Photoredox Oxidation of Alkanes by Monometallic Copper-Oxygen Complexes Using Visible Light Including One Sun Illumination.

Oxygenation of hydrocarbons offers versatile catalytic routes to more valuable compounds, such as alcohols, aldehydes, and ketones. Despite the importance of monometallic copper-oxygen species as hydroxylating agents in biology, few synthetic model compounds are known to react with hydrocarbons, owing to high C-H bond dissociation energies. To overcome this challenge, the photoredox chemistry of monometallic copper (pyrazolyl)borate complexes coordinated by chlorate has been explored in the presence of C1-C6 alkanes with BDEs ≥ 93 kcal/mol. Ethane is photooxidized at room temperature under N2 with yields of 15-30%, which increases to 77% for the most oxidizing tris(3,5-trifluoromethyl-pyrazolyl)borate complex (Cu-3). This complex also promotes the photooxidation of methane to methanol in significant yield (38%) when the photoredox reaction is run under aerobic conditions. Ligand modification alters the reaction selectivity by tuning the redox potential. The ability to activate 1° C-H bonds of C1-C6 alkanes using visible light is consistent with the photogeneration of a powerfully oxidizing copper-oxyl, which is supported by photocrystallographic studies of the tris(3,4,5-tribromopyrazolyl)borate chlorate complex. Mechanistic studies are consistent with the hydrogen atom abstraction of the C-H bond by the copper-oxyl intermediate. We demonstrate for Cu-3 with hexane as an exemplar, that the photoredox chemistry may be achieved under solar conditions of one-sun illumination.

Exploring the binding characteristics between lorlatinib and human alpha-1-acid glycoprotein: Multispectral and molecular modeling techniques.

Approval in 2019 was granted for the highly selective, targeted agent lorlatinib, which primary target is ROS1 and ALK. The purpose of this work was to examine the binding mechanism between lorlatinib (LOR) and HAG employing multispectral and molecular modeling techniques. Fluorescence data demonstrated that LOR quenched HAG fluorescence as a static quenching, interecalated into the hydrophobic cavity of HAG with a moderate affinity. Thermodynamic and competitive experiments pointed out that LOR bound with HAG primarily through hydrogen bonding, hydrophobic, and van der Waals forces. Circular dichroism, three-dimensional and synchronous fluorescence spectroscopic studies noted that the secondary structure of HAG and microenvironments around tyrosine (Tyr) and tryptophan (Trp) residues were altered due to binding with LOR. The contribution of each energy involved in binding process of LOR and HAG has been analyzed by molecular simulation techniques. Besides, the environmental conditions with metal ions have also been studied. The present study is expected to provide a theoretical basis for further studying the metabolism of LOR in vivo, which may help to gain a deeper understanding of the general pharmacological activity of the drug.

Short-Term Dual Antiplatelet Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndromes: A Systematic Review and Network Meta-Analysis.

