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Feifei Pu,1,* Fengxia Chen,2,* Songfeng Chen,1 Baichuan Wang,1 Jianxiang Liu,1 Zengwu Shao1 1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Medical Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Objective: The aim of this study was to evaluate the relationship between GSTP1 polymorphisms and prognosis of osteosarcoma in patients treated with chemotherapy, by performing a meta-analysis.Methods: The studies of effects of GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy were collected. STATA (version 12.0) was used to perform data synthesis.Results: Six studies involving 898 participants were included. A meta-analysis was performed on studies in GSTP1 313A>G(rs1695) assessing the association between tumor response and the polymorphisms in GSTP1 (AA vs AG, AA vs GG), the pooled odds ratios (ORs) were 2.06 (95% confidence interval [CI]: 1.48–2.86, P=0.628, I2=0.0%). There was significant association between the polymorphisms in GSTP1 (AA vs AG, AA vs GG) and the events that happened, the pooled ORs were 1.86 (95% CI: 1.14–3.06, P=0.034, I2=58.6%), and there was significant association between the polymorphisms in GSTP1 (AA vs AG, AA vs GG) and survival times (overall survival and progression-free survival) in osteosarcoma patients treated with chemotherapy, and the pooled ORs were 2.14 (95% CI: 1.51–3.04, P=0.675, I2=0.0%) and 2.77 (95% CI: 1.56–4.91, P=0.347, I2=9.3%), respectively. Two studies assessed the association of polymorphisms in GSTP1 I105V (IIe/IIe vs IIe/Val, IIe/IIe vs Val/Val) with overall survival in human osteosarcoma. The pooled ORs were 1.20 (95% CI: 0.64–2.27, P=0.010, I2=73.5%). The study showed an insignificant difference in overall survival for the polymorphisms in GSTP1 (IIe/IIe vs IIe/Val, IIe/IIe vs Val/Val).Conclusion: This meta-analysis indicated that GSTP1 polymorphisms might influence osteosarcoma risk and suggests that GSTP1 polymorphisms may be an important risk factor for osteosarcoma.Keywords: GSTP1, polymorphisms, osteosarcoma, chemotherapy, prognosis, meta-analysis

In fish species, there is limited analysis of signature transcriptome profiles at the single-cell level in gonadal cells. Here, the molecular signatures of distinct ovarian cell categories in adult Nile tilapia (Oreochromis niloticus) were analysed using single-nucleus RNA sequencing (snRNA-seq). We identified four cell types (oogonia, oocytes, granulosa cell, and thecal cell) based on their specifically expressed genes and biological functions. Similarly, we found some key pathways involved in ovarian development that may affect germline-somatic interactions. A cell-to-cell communication network between the distinct cell types was constructed. We found that the bidirectional communication is mandatory for the development of germ cells and somatic cells in fish ovaries, and the granulosa cells and thecal cells play a central regulating role in the cell network in fish ovary. Additionally, we identified some novel candidate marker genes for various types of ovarian cells and also validated them using in situ hybridization. Our work reveals an ovarian atlas at the cellular and molecular levels and contributes to providing insights into oogenesis and gonad development in fish., (© 2024 Fisheries Society of the British Isles.)

