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The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.

The present era faces adverse effects of the strides recorded in economic advancements of the prior generations thus leading the present generation to growth dilemma. Consequently, there is a conscientious consideration for the ecological effects of economic growth. To resolve the preceding issue, due consideration must be given to harmless growth of which eco-digitalization, green financing, green technology, energy transition, and regularity quality are key determinants. Despite the aforesaid importance, empirical studies advancing this nexus are scarce. Hence, this study contributes to environment empirics by providing empirical evidence for the impacts of the highlighted indicators on sustainable environment in the USA. The study explores quarterly data from 1996Q1 to 2019Q4 based on the novel non-linear autoregressive distributed lag (ARDL) model. The pretests’ outcomes show that long-run nexus exists among the variables, whereas the Zivot-Andrew uncovers breakpoint years in the observations. The main findings show that eco-digitalization, green financing, green technology, and renewable energy promote sustainable environment. On the flip side, non-renewable energy and regulatory quality hinder the pathways to sustaining the environment in the USA. Robustness analyses conducted based on FMOL, DOLS, and CCR provide substantial support and validity for the main results. Furthermore, the causality nexus lends empirical support for the existence of bidirectional and unidirectional causalities in the empirical model. Policy insights that drive the paths to sustainability in the US are suggested based on the findings.

We develop a method for universally resolving the important issue of separating the inverse spin Hall effect (ISHE) from spin rectification effect (SRE) signal. This method is based on the consideration that the two effects depend on the spin injection direction: The ISHE is an odd function of the spin injection direction while the SRE is independent on it. Thus, inversion of the spin injection direction changes the ISHE voltage signal, while SRE voltage remains. It applies generally to analyzing the different voltage contributions without fitting them to special line shapes. This fast and simple method can be used in a wide frequency range, and has the flexibility of sample preparation.

When ascending to high altitude, it is a rigorous challenge to people who living in the low altitude area to acclimatize to hypoxic environment. Hypoxia exposure can cause dramatic disturbances of metabolism. This longitudinal cohort study was conducted to delineate the plasma metabolomics profile following exposure to altitude environments and explore potential metabolic changes after return to low altitude area. 25 healthy volunteers living in the low altitude area (Nor; 40m) were transported to high altitude (HA; 3,650m) for a 7-day sojourn before transported back to the low altitude area (HAP; 40m). Plasma samples were collected on the day before ascending to HA, the third day on HA(day 3) and the fourteenth day after returning to low altitude(14 day) and analyzed using UHPLC-MS/MS tools and then the data were subjected to multivariate statistical analyses. There were 737 metabolites were obtained in plasma samples with 133 significantly changed metabolites. We screened 13 differential metabolites that were significantly changed under hypoxia exposure; enriched metabolic pathways under hypoxia exposure including tryptophan metabolism, purine metabolism, regulation of lipolysis in adipocytes; We verified and relatively quantified eight targeted candidate metabolites including adenosine, guanosine, inosine, xanthurenic acid, 5-oxo-ETE, raffinose, indole-3-acetic acid and biotin for the Nor and HA group. Most of the metabolites recovered when returning to the low altitude area, however, there were still 6 metabolites that were affected by hypoxia exposure. It is apparent that high-altitude exposure alters the metabolic characteristics and two weeks after returning to the low altitude area a small portion of metabolites was still affected by high-altitude exposure, which indicated that high-altitude exposure had a long-term impact on metabolism. This present longitudinal cohort study demonstrated that metabolomics can be a useful tool to monitor metabolic changes exposed to high altitude, providing new insight in the attendant health problem that occur in response to high altitude.

ObjectivesWe aimed to compare the long-term outcomes and surgical benefits between moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) using high-resolution MRI (HRMRI).MethodsMMV patients were retrospectively included and divided into the MMD and AS-MMV groups according to vessel wall features on HRMRI. Kaplan-Meier survival and Cox regression were performed to compare the incidence of cerebrovascular events and prognosis of encephaloduroarteriosynangiosis (EDAS) treatment between MMD and AS-MMV.ResultsOf the 1173 patients (mean age: 42.4±11.0 years; male: 51.0%) included in the study, 881 were classified into the MMD group and 292 into the AS-MMV group. During the average follow-up of 46.0±24.7 months, the incidence of cerebrovascular events in the MMD group was higher compared with that in the AS-MMV group before (13.7% vs 7.2%; HR 1.86; 95% CI 1.17 to 2.96; p=0.008) and after propensity score matching (6.1% vs 7.3%; HR 2.24; 95% CI 1.34 to 3.76; p=0.002). Additionally, patients treated with EDAS had a lower incidence of events than those not treated with EDAS, regardless of whether they were in the MMD (HR 0.65; 95% CI 0.42 to 0.97; p=0.043) or AS-MMV group (HR 0.49; 95% CI 0.51 to 0.98; p=0.048).ConclusionsPatients with MMD had a higher risk of ischaemic stroke than those with AS-MMV, and patients with both MMD and AS-MMV could benefit from EDAS. Our findings suggest that HRMRI could be used to identify those who are at a higher risk of future cerebrovascular events.