Importance: The optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) remains under debate. Objectives: To analyze the efficacy and safety of DAPT strategies in patients with ACS using a bayesian network meta-analysis. Data Sources: MEDLINE, Embase, Cochrane, and LILACS databases were searched from inception to April 8, 2024. Study Selection: Randomized clinical trials (RCTs) comparing DAPT duration strategies in patients with ACS undergoing PCI were selected. Short-term strategies (1 month of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by aspirin, and 6 months of DAPT followed by aspirin) were compared with conventional 12 months of DAPT. Data Extraction and Synthesis: This systematic review and network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The risk ratio (RR) with a 95% credible interval (CrI) was calculated within a bayesian random-effects network meta-analysis. Treatments were ranked using surface under the cumulative ranking (SUCRA). Main Outcomes and Measures: The primary efficacy end point was major adverse cardiac and cerebrovascular events (MACCE); the primary safety end point was major bleeding. Results: A total of 15 RCTs randomizing 35 326 patients (mean [SD] age, 63.1 [11.1] years; 26 954 male [76.3%]; 11 339 STEMI [32.1%]) with ACS were included. A total of 24 797 patients (70.2%) received potent P2Y12 inhibitors (ticagrelor or prasugrel). Compared with 12 months of DAPT, 1 month of DAPT followed by P2Y12 inhibitors reduced major bleeding (RR, 0.47; 95% CrI, 0.26-0.74) with no difference in MACCE (RR, 1.00; 95% CrI, 0.70-1.41). No significant differences were observed in MACCE incidence between strategies, although CrIs were wide. SUCRA ranked 1 month of DAPT followed by P2Y12 inhibitors as the best for reducing major bleeding and 3 months of DAPT followed by P2Y12 inhibitors as optimal for reducing MACCE (RR, 0.85; 95% CrI, 0.56-1.21). Conclusion and Relevance: Results of this systematic review and network meta-analysis reveal that, in patients with ACS undergoing PCI with DES, 1 month of DAPT followed by potent P2Y12 inhibitor monotherapy was associated with a reduction in major bleeding without increasing MACCE when compared with 12 months of DAPT. However, an increased risk of MACCE cannot be excluded, and 3 months of DAPT followed by potent P2Y12 inhibitor monotherapy was ranked as the best option to reduce MACCE. Because most patients receiving P2Y12 inhibitor monotherapy were taking ticagrelor, the safety of stopping aspirin in those taking clopidogrel remains unclear.

The protective effect of Ghrelin peptide on doxorubicin hydrochloride induced heart failure in rats.

BACKGROUND: To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. METHODS: 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. RESULTS: After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P < 0.05), and left ventricular ejection fraction (LVEF) was significantly increased (P < 0.05). Compared with HF group, the left ventricular systolic pressure (LVSP), maximum rate of increase in left ventricular pressure (+ dP/dtmax) and maximum rate of decrease in left ventricular pressure (- dP/dtmax) of Ghrelin group was remarkedly increased (P < 0.05), left ventricular diastolic pressure (LVDP) decreased (P < 0.05). In the Ghrelin group, the degree and extent of cardiomyocyte degeneration and necrosis were remarkedly reduced compared with the HF group. The levels of TNF-α and iNOS in Ghrelin group were notably lower than those in HF group (P < 0.05), the IL-10 level increased markedly (P < 0.05). CONCLUSION: Ghrelin may reduce Dox-induced myocardial injury and improve cardiac function in rats by regulating inflammation and oxidative stress.

High-Spin [FeI3] Cluster Capable of Pnictogen Atom Capture.

Using a new hexanucleating anildophosphine ligand tBuLH3 (1,3,5-C6H9(NHC6H3-5-F-2-P(tBu)2)3), the all-monovalent [FeI3] compound (tBuL)Fe3 (1) was isolated and characterized by X-ray diffraction analysis, SQUID magnetometry, 57Fe Mössbauer spectroscopy, and cyclic voltammetry. The molecular structure of 1 reveals very close Fe-Fe distances of 2.3825(7), 2.4146(8), and 2.3913(8) Å which results in significant Fe-Fe interactions and a maximum high-spin S = 9/2 spin state as determined by SQUID magnetometry and further supported by quantum chemical calculations. Compound 1 mediates the multielectron, oxidative atom transfer from inorganic azide ([Bu4N][N3]), cyanate (Na[NCO]), and phosphonate (Na(dioxane)2.5[PCO]) to afford the [Fe3]-nitrido (N3-) and [Fe3]-phosphido (P3-) pnictides, (tBuL)Fe3(µ3-N) (2) and [(tBuL)Fe3(µ3-P)(CO)]- (3), respectively. Compounds 1-3 exhibit rich electrochemical behavior with three (for 1), four (for 2) and five (for 3) distinct redox events being observed in the cyclic voltammograms of these compounds. Finally, the all-monovalent 1 and the formally FeII/FeII/FeI compound 3, were investigated by alternating current (ac) SQUID magnetometry, revealing slow magnetic relaxation in both compounds, with 3 being found to be a unique example of a [Fe3]-phosphido single-molecule magnet having an energy barrier relaxation reversal of U = 30.7(6) cm-1 in the absence of an external magnetic field. This study demonstrates the utility of an all low-valent polynuclear cluster to perform multielectron redox chemistry and exemplifies the redox flexibility and unique physical properties that are present in the corresponding midvalent oxidation products.