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth., Competing Interests: Declaration of interests J.M. owns company stock in Scholar Rock. C.M.R. has consulted regarding oncology drug development with Amgen, Astra Zeneca, Chugai, Daiichi Sankyo, Hoffman-La Roche, and Jazz Pharmaceuticals; C.M.R. serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. S.W.L. is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, PMV Pharmaceuticals, Faeth Therapeutics, and Senecea Therapeutics, and is a consultant for Fate Therapeutics. T.T. is a consultant and holds equity in Lime Therapeutics; the Tammela Lab receives research support from Ono Pharmaceuticals Co., Ltd. (unrelated to this work). T.T.’s spouse is an employee of Recursion Pharmaceuticals. R.P.K. is a co-founder of and consultant for Econic Biosciences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Coronal shear fractures of the distal humerus are not only rare and prone to misdiagnosis, but their surgical treatment can be challenging. We aimed to investigate the feasibility of exposing distal humeral coronal shear fractures with a combined lateral approach that preserves the extensors and lateral ulnar collateral ligament (LUCL) and to analyze the clinical efficacy of open reduction and internal fixation in the treatment of these injuries., Methods: We included 45 patients who sustained coronal shear fractures of the distal humerus with the lateral epicondyle intact and were treated with open reduction and internal fixation from January 2013 to August 2020. The fractures were exposed by the lateral combined approach in which the tendons involving the common extensor, the extensor carpi ulnaris, and the LUCL were preserved. Two observation windows were formed anterior to and posterior to these tendons and the LUCL was used to achieve fracture reduction. Countersunk screws, with or without a plate placed on the posterior lateral condyle, were used to fix the fragments. The functional outcomes of these patients were reviewed and assessed with physical and radiographic examinations, range of motion measurements, and self-evaluation Mayo Elbow Performance Index and the Disabilities of the Arm, Shoulder, and Hand scores., Results: In total, 40 patients were followed up with for over 1 year and were included in the final analysis. The mean follow-up duration was 42 ± 30 months (range, 12-107 months). The patients' mean age was 42 years (range, 14-74 years). According to the Dubberley Classification, there were 15 type I, 17 type II, and 8 type III fractures. At the final follow-up, the mean flexion-extension arc was 131° (range, 65-150) and mean pronation and supination was 73° (range, 45-80) and 71° (range, 40-80), respectively. The mean Mayo Elbow Performance Index score was 88 (range, 61-97) points; the results were excellent in 21, good in 13, fair in 4, and poor in 2 patients. The mean Disabilities of the Arm, Shoulder, and Hand score was 11 (range, 0-42) points. Neither functional score nor range of movement was associated with age, sex, fracture type, injury type, or surgical timing., Conclusion: Reduction and stable fixation with internal fixation for coronal shear fractures of the distal humerus can be achieved by the lateral combined approach. Early functional mobilization allows for satisfactory restoration of elbow function., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The construction and modification of novel energetic frameworks to achieve an ideal balance between high energy density and good stability are a continuous pursuit for researchers. In this work, a fused [5,6,5]-tricyclic framework was utilized as the energetic host to encapsulate the oxidant molecules for the first time. A series of new pyridazine-based [5,6] and [5,6,5] fused polycyclic nitrogen-rich skeletons and their derivatives were designed and synthesized. Two strategies, amino oxidation and host-guest inclusion, were used to modify the skeleton in only one step. All compounds exhibit good comprehensive properties ( T d (onset) > 200 °C, ρ > 1.85 g cm -3 , D v > 8400 m s -1 , IS > 20 J, FS > 360 N). Benefiting from the pyridazine-based fused tricyclic structure with more hydrogen bonding units and larger conjugated systems, the first example of [5,6,5]-tricyclic host-guest energetic material triamino-9 H -pyrazolo[3,4- d ][1,2,4]triazolo[4,3- b ]pyridazine-diperchloric acid ( 10 ), shows high decomposition temperature ( T d (onset) = 336 °C), high density and heats of formation (ρ = 1.94 g cm -3 , Δ H f = 733.4 kJ mol -1 ), high detonation performance ( D v = 8820 m s -1 , P = 36.2 GPa), high specific impulse ( I sp = 269 s), and low sensitivity (IS = 30 J, FS > 360 N). The comprehensive performance of 10 is superior to that of high-energy explosive RDX and heat-resistant explosives such as HNS and LLM-105. 10 has the potential to become a comprehensive advanced energetic material that simultaneously satisfies the requirements of high-energy and low-sensitivity explosives, heat-resistant explosives, and solid propellants. This work may give new insights into the construction and modification of a nitrogen-rich polycyclic framework and broaden the applications of fused polycyclic framework for the development of host-guest energetic materials.

To investigate the impact of chlorantraniliprole on Procambarus clarkii, acute toxicity tests were performed. Results indicated that 96 h post-exposure to chlorantraniliprole (60 mg/L) led to the separation of the hepatopancreas basement membrane, causing cell swelling, rupture, and vacuolation. Moreover, acid phosphatase (ACP) and alkaline phosphatase (AKP) activities exhibited divergent trends across four concentrations of chlorantraniliprole (0, 30, 60, and 90 mg/L). Hydrogen peroxide (H 2 O 2 ) and catalase (CAT) levels significantly increased, while total superoxide dismutase (T-SOD) and malonaldehyde (MDA) activities decreased, indicating oxidative stress in the hepatopancreas. A total of 276 differentially expressed genes (DEGs) were identified, with 204 up-regulated and 72 down-regulated. Out of these, 114 DEGs were successfully annotated and classified into 99 pathways, with a primary focus on the cytochrome P450-mediated xenobiotic metabolism pathway. The DEGs enriched in this pathway, along with transcriptome data, were validated using quantitative-polymerase chain reaction. This study enhances the transcriptome database of P. clarkii and provides fundamental insights into its immune defense and antioxidant mechanisms. Additionally, it lays a theoretical foundation for future research on disease prevention in P. clarkii within rice-shrimp culture systems., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Twin-field quantum key distribution (TFQKD) overcomes the linear rate-loss limit, which promises a boost of secure key rate over long distance. However, the complexity of eliminating the frequency differences between the independent laser sources hinders its practical application. We analyzed and determined the frequency stability requirements for implementing TFQKD using frequency-stabilized lasers. Based on this analysis, we proposed and demonstrated a simple and practical approach that utilizes the saturated absorption spectroscopy of acetylene as an absolute reference, eliminating the need for fast frequency locking to achieve TFQKD. Adopting the 4-intensity sending-or-not-sending TFQKD protocol, we experimentally demonstrated the TFQKD over 502, 301, and 201 km ultralow-loss optical fiber, respectively. We expect this high-performance scheme will find widespread usage in future intercity and free-space quantum communication networks.

The remote C(sp 3 )-SCN bond formation via ring-opening functionalization of cycloalkanols with N-thiocyanatosaccharin as the precursor of SCN radicals and pyrylium salt as the organic photocatalyst under visible light has been developed. Thus, various terminal keto thiocyanates were prepared without transition metals and oxidants in moderate to good yields. The simplicity, wide substrate scope and mild conditions feature its synthetic application capability., (© 2024 Wiley-VCH GmbH.)

