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Abstract Aims Rhythm control therapy has shown great benefits for patients with atrial fibrillation (AF) and heart failure (HF). However, few studies have evaluated the effects of rhythm control on left ventricular ejection fraction (LVEF) trajectory across the whole HF spectrum. Our study explored the prevalence and predictors of LVEF trajectory changes and their prognostic implications following rhythm control. Methods and results Depending on the treatment strategy, the cohort was classified into rhythm and rate control groups. Alterations in HF types and LVEF trajectory were recorded. The observational endpoints were all‐cause mortality and HF‐related admission. Predictors of LVEF trajectory improvement in the rhythm control group were evaluated. After matching, the two groups had similar age [mean age (years): rhythm/rate control: 63.96/65.13] and gender [male: rhythm/rate control: n = 228 (55.6%)/233 (56.8%)]. Based on baseline LVEF measurement, the post‐matched cohort had 490 HF with preserved ejection fraction (rhythm/rate control: n = 260/230; median LVEF: 58.00%/57.00%), 99 HF with mildly reduced ejection fraction (rhythm/rate control: n = 50/49; median LVEF: 45.00%/46.00%), and 231 HF with reduced ejection fraction (rhythm/rate control: n = 100/131; median LVEF: 32.50%/33.00%). Trajectory analysis found that the rhythm control group had a greater percentage of LVEF trajectory improvement than the rate control group [80 (53.3%) vs. 71 (39.4%), P = 0.012]. Cox regression analysis also showed that the rhythm control group was more likely to have improved LVEF trajectory compared with the rate control group {hazard ratio [HR] 1.671 [95% confidence interval (CI) 1.196–2.335], P = 0.003}. In the survival analysis, the rhythm control group experienced significant lower risks of all‐cause mortality [HR 0.600 (95% CI 0.366–0.983), P = 0.043] and HF‐related admission [HR 0.611 (95% CI 0.496–0.753), P

Background The accurate selection of patients likely to respond to renal denervation (RDN) is crucial for optimizing treatment outcomes in patients with hypertension. This systematic review was designed to evaluate patient‐specific factors predicting the RDN response. Methods and Results We focused on individuals with hypertension who underwent RDN. Patients were categorized based on their baseline characteristics. The primary outcome was blood pressure (BP) reduction after RDN. Both randomized controlled trials and nonrandomized studies were included. We assessed the risk of bias using corresponding tools and further employed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the overall quality of evidence. A total of 50 studies were ultimately included in this systematic review, among which 17 studies were for meta‐analysis. Higher baseline heart rate and lower pulse wave velocity were shown to be associated with significant antihypertensive efficacy of RDN on 24‐hour systolic BP reduction (weighted mean difference, −4.05 [95% CI, −7.33 to −0.77]; weighted mean difference, −7.20 [95% CI, −9.79 to −4.62], respectively). In addition, based on qualitative analysis, higher baseline BP, orthostatic hypertension, impaired baroreflex sensitivity, and several biomarkers are also reported to be associated with significant BP reduction after RDN. Conclusions In patients with hypertension treated with the RDN, higher heart rate, and lower pulse wave velocity were associated with significant BP reduction after RDN. Other factors, including higher baseline BP, hypertensive patients with orthostatic hypertension, BP variability, impaired cardiac baroreflex sensitivity, and some biomarkers are also reported to be associated with a better BP response to RDN.

Abstract In recent years, humanized immune system (HIS) mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields, better mimicking the human immune system and the tumor immune microenvironment, compared to traditional immunodeficient mice. To better promote the application of HIS mice in preclinical research, we selectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor (CAR) ‐T cells in various antiviral and antitumor treatments. By exploring its application in preclinical research, we find that it can better reflect the actual clinical patient condition, with the advantages of providing high‐efficiency detection indicators, even for progressive research and development. We believe that it has better clinical patient simulation and promotion for the updated design of CAR‐T cell therapy than directly transplanted immunodeficient mice. The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction, combining multiple models, and unifying sources and organoid substitution. Strategy study of relapse and toxicity after CAR‐T treatment also provides more possibilities for application and development.

Background A high fibrinogen‐to‐albumin ratio (FAR), a novel inflammatory marker, is considered to be a prognostic marker in vascular diseases. However, the association of FAR with large artery atherosclerosis (LAA) stroke is still unknown. This study was conducted to evaluate the association between FAR levels and clinical outcomes in patients with acute LAA stroke. Methods and Results A total of 809 patients within 72 hours of LAA stroke were included and followed up to 1 year. FAR was calculated as fibrinogen (g/L)/albumin (g/L). The associations of FAR with clinical outcomes were assessed by multivariate Cox regression or logistic regression analysis. Clinical outcomes included stroke recurrence, all‐cause death, poor functional outcome (modified Rankin Scale score 3–6), and dependence (modified Rankin Scale score 3–5). Among the 809 patients with acute LAA stroke, the median FAR was 0.075 (interquartile range, 0.064–0.087). At 1 year, 103 (12.7%) patients had stroke recurrence, 105 (13.0%) had poor functional outcome, 76 (9.8%) had dependence, and 29 (3.6%) had died. After adjusting for all confounding risk factors, a high FAR level was associated with stroke recurrence (hazard ratio, 2.57 [95% CI, 1.32–5.02]), poor functional outcome (odds ratio, 3.30 [95% CI, 1.57–6.94]), and dependence (odds ratio, 3.49 [95% CI, 1.49–8.19]). Conclusions A high FAR level was associated with an increased risk of stroke recurrence, poor functional outcome, and dependence in patients with acute LAA stroke.

