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Abstract Two-thirds of signaling hormones and one-third of approved drugs exert their effects by binding and modulating the G protein-coupled receptors (GPCRs) activation. While the activation mechanism for monomeric GPCRs has been well-established, little is known about GPCRs in dimeric form. Here, by combining transition pathway generation, extensive atomistic simulation-based Markov state models, and experimental signaling assays, we reveal an asymmetric, stepwise millisecond allosteric activation mechanism for the metabotropic glutamate receptor subtype 5 receptor (mGlu5), an obligate dimeric class C GPCR. The dynamic picture is presented that agonist binding induces dimeric ectodomains compaction, amplified by the precise association of the cysteine-rich domains, ultimately loosely bringing the intracellular 7-transmembrane (7TM) domains into proximity and establishing an asymmetric TM6-TM6 interface. The active inter-domain interface enhances their intra-domain flexibility, triggering the activation of micro-switches crucial for downstream signal transduction. Furthermore, we show that the positive allosteric modulator stabilizes both the active inter-domain 7TM interface and an open, extended intra-domain ICL2 conformation. This stabilization leads to the formation of a pseudo-cavity composed of the ICL2, ICL3, TM3, and C-terminus, which facilitates G protein coordination. Our strategy may be generalizable for characterizing millisecond events in other allosteric systems.

Abstract Background Diabetes mellitus (DM) and coronary microvascular dysfunction (CMD) increase the risk of adverse cardiac events in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to evaluate the combined risk estimates of DM and CMD, assessed by the angiography-derived index of microcirculatory resistance (angio-IMR), in patients with NSTEMI. Methods A total of 2212 patients with NSTEMI who underwent successful percutaneous coronary intervention (PCI) were retrospectively enrolled from three centers. The primary outcome was a composite of cardiac death or readmission for heart failure at a 2-year follow-up. Results Post-PCI angio-IMR did not significantly differ between the DM group and the non-DM group (20.13 [17.91–22.70] vs. 20.19 [18.14–22.77], P = 0.530). DM patients exhibited a notably higher risk of cardiac death or readmission for heart failure at 2 years compared to non-DM patients (9.5% vs. 5.4%, P

Abstract Heart failure (HF) is a significant global public health concern with a high readmission rate, posing a serious threat to the health of the elderly population. While several studies have used machine learning (ML) to develop all-cause readmission risk prediction models for elderly patients with HF, few have integrated ML-selected features with those chosen by human experts to assess HF patients readmission. A retrospective analysis of 8396 elderly HF patients hospitalized at the Affiliated Hospital of North Sichuan Medical College from January 1, 2018 to December 31, 2021 was conducted. Variables selected by XGBoost, LASSO regression, and random forest constituted the machine group, while the human expert group comprised variables chosen by two experienced cardiovascular professors. The variables selected by both groups were combined to form a human–machine collaboration group. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) method was used to elucidate the importance of each predictive feature, explain the impact of individual features on the model, and provide visual representation. A total of 73 features were included for model development. The human–machine collaboration model, utilizing CatBoost, achieved an AUC of 0.83617, an F1-score of 0.73521, and a Brier score of 0.16536 on the validation set. This model demonstrated superior predictive performance compared to those created solely by human experts or machine. The SHAP plot was then used to visually display the feature analysis of the human–machine collaboration model, revealing HGB, NT-proBNP, smoking history, NYHA classification, and LVEF as the 5 most important features. This study indicate that the human–machine collaboration model outperforms those relying solely on human expert selection or machine algorithm at predicting all-cause readmission in elderly HF patients. The application of the SHAP method enhanced the interpretability of the model outcomes, aiding clinicians in accurately pinpointing risk factors associated with HF readmission. This advancement enables the formulation of tailored treatment strategies, offering a more personalized approach to patient care.

Abstract Background Long non-coding RNAs (lncRNAs) are abundant and closely related to the occurrence and development of human diseases. LncRNAs are known to play a key role in many cardiovascular diseases. The purpose of this study was to investigate the effect of the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) on the degree of coronary artery lesions and prognosis in patients with coronary artery disease (CAD). Methods Patients who underwent coronary angiography (CAG) and dynamical-single photon emission computed tomography (D-SPECT) were selected as study subjects, and the results of CAG were reviewed, and the patients were grouped according to SYNTAX score. Evaluate the factors affecting SYNTAX scores. The follow-up analysis was conducted, and the endpoint events were major adverse cardiovascular events (MACEs). Kaplan–Meier method was used to estimate the survival rate, and multivariate Cox regression was used to analyze the relationship between RMRP and MACEs. Results The expression level of serum RMRP in patients with CAD was significantly higher than that in healthy people. Multivariate Logistic regression analysis showed that age, low-density lipoprotein cholesterol (LDL-C), RMRP and rest left ventricular ejection fraction (LVEF) were independent factors that affected SYNTAX scores. There were 19 cases of MACEs in the high RMRP group and 9 cases in the low RMRP group, and there was a significant difference in the MACE free survival curve between the two groups. Multivariate Cox regression analysis showed that age, SYNTAX score, rest LVEF and RMRP were risk factors for MACEs. Conclusions Serum RMRP is a key factor affecting the degree of coronary artery disease and prognosis in CAD patients.

Abstract N6‐methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells. Previous studies have shown that m6A plays a critical role under both normal physiological and pathological conditions. Hematopoiesis and differentiation are highly regulated processes, and recent studies on m6A mRNA methylation have revealed how this modification controls cell fate in both normal and malignant hematopoietic states. However, despite these insights, a comprehensive understanding of its complex roles between normal hematopoietic development and malignant hematopoietic diseases remains elusive. This review first provides an overview of the components and biological functions of m6A modification regulators. Additionally, it highlights the origin, differentiation process, biological characteristics, and regulatory mechanisms of hematopoietic stem cells, as well as the features, immune properties, and self‐renewal pathways of leukemia stem cells. Last, the article systematically reviews the latest research advancements on the roles and mechanisms of m6A regulatory factors in normal hematopoiesis and related malignant diseases. More importantly, this review explores how targeting m6A regulators and various signaling pathways could effectively intervene in the development of leukemia, providing new insights and potential therapeutic targets. Targeting m6A modification may hold promise for achieving more precise and effective leukemia treatments.

Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate [Ca3(PO4)2]. The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA.