Lead (Pb) is a major source of heavy metal contamination, and poses a threat to biodiversity and human health. Elevated levels of Pb can hinder insect growth and development, leading to apoptosis via mechanisms like oxidative damage. The midgut of silkworms is the main organ exposed to heavy metals. As an economically important lepidopteran model insect in China, heavy metal-induced stress on silkworms causes considerable losses in sericulture, thereby causing substantial economic damage. This study aimed to investigate Pb-induced detoxification-related genes in the midgut of silkworms using high-throughput sequencing methods to achieve a deeper comprehension of the genes' reactions to lead exposure. This study identified 11,567 unigenes and 14,978 transcripts. A total of 1265 differentially expressed genes (DEGs) were screened, comprising 907 upregulated and 358 downregulated genes. Subsequently, Gene Ontology (GO) classification analysis revealed that the 1265 DEGs were distributed across biological processes, cellular components, and molecular functions. This suggests that the silkworm midgut may affect various organelle functions and biological processes, providing crucial clues for further exploration of DEG function. Additionally, the expression levels of 12 selected detoxification-related DEGs were validated using qRT-PCR, which confirmed the reliability of the RNA-seq results. This study not only provides new insights into the detoxification defense mechanisms of silkworms after Pb exposure, but also establishes a valuable foundation for further investigation into the molecular detoxification mechanisms in silkworms.

A Lewis acid-promoted electrophilic thiocyanation/cyclization of ortho -alkynylanilines for the synthesis of indole derivatives has been developed. The reaction utilizes Me 3 SiBr as the Lewis acid and N -thiocyanatosuccinimide as the thiocyanation reagent. A series of 2-aryl-3-thiocyanato indoles were prepared in moderate to high yields under mild conditions without metals and oxidants. It provides an efficient protocol for the construction of the indole skeleton and C-SCN and C-N bonds in one step as well.

We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy., (© 2024. Controlled Release Society.)

Individuals unvaccinated against COVID-19 (C19) experienced prejudice and blame for the pandemic. Because people vastly overestimate C19 risks, we examined whether these negative judgements could be partially understood as a form of scapegoating (ie, blaming a group unfairly for an undesirable outcome) and whether political ideology (previously shown to shape risk perceptions in the USA) moderates scapegoating of the unvaccinated. We grounded our analyses in scapegoating literature and risk perception during C19. We obtained support for our speculations through two vignette-based studies conducted in the USA in early 2022. We varied the risk profiles (age, prior infection, comorbidities) and vaccination statuses of vignette characters (eg, vaccinated, vaccinated without recent boosters, unvaccinated, unvaccinated-recovered), while keeping all other information constant. We observed that people hold the unvaccinated (vs vaccinated) more responsible for negative pandemic outcomes and that political ideology moderated these effects: liberals (vs conservatives) were more likely to scapegoat the unvaccinated (vs vaccinated), even when presented with information challenging the culpability of the unvaccinated known at the time of data collection (eg, natural immunity, availability of vaccines, time since last vaccination). These findings support a scapegoating explanation for a specific group-based prejudice that emerged during the C19 pandemic. We encourage medical ethicists to examine the negative consequences of significant C19 risk overestimation among the public. The public needs accurate information about health issues. That may involve combating misinformation that overestimates and underestimates disease risk with similar vigilance to error., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We established the optimal model by using the automatic machine learning method to predict the degradation efficiency of herbicide atrazine in soil, which could be used to assess the residual risk of atrazine in soil. We collected 494 pairs of data from 49 published articles, and selected seven factors as input features, including soil pH, organic matter content, saturated hydraulic conductivity, soil moisture, initial concentration of atrazine, incubation time, and inoculation dose. Using the first-order reaction rate constant of atrazine in soil as the output feature, we established six models to predict the degradation efficiency of atrazine in soil, and conducted comprehensive analysis of model performance through linear regression and related evaluation indicators. The results showed that the XGBoost model had the best performance in predicting the first-order reaction rate constant ( k ). Based on the prediction model, the feature importance ranking of each factor was in an order of soil moisture > incubation time > pH > organic matter > initial concentration of atrazine > saturated hydraulic conductivity > inoculation dose. We used SHAP to explain the potential relationship between each feature and the degradation ability of atrazine in soil, as well as the relative contribution of each feature. Results of SHAP showed that time had a negative contribution and saturated hydraulic conductivity had a positive contribution. High values of soil moisture, initial concentration of atrazine, pH, inoculation dose and organic matter content were generally distributed on both sides of SHAP=0, indicating their complex contributions to the degradation of atrazine in soil. The XGBoost model method combined with the SHAP method had high accuracy in predicting the performance and interpretability of the k model. By using machine learning method to fully explore the value of historical experimental data and predict the degradation efficiency of atrazine using environmental parameters, it is of great significance to set the threshold for atrazine application, reduce the residual and diffusion risks of atrazine in soil, and ensure the safety of soil environment.