De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials.

BACKGROUND: Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation. METHODS: A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y12 inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083). FINDINGS: A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ2<0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ2=0·079) and all-cause death (Kaplan-Meier estimate 0·9% vs 1·2%; 0·76 [0·59-0·98]; p=0·034 for superiority; τ2<0·0001) were lower with ticagrelor monotherapy. Trial sequential analysis showed strong evidence of non-inferiority for MACCE and superiority for bleeding among the overall and ACS populations (the z-curve crossed the monitoring boundaries or the required information size without crossing the futility boundaries or approaching the null). The treatment effects were heterogeneous by sex for MACCE (p interaction=0·041) and all-cause death (p interaction=0·050), indicating a possible benefit in women with ticagrelor monotherapy, and by clinical presentation for bleeding (p interaction=0·022), indicating a benefit in ACS with ticagrelor monotherapy. INTERPRETATION: Our study found robust evidence that, compared with 12 months of DAPT, de-escalation to ticagrelor monotherapy does not increase ischaemic risk and reduces the risk of major bleeding, especially in patients with ACS. Ticagrelor monotherapy might also be associated with a mortality benefit, particularly among women, which warrants further investigation. FUNDING: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale.

Multispectral and molecular simulation of the interaction of human α1-acid glycoprotein with palbociclib.

Palbociclib, a selective CDK4/6 inhibitor with potent anti-tumor effects, was investigated for its interaction with human α1-acid glycoprotein (HAG). Spectral analysis revealed that palbociclib forms a ground state complex with HAG, exhibiting binding constant (Kb) of 104 M-1 at the used temperature range. The interaction between the two was determined to be driven mainly by hydrogen bonding and hydrophobic forces. Multispectral studies indicated that the bound palbociclib altered the secondary structure of HAG and reduced polarity around Trp and Tyr amino acids. And, molecular docking and dynamics simulations verified the experimental findings. Finally, most of the metal ions present in plasma, such as K+, Cu2+, Ca2+, Mg2+, Ni2+, Fe3+, and Co2+, are detrimental to the binding of palbociclib to HAG, with the exception of Zn2+, which is favorable.

Effect of aortic smooth muscle BK channels on mediating chronic intermittent hypoxia-induced vascular dysfunction.

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calciumactivated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca2+ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKß) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca2+ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction.

Chinese guidelines for integrated diagnosis and treatment of intestinal microecology technologies in tumor application (2024 Edition).

ABSTRACT: Intestinal microecology (IM) is the largest and most important microecological system of the human body. Furthermore, it is the key factor for activating and maintaining the physiological functions of the intestine. Numerous studies have investigated the effects of the gut microbiota on the different tissues and organs of the human body as well as their association with various diseases, and the findings are gradually being translated into clinical practice. The gut microbiota affects the occurrence, progression, treatment response, and toxic side effects of tumors. The deepening of research related to IM and tumors has opened a new chapter in IM research driven by methods and technologies such as second-generation sequencing and bioinformatics. The IM maintains the function of the host immune system and plays a pivotal role in tumor-control drug therapy. Increasing evidence has proven that the efficacy of tumor-control drugs largely depends on the IM balance, and strategies based on the IM technology show promising application prospects in the diagnosis and treatment of tumor. The Tumor and Microecology Professional Committee of the Chinese Anti-cancer Association gathered relevant experts to discuss and propose the "Chinese guidelines for integrated diagnosis and treatment of IM technologies in tumor application (2024 Edition)," which was established based on the research progress of the application of the IM technology in tumor to provide a basis for the standardization of the diagnosis and treatment of the IM technology in the tumor.

