data. In patients with iRBD, we explored the associations between baseline and longitudinal changes of free-water values in the NBM and clinical characteristics and whether baseline free-water values in the NBM could predict cognitive decline., Results: IRBD, PD-NC, and PD-CI groups had significantly increased free-water values in the NBM compared with HCs, whereas PD-CI had higher free-water values compared with iRBD and PD-NC. In patients with iRBD, free-water values in the NBM were progressively elevated over follow-up and correlated with the progression of cognitive impairment and depression. Free-water values in the NBM could predict cognitive decline in the iRBD group. Furthermore, we found that patients with iRBD with cognitive impairment had higher relative change of free-water value in the NBM compared with patients with iRBD with normal cognition over follow-up., Discussion: This study proves that free-water values in the NBM are elevated cross-sectionally and longitudinally and are associated with the progression of cognitive impairment and depression in patients with iRBD. Moreover, the free-water value in the NBM can predict cognitive decline in patients with iRBD. Whether free-water imaging of the NBM has the potential to be a marker for monitoring progressive cognitive impairment and predicting the conversion to dementia in synucleinopathies needs further investigation.

Introduction and Hypothesis: We hypothesized that applying cervical suction and persistent tension can develop a novel and efficient rat model of pelvic organ prolapse., Methods: Fifteen rats underwent pilot testing to optimize the protocol. Sixteen rats were subjected to pelvic organ prolapse induction by cervical suction and constant traction, while five rats served as controls. The pelvic organ prolapse rats were assessed by a Rat Pelvic Organ Prolapse Quantification system at different time points, and their diet, urine, and stool were monitored for 21 days. The pelvic organ prolapse rats were also evaluated for urinary incontinence, urinary retention, leak point pressure, and vaginal histopathology at 21 days after operation., Results: This rat model demonstrated pelvic floor prolapse in anatomic level, as well as physiological variations (urine incontinence, urinary retention) and pathological changes (collagen fracture, decreased collagen density)., Conclusions: This is the first establishment of the pelvic organ prolapse rat model with all compartment defects, which provides a valuable tool for elucidating pelvic organ prolapse mechanisms and evaluating potential interventions., (© 2024. The Author(s).)

Cardiac insufficiency is a common complication of sepsis with high mortality. Inflammatory programmed cell death (pyroptosis) executed by NLRP3/gasdermin D (GSDMD) is intrinsically correlated with septic myocardial injury. However, it remains unclear whether PIK3CG, a classical target of septic myocardial injury, can affect pyroptosis by regulating NLRP3/GSDMD signaling. In this study, a series of experimental methods were used to observe the effect of PIK3CG on NLRP3/GSDMD-mediated pyroptosis in Cecal ligation and puncture (CLP)-injured BALB/c mice and lipopolysaccharide (LPS)-injured HL-1 cardiomyocytes. Transcriptome analysis of CLP-injured myocardium revealed a regulatory relationship between PIK3CG and NLRP3/GSDMD signaling, which was further verified in clinical myocardium samples from GEO database. Both in vitro and in vivo experiments showed that the protein and mRNA levels of PIK3CG, GSDMD, NLRP3, IL-1β, Caspase-1, and IL-18 were significantly increased. Importantly, PIK3CG siRNA was found to improve these changes, while PIK3CG overexpression worsened them. Notably, pyroptosis induced by CLP in the myocardium was reversed by the PIK3CG inhibitor (AS-604850). In conclusion, PIK3CG activates NLRP3 inflammasomes, thus promoting pyroptosis in septic myocardial injury., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of interests We declare no competing interests.

Flexible magnetoelectronic devices (based on magnetic films) have great application prospects in the fields of information storages, bionic robotics, and electronic skins. The intrinsic stress and external loading are very important to modulate the structures and properties of flexible magnetic films due to the magnetoelastic coupling effect. Here, we report on tunable magnetic domain patterns in thickness-gradient nickel (Ni) films deposited on flexible polydimethylsiloxane substrates. It is found that stripe magnetic domains spontaneously form in the Ni films and their sizes increase with the film thickness. The internal stress evolves from tensile to compressive states with decreasing film thickness, leading to the formation of cracks in thicker regions and wrinkles in thinner regions. Meanwhile, the orientations of stripe magnetic domains change from the gradient direction to the orthogonal direction. The structural features, evolution behaviors, and physical mechanisms of the cracks, wrinkles, and magnetic domains are analyzed based on the stress theory and magnetoelastic coupling. Periodic gradient Ni films with large-scale regulations of stripe magnetic domains are also realized by masking of copper grids. This study helps to better understand the magnetoelastic coupling effect in gradient flexible magnetic films and provides a technique to modulate anisotropic magnetic properties by designing specific film systems., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury., Methods and Results: Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin., Conclusion: Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury., (© 2023. The Author(s).)