Objective: Depression is a common mental illness. Neural stem cell-derived extracellular vesicles (NSC-EVs) are involved in repairing neuronal injury. We estimated the mechanism of miR-16-5p in depression rats., Methods: EVs were extracted from NSCs. The depression rat model was established by corticosterone (CORT) induction and treated with NSC-EVs. The depression behavioral/pathological changes in rats were assessed using forced swimming test, open field test, sucrose consumption test and western blotting. The neuronal apoptosis in hippocampal tissue were detected. CORT-induced PC12 cell model was established. EV uptake by PC12 cells was measured and PC12 cell apoptosis was detected. The downstream targets of miR-16-5p were predicted and verified. The expressions of miR-16-5p and MYB in rats, PC12 cells, and EVs were measured. Functional rescue experiments were conducted to verify the role of miR-16-5p and MYB in PC12 cell apoptosis., Results: CORT induction increased neuronal apoptosis in hippocampal tissue and induced depression-like behaviors in rats, while NSC-EV treatment improved depression-like behaviors and apoptosis in rats. In PC12 cells, NSC-EVs decreased CORT-induced PC12 cell apoptosis. NSC-EVs carried miR-16-5p into PC12 cells. miR-16-5p knockdown in EVs partially reversed the inhibitory effects of NSC-EVs on CORT-induced PC12 cell apoptosis. miR-16-5p targeted to inhibit MYB to repress CORT-induced PC12 cell apoptosis. In vivo experiments further verified that NSC-EVs reduced neuronal injury in CORT-induced depression rats via the miR-16-5p/MYB axis., Conclusion: NSC-EVs-mediated alleviation on neuronal injury by carrying miR-16-5p to target MYB was highly likely one of the mechanisms by which NSC-EVs mediated miR-16-5p in neuroprotection of depression rats., (Copyright © 2023 IBRO. Published by Elsevier Inc. All rights reserved.)

Background: Early systemic anticoagulation (SAC) is a common practice in acute necrotizing pancreatitis (ANP), and its impact on in-hospital clinical outcomes had been assessed. However, whether it affects long-term outcomes is unknown. This study aimed to evaluate the effect of SAC on 90-day readmission and other long-term outcomes in ANP patients., Methods: During January 2013 and December 2018, ANP patients admitted within 7 days from the onset of abdominal pain were screened. The primary outcome was 90-day readmission after discharge. Cox proportional-hazards regression model and mediation analysis were used to define the relationship between early SAC and 90-day readmission., Results: A total of 241 ANP patients were enrolled, of whom 143 received early SAC during their hospitalization and 98 did not. Patients who received early SAC experienced a lower incidence of splanchnic venous thrombosis (SVT) [risk ratio (RR) = 0.40, 95% CI: 0.26-0.60, P < 0.01] and lower 90-day readmission with an RR of 0.61 (95% CI: 0.41-0.91, P = 0.02) than those who did not. For the quality of life, patients who received early SAC had a significantly higher score in the subscale of vitality (P = 0.03) while the other subscales were all comparable between the two groups. Multivariable Cox regression model showed that early SAC was an independent protective factor for 90-day readmission after adjusting for potential confounders with a hazard ratio of 0.57 (95% CI: 0.34-0.96, P = 0.04). Mediation analysis showed that SVT mediated 37.0% of the early SAC-90-day readmission causality., Conclusions: The application of early SAC may reduce the risk of 90-day readmission in the survivors of ANP patients, and reduced SVT incidence might be the primary contributor., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

While several inhibitors targeting RNA polymerase II (Pol II) kinases have been applied for inhibiting RNA Pol II phosphorylation, there are few approaches for inducing RNA Pol II hyperphosphorylation. Here, we present a protocol for constructing the INTS8 degradation tag (dTAG) system combined with ectopic expression of N-terminally truncated INTS8 (INTS8-ΔN) in DLD-1 cells. We describe steps for INTS8-dTAG cell line construction, validation of knockin and degradation, and INTS8-ΔN rescue. We then detail validation of RNA Pol II phosphorylation upregulation. For complete details on the use and execution of this protocol, please refer to Hu et al. (2023). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: There is an urgent need for biomarkers and new actionable targets to improve radiosensitivity of triple-negative breast cancer (TNBC) tumors. We characterized the radiosensitizing effects and underlying mechanisms of combined Aurora kinase A (AURKA) and CHK1 inhibition in TNBC., Methods and Materials: Different TNBC cell lines were treated with AURKA inhibitor (AURKAi, MLN8237) and CHK1 inhibitor (CHK1i, MK8776). Cell responses to irradiation (IR) were then evaluated. Cell apoptosis, DNA damage, cell cycle distribution, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and Phosphoinositide 3-Kinase (PI3K) pathways were evaluated in vitro. Transcriptomic analysis was performed to facilitate the identification of potential biomarkers. Xenograft and immunohistochemistry were carried out to investigate the radiosensitizing effects of dual inhibition in vivo. Finally, the prognostic effect of CHEK1/AURKA in TNBC samples in the The Cancer Genome Atlas (TCGA) database and our center were analyzed., Results: AURKAi (MLN8237) induced overexpression of phospho-CHK1 in TNBC cells. The addition of MK8776 (CHK1i) to MLN8237 greatly reduced cell viability and increased radiosensitivity compared with either the control or MLN8237 alone in vitro. Mechanistically, dual inhibition resulted in inducing excessive DNA damage by prompting G2/M transition to cells with defective spindles, leading to mitotic catastrophe and induction of apoptosis after IR. We also observed that dual inhibition suppressed the phosphorylation of ERK, while activation of ERK with its agonist or overexpression of active ERK1/2 allele could attenuate the apoptosis induced by dual inhibition with IR. Additionally, dual inhibition of AURKA and CHK1 synergistically enhanced radiosensitivity in MDA-MB-231 xenografts. Moreover, we detected that both CHEK1 and AURKA were overexpressed in patients with TNBC and negatively correlated with patient survival., Conclusions: Our findings suggested that AURKAi in combination with CHK1i enhanced TNBC radiosensitivity in preclinical models, potentially providing a novel strategy of precision treatment for patients with TNBC., (Copyright © 2023. Published by Elsevier Inc.)