Liver fibrosis is a dynamic pathological consequence of chronic liver injury, in which persistent oxidative stress and inflammation drive progressive extracellular matrix deposition. Cyclic nitroxide radicals exhibit diverse biological activities, but their effects on liver fibrosis remain unclear. This study systematically evaluates the therapeutic potential of 3-carbamoyl proxyl nitroxide (3-CP) against carbon tetrachloride (CCl₄)-induced liver fibrosis. In vitro, 3-CP inhibited hepatic stellate cell (HSC) activation, migration, and proliferation, and reduced α-smooth muscle actin (α-SMA) and collagen I (COL1) expression. In a BALB/c mouse model of CCl4-induced liver fibrosis, 20 and 40 mg/kg 3-CP reduced the fibrosis area from 13.6 ± 1.0% (model group) to 6.9 ± 0.9% and 5.7 ± 1.3%, respectively, accompanied by decreased serum transaminase levels, restored liver architecture, and diminished collagen deposition. Mechanistic studies revealed that 3-CP modulated the TLR4/NF-κB signaling pathway, downregulating phosphorylated NF-κB p65 (p-p65) and reducing hepatic mRNA levels of pro-inflammatory (IL-1β, IL-6, TNF-α) and pro-fibrotic (TGF-β) cytokines by approximately 35–55%. Supportive in silico analysis suggested potential interactions between 3-CP and key pathway proteins (TLR4, MyD88, IKKβ, p65, IκBα). These findings indicate that 3-CP represents a promising therapeutic candidate that concurrently addresses oxidative damage and inflammatory signaling during liver fibrogenesis.

Background Substitutions are generally used to promote the match performance of the whole team. This study aimed to analyze the performance of substitute players and explore the performance difference among substitute players, completed players, and replaced players across each position. Methods Chinese Super Soccer League (CSL) matches in the season 2018 including 5871 individual observation from 395 professional soccer players were analyzed by establishing linear mixed models to quantify the performance difference among substitute players (SP) ( n  = 1,071), entire match players (EMP) ( n  = 3,454), and replaced players (RP) ( n  = 1,346), and then separately for each position (central defenders, fullbacks, central midfielders, wide midfielders, and attackers). Results The results show SP display higher high intensity distance and sprint distance significantly ( p  < 0.05) relative to playing time than RP and EMP. SP in offensive positions (attackers, wide midfielders) showed significantly higher ( p  < 0.05) passing and organizing performance such as passes, ball control, short passes, and long passes than RP or EMP. The scoring performances of central midfielders of SP including goals, shots, and shots on target are significantly higher ( p  < 0.05) than RP or EMP. Central defenders of SP showed higher shot blocks and pass blocks ( p  < 0.05) while lower passing and organizing performance ( p  < 0.05). Conclusion Depending on different playing positions, substitute players could indeed improve physical and technical performance related to scoring, passing, and defending as offensive substitute players can boost organizing performance and substitute defenders enhance defending performance. These could help coaches better understand substitute players’ influence on match performance and optimize the substitution tactic.