Purpose The objective of this study was to assess the accuracy of FreeStyle Libre Pro (FSL-Pro) flash continuous glucose monitoring (CGM) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction (AMI). Methods A single-arm, single-center prospective study was conducted in the cardiac care unit from January 2021 to September 2023. Patients underwent finger-prick blood glucose (FPBG) testing before breakfast (6:00 am) and after meals (at 9:00, 13:00, 19:00 pm), along with CGM during their hospitalization. Statistical analyses included mean differences (MDs), mean absolute relative difference (MARDs) of blood glucose levels, and hypoglycemia occurrences. A Bland–Altman plot analysis and Pearson correlation were performed. Results Ninety-seven T2DM and AMI patients underwent CGM for up to 72 h (1142 monitoring point). Mean daily BG, Fasting plasma glucose (FPG) and mean postprandial plasma glucose (PPG) were significantly lower by CGM than by FPBG with an estimated MD of −0.89 mmol/L in BG, −0.88 mmol/L in FPG, and −0.90 mmol/L in PPG, respectively. The maximum effect was mainly in the first day and then the difference was gradually declined (falling range, Day1, −1.24; Day 2, −0.70; Day 3, −0.68, mmol/L, respectively). The incidence rates of hypoglycemia and potential hypoglycemia was 1.57% and 8.5% higher, respectively, in CGM than in FBPG. A Bland–Altman Plot revealed some variability and bias between the two methods of measurement of glucose monitoring ( p

Abstract Sequestering CO2 in depleted oil reservoirs provides one of the most appealing measures to reduce greenhouse gases (GHG) concentration in the atmosphere. The remaining liquids after enhanced oil recovery (EOR) processes, including residual oil and remaining water, lead to the main challenges to this approach. How to effectively evacuate a depleted oil reservoir by recovering not only residual oil but also remaining water is a critical consideration for this type of CO2 sequestration. This paper presents conceptual investigations concerning the methods which effectively evacuate depleted oil reservoirs from both the displacement efficiency and the sweep efficiency points of view. To improve the displacement efficiency, surfactant slug and solvent slug injection was examined using a core scale numerical model. Investigations regarding improving sweep efficiency, such as horizontal well pattern infilling and foam injection, were carried out based on a typical row well pattern. Simulation results showed that surfactant slug which modified the relative permeability and capillary pressure remarkably reduced both residual oil saturation and remaining water saturation. A CO2 slug injected before surfactant slug can help improve the oil recovery. Solvent enriched CO2 slug also remarkably reduced the residual oil saturation to as low as 2%. Horizontal well pattern infilling had great advantage for thick or inclined reservoirs, and foam slug injection greatly improved CO2 storage capacity in thin reservoirs by improving the sweep efficiency. Maximum mobility reduction (MRF) is the most important parameter to maximize the storage capacity and the benefit. The variation of CO2 storage capacity along with CO2 slug size. Larger foam slug size will play a better storage performance. The conceptual simulation investigations confirmed that depleted oil reservoirs can be effectively evacuated for CO2 storage. Depleted oil reservoirs with maximum evacuation are the best candidates for CO2 sequestrations.

Abstract Purpose The temporal evolution of ventricular trabecular complexity and its correlation with major adverse cardiovascular events (MACE) remain indeterminate in patients presenting with acute ST elevation myocardial infarction (STEMI). Methods This retrospective analysis enrolled patients undergoing primary percutaneous coronary intervention (pPCI) for acute STEMI, possessing cardiac magnetic resonance (CMR) data in the acute (within 7 days), subacute (1 month after pPCI), and chronic phases (6 months after pPCI) from January 2015 to January 2020 at the three participating sites. Fractal dimensions (FD) were measured for the global, infarct, and remote regions of left ventricular trabeculae during each phase. The potential association of FD with MACE was analyzed using multivariate Cox regression. Results Among the 200 analyzed patients (182 men; median age, 61 years; age range, 50–66 years), 37 (18.5%) encountered MACE during a median follow-up of 31.2 months. FD exhibited a gradual decrement (global FD at acute, subacute, and chronic phases: 1.253 ± 0.049, 1.239 ± 0.046, 1.230 ± 0.045, p

Introduction Heart failure with preserved ejection fraction (HFpEF) is a prevalent comorbidity among patients with end-stage kidney disease. Although sodium-glucose cotransporter 2 inhibitors are validated in treating heart failure and ameliorating left ventricular hypertrophy among non-dialysis patients, the effects on dialysis patients are unknown. We previously investigated the pharmacokinetics of henagliflozin in patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) and clarified its safety.Methods and analysis This multicentre, randomised, double-blind, placebo-controlled trial is being conducted at three hospitals in Shanghai, China. A target of 108 HD or PD patients with HFpEF are randomly allocated to treatment group (henagliflozin 5 mg/day in addition to standard therapy) or control group (placebo with standard therapy) at a ratio of 1:1. All subjects will be followed up for 24 weeks. The primary outcome is change in echocardiography-measured left ventricular mass index. The secondary interests include changes in left atrial volume index, E/e’, e’ and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Intergroup comparisons of change in echocardiography-related outcomes from baseline to 24 weeks are based on a linear regression model adjusted for baseline values (analysis of covariance), and repeated measure analysis of variance with Bonferroni adjustment is employed for comparison of change in NT-proBNP. Subgroup analyses of the primary and secondary outcomes are conducted to determine whether the effect of henagliflozin varies according to dialysis modality. The χ2 method is used to compare the occurrence of adverse events and severe adverse events.Ethics and dissemination This trial has been approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (LY2023-127-B). All participants provide written informed consent before screening. The results of the trial will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported.Trial registration number ChiCTR2300073169.

Summary: Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs.

In 2019 as a national key research program, the Development and Effectiveness Evaluation of an Innovative Health Management Model – Internet plus Medical Alliance-based Co-prevention and Co-management on Cardio-cerebrovascular Diseases was initiated in several regions including Shanghai and Guangzhou municipality and Xinjiang Uygur Autonomous Region. The ROCCIPI framework refers to a way of identifying and analyzing fundamental causes of problems in health policy through interrelated thinking patterns of seven elements: rule, opportunity, capacity, communication, interest, process and ideology. The framework could provide an evidence-based strategic approach to solve health policy problems. In this article, we try to identify and analyze the progress and problems in the implementation of the innovative health management at 21 comprehensive demonstration regions in China based on the ROCCIPI framework. Specific suggestions are also presented for promoting the comprehensive disease prevention and management project.