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS) 3 and the transcription regulator Integrator-PP2A (INTAC) 4-6 . Through SSB1-mediated recognition of single-stranded DNA, SOSS-INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS-INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS-INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability., (© 2023. The Author(s).)

Goals: To explore factors associated with inadequate gastric preparation for MCE. Background: Factors associated with inadequate gastric preparation for magnetically controlled capsule endoscopy (MCE) remains unclear. Study: Data of patients who underwent MCE from June 2021 to July 2022 were prospectively collected. The gastric cleanliness score (GCS) of the six stomach regions (gastric cardia, fundus, body, angulus, antrum, and pylorus) was recorded. Patients with GCS score ≥18 were defined as the adequate preparation. Factors related to inadequate gastric preparation were analyzed using a logistic regression model with estimated odds ratios (OR). Results: The mean GCS score of 211 patients was 17.01 ± 2.82. In the multivariable analysis, proton pump inhibitor (PPI) use (OR 3.57; 95% CI 1.69-7.95; p < 0.01) and premedication time after administering simethicone <30 min (OR 2.86; 95% CI 1.10-7.39; p = 0.03) were independent risk factors for inadequate gastric preparation. Comparing the gastric cleanliness of different locations, the median GCS of the lower stomach [10.00, IQR (9.50, 11.00)] was significantly higher than that of the upper stomach [7.00, IQR (6.00, 8.00)] ( p <0.001). Conclusion: PPI use and inadequate premedication time (<30 min) may reduce the quality of gastric preparation for MCE. The type, dose, duration of medication, and discontinuation time of PPIs was well worth further exploration. Appropriate control of the type and time of premedication may be the key to improving overall gastric cleanliness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kong, Peng, Li, Tian, Li, Chen, Zuo and Li.)

The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 has a mild impact on gene expression and cellular differentiation whereas the loss of LSD1 protein de-represses enhancers globally and impairs cell fate transition. LSD1 deletion increases H3K27ac levels and P300 occupancy at LSD1-targeted enhancers. The gain of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into treating diseases driven by LSD1 mutations and misregulation., (© 2023. Springer Nature Limited.)

A Lewis acid-catalyzed electrophilic dearomatizative thiocyanation and cyclization of benzofurans with N -thiocyanatosuccinimide has been accomplished by Lewis acid catalysis with CuOTf under mild conditions. It was suggested that the electrophilic thiocyanating reagent was activated by CuOTf, and difunctionalization was achieved through a thiocyanation/spirocyclization pathway. Thus, a series of thiocyanato-containing spiroketals were obtained in moderate to high yields. It provides an alternative approach for the synthesis of functionalized [6,5]/[5,5]-spiroketals.

Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or promoter-proximal termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here, we establish a rapid degradation system to dissect the functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces promoter-proximal termination, with its disruption leading to accumulation of elongation-incompetent polymerases and downregulation of highly expressed genes, while elongation-competent polymerases accumulate at lowly expressed genes and non-coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus, both INTAC catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The functional food ingredients of apple juice can significantly change during processing, transportation, and storage, thus affecting the quality of the product. A simple and derivation-free analytical method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and optimized for the simultaneous determination of functional food ingredients in apple juice bought in the market. Cleanup steps and chromatographic conditions were optimized to remove interference and decrease the matrix effect. The nine target analytes were separated on an Acquity UPLC system equipped with a BEH C18 column and detected by electrospray ionization source (ESI) operating in positive subsection acquisition mode under multiple reaction monitoring (MRM) conditions. The results showed that p-hydroxybenzoic acid, protocatechuate, caffeic acid, chlorogenic acid, epicatechin, phloridzin, hyperoside, procyanidin B 2 , and rutin could be sufficiently separated for content determination within 6 min. In the concentration range of 20 μg/L-50 mg/L, nine standard samples exhibited a good linear fit with correlation coefficients above .985., Competing Interests: The authors declare that there is no conflict of interest and that they do not have any possible conflicts of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Substance P (SP), a neuropeptide consisting of 11 amino acid residues, is involved in the pathogenesis of encephalomyocarditis virus (EMCV)-induced myocarditis by stimulating the production of proinflammatory cytokines. However, the underlying mechanism that regulates SP production is still unknown. In this study, we report the transcriptional regulation of the Tachykinin Precursor 1 (TAC1) gene that encodes SP by a transcriptional complex composed of Steroid Receptor Coactivator 1 (Src1), Peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC1α), and Activator Protein 1 (AP1) transcription factor. Infection of mice with EMCV induced the accumulation of PGC1α and increased TAC1 expression, thereby promoting the secretion of SP, initiating apoptosis, and elevating proinflammatory cytokine levels. In vitro overexpression of the Src1-PGC1α-AP1 members also induced TAC1 expression, increased the SP concentration, initiated apoptosis, and elevated proinflammatory cytokine concentrations. Depletion or inhibition of the Src1-PGC1α-AP1 complex reversed these effects. The administration of gossypol, an Src1 inhibitor, or SR1892, a PGC1α inhibitor, to EMCV-infected mice attenuated myocarditis. Taken together, our results reveal that the upregulation of TAC1 and the secretion of SP in EMCV-induced myocarditis are dependent on the Src1-PGC1α-AP1 complex. Targeting the Src1-PGC1α-AP1 complex may represent a new therapeutic strategy for myocarditis., 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 Elsevier Ltd. All rights reserved.)