We constructed a frequently updated, near-real-time global power generation dataset: CarbonMonitor-Power since January, 2016 at national levels with near-global coverage and hourly-to-daily time resolution. The data presented here are collected from 37 countries across all continents for eight source groups, including three types of fossil sources (coal, gas, and oil), nuclear energy and four groups of renewable energy sources (solar energy, wind energy, hydro energy and other renewables including biomass, geothermal, etc.). The global near-real-time power dataset shows the dynamics of the global power system, including its hourly, daily, weekly and seasonal patterns as influenced by daily periodical activities, weekends, seasonal cycles, regular and irregular events (i.e., holidays) and extreme events (i.e., the COVID-19 pandemic). The CarbonMonitor-Power dataset reveals that the COVID-19 pandemic caused strong disruptions in some countries (i.e., China and India), leading to a temporary or long-lasting shift to low carbon intensity, while it had only little impact in some other countries (i.e., Australia). This dataset offers a large range of opportunities for power-related scientific research and policy-making., (© 2023. The Author(s).)

Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects of GAS6 were evaluated against hydrogen peroxide (H 2 O 2 ) ‑induced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H 2 O 2 ‑injured HL-1 cells. In this study, we found that H 2 O 2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H 2 O 2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H 2 O 2 ‑injured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H 2 O 2 ‑induced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Myocardial injury is a serious complication of sepsis associated with high morbidity and mortality. Our previous work has confirmed that silibinin (SIL) alleviates septic myocardial injury, but the specific molecular mechanism has not been fully elucidated. This study aimed to identify its potential targets through network pharmacology combined with experimental verification. Firstly, a total of 29 overlapping genes between sepsis and SIL targets were obtained from RNA-seq analysis and the known databases. Subsequently, KEGG and GO analysis showed that these genes were enriched in immune response and cytokine-cytokine receptor interaction pathways. Notably, CCR2 was identified as an important candidate hub by protein-protein interaction analysis and molecular docking approach. In vivo experiments showed that SIL treatment significantly improved survival rate and cardiac function in septic mice, accompanied by decreased CCR2 expression. Moreover, in vitro experiments obtained the similar results. Especially, CCR2 siRNA attenuated inflammation response. In conclusion, this study systematically elucidated the key target of SIL in the treatment of septic myocardial injury. These findings provide valuable insights into the targets of sepsis and offer new avenues for exploring drug effect systematically., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments., Methods: We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination., Results: The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity., Conclusions: These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration., (© 2022. The Author(s).)

Competing Interests: Declaration of interests We declare no competing interests.

Building on near-real-time and spatially explicit estimates of daily carbon dioxide (CO 2 ) emissions, here we present and analyze a new city-level dataset of fossil fuel and cement emissions, Carbon Monitor Cities, which provides daily estimates of emissions from January 2019 through December 2021 for 1500 cities in 46 countries, and disaggregates five sectors: power generation, residential (buildings), industry, ground transportation, and aviation. The goal of this dataset is to improve the timeliness and temporal resolution of city-level emission inventories and includes estimates for both functional urban areas and city administrative areas that are consistent with global and regional totals. Comparisons with other datasets (i.e. CEADs, MEIC, Vulcan, and CDP-ICLEI Track) were performed, and we estimate the overall annual uncertainty range to be ±21.7%. Carbon Monitor Cities is a near-real-time, city-level emission dataset that includes cities around the world, including the first estimates for many cities in low-income countries., (© 2022. The Author(s).)

Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. These results extend the tuning scope of chemical reactions from the macroscopic view to the single-molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena., (© 2022. The Author(s).)