ObjectiveDouble pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure.MethodsTwo cases of DPA patients with Cushing’s disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission.ResultsAmong 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing’s syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (

Abstract Background Pulmonary vein perforation is an uncommon complication during cardiac intervention. We present a rare case of pulmonary vein perforation into the respiratory tract with systemic air embolism during left atrial appendage closure (LAAC). Case presentation A 77-year-old man with persistent nonvalvular atrial fibrillation was referred for percutaneous LAAC under local anaesthesia (CHA2DS2-VASc score of 4, HAS-BLED score of 3, and prior ischaemic stroke). During the procedure, after delivering a super-stiff guidewire into the left superior pulmonary vein (LSPV), the patient suddenly developed a severe cough with haemoptysis upon advancement of a delivery sheath along the guidewire. Fluoroscopy showed signs of blood entering the left main bronchus, and fast transthoracic echocardiography revealed bubbles in the left heart without pericardial effusion. The procedure was terminated because of a major complication indicated by the repeated haemoptysis and headache, and haemostatic drugs were immediately administered. Subsequent chest computed tomography angiography (CTA) revealed a filling defect in the LSPV branches and bubbles in the aorta. The patient was transferred to the critical care unit for haemostasis and antibacterial treatment. Transthoracic echocardiography later that day showed no bubbles in the heart. The headache and haemoptysis significantly abated the following day. The bubbles in the aorta disappeared on chest CTA 7 days later. Conclusions Interventional cardiologists should pay attention to anatomical variations of the pulmonary vein, which are associated with a high risk of complications of pulmonary vein perforation during LAAC. Preoperative CTA examination and intraoperative transoesophageal echocardiography might be helpful to avoid this complication.

Background: Platelet endothelial cell adhesion molecule (PECAM-1) is present in the vascular endothelium and plays important roles in various biological processes. Several recent studies have reported associations between PECAM-1 and certain subtypes of cardiovascular diseases (CVDs). However, further research is necessary to clarify the causal effects of PECAM-1 on CVDs. To determine whether PECAM-1 and CVDs are causally associated, we conducted a two-sample Mendelian randomization (TSMR) study. Methods: Single nucleotide polymorphisms (SNPs) associated with PECAM-1 were used as instrumental variants (IVs) to estimate the causal effects of PECAM-1 on CVDs. Six SNPs were included in our TSMR study. The inverse-variance weighted (IVW) method was applied in the primary analysis. To confirm the initial results, we conducted several complementary analyses and pleiotropy analyses. Results: In the IVW analysis, higher genetically predicted PECAM-1 levels were associated with lower risk of coronary artery disease (CAD) (OR, 0.835; CI, 0.757–0.92; P = 3 × 10 −4 ) and myocardial infarction (MI) (OR, 0.79; CI, 0.709–0.881; P = 2.03 × 10 −5 ). Conclusions: The findings confirmed that elevated PECAM-1 levels may decrease the risk of CAD and MI. These results confirm the causal effect of PECAM-1 on CVDs and may facilitate further investigation of the mechanism of PECAM-1 in CVD pathogenesis.

Motion devices in high temperature environments suffer serious friction and wear damage，which puts forward strict requirements for their surface protective coatings.High-entropy alloys have good composition design flexibility and excellent comprehensive properties.Low friction and high wear resistant coatings can be obtained through composition regulation，thereby achieving efficient protection of high temperature service components.In order to obtain low friction and wear resistant protective coatings for moving parts servicing in high temperatures in this paper，VAlTiCr-based high-entropy alloy coatings were prepared by magnetron sputtering.The effects of different elements (Mo，W，and Si) and heat treatment temperatures (700，800，and 900 ℃) on the crystal structure and high temperature friction properties of high-entropy alloy coatings were studied.Results showed that the as-prepared VAlTiCrSi coating was amorphous，while the VAlTiCrMo and VAlTiCrW coatings exhibited BCC solid solution structure.The tribological properties of the coatings after heat treatment were tested at 700 ℃，which showed that with the increase of heat treatment temperature，the friction coefficient and wear rate of the three coatings decreased first and then increased；And after heat treatment at 800 ℃，VAlTiCrMo，VAlTiCrW and VAlTiCrSi coatings all had the best tribological properties.Oxides such as V2O5 and AlVO4 played a major role in lubrication.VAlTiCrMo coating has better comprehensive friction performance than VAlTiCrSi and VAlTiCrW coatings.The friction coefficient was as low as 0.21，and the wear rate was only 9.98×10-5mm3/(N·m).Therefore，the element regulation and heat treatment of high-entropy alloy coating could provide data reference for the research of the high-performance protective coating serving in harsh environments.

Nonmetal doped high-entropy alloys have excellent mechanical properties，wear resistance and corrosion resistance，but there is still much room for improvement friction properties in high temperature.It is expected to achieve low friction through utilizing the characteristics of high-entropy alloys，when they are applied to high temperature working moving parts.In this work，(VAlTiCrW)Oxhigh-entropy alloy coatings with various oxygen content were prepared on the substrate surface by magnetron sputtering.The microstructure and tribological properties of the coating were evaluated by scanning electron microscope，atomic force microscope，X-ray diffractometer，high temperature friction testing machine，surface profiler，3D optical profiler and Raman spectroscopy.Results showed that with the increase of oxygen content，the coating structure gradually changed from BCC to indefinite amorphous structure，the hardness of the coating increased from 3.3 GPa to 11.9 GPa，and the elastic modulus increased from 97.92G Pa to 181.70 GPa.The average friction coefficient of the coating decreased from 0.49 to 0.39 at 700 ℃，but the wear rateincreased from 1.97× 10-5mm3/(N·m) to 6.41×10-4mm3/(N·m).Moreover，lowfriction coefficientresultedfrom the fact that oxygen doped coatings were more likely to form V2O5with lubricating effect at high temperatures，and correspondingly the wear rate of the coating increases due to the softening effect of V2O5.