Single-center experience with self-expanding transcatheter aortic valve system for symptomatic high-risk patients with severe aortic regurgitation: One-year outcomes.

AIMS: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for the treatment of aortic regurgitation (AR). METHODS: From September 2019 to February 2022, 62 patients who underwent transfemoral TAVI procedure for pure, symptomatic severe AR with the VitaFlow system were enrolled in the current study. The outcomes were assessed according to the Valve Academic Research Consortium 3 criteria. Procedural results and clinical outcomes for 1 year were analyzed. RESULTS: The mean age was 71.56 ± 7.34 years and 58.1% were male. The mean Society of Thoracic Surgeons score was 5.44 ± 3.22%. The device success rate was 79.0%. Only one patient was converted to open surgery. The in-hospital mortality rate was 1.6%. The 1-year all-cause mortality rate was 6.5%. The new permanent pacemaker implantation rate was 29.0% in-hospital and 30.7% at 1-year follow-up. The second valve implantation rate was 14.5%. No patient developed more than moderate paravalvular leakage during follow-up. The mean ejection fraction improved from 54.05 ± 10.83% at baseline to 59.32 ± 8.70% (p < 0.001 compared with baseline) at 12 months. Left ventricular end-diastolic diameter decreased from 61.62 ± 5.58 mm at baseline to 55.20 ± 4.51 mm (p < 0.001 compared with the baseline) at 12 months. CONCLUSIONS: Transfemoral TAVI procedure shows efficacy in treating patients with severe pure native AR. The safety is improved with the development of the VitaFlow system.

Effect of SBRT plus immunotherapy on immune status and survival quality of NSCLC patients: A study of combined radiotherapy and immunotherapy.

BACKGROUND: non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer populations. Stereotactic radiotherapy (SBRT) is mainly suitable for early NSCLC patients who are not suitable for surgery or refuse surgery. OBJECTIVE: To analyze the effects of stereotactic radiotherapy (SBRT) plus immunotherapy for non-small cell lung cancer (NSCLC) patients on their immune status and survival quality. METHODS: NSCLC patients admitted to our hospital from 2019-2022 were divided into 61 cases in control group (SBRT) and 60 cases in observation group (SBRT plus immunotherapy) by the randomized numerical table method to compare the efficacy, the level of tumor markers in the serum, the level and activity of the immune cells in the peripheral blood and the Kahlil's functional status (KPS) scores. RESULTS: The observation group had a higher efficacy rate than that of the control group (P< 0.05). There was no statistical difference between the two groups in serum tumor marker content, immune cell level and activity in peripheral blood and KPS score before treatment (P> 0.05). After treatment, serum tumor markers were lower than those in control group, and immune cell level, NK cell-related activity and KPS score were higher than those in control group (P< 0.05). CONCLUSION: SBRT plus immunotherapy can reduce the level of various tumor markers, improve the immune status and quality of survival for NSCLC patients.

How does chronic disease influence subjective life expectancy among middle-aged and older adults? Evidence from the China Health and Retirement Longitudinal Study (CHARLS) 2018 cross-sectional data.