Background: There is limited knowledge on the distribution of the health co-benefits of reduced air pollutants and carbon emissions in the transport sector across populations., Methods: This Article describes a health impact assessment used to estimate the health co-benefits of alternative land passenger transport scenarios for the city of Beijing, China, testing the effect of five transport-based scenarios from 2020 to 2050 on health outcomes. New potential scenarios range from implementing a green transport infrastructure, to scenarios primarily based on the electrification of vehicle fleets and a deep decarbonisation scenario with near zero carbon emissions by 2050. The health co-benefits are disaggregated by age and sex and estimated in monetary terms., Findings: The results show that all the alternative mitigation scenarios result in reduced PM 2·5 and CO 2 emissions compared to a business-as-usual scenario during 2020-50. The near zero scenario achieves the largest health co-benefits and economic benefits annually relative to the sole mitigation strategy, preventing 300 (95% CI 229-450) deaths, with health co-benefits and CO 2 cost-saving an equivalent of 0·01% (0·00-0·03%) of Beijing's Gross domestic product in 2015 by 2050. Given Beijing's ageing population and higher mortality rate, individuals aged 50 years and older experience the greatest benefit from the mitigation scenarios. Regarding sex, the greatest health benefits occur in men., Interpretation: This assessment provides estimates of the demographic distribution of benefits from the effects of combinations of green transport and decarbonising vehicles in transport futures. The results show that there are substantial positive health outcomes from decarbonising transport in Beijing. Policies aimed at encouraging active travel and use of public transport, increasing the safety of active travel, improving public transport infrastructure, and decarbonising vehicles lead to differential benefits. In addition, disaggregation by age and sex shows that the health impacts related to transport pollution disproportionately influence different age cohorts and genders., Funding: National Natural Science Foundation of China and FRIEND Project (through the National Research Foundation of Korea, funded by the Ministry of Science and ICT)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of interests AM, PL, and IH were supported by the Wellcome Trust during this report. All other authors declare no conflicts of interests.

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O -trifluoracetylthianthrene S -oxide ( TT + -TFA ) or to the thianthrene dication ( TT 2+ ) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

The S N 2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an S N 2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an S N 2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective S N 2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an S N 2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric S N 2 dynamic kinetic resolution to be used for a variety of future reactions.

Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins., Competing Interests: The authors declare no competing interest.

Precise time trajectories and detailed reaction pathways of the Diels-Alder reaction were directly observed using accurate single-molecule detection on an in situ label-free single-molecule electrical detection platform. This study demonstrates the well-accepted concerted mechanism and clarifies the role of charge transfer complexes with endo or exo configurations on the reaction path. An unprecedented stepwise pathway was verified at high temperatures in a high-voltage electric field. Experiments and theoretical results revealed an electric field-catalyzed mechanism that shows the presence of a zwitterionic intermediate with one bond formation and variation of concerted and stepwise reactions by the strength of the electric field, thus establishing a previously unidentified approach for mechanistic control by electric field catalysis., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Advances in radical-based catalytic reactions have created a demand for understanding their mechanistic underpinnings. Here, we present the isolation, structural elucidation, and theoretical analysis of a catalytically relevant charge-transfer species formed between the azidyl radical and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). The unusual bond angles and pancake bonding between these two fragments highlight the weak bonding interactions present in this complex. This X-ray structure validates computational predictions as well as mechanistic proposals of TEMPO-mediated radical azidation reactions.

The clinical relevance of variant allele frequency (VAF) of recurrent mutations in myelodysplastic syndromes (MDS) has been increasingly reported. However, the prognostic value of mutational VAF across the genetic spectrum of MDS has not been extensively evaluated. In this study, we profiled the mutational spectrum of 382 newly diagnosed MDS patients using targeted next-generation sequencing. Exploratory analysis found that mutational VAF of some genes including TET2 , TP53 , and SF3B1 had significant associations with patient survival. Specifically, TET2 VAF ≥ 32% (HR 1.69, P = 0.025) and TP53 VAF ≥ 27% (HR 3.58, P < 0.001) were independently associated with shorter overall survival (OS). In contrast, SF3B1 VAF ≥ 15% had an independent association with better prognosis (HR 0.52, P = 0.048). In addition, high TET2 VAF was associated with an increased response to hypomethylating agents relative to low TET2 VAF (P = 0.009). Patients with high TP53 VAF more often possessed complex karyotypes than those with low VAF (P = 0.034). And patients with high SF3B1 VAF were more frequently classified as MDS with ring sideroblasts (MDS-RS) category than those with low VAF (P = 0.012). Meanwhile, we found that for some other genes like EZH2 and NRAS , once their mutations appeared, it meant poor survival regardless of mutational VAF. These findings suggest that mutational VAF of certain genes should be considered into the routine prognostic prediction and risk stratification of MDS patients., Competing Interests: None., (AJCR Copyright © 2020.)