Abstract Background Chronic remote ischemic conditioning (CRIC) has been shown to improve myocardial ischemia in experimental animal studies; however, its effectiveness in patients with chronic stable angina (CSA) has not been investigated. We conducted a proof-of-concept study to investigate the efficacy and safety of a six-month CRIC treatment in patients with CSA. Methods The EARLY-MYO-CSA trial was a prospective, randomized, controlled trial evaluating the CRIC treatment in patients with CSA with persistent angina pectoris despite receiving ≥ 3-month guideline-recommended optimal medical therapy. The CRIC and control groups received CRIC (at 200 mmHg) or sham CRIC (at 60 mmHg) intervention for 6 months, respectively. The primary endpoint was the 6-month change of myocardial flow reserve (MFR) on single-photon emission computed tomography. The secondary endpoints were changes in rest and stress myocardial blood flow (MBF), angina severity according to the Canadian Cardiovascular Society (CCS) classification, the Seattle Angina Questionnaire (SAQ), and a 6-min walk test (6-MWT). Results Among 220 randomized CSA patients, 208 (105 in the CRIC group, and 103 in the control group) completed the treatment and endpoint assessments. The mean change in MFR was significantly greater in the CRIC group than in the control group (0.27 ± 0.38 vs. − 0.04 ± 0.25; P

Abstract Background In a large randomized controlled trial (PARADIGM-HF), ARNI has been shown to significantly reduce cardiovascular mortality and hospitalization for patients with reduced ejection fraction in heart failure. This study analyzed the efficacy and safety of ARNI on the basis of various types of heart failure patients in southwestern Sichuan Province. Methods This study included patients with heart failure who were treated at the Affiliated Hospital of North Sichuan Medical College from July 2017 to June 2021. This study analyzed the efficacy and safety of ARNI in the treatment of heart failure, and analyzed the risk factors for readmission after ARNI treatment. Results After propensity score matching, a total of 778 patients were included in the study. The readmission rate for heart failure in patients treated with ARNI (8.7%) was significantly lower than that in the standard treatment group (14.5%) (P = 0.023). Both the proportion of patients with increased LVEF and with decreased LVEF were higher in the ARNI treatment group than in the conventional therapy group. Compared with receiving standard medical treatment, combined ARNI treatment resulted in a greater reduction in SBP (-10.00, 95%CI: -24.00-1.50 vs. -7.00, 95%CI: -20.00-4.14; P = 0.016) in HF patients. Combination ARNI therapy did not increase the risk of adverse events. The study found that age (> 65 vs. ≤65 years) (OR = 4.038, 95%CI: 1.360-13.641, P = 0.013) and HFrEF (OR = 3.162, 95%CI: 1.028–9.724, P = 0.045) were independent predictors of readmission in HF patients treated with ARNI. Conclusion Patients with heart failure treated with ARNI can improve clinical symptoms and reduce the risk of readmitted hospital admission. Age > ~ 65 years and HFrEF were independent predictors of readmission in HF patients treated in ARNI group.

Abstract Background Wheat (Triticum aestivum L.) is a major cereal crop that is grown worldwide, and it is highly dependent on sufficient N supply. The molecular mechanisms associated with nitrate uptake and assimilation are still poorly understood in wheat. In plants, NRT2 family proteins play a crucial role in NO3 – acquisition and translocation under nitrate limited conditions. However, the biological functions of these genes in wheat are still unclear, especially their roles in NO3 – uptake and assimilation. Results In this study, a comprehensive analysis of wheat TaNRT2 genes was conducted using bioinformatics and molecular biology methods, and 49 TaNRT2 genes were identified. A phylogenetic analysis clustered the TaNRT2 genes into three clades. The genes that clustered on the same phylogenetic branch had similar gene structures and nitrate assimilation functions. The identified genes were further mapped onto the 13 wheat chromosomes, and the results showed that a large duplication event had occurred on chromosome 6. To explore the TaNRT2 gene expression profiles in wheat, we performed transcriptome sequencing after low nitrate treatment for three days. Transcriptome analysis revealed the expression levels of all TaNRT2 genes in shoots and roots, and based on the expression profiles, three highly expressed genes (TaNRT2-6A.2, TaNRT2-6A.6, and TaNRT2-6B.4) were selected for qPCR analysis in two different wheat cultivars (‘Mianmai367’ and ‘Nanmai660’) under nitrate-limited and normal conditions. All three genes were upregulated under nitrate-limited conditions and highly expressed in the high nitrogen use efficiency (NUE) wheat ‘Mianmai367’ under low nitrate conditions. Conclusion We systematically identified 49 NRT2 genes in wheat and analysed the transcript levels of all TaNRT2s under nitrate deficient conditions and over the whole growth period. The results suggest that these genes play important roles in nitrate absorption, distribution, and accumulation. This study provides valuable information and key candidate genes for further studies on the function of TaNRT2s in wheat.

Tight oil reservoirs in the south Ordos Basin are characterized by fractured, heterogeneous oil-bearing strata (an oil saturation of less than 55% on average), normal pressure (0.8±) and extra-low permeability (less than 0.3 mD). In the Chang 8 tight sandstone reservoir in Honghe oilfield, micro- and nano-pores, especially those with a pore-throat radius of less than 1 μm, account for more than 90%. Fluid flow in the matrix is non-linear and crude oil flow rates are very low under normal pressure gradients. An improved understanding of oil mobility in a tight matrix is key to further development of normal-pressure tight-oil resources in the continental basin. In this study, constant-velocity and high-pressure mercury injection experiments were conducted using samples of typical tight sandstone cores obtained from the south of Ordos Basin. A new method for reconstructing the full-scale pore-throat distribution characteristics of tight sandstone reservoirs was established successfully, based on which multistage centrifugal tests, tests of low-pressure differential displacement of oil by water, and nuclear magnetic resonance tests were conducted in order to obtain the distribution characteristics of moveable fluid in different pores. The moveable oil saturation (MOS) and degree of oil recovery (i.e. ratio of accumulative oil production to producing geologic reserves) of the core samples under different differential pressures for displacement were determined. As for the tight oil reservoirs in the south Ordos Basin, the moveable fluids are mainly stored in sub-micron (0.10–0.5 μm) pores. For Type Ⅰ reservoirs (k > 0.1 mD), the volume percentage of moveable fluid in pores with a radius larger than 0.5 μm is relatively high (greater than 40%). The degree of oil recovery of water flooding serves as the basis for forecasting recoverable reserves for tight oil reservoirs. Recoverable reserves under water flooding, mainly occur in pores with a radius greater than 0.5 μm. The contribution of Type Ⅰ reserves to oil production is observed to be greater than 60%, and the degree of oil recovery reaches up to 17.1%. These results help improve our understanding on the evaluation and classification of Chang 8 tight sandstone reservoirs in Honghe oilfield and serve as theoretical basis for pilot tests to explore effective injection media and development methods to improve the matrix-driven pressure differences and displacement efficiency for oil.