Chronic diseases have become one of the most important factors threatening human health. Subjective life expectancy (SLE) describes an individual's expectation or subjective perception of lifespan. This article aims to explore the relationship between chronic diseases and SLE, as well as the differences among different age groups and different types of chronic diseases in this relationship. China Health and Retirement Longitudinal Study (CHARLS) is a nationwide longitudinal study that evaluates the social, economic, and health conditions of middle-aged and older adult families and individuals aged 45 and above in China. In this study, CHARLS used probability proportional to size sampling (PPS sampling) to ensure the breadth and representativeness of the sample. This study selected cross-sectional data from CHARLS 2018, removed missing values, and obtained a valid sample of 10,658 middle-aged and older individuals, of whom 8564 had chronic diseases. After controlling demographic, health behavior, socioeconomic, psychological, and social security factors, an ordered logistic regression was performed to explore the relationship between chronic disease and SLE in middle-aged and older adults. The results show that chronic diseases negatively correlate with SLE in middle-aged and older adults. Middle-aged and older adults with chronic diseases are 36.2% less likely to have high life expectancy than those without chronic diseases. Many different types of chronic diseases are negatively correlated with SLE. Cancer is most negatively correlated with SLE, far exceeding other chronic diseases. Chronic disease and SLE of middle-aged and older adults have age-heterogeneous differences. For middle-aged people aged 45-59 and young older adults aged 60-79, there is a significant correlation between chronic diseases and SLE. However, there is no correlation between chronic diseases and subjective life expectancy in the older population aged 80 and above. The government and society should pay close attention to the prevention and treatment of chronic diseases among middle-aged and older adults and adjust policies and measures according to the population's age structure. In addition, the government and society should pay attention to the spiritual needs of middle-aged and older adults. The government and society should pay more attention to cancer patients. Finally, the scientific research team should also strengthen research on chronic diseases, research and development of specific drugs and vaccines, improve the cure rate of chronic diseases, promote people's health, and make people no longer afraid of diseases.

Exploring the binding characteristics of bovine serum albumin with CDK4/6 inhibitors Ribociclib: Multi-spectral analysis and molecular simulation studies.

Ribociclib (RIB), a tyrosine kinase inhibitor, exhibits promising antitumor efficacy and controlled toxicity in HR+/HER2- breast cancer patients, which is closely related to the binding with plasma proteins. This study utilized a combination of spectroscopic techniques including UV spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) as well as molecular docking and molecular dynamic simulation to clarify the binding mechanism between bovine serum albumin (BSA) and RIB. The findings demonstrated that RIB produced a 1:1 stoichiometric complex with BSA, which quenched BSA's fluorescence in the manner of the static quenching mechanism. Site labelling experiments pinpointed Site III on BSA as the primary binding site for RIB, a finding validated by molecular docking. Van der Waals forces and hydrogen bonding interactions as key drivers in the formation of RIB-BSA complexes, a conclusion supported by molecular docking. Molecular simulation studies suggested that the insertion of RIB into the hydrophobic cavity (Site III) of BSA induced subtle conformational changes in the BSA protein, and CD measurements confirmed alterations in BSA secondary structure content. Synchronous and three-dimensional fluorescence spectroscopy further demonstrated that RIB decreased the hydrophobicity of the microenvironment surrounding tyrosine and tryptophan residues. These findings offer valuable insights into the pharmacokinetics and structural modifications of RIB.

Comprehending the inhibition mechanism of indole-based bis-acylhydrazone compounds on α-glucosidase: Spectral and theoretical approaches.

Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.

Dual domain distribution disruption with semantics preservation: Unsupervised domain adaptation for medical image segmentation.

Recent unsupervised domain adaptation (UDA) methods in medical image segmentation commonly utilize Generative Adversarial Networks (GANs) for domain translation. However, the translated images often exhibit a distribution deviation from the ideal due to the inherent instability of GANs, leading to challenges such as visual inconsistency and incorrect style, consequently causing the segmentation model to fall into the fixed wrong pattern. To address this problem, we propose a novel UDA framework known as Dual Domain Distribution Disruption with Semantics Preservation (DDSP). Departing from the idea of generating images conforming to the target domain distribution in GAN-based UDA methods, we make the model domain-agnostic and focus on anatomical structural information by leveraging semantic information as constraints to guide the model to adapt to images with disrupted distributions in both source and target domains. Furthermore, we introduce the inter-channel similarity feature alignment based on the domain-invariant structural prior information, which facilitates the shared pixel-wise classifier to achieve robust performance on target domain features by aligning the source and target domain features across channels. Without any exaggeration, our method significantly outperforms existing state-of-the-art UDA methods on three public datasets (i.e., the heart dataset, the brain dataset, and the prostate dataset). The code is available at https://github.com/MIXAILAB/DDSPSeg.