A tandem electrophilic thiocyanation and cyclization of arene-alkynes has been developed under mild conditions, affording thiocyanato-substituted phenanthrenes, dihydronaphthalenes, 2 H -chromenes and dihydroquinolines in moderate to excellent yields. This reaction provides an efficient protocol for the construction of C-SCN and C-C bonds in one step. In this transformation, N -thiocyanato reagent serves as a convenient precursor to transfer SCN + in the presence of trimethylchlorosilane, and the cyclization exhibited exclusive 6-endo-dig selectivity. Finally, a gram scale reaction and further derivatizations highlight the utility of this synthetic strategy.

We examined how observers assess information-poor allegations of harm (e.g., "my word against yours" cases), in which the outcomes of procedurally fair investigations may favor the alleged perpetrator because the evidentiary standards are unmet. Yet this lack of evidence does not mean no harm occurred, and some observers may be charged with deciding whether the allegation is actionable within a collective. On the basis of theories of moral typecasting, procedural justice, and uncertainty management, we hypothesized that observers would be more likely to prioritize the victim's safety (vs. to prioritize due process for the perpetrator) and view the allegation as actionable when the victim-alleged perpetrator dyad members exhibit features that align with stereotypes of victims and perpetrators. We supported our hypothesis with four studies using various contexts, sources of perceived prototypicality, due-process prioritization, and samples (students from New Zealand, N s = 137 and 114; Mechanical Turk workers from the United States; N s = 260 and 336).

Introduction: Considerable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered., Objectives: To characterize the alterations of oral and gut microbiota and their roles in HTN., Methods: We performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN., Results: BP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition., Conclusions: PD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN., 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. Production and hosting by Elsevier B.V.)

Apigenin is a kind of flavonoid with many beneficial biological effects. It not only has direct cytotoxicity to tumor cells, but also can boost the antitumor effect of immune cells by modulating immune system. The purpose of this study was to investigate the proliferation of NK cells treated with apigenin and its cytotoxicity to pancreatic cancer cells in vitro, and explore its potential molecular mechanism. In this study, the effect of apigenin on NK cell proliferation and killing pancreatic cancer cells were measured by CCK-8 assay. Perforin, granzyme B (Gran B), CD107a, and NKG2D expressions of NK cells induced with apigenin were detected by flow cytometry (FCM). The mRNA expression of Bcl-2, Bax and protein expression of Bcl-2, Bax, p-ERK, and p-JNK in NK cells were evaluated by qRT-PCR and western blotting analysis, respectively. The results showed that appropriate concentration of apigenin could significantly promote the proliferation of NK cells in vitro and enhance the killing activity of NK cells against pancreatic cancer cells. The expressions of surface antigen NKG2D and intracellular antigen perforin and Gran B of NK cells were upregulated after treating with apigenin. Bcl-2 mRNA expression was increased, while Bax mRNA expression was decreased. Similarly, the expression of Bcl-2, p-JNK, and p-ERK protein was upregulated, and the expression of Bax protein was downregulated. The molecular mechanism of the immunopotentiation effects of apigenin may be that it up-regulates Bcl-2 and down-regulates Bax expression at the gene and protein levels to facilitate NK cell proliferation, and up-regulates the expression of perforin, Gran B, and NKG2D through the activation of JNK and ERK pathways to enhance NK cell cytotoxicity.

Currently available commercial nerve guidance conduits have been applied in the repair of peripheral nerve defects. However, a conduit exhibiting good biocompatibility remains to be developed. In this work, a series of chitosan/graphene oxide (GO) films with concentrations of GO varying from 0-1 wt% (collectively referred to as CHGF-n) were prepared by an electrodeposition technique. The effects of CHGF-n on proliferation and adhesion abilities of Schwann cells were evaluated. The results showed that Schwann cells exhibited elongated spindle shapes and upregulated expression of nerve regeneration-related factors such as Krox20 (a key myelination factor), Zeb2 (essential for Schwann cell differentiation, myelination, and nerve repair), and transforming growth factor β (a cytokine with regenerative functions). In addition, a nerve guidance conduit with a GO content of 0.25% (CHGFC-0.25) was implanted to repair a 10-mm sciatic nerve defect in rats. The results indicated improvements in sciatic functional index, electrophysiology, and sciatic nerve and gastrocnemius muscle histology compared with the CHGFC-0 group, and similar outcomes to the autograft group. In conclusion, we provide a candidate method for the repair of peripheral nerve defects using free-standing chitosan/GO nerve conduits produced by electrodeposition.