Introduction Percutaneous coronary intervention (PCI) guided by coronary angiography-derived fractional flow reserve (FFR) or intravascular ultrasound (IVUS) has shown improved clinical outcomes compared with angiography-only-guided PCI. In patients with intermediate stenoses, FFR resulted in fewer coronary interventions and was non-inferior to IVUS with respect to clinical outcomes. However, whether this finding can be applied to angiography-derived FFR in significant coronary artery disease (CAD) remains unclear.Method and analysis The comparison of angiography-derived FFR-guided and IVUS-guided intervention strategies for clinical outcomes in patients with coronary artery disease (FLAVOUR II) trial is a multicentre, prospective, randomised controlled trial. A total of 1872 patients with angiographically significant CAD (stenoses of at least 50% as estimated visually through angiography) in a major epicardial coronary artery will be randomised 1:1 to receive either angiography-derived FFR-guided or IVUS-guided PCI. Patients will be treated with second-generation drug-eluting stent according to the predefined criteria for revascularisation: angiography-derived FFR≤0.8 and minimal lumen area (MLA)≤3 mm2 or 3 mm270%. The primary endpoint is a composite of all-cause death, myocardial infarction and revascularisation at 12 months after randomisation. We will test the non-inferiority of the angiography-derived FFR-guided strategy compared with the IVUS-guided decision for PCI and the stent optimisation strategy.The FLAVOUR II trial will provide new insights into optimal evaluation and treatment strategies for patients with CAD.Ethics and dissemination FLAVOUR II was approved by the institutional review board at each participating site (The Second Affiliated Hospital of Zhejiang University School of Medicine Approval No: 2020LSYD410) and will be conducted in line with the Declaration of Helsinki. Informed consent would be obtained from each patient before their participation. The study results will be submitted to a scientific journal.Trial registration number NCT04397211.

ABSTRACTOver 3 billion doses of inactivated vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been administered globally. However, our understanding of the immune cell functional transcription and T cell receptor (TCR)/B cell receptor (BCR) repertoire dynamics following inactivated SARS-CoV-2 vaccination remains poorly understood. Here, we performed single-cell RNA and TCR/BCR sequencing on peripheral blood mononuclear cells at four time points after immunization with the inactivated SARS-CoV-2 vaccine BBIBP-CorV. Our analysis revealed an enrichment of monocytes, central memory CD4+ T cells, type 2 helper T cells and memory B cells following vaccination. Single-cell TCR-seq and RNA-seq comminating analysis identified a clonal expansion of CD4+ T cells (but not CD8+ T cells) following a booster vaccination that corresponded to a decrease in the TCR diversity of central memory CD4+ T cells and type 2 helper T cells. Importantly, these TCR repertoire changes and CD4+ T cell differentiation were correlated with the biased VJ gene usage of BCR and the antibody-producing function of B cells post-vaccination. Finally, we compared the functional transcription and repertoire dynamics in immune cells elicited by vaccination and SARS-CoV-2 infection to explore the immune responses under different stimuli. Our data provide novel molecular and cellular evidence for the CD4+ T cell-dependent antibody response induced by inactivated vaccine BBIBP-CorV. This information is urgently needed to develop new prevention and control strategies for SARS-CoV-2 infection. (ClinicalTrials.gov Identifier: NCT04871932).

Abstract Background Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR‐LFD have not been studied in the Asian cancer population. Method Here we retrospectively analyzed the targeted sequencing data from a large cancer database. Results EGFR‐LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR‐LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal‐level and arm‐level CNV in this cohort. EGFR exon2–17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. Conclusion Our study provided valuable insights into the distribution and molecular characteristics of EGFR‐LFD, hoping to shed light on the treatment management for EGFR‐LFD carriers.

Abstract Background Left atrial (LA) appendage flow velocity (LAAFV) is a classic but invasive predictor of thromboembolic events in patients with atrial fibrillation (AF). We aimed to explore the usefulness of LA diameter (LAD) combined with CHA2DS2-VASc score, which is easily available and non-invasive, as a novel score for predicting a decrease in LAAFV in non-valvular AF (NVAF). Methods In total, 716 consecutive NVAF patients who underwent transesophageal echocardiography were divided into the decreased LAAFV (

Key points Microvascular impairment correlated with native T1 of remote myocardium. Native T1 values of remote myocardium changed dynamically. Native30D T1 and LGE were joint independent predictors of MACE.

Abstract Background and Purpose Diagnosis of retroperitoneal schwannoma (RS), especially cystic RS, is frequently missed or delayed owing to its rarity, location, nonspecific symptoms, and similarities with other tumors on various imaging modalities. This study aimed to determine associations between clinical, radiological, and histopathologic features and outcome. Materials and Methods Seventy‐nine patients with pathologically confirmed RS who underwent tumor resection between June 2010 and June 2020 were retrospectively reviewed and analyzed. Patients were stratified into three groups according to degree of tumoral cystic degeneration. Results Cystic degeneration was significantly associated with multiple foci (p = 0.025), calcification (p = 0.012), and hemorrhage (p = 0.000), but not size (p = 0.08), high Ki‐67 (p = 0.094), malignancy (p = 0.115; prevalence of cystic degeneration in the benign and malignant groups were 53.9% vs 100%), rough margin (p = 0.162), or irregular shape (p = 0.369). Malignant RS was significantly associated with multiple lymph nodes enlargement (p = 0.034). Tumor size, margins, shape, or/and multiplicity did not significantly differ between benign and malignant tumors. No recurrence occurred in patients with benign RS (mean follow‐up, 45 months). All malignant tumors recurred; mean time to recurrence was 11.4 months (mean follow‐up, 33 months). Conclusion Since RS is misdiagnosed mostly as malignancy and diagnosis is often delayed, a suspicion is necessary for diagnosis when atypical features are present. In RS, cystic degeneration was not associated with tumor size, Ki‐67, or malignancy; however, it was significantly associated with multiple foci, calcification, and hemorrhage. Cystic degeneration and related factors are useful for the diagnosis of RS. Malignant RS should be considered when a mass involves multiple lymph nodes. Margins, morphology, and size are not associated with malignancy. Pathological tumor type, tumor location, and adjacent anatomic structures are associated with outcome.