Health and wellbeing of staff working at higher education institutions globally during the post-COVID-19 pandemic period: evidence from a cross-sectional study.

BACKGROUND: The ongoing global crisis of Higher Education (HE) institutions during the post-COVID-19 pandemic period has increased the likelihood of enduring psychological stressors for staff. This study aimed to identify factors associated with job insecurity, burnout, psychological distress and coping amongst staff working at HE institutions globally. METHODS: An anonymous cross-sectional study was conducted in 2023 with staff at HE institutions across 16 countries. Job insecurity was measured using the Job Insecurity Scale (JIS), burnout using the Perceived Burnout measure question, psychological distress using the Kessler Psychological Distress Scale (K10), and coping using the Brief Resilient Coping Scale. Multivariable logistic regression with a stepwise variable selection method was used to identify associations. RESULTS: A total of 2,353 staff participated; the mean age (± SD) was 43(± 10) years and 61% were females. Most staff (85%) did not feel job insecurity, one-third (29%) perceived burnout in their jobs, more than two-thirds (73%) experienced moderate to very high levels of psychological distress, and more than half (58%) exhibited medium to high resilient coping. Perceived job insecurity was associated with staff working part-time [Adjusted Odds Ratio 1.53 (95% Confidence Intervals 1.15-2.02)], having an academic appointment [2.45 (1.78-3.27)], having multiple co-morbidities [1.86 (1.41-2.48)], perceived burnout [1.99 (1.54-2.56)] and moderate to very high level of psychological distress [1.68 (1.18-2.39)]. Perceived burnout was associated with being female [1.35 (1.12-1.63)], having multiple co-morbidities [1.53 (1.20-1.97)], perceived job insecurity [1.99 (1.55-2.57)], and moderate to very high levels of psychological distress [3.23 (2.42-4.30)]. Staff with multiple co-morbidities [1.46 (1.11-1.92)], mental health issues [2.73 (1.79-4.15)], perceived job insecurity [1.61 (1.13-2.30)], and perceived burnout [3.22 (2.41-4.31)] were associated with moderate to very high levels of psychological distress. Staff who perceived their mental health as good to excellent [3.36 (2.69-4.19)] were more likely to have medium to high resilient coping. CONCLUSIONS: Factors identified in this study should be considered in reviewing and updating current support strategies for staff at HE institutions across all countries to reduce stress and burnout and improve wellbeing.

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque.