Networks of optical clocks find applications in precise navigation 1,2 , in efforts to redefine the fundamental unit of the 'second' 3-6 and in gravitational tests 7 . As the frequency instability for state-of-the-art optical clocks has reached the 10 -19 level 8,9 , the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10 -19 . However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres 10,11 . Here we report time-frequency dissemination with an offset of 6.3 × 10 -20  ± 3.4 × 10 -19 and an instability of less than 4 × 10 -19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time-frequency dissemination., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In order to explore the impact of optimized land use allocation on phosphorus loss in the runoff process of a small watershed in the Three Gorges Reservoir area, a traditional agricultural model catchment area (CG) and a catchment area after optimized land use allocation in the Shipanqiu watershed in Zhong County, Chongqing (EG) were selected as the research object, sampling at the outlets of the two catchment areas, respectively, to monitor the runoff process and different forms of phosphorus in rainfall events and to analyze the influence of land use configuration on the law of phosphorus loss. The results showed that:① in the 10 monitored rainfall and runoff processes, the ρ [total phosphorus (TP)] of EG was lower than that of CG, and the ranges of the two were 0.09-0.75 mg·L -1 and 0.13-2.82 mg·L -1 , respectively. Compared with that of CG, EG significantly reduced the peak value of TP. ② The average EMC of TP, total dissolved phosphorus (TDP), dissolved inorganic phosphorus (DIP), and particulate phosphorus (PP) in the process of rainfall and runoff was lower than that of CG, and EG and CG showed significant differences in EMC of TP, TDP, and DIP ( P <0.05); the main form of phosphorus loss in the two catchment areas in the process of rainfall and runoff was TDP, but the average TDP/TP of EG was larger. ③ The output load of EG was 45%, 43%, 57%, and 47% lower than that of the TP, TDP, DIP, and PP in CG. The output load of EG and CG of various forms of phosphorus was significantly correlated with the total runoff ( P <0.01). In addition, the slope of the linear fitting of various phosphorus forms in the CG catchment area to the total amount of runoff was 1.66 to 1.75 times that of EG. The output load of various phosphorus forms of CG was more sensitive to runoff than that of EG, and the output per unit area in the process of rainfall and runoff was more sensitive than that of EG. The amount of sand could have caused the difference in phosphorus concentration and output load more than the output per unit area. Optimizing land use configuration can effectively reduce the loss of various forms of phosphorus and provide a reference for the prevention and control of phosphorus loss in small watersheds in the Three Gorges Reservoir area.

We draw from an interdisciplinary literature on convictions to examine the manifestations and consequences of firmly held beliefs in Covid-19 (C19) science. Across three studies ( N  = 743), we assess participants' beliefs in C19 experts, and beliefs in supported and unsupported empirical evidence. Study 1 establishes the basic theoretical links and we show that an individual's belief in science on C19 is associated with dispositional belief in science and moralization of C19 mitigation measures. Our subsequent two studies show how stronger belief in C19 science influences distrust in unmasked individuals past the mandates, and greater endorsement of pandemic mitigation authoritarianism. We document the dark side that emerges when belief in C19 science extends beyond the generally desirable scientific literacy and manifests as a conviction that public health experts are the only ones who can handle the pandemic, and that even unsupported claims about C19 are supported by scientific evidence (e.g., risk of outdoor transmission is high). We also highlight our political ideology findings showing that both liberals and conservatives mis-calibrate C19 risks in different ways, and we conclude with discussing how examining the darker side of scientific beliefs can inform our understanding of people's reactions to the pandemic., (© 2022 Elsevier Ltd. All rights reserved.)

Twin-field quantum key distribution (TFQKD) promises ultralong secure key distribution which surpasses the rate distance limit and can reduce the number of the trusted nodes in long-haul quantum network. Tremendous efforts have been made toward implementation of TFQKD, among which, the secure key with finite size analysis can distribute more than 500 km in the lab and in the field. Here, we demonstrate the sending-or-not-sending TFQKD experimentally, achieving a secure key distribution with finite size analysis over a 658 km ultra-low-loss optical fiber. Meanwhile, in a TFQKD system, any phase fluctuation due to temperature variation and ambient variation during the channel must be recorded and compensated, and all this phase information can then be utilized to sense the channel vibration perturbations. With our quantum key distribution system, we recovered the external vibrational perturbations generated by artificial vibroseis on both the quantum and frequency calibration link, and successfully located the perturbation position in the frequency calibration fiber with a resolution better than 1 km. Our results not only set a new distance record of quantum key distribution, but also demonstrate that the redundant information of TFQKD can be used for remote sensing of the channel vibration, which can find applications in earthquake detection and landslide monitoring besides secure communication.

Background: Superior mesenteric artery embolism (SMAE) has acute onset and fast progression, which seriously threatens the life of patients. Multidetector computed tomography (MDCT) is one of the most important diagnostic methods for SMAE, which plays an important role in the diagnosis and prognosis of SMAE., Aim: To evaluate the value of combined clinical data and MDCT findings in the diagnosis of acute SMAE and predict the risk factors for SMAE-related death., Methods: Data from 53 SMAE patients who received abdominal MDCT multi-phase enhancement and superior mesenteric artery digital subtraction angiography examinations were collected. Univariate cox regression and multivariate cox model were used to analyze the correlation between death risk and clinical and computed tomography features in SMAE patients., Results: Univariate Cox regression model showed that intestinal wall thinning, intestinal wall pneumatosis, blood lactate > 2.1 mmol/L and blood pH < 7.35 increased the risk of death in patients with SMAE. After adjusting for age, sex, embolic involvement length and embolic distribution region, multivariate Cox regression model I showed that blood lactate > 2.1 mmol/L (HR = 5.26, 95%CI: 1.04-26.69, P = 0.045) and intestinal wall thinning (HR = 9.40, 95%CI: 1.05-83.46, P = 0.044) were significantly increases the risk of death in patients with SMAE., Conclusion: For patients with SAME, increased blood lactate and intestinal wall thinning are the risk factors for death; hence, close monitoring may reduce the mortality rate. Clinical observation combined with MDCT signs can significantly improve SMAE diagnosis., Competing Interests: Conflict-of-interest statement: No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