Objectives Intracranial vessel wall enhancement (VWE) on high-resolution magnetic resonance imaging (HRMRI) is associated with the progression and poor prognosis of moyamoya disease (MMD). This study assessed potential risk factors for VWE in MMD. Methods We evaluated MMD patients using HRMRI and traditional angiography examinations. The participants were divided into VWE and non-VWE groups based on HRMRI. Logistic regression was performed to compare the risk factors for VWE in MMD. The incidence of cerebrovascular events of the different subgroups according to risk factors was compared using Kaplan–Meier survival and Cox regression. Results We included 283 MMD patients, 84 of whom had VWE on HRMRI. The VWE group had higher modified Rankin Scale scores at admission ( p  = 0.014) and a higher incidence of ischaemia and haemorrhage ( p  = 0.002) than did the non-VWE group. Risk factors for VWE included the ring finger protein 213 ( RNF213 ) p.R4810K variant (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.08–3.76, p  = 0.028), hyperhomocysteinaemia (HHcy) (OR 5.08, 95% CI 2.34–11.05, p  < 0.001), and smoking history (OR 3.49, 95% CI 1.08–11.31, p  = 0.037). During the follow-up of 63.9 ± 13.2 months (median 65 months), 18 recurrent stroke events occurred. Cox regression showed that VWE and the RNF213 p.R4810K variant were risk factors for stroke. Conclusion The RNF213 p.R4810K variant is strongly associated with VWE and poor prognosis in MMD. HHcy and smoking are independent risk factors for VWE. Clinical relevance statement Vessel wall enhancement in moyamoya disease is closely associated with poor prognosis, especially related to the ring finger protein 213 p.R4810K variant, hyperhomocysteinaemia, and smoking, providing crucial risk assessment information for the clinic. Key Points • The baseline presence of vessel wall enhancement is significantly associated with poor prognosis in moyamoya disease. • The ring finger protein 213 p.R4810K variant is strongly associated with vessel wall enhancement and poor prognosis in moyamoya disease. • Hyperhomocysteinaemia and smoking are independent risk factors for vessel wall enhancement in moyamoya disease.

When ascending to high altitude, it is a rigorous challenge to people who living in the low altitude area to acclimatize to hypoxic environment. Hypoxia exposure can cause dramatic disturbances of metabolism. This longitudinal cohort study was conducted to delineate the plasma metabolomics profile following exposure to altitude environments and explore potential metabolic changes after return to low altitude area. 25 healthy volunteers living in the low altitude area (Nor; 40m) were transported to high altitude (HA; 3,650m) for a 7-day sojourn before transported back to the low altitude area (HAP; 40m). Plasma samples were collected on the day before ascending to HA, the third day on HA(day 3) and the fourteenth day after returning to low altitude(14 day) and analyzed using UHPLC-MS/MS tools and then the data were subjected to multivariate statistical analyses. There were 737 metabolites were obtained in plasma samples with 133 significantly changed metabolites. We screened 13 differential metabolites that were significantly changed under hypoxia exposure; enriched metabolic pathways under hypoxia exposure including tryptophan metabolism, purine metabolism, regulation of lipolysis in adipocytes; We verified and relatively quantified eight targeted candidate metabolites including adenosine, guanosine, inosine, xanthurenic acid, 5-oxo-ETE, raffinose, indole-3-acetic acid and biotin for the Nor and HA group. Most of the metabolites recovered when returning to the low altitude area, however, there were still 6 metabolites that were affected by hypoxia exposure. It is apparent that high-altitude exposure alters the metabolic characteristics and two weeks after returning to the low altitude area a small portion of metabolites was still affected by high-altitude exposure, which indicated that high-altitude exposure had a long-term impact on metabolism. This present longitudinal cohort study demonstrated that metabolomics can be a useful tool to monitor metabolic changes exposed to high altitude, providing new insight in the attendant health problem that occur in response to high altitude.

ObjectiveThe aim of this study was to investigate the function of the contralateral testis after unilateral testicular torsion (UTT) and its possible mechanism.Methods56 rats were randomly divided into four groups: Group A: Sham operation, Group B: Testicular torsion (TT)+normal saline (NS), Group C: Testicular torsion (TT)+cyclosporine, Group D: Testicular torsion (TT)+NG-Monomethyl-l-arginine (l-NMMA). The right testes were removed 1 week and 8 weeks after surgery, respectively. Biochemistry and histopathologic evaluations were used to evaluate the germ cell damage.ResultsCompared with Group A, the levels of malondialchehyche (MDA) and nitric oxide (NO)/nitricoxide synthase (NOS) were increased remarkably in Group B. Significant differences were shown between histopathological damages and density and motility of sperm in two groups. Compared with Group B, the levels of MDA and NO/NOS in Group D decreased significantly while mean seminiferous tubule diameter (MSTD) and mean testicular biopsy scoring (MTBS) maintained in a better condition. The levels of major histocompatibility complex (MHC) peptide-tetramer complex in Group C and Group D decreased significantly than Group B, while sperm density and motility were significantly higher than Group B. It was also known that the histopathological damages in Group C and Group D were less than those in Group B in the 8 weeks after operation.ConclusionUTT can cause impairment of contralateral testicular function and decrease of spermatogenic function. The mechanism may be related to ischemia–reperfusion (IR) in early stage and autoimmune response in late stage.