We constructed a near-real-time daily CO 2 emission dataset, the Carbon Monitor, to monitor the variations in CO 2 emissions from fossil fuel combustion and cement production since January 1, 2019, at the national level, with near-global coverage on a daily basis and the potential to be frequently updated. Daily CO 2 emissions are estimated from a diverse range of activity data, including the hourly to daily electrical power generation data of 31 countries, monthly production data and production indices of industry processes of 62 countries/regions, and daily mobility data and mobility indices for the ground transportation of 416 cities worldwide. Individual flight location data and monthly data were utilized for aviation and maritime transportation sector estimates. In addition, monthly fuel consumption data corrected for the daily air temperature of 206 countries were used to estimate the emissions from commercial and residential buildings. This Carbon Monitor dataset manifests the dynamic nature of CO 2 emissions through daily, weekly and seasonal variations as influenced by workdays and holidays, as well as by the unfolding impacts of the COVID-19 pandemic. The Carbon Monitor near-real-time CO 2 emission dataset shows a 8.8% decline in CO 2 emissions globally from January 1 st to June 30 th in 2020 when compared with the same period in 2019 and detects a regrowth of CO 2 emissions by late April, which is mainly attributed to the recovery of economic activities in China and a partial easing of lockdowns in other countries. This daily updated CO 2 emission dataset could offer a range of opportunities for related scientific research and policy making.

The COVID-19 pandemic is impacting human activities, and in turn energy use and carbon dioxide (CO 2 ) emissions. Here we present daily estimates of country-level CO 2 emissions for different sectors based on near-real-time activity data. The key result is an abrupt 8.8% decrease in global CO 2 emissions (-1551 Mt CO 2 ) in the first half of 2020 compared to the same period in 2019. The magnitude of this decrease is larger than during previous economic downturns or World War II. The timing of emissions decreases corresponds to lockdown measures in each country. By July 1st, the pandemic's effects on global emissions diminished as lockdown restrictions relaxed and some economic activities restarted, especially in China and several European countries, but substantial differences persist between countries, with continuing emission declines in the U.S. where coronavirus cases are still increasing substantially.

Objective: To investigate the effect of Danggui Buxue Tang (DBT), a decoction from Traditional Chinese Medicine, on bleomycin-induced pulmonary fibrosis in rats, and to propose the possible underlying mechanism., Methods: Forty male Sprague-Dawley rats were randomly divided into sham group, model group, prednisone group and DBT group. Pulmonary fibrosis rat model was established by intratracheal injection with bleomycin. Body weight and lung index were monitored. Histopathologic examination and collagen deposition were determined using Hematoxylin and eosin (HE) and Masson's trichrome staining. Immunohistochemistry staining was applied to observe the expression of alpha-smooth muscle actin (α-SMA). mRNA expression of α-SMA, collagen Ⅰ and collagen Ⅲ were measured by real-time fluorescence quantitative PCR (RT-qPCR). Inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and IL-1β in serum were detected by Enzyme-linked immunosorbent assay. Alkali hydrolysis method was conducted to investigate the content of hydroxyproline (HYP). Transforming growth factor-β1 (TGF-β1), Smad3 and plasminogen activator inhibitor-1 (PAI-1) protein level were examined by Western blot assay., Results: DBT significantly reduced the severity of bleomycin-induced pulmonary fibrosis and inflammation as indicated by minimizing the lost of weight, and by lowering the levels of lung index, inflammation score, Ashcroft score, collagen volume fraction (%), HYP, α-SMA, collagen Ⅰ, collagen Ⅲ, TNF-α, IL-6, IL-1β, TGF-β1, Smad3 and PAI-1, consistent with the effect of prednisone., Conclusion: Our findings suggest that DBT is able to ameliorate the pulmonary fibrosis, the possible mechanism may involve inhibition of pulmonary inflammation and collagen deposition, possibly via suppressing TGF-β1/Smad3/PAI-1 signaling pathway.

We report angle-resolved photoelectron spectroscopy results of the Fermi surface of Ca1.5Sr0.5RuO4, which is at the boundary of magnetic/orbital instability in the phase diagram of the Ca-substituted Sr ruthenates. Three t(2g) energy bands and the corresponding Fermi surface sheets are observed, which are also present in the Ca-free Sr2RuO4. We find that while the Fermi surface topology of the alpha,beta (d(yz,zx)) sheets remains almost the same in these two materials, the gamma (d(xy)) sheet exhibits a holelike Fermi surface in Ca1.5Sr0.5RuO4 in contrast to being electronlike in Sr2RuO4. Our observation of all three volume conserving Fermi surface sheets clearly demonstrates the absence of orbital-selective Mott transition, which was proposed theoretically to explain the unusual transport and magnetic properties in Ca1.5Sr0.5RuO4.