Abstract The safety problems encountered with lithium–sulfur batteries (LSBs) hinder their development for practical applications. Herein, a highly thermally conductive separator was constructed by cross‐weaving super‐aligned carbon nanotubes (SA‐C) on super‐aligned boron nitride@carbon nanotubes (SA‐BC) to create a composite film (SA‐BC/SA‐C). This separator was used to fabricate safe LSBs with improved electrochemical performance. The highly aligned separator structure created a uniform thermal field that could rapidly dissipate heat accumulated during continuous operation due to internal resistance, which prevented the development of extremely high temperatures. The array of boron nitride nanosheets endowed the composite separator with a large number of adsorption sites, while the highly graphitized carbon nanotube skeleton accelerated the catalytic conversion of high‐valence polysulfides into low‐valence polysulfides. The arrayed molecular brush design enabled the regulation of local current density and ion flux, and considerably alleviated the growth of lithium dendrites, thus promoting the smooth deposition of Li metal. Consequently, a battery constructed with the SA‐BC/SA‐C separator showed a good discharge capacity of 685.2 mAh g−1 over 300 cycles (a capacity decay of 0.026% per cycle) at 2 C and 60°C. This “three‐in‐one” multifunctional separator design strategy constitutes a new path forward for overcoming the safety problems of LSBs.

Background The presence of intraventricular hemorrhage (IVH) was extensively investigated and was associated with poor outcome in patients with intracerebral hemorrhage (ICH). However, the effect of the speed of ventricular bleeding on outcomes is unknown. Methods and Results We prospectively included patients with ICH who had baseline computed tomography scans within 6 hours after ictus between January 2016 and October 2021. The clinical characteristics were compared between patients with and without early neurologic deterioration (END). Ultraearly IVH growth (uIVHG) was defined as baseline IVH volume by onset‐to‐imaging time. The association between uIVHG and outcomes was assessed by using multivariable logistic regression analysis. We established the ultraearly IVH growth (uIVH) score and compared the areas under the receiver operating characteristic curves of the existing scores for predicting END. A total of 299 patients were finally enrolled. Of those, 38 patients (12.7%) experienced END at 24 hours and 89 patients (29.8%) had poor outcomes at 90 days. After adjustment for confounding factors, uIVHG (odds ratio, 1.061 [95% CI, 1.011–1.113]; P=0.016) was independently associated with END in multivariable analysis. A prediction score was developed on the basis of the logistic model. The uIVH score was developed as a sum of individual points (0–6) based on age, hematoma volume, National Institutes of Health Stroke Scale, hematoma expansion, and uIVHG ≥2.5 mL/h. In comparison with the ICH score and modified Emergency Department ICH Scale, the uIVH score exhibited best performance in the prediction of END. Conclusions uIVHG is associated with early neurologic deterioration and poor functional outcome in patients with ICH.

Objectives The aim of our observational study was to investigate the incidence, clinical characteristics and outcome of post-stroke recrudescence (PSR) in the Chinese population.Design and setting Single-centre prospective observational study in China.Participants A total of 1114 patients who had a suspected stroke were prospectively screened from October 2020 to February 2022.Outcome measures The primary outcome was the proportion of patients with functional independence defined as a score of 0–2 on the modified Rankin Scale (mRS) at 3 months. Secondary outcomes were: early neurological improvement (ENI), defined as a National Institutes of Health Stroke Scale (NIHSS) score of 0 or an improvement of ≥2 points from admission at 24 hours; mortality within 3 months; stroke recurrence within 3 months and length of stay in hospital.Results A total of 959 patients with cerebral infarction and 30 patients without an available magnetic resonance imaging (MRI) scan were excluded. Among the 125 included patients, 27 cases of PSR (2.4%), 50 cases of transient ischaemic attack (TIA) (4.5%) and 48 cases of stroke mimics (SMs) (4.3%) were identified. A higher frequency of infection at admission (22.2% vs 2%, p=0.007) was observed in patients with PSR compared with patients with TIA, and a lower proportion of functional independence at 3 months (80% vs 98%, p=0.015) was seen. Patients with TIA had a higher frequency of ENI compared with patients with PSR and SMs (98% vs 59.3%, p

The tumor microenvironment (TME) is an intricate ecosystem that is actively involved in various stages of cancer occurrence and development. Some characteristics of tumor biological behavior, such as proliferation, migration, invasion, inhibition of apoptosis, immune escape, angiogenesis, and metabolic reprogramming, are affected by TME. Studies have shown that non-coding RNAs, especially long-chain non-coding RNAs and microRNAs in cancer-derived exosomes, facilitate intercellular communication as a mechanism for regulating angiogenesis. They stimulate tumor growth, as well as angiogenesis, metastasis, and reprogramming of the TME. Exploring the relationship between exogenous non-coding RNAs and tumor-associated endothelial cells, as well as their role in angiogenesis, clinicians will gain new insights into treatment as a result.

BackgroundAcute myocardial infarction (AMI) poses a significant threat to cardiovascular diseases (CVDs), leading to a high risk of heart failure (HF) and cardiovascular death. Growing evidence has unveiled the potential of sodium-glucose cotransporter-2 (SGLT2) inhibitors to improve cardiovascular outcomes in patients with CVD regardless of diabetes, but there is limited evidence in AMI patients. Furthermore, it is controversial whether the effects can be ascribed to the amelioration of left ventricular (LV) function, which further complicates the understanding of their underlying mechanism.MethodsThis study is a prospective, phase IV, open-label, parallel group, single-center trial conducted in a large tertiary teaching hospital in China. A total of 120 patients with AMI and type 2 diabetes mellitus (T2DM) will be included. Those who received SGLT2 inhibitors are considered as the experimental group, and those taking other antidiabetic agents are considered as the control group. The primary outcome is change in LV end-systolic volume index (LVESVi) measured by cardiac magnetic resonance (CMR) imaging from baseline during 1-year follow-up period. Secondary outcomes include other LV parameters such as LV mass, LV volume, and LV ejection fraction (EF); quality of life and functional capacity such as Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) and EuroQol-5 dimension (EQ-5D); biomarkers associated with diagnostic parameters of AMI and possible mechanisms on cardiovascular protection, such as creatine kinase, troponin T (TnT) level, troponin I (TnI) level, soluble suppression of tumorigenicity-2 (sST2), galectin-3 (Gal-3), fibroblast growth factor 21 (FGF21), and microRNA (miRNA) level.DiscussionThis study aims to investigate whether SGLT2 inhibitors could improve LV function by measuring CMR, quality of life, and functional capacity in patients with AMI in real-world settings, providing evidence on the underlying mechanism of SGLT2 inhibitors on cardioprotection.Clinical trial registrationhttps://www.chictr.org.cn/showproj.html?proj=173672, identifier ChiCTR2200065792.