RNA polymerase II (Pol II)-mediated transcription in metazoans requires precise regulation. RNA Pol II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). Here, we show that RPAP2 binds hypo-/hyper-phosphorylated Pol II with undetectable phosphatase activity. The structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents and disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in inhibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating a critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to inhibit PIC assembly and transcription initiation and suggests a transcription checkpoint., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to investigate whether cytokine profiles and virological markers might add value in monitoring the effects of peginterferon (PEG-IFN) therapy for hepatitis B e-antigen (HBeAg) positive chronic hepatitis B (CHB)., Methods: HBeAg positive patients with CHB were treated with PEG-IFN for 48 weeks. Clinical biochemical, and HBV serological indexes, as well as cytokines, were detected at baseline and every 12 weeks., Results: A total of 116 patients with CHB were enrolled in this study; 100 patients completed the 48-week treatment and follow-up, of whom 38 achieved serum HBeAg disappearance, 25 achieved HBeAg seroconversion, 37 showed HBsAg decreases ≥ 1 log 10 IU/mL, 9 showed HBsAg disappearance, and 8 became HBsAb positive. The cytokine levels at baseline and during treatment were similar between the HBeAg disappearance group and non-disappearance group. The disappearance of HBeAg was independently associated with HBeAg levels at weeks 12 and 24, and with the HBeAg decline at week 24 ( P < 0.05). The HBsAg response was independently associated with HBsAg, the HBsAg decline, HBeAg, the HBeAg decline at week 12, and HBsAg at week 24 ( P < 0.05)., Conclusion: There was no significant correlation between the response to interferon (IFN) and cytokines during PEG-IFN treatment. The changes in virological markers predicted the response to IFN after 48 weeks., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Pleiotropic transcription regulator RNA polymerase II (Pol II)-associated factor 1 (PAF1) governs multiple transcriptional steps and the deposition of several epigenetic marks. However, it remains unclear how ultimate transcriptional outcome is determined by PAF1 and whether it relates to PAF1-controlled epigenetic marks. We use rapid degradation systems and reveal direct PAF1 functions in governing pausing partially by recruiting Integrator-PP2A (INTAC), in addition to ensuring elongation. Following acute PAF1 degradation, most destabilized polymerase undergoes effective release, which presumably relies on skewed balance between INTAC and P-TEFb, resulting in hyperphosphorylated substrates including SPT5. Impaired Pol II progression during elongation, along with altered pause release frequency, determines the final transcriptional outputs. Moreover, PAF1 degradation causes a cumulative decline in histone modifications. These epigenetic alterations in chromatin likely further influence the production of transcripts from PAF1 target genes.

The function of substance P (SP) in myocardial ischemia is well understood, but its effects on congestive heart failure are unclear. The present study aimed to use in vitro and in vivo approaches to investigate the effects of SP on doxorubicin‑induced cardiomyocyte injury. Pathological changes, apoptosis, cardiomyocyte ultrastructure and molecular mechanisms were evaluated in vitro and in vivo . The effects of SP on cell viability of H9c2 myocardial cells were evaluated using the Cell Counting Kit‑8 and flow cytometry. B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), Beclin‑1 and microtubule‑associated protein 1A/1B‑light chain 3 (LC3) were detected by western blotting. Heart failure in rats was established by intraperitoneal injection of doxorubicin. The in vitro data demonstrated that SP at concentrations of 1  µ g/ml inhibited doxorubicin‑induced apoptosis of H9c2 cells. Administration of doxorubicin reduced Bcl‑2, Beclin‑1 and LC3 expression levels in H9c2 cells, while having no effect on Bax levels. Administration of SP to these doxorubicin‑treated cells did not affect Bcl‑2 or Bax expression, but further reduced Beclin‑1 while inhibiting the reduction in LC3 expression. In vivo , food intake was significantly increased in rats in the SP group compared with the model group. Cardiomyocytes in the heart‑failure group underwent dysfunctional autophagy as ascertained by transmission electron microscopy. Compared with the heart‑failure group, these pathological changes, including loss of striations and vacuolation, were inhibited by SP treatment, which promoted Bax expression, reduced Beclin‑1 expression and inhibited the reduction in LC3 expression. Taken together, SP reduced cardiomyocyte apoptosis in doxorubicin‑induced cardiomyocyte injury, likely by promoting autophagy, which suggested that SP is a potential therapeutic target for doxorubicin‑induced heart failure.

Initially discovered by genetic screens in budding yeast, SPT5 and its partner SPT4 form a stable complex known as DSIF in metazoa, which plays pleiotropic roles in multiple steps of transcription. SPT5 is the most conserved transcription elongation factor, being found in all three domains of life; however, its structure has evolved to include new domains and associated posttranslational modifications. These gained features have expanded transcriptional functions of SPT5, likely to meet the demand for increasingly complex regulation of transcription in higher organisms. This review discusses the pleiotropic roles of SPT5 in transcription, including RNA polymerase II (Pol II) stabilization, enhancer activation, Pol II pausing and its release, elongation, and termination, with a focus on the most recent progress of SPT5 functions in regulating metazoan transcription.

A route for thiocyanation-functionalization of the electron-deficient C═C double bond was developed. Regioselective thiocyanation-etherification of α,β-unsaturated ketones was achieved. The desired products were obtained in moderate to high yields under mild conditions. It was suggested that the nucleophile was activated by the electrophilic thiocyanato reagent, and difunctionalization was achieved through a 1,4-addition/thiocyanation pathway.