BACKGROUND: The heightened risk of cardiovascular and cerebrovascular events is associated with the increased instability of atherosclerotic plaques. However, the lack of effective diagnostic biomarkers has impeded the assessment of plaque instability currently. This study was aimed to investigate and identify hub genes associated with unstable plaques through the integration of various bioinformatics tools, providing novel insights into the detection and treatment of this condition. METHODS: Weighted Gene Co-expression Network Analysis (WGCNA) combined with two machine learning methods were used to identify hub genes strongly associated with plaque instability. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was utilized to assess immune cell infiltration patterns in atherosclerosis patients. Additionally, Gene Set Variation Analysis (GSVA) was conducted to investigate the potential biological functions, pathways, and mechanisms of hub genes associated with unstable plaques. To further validate the diagnostic efficiency and expression of the hub genes, immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were performed on collected human carotid plaque and blood samples. Immunofluorescence co-staining was also utilized to confirm the association between hub genes and immune cells, as well as their colocalization with mitochondria. RESULTS: The CIBERSORT analysis demonstrated a significant decrease in the infiltration of CD8 T cells and an obvious increase in the infiltration of M0 macrophages in patients with atherosclerosis. Subsequently, two highly relevant modules (blue and green) strongly associated with atherosclerotic plaque instability were identified. Through intersection with mitochondria-related genes, 50 crucial genes were identified. Further analysis employing least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) algorithms revealed six hub genes significantly associated with plaque instability. Among them, NT5DC3, ACADL, SLC25A4, ALDH1B1, and MAOB exhibited positive correlations with CD8 T cells and negative correlations with M0 macrophages, while kynurenine 3-monooxygenas (KMO) demonstrated a positive correlation with M0 macrophages and a negative correlation with CD8 T cells. IHC and RT-qPCR analyses of human carotid plaque samples, as well as ELISA analyses of blood samples, revealed significant upregulation of KMO and MAOB expression, along with decreased ALDH1B1 expression, in both stable and unstable samples compared to the control samples. However, among the three key genes mentioned above, only KMO showed a significant increase in expression in unstable plaque samples compared to stable plaque samples. Furthermore, the expression patterns of KMO in human carotid unstable plaque tissues and cultured mouse macrophage cell lines were assessed using immunofluorescence co-staining techniques. Finally, lentivirus-mediated KMO silencing was successfully transduced into the aortas of high-fat-fed ApoE-/- mice, with results indicating that KMO silencing attenuated plaque formation and promoted plaque stability in ApoE-/- mice. CONCLUSIONS: The results suggest that KMO, a mitochondria-targeted gene associated with macrophage cells, holds promise as a valuable diagnostic biomarker for assessing the instability of atherosclerotic plaques.

Circ-0006332 stimulates cardiomyocyte pyroptosis via the miR-143/TLR2 axis to promote doxorubicin-induced cardiac damage.

Doxorubicin (DOX)-mediated cardiotoxicity can impair the clinical efficacy of chemotherapy, leading to heart failure (HF). Given the importance of circRNAs and miRNAs in HF, this paper intended to delineate the mechanism of the circular RNA 0006332 (circ -0,006,332)/microRNA (miR)-143/Toll-like receptor 2 (TLR2) axis in doxorubicin (DOX)-induced HF. The binding of miR-143 to circ -0,006,332 and TLR2 was assessed with the dual-luciferase assay, and the binding between miR-143 and circ -0,006,332 was determined with FISH, RIP, and RNA pull-down assays. miR-143 and/or circ -0,006,332 were overexpressed in rats and cardiomyocytes, followed by DOX treatment. In cardiomyocytes, miR-143 and TLR2 expression, cell viability, LDH release, ATP contents, and levels of IL-1ß, IL-18, TNF-α, and pyroptosis-related molecules were examined. In rats, cardiac function, serum levels of cardiac enzymes, apoptosis, myocardial fibrosis, and levels of IL-1ß, IL-18, TNF-α, TLR2, and pyroptosis-related molecules were detected. miR-143 diminished TLR2 expression by binding to TLR2, and circ -0,006,332 bound to miR-143 to downregulate miR-143 expression. miR-143 expression was reduced and TLR2 expression was augmented in DOX-induced cardiomyocytes. miR-143 inhibited DOX-induced cytotoxicity by suppressing pyroptosis in H9C2 cardiomyocytes. In DOX-induced rats, miR-143 reduced cardiac dysfunction, myocardial apoptosis, myocardial fibrosis, TLR2 levels, and pyroptosis. Furthermore, overexpression of circ -0,006,332 blocked these effects of miR-143 on DOX-induced cardiomyocytes and rats. Circ -0,006,332 stimulates cardiomyocyte pyroptosis by downregulating miR-143 and upregulating TLR2, thus promoting DOX-induced cardiac injury.

PCSK9 inhibitor added to high-intensity statin therapy to prevent cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention: a randomized, double- blind, placebo-controlled, multicenter SHAWN study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1,212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at 1-year follow-up between 2 groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.