Abstract Background The cardiac repair process following a myocardial infarction is a key factor in patient prognosis. In this repair process, cardiac fibrosis takes a critically important role. Among those featured genes for fibrosis, transforming growth factor beta (TGF‐β) is known to be involved in the fibrosis in various organs. And bone morphogenetic protein (BMP)6 belongs to the TGF‐β superfamily. Although BMPs are known to play exclusive roles in cardiac repair processes, the character of BMP6 in cardiac remodelling remains unclear. Purpose This study aimed to investigate how BMP6 functioned in cardiac fibrosis following myocardial infarction (MI). Results In this paper, we demonstrated that BMP6 expression was upregulated after myocardial infarction in wild‐type (WT) mice. Furthermore, BMP6−/− mice showed a more significant decline in cardiac function and lower survival curves after MI. An enlarged infarct area, increased fibrosis and more pronounced inflammatory infiltration were observed in BMP6−/− mice compared to WT mice. The expression of collagen I, collagen III and α‐SMA was increased in BMP6−/− mice. In vitro, through gain‐of‐function and loss‐of‐function experiments, it was demonstrated that BMP6 decreases collagen secretion in fibroblasts. Mechanistically, knocking down BMP6 promoted AP‐1 phosphorylation, which in turn promotes CEMIP expression, led to an acceleration in the progression of cardiac fibrosis. Finally, it was found that rhBMP6 would alleviate ventricular remodelling abnormalities after myocardial infarction. Conclusion Therefore, BMP6 may be a novel molecular target for improving myocardial fibrosis and cardiac function after myocardial infarction.

Abstract Gliomas, the most lethal brain tumors, often exhibit resistance to conventional chemotherapy and/or radiotherapy. This study reveals that sertindole, a potent dopamine D2 receptor antagonist primarily designed as an antipsychotic medication for schizophrenia, effectively inhibits glioma progression. Our findings demonstrate that sertindole suppresses the proliferation of U251 and U87 tumor cells, impedes cell cycle progression in vitro, and curtails xenograft tumor growth in vivo. Moreover, we present compelling evidence demonstrating the ability of sertindole to enhance the cellular response to the chemotherapeutic agent temozolomide both in vitro and in vivo. Additionally, our findings reveal that sertindole effectively suppresses the self‐renewal capacity and expression of stemness‐associated genes, such as Nanog and Sox2, in glioma tumor cells and glioma stem cells. A mechanistic investigation demonstrated that sertindole enhances the formation of autophagosome–lysosome complexes while concurrently impeding autophagic flux through the inhibition of lysosomal hydrolytic enzymes CTSD and CTSB, ultimately resulting in decreased growth of tumor cells. In conclusion, our findings suggest that sertindole has the potential to develop into a potent antiglioma therapeutic agent.

BackgroundThe purpose of this study was to investigate the diagnostic performance of the neutrophil percentage-to-albumin ratio (NPAR) for predicting stroke-associated pneumonia (SAP) and functional outcome in patients with intracerebral hemorrhage (ICH).MethodsWe analyzed our prospective database of consecutive ICH patients who were admitted to the First Affiliated Hospital of Chongqing Medical University from January 2016 to September 2021. We included subjects with a baseline computed tomography available and a complete NPAR count performed within 6h of onset. The patients’ demographic and radiological characteristics were analyzed. Good outcome was defined as a modifed Rankin Scale score of 0-3 at 90 days. Poor outcome was defined as a modifed Rankin Scale score of 4-6 at 90 days. Multivariable logistic regression models were used to investigate the association between NPAR, SAP, and functional outcome. Receiver operating characteristic (ROC) curve analysis was conducted to identify the optimal cutoff of NPAR to discriminate between good and poor outcomes in ICH patients.ResultsA total of 918 patients with ICH confirmed by non-contrast computed tomography were included. Of those, 316 (34.4%) had SAP, and 258 (28.1%) had poor outcomes. Multivariate regression analysis showed that higher NPAR on admission was an independent predictor of SAP (adjusted odds ratio: 2.45; 95% confidence interval, 1.56-3.84; P

Thrombin is an important ischemia/reperfusion injury (IRI) mediator in patients with ST-elevation myocardial infarction (STEMI). This study examines the use of bivalirudin, a direct thrombin inhibitor, in reducing IRI in STEMI patients. STEMI patients (n = 21) were treated with bivalirudin and compared to 21 patients treated with unfractionated heparin (UFH) from the EARLY Assessment of Myocardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry (NCT03768453). Infarct size (IS) and left ventricular ejection fraction (LVEF) were comparable between the two groups at follow up. During the first cardiac magnetic resonance (CMR) scan within the first week after percutaneous coronary intervention (PCI), all patients in both the bivalirudin and UFH groups exhibited myocardial edema. However, the myocardium edema volume was significantly less in the bivalirudin group (p < 0.05). At the one-month follow-up, a smaller proportion of patients in the bivalirudin group than in the UFH group exhibited myocardial edema (4.7% vs. 33.3%, p < 0.05). At the three-month follow-up, myocardial edema had completely resolved in the bivalirudin group, while it persisted in two patients in the UFH group. The incidence and volume of microvascular obstruction (MVO) were significantly lower in the bivalirudin group during the acute phase. Additionally, the incidence of intramyocardial hemorrhage (IMH) was significantly lower in the bivalirudin group during both the acute and follow up (p < 0.05). These findings were corroborated by T2 and T1 mapping results. The study concluded that the use of bivalirudin for anticoagulation is associated with attenuated IRI in STEMI patients who receive primary PCI.

Myocardial fibrosis, a common pathophysiological consequence of various cardiovascular diseases, is characterized by fibroblast activation and excessive deposition of extracellular matrix (ECM) collagen. Accumulating evidence indicates that myocardial fibrosis contributes to ventricular stiffness, systolic and diastolic dysfunction, and ultimately leads to the development of heart failure (HF). Early detection and targeted treatment of myocardial fibrosis is critical to reverse ventricular remodeling and improve clinical outcomes in patients with cardiovascular diseases. However, despite considerable progresses made in understanding molecular mechanisms of myocardial fibrosis, non-invasive imaging to assess myocardial fibrosis and guide clinical treatment is still not widely available, limiting the development of innovative treatment strategies. This review summarizes recent progresses of imaging modalities for detecting myocardial fibrosis, with a focus on nuclear medicine, echocardiography and cardiac magnetic resonance (CMR).

Abstract During an ischemic stroke, the brain releases various factors, including glutamate and γ-aminobutyric acid. Glutamate can cause neurotoxic effects through certain receptors and exacerbate neurological damage, while γ-aminobutyric acid as an inhibitory neurotransmitter can antagonize the excitotoxic effects of glutamate and enhance the tolerance of neurons to ischemia. Therefore, in this study, the content of amino acid neurotransmitters in brain tissue before ischemia, after 10 min of ischemia, hypothermic perfusion, and rewarming were analyzed by high-performance liquid chromatography-UV in an animal model of ischemic stroke generated by blocking the bilateral common carotid arteries of rhesus monkeys. The changes in amino acid neurotransmitters in the rhesus monkey brain during post-ischemia hypothermic perfusion and rewarming were investigated by statistical methods of repeated measures ANOVA, showing that the concentration change of glutamate had not only a temporal factor but also was influenced by temperature, and there was an interaction effect between the two. Time but not temperature affected the change in γ-aminobutyric acid concentration, and there was an interaction effect between the two. Accordingly, hypoperfusion exerts a protective effect during ischemia by inhibiting the release of excitatory amino acid neurotransmitters, while the antagonistic effect of GABA on Glu is not significant.

Background A predictive tool is required to identify the cancer-specific survival in rectal cancer (RC) patients who have opted to receive preoperative radiotherapy. Methods A database containing the data on RC patients’ records of Surveillance, Epidemiology, and End Results (SEER) receiving surgery during 2000–2014 was selected. All patients received neoadjuvant radiotherapy (NR). The correlation of clinicopathological parameters was analyzed using the Chi-square test and the survival risk factors were analyzed using the Cox proportional hazards analysis (univariate and multivariate). Finally, the nomogram was developed and validated to visually represent an accurate prediction of the probability of 3- and 5-year cancer-specific survival (CSS) based on the screened variables of the cohort. Results 11,499 rectal cancer patients were included in our cohort. Patients’ records were randomly allocated to either the development or validation cohorts based on an equal ratio (1:1). Performing the multivariate Cox regression analysis incorporating these variables in the development cohort determined 11 independent prognostic factors. Statistically significant differences were recorded among subgroups using log-rank tests, which confirmed the appropriateness and acceptability of factor stratifications. Then, the nomogram was constructed and its concordance index (C-index) values in the development cohort (0.720) and validation cohort (0.717) were evaluated to be higher (P

Background The sirtuins (SIRTs) family is a nicotinamide adenine dinucleotide (NAD+) family of dependent deacetylases, which includes SIRT1-7. This family is related to the development and progression of various tumors. However, a comprehensive analysis of the role of SIRTs in clear cell renal cell carcinoma (ccRCC) is still lacking, and there are few reports on the inhibitory role of SIRT5 in ccRCC. Methods We used immunohistochemical analysis, and several bioinformatic databases to perform an integrated analysis of the expression and prognostic value of SIRT5 and other SIRT family members in ccRCC along with the associated immune cell infiltration. These databases include TIMER, THPA, cell culture, UALCAN, cBioPortal, WebGestalt, Metascape, DiseaseMeth, STRING database, and Cytoscape. Results The protein expression of SIRT1, 2, 3, 6, and 7 were upregulated in ccRCC for the Human Protein Atlas database, whereas the expression of SIRT4 and SIRT5 was decreased. The expression based on tumor stage, and grade followed a similar trend. Kaplan–Meier analysis showed that high SIRT4 and SIRT5 expression was positively related to better overall survival (OS), whereas SIRT6 and SIRT7 expression was positively related to worse OS. Further, high SIRT3 expression was related to worse relapse-free survival (RFS), whereas high SIRT5 expression was related to better RFS. To explore the mechanism underlying the function of SIRTs in ccRCC, we also used several databases to perform the functional enrichment analysis and explore the relationship between infiltrating immune cells and seven SIRT family members in ccRCC. The results showed that several SIRT family members, and particularly SIRT5, are correlated with the infiltration of some important immune cells. The protein expression of SIRT5 was significantly lower in tumor tissue compared to normal tissue and was negatively related to the age of the patient ccRCC individual tumor stages, and grades. In human ccRCC samples, strong IHC staining expression of SIRT5 was displayed in adjacent normal tissue than in tumor tissues. Conclusion SIRT5 may be a prognostic marker and a novel strategy for the treatment of ccRCC.

Abstract Endoplasmic reticulum (ER) stress plays a central role in myocardial ischemia/reperfusion (I/R) injury. Irisin has been reported to have protective properties in ischemia disease. In this study, we aimed at investigating whether irisin could alleviate myocardial I/R injury by ER stress attenuation. The in vitro model of hypoxia/reoxygenation (H/R) was established, which resembles I/R in vivo. Cell viability and apoptosis were estimated. Expressions of cleaved caspase-3, cytochrome c, GRP78, pAMPK, CHOP, and eIF2α were assessed by western blot. Our results revealed that pre-treatment with irisin significantly decreased cytochrome c release from mitochondria and caspase-3 activation caused by H/R. Irsin also reduced apoptosis and increased cell viability. These effects were abolished by AMPK inhibitor compound C pre-treatment. Also, GRP78 and CHOP expressions were up-regulated in the H/R group compared to the control group; however, irisin attenuated their expression. The pAMPK level was significantly decreased compared to the control, and this effect could be partly reversed by metformin pre-treatment. These results suggest that ER stress is associated with cell viability decreasing and cardiomyocytes apoptosis induced by H/R. Irisin could efficiently protect cardiomyocytes from H/R-injury via attenuating ER stress and ER stress-induced apoptosis.

Abstract Introduction and objectives The aging population is expected to reach 2 billion by 2050, but the impact of somatic symptom disorder (SSD) on the elderly has been insufficiently addressed. We aimed to clarify the prevalence of SSD in China and to identify physical and psychological differences between the elderly and non-elderly. Methods In this prospective multi-center study, 9020 participants aged (2206 non-elderly adults and 6814 elderly adults) from 105 communities of Shanghai were included (Assessment of Somatic Symptom in Chinese Community-Dwelling People, clinical trial number NCT04815863, registered on 06/12/2020). The Somatic Symptom Scale-China (SSS-CN) questionnaire was used to measure SSD. Depressive and anxiety disorders were assessed by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Results The prevalence of SSD in the elderly was higher than that in the non-elderly (63.2% vs. 45.3%). The elderly suffered more severe SSD (20.4% moderate and severe in elderly vs. 12.0% in non-elderly) and are 1.560 times more likely to have the disorder (95%CI: 1.399–1.739; p