Abstract Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular disease that is inherited from a single gene. Its clinical manifestations range from asymptomatic mutant gene carriers to patients with severe left ventricular effluent tract obstruction and end‐stage HCM with motor restriction. In this case, we present a patient with the main presentation of heart failure and ST‐segment elevation of the lateral wall, as determined by electrocardiogram. The patient was finally diagnosed with HCM because of genetic testing and the presentation of extensive myocardial fibrosis with reduced systolic function on cardiac magnetic resonance imaging. The patient's clinical findings, electrocardiogram, and cardiac magnetic resonance imaging were different from those of typical patients with HCM.

Objectives Osteosarcoma (OS) is a malignant tumor with frequent occurrence among teenagers. Long non‐coding RNAs (lncRNAs) play pro‐cancer roles in many tumors. The purpose of this study was to figure out the functional role of a novel lncRNA long intergenic non‐protein coding RNA 665 (LINC00665) in OS by observing the OS cell behaviors. Methods Quantitative reverse transcription polymerase chain reaction (RT‐qPCR) was used to analyze LINC00665 expression in OS cells. Cell function assays assessed the impacts of LINC00665 on OS cell phenotype. Immunofluorescence and western blot analyzed the function of LINC00665 on epithelial‐mesenchymal transition (EMT) in OS. Moreover, mechanistic assays analyzed the downstream mechanism of LINC00665 in OS cells. Results LINC00665 was significantly up‐regulated in OS cells. LINC00665 silence facilitated OS cell proliferation, migration, invasion, and EMT while inhibiting cell apoptosis. Mechanically, LINC00665 acted as a competing endogenous RNA (ceRNA) to sponge miR‐1249‐5p and thereby modulated Wnt family member 2B (WNT2B) to activate Wnt pathway. Wnt pathway activated LINC00665 expression transcriptionally. Conclusions Our study uncovered the cancer‐promoting role of LINC00665 in OS, and the feedback loop of LINC00665/miR‐1249‐5p/WNT2B/Wnt might be a potential target for OS treatment.

Abstract Derived from the D‐luciferin regeneration pathway in firefly body, the click condensation reaction between 2‐cyanobenzothiazole (CBT) and D‐cysteine (Cys) (CBT‐Cys click reaction) possesses unique advantages, including superior biocompatibility, high second order reaction rate, and metal‐free mild conditions, emerging as a powerful bioorthogonal tool for a variety of chemical biological applications. Moreover, owing to its programmable controllability (e.g., pH, reduction, or enzyme), CBT‐Cys click reaction is exploited to fabricate stimuli‐activatable imaging probes with self‐assembling behaviors in physiological context. At stimuli‐rich pathological lesions of interest, these probes undergo CBT‐Cys click reaction to form cyclic dimers/oligomers or linear polymers, and further self‐assemble into nanostructures. The in situ formed nanostructures promote the selective accumulation and retention of imaging agent cargos at pathological lesions, thus enabling precise and enhanced in vivo imaging of diseases (especially tumors). To address the significance and recent breakthroughs of smart CBT‐Cys probes for enhanced optical imaging of tumors/other diseases, we herein propose this mini‐review, in which advances (particularly in recent 5 years) and potential challenges (or chances) in this field are emphasized.

Mouse bone marrow mesenchymal stem cells (mBM‐MSCs) are important for preclinical tissue regeneration and repair studies. In the present study, we isolated mBM‐MSCs using three easy‐to‐perform methods (whole bone marrow‐adherent culture, density‐gradient centrifugation, and bone digestion), and then compared the morphology, proliferation, differentiation, and paracrine factor profiles of the isolated mBM‐MSCs. Of these three isolation methods, the bone digestion method resulted in the highest quantity of mBM‐MSCs with high growth potential and moderate differentiation. Conversely, the mBM‐MSCs isolated through the whole bone marrow‐adherent method exhibited the lowest potency for proliferation and differentiation. The differentially expressed factors between mBM‐MSCs were primarily those involved in immune responses. The highly expressed secreted factors included cytokines/members of the chemokine family, growth factors, and protein binding/proteinase activity. These findings provide a fundamental reference for development of MSC isolation methods.

Abstract Background Tanshinone IIA (TSA), a major lipophilic component extracted from the roots of Salvia miltiorrhiza Bunge, has been widely used in China for its various biological activities. However, its effect on ovarian reserve in aged mice was not studied elsewhere. Objectives This study aimed to explore the effect of TSA on the ovarian reserve of aged mice as well as young mice. Forty weeks old mice (N = 40) were considered as aged group compared to 4 weeks old mice (N = 40), and these groups were subdivided into four subgroups (N = 10) to receive different doses of TSA (0, 10, 20, and 40 μg/g/day). Methods The effect of TSA was evaluated by counting follicular number by histological examination. Basal serum levels of FSH, LH, E2, and anti‐Mullerian hormone (AMH) were measured by ELISA. Moreover, the expression levels of antioxidant genes (CAT, Nrf2, GPX1), gap junction (Cx37), ERK1/2, and Smad5 family gene were examined at both mRNA (qPCR) and protein levels (western blot). Results Follicular number, level of AMH and E2, and the expression of CAT, Nrf2, and GPX1 genes increased significantly (p

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder. The pathology of AD is characterized by extracellular amyloid beta (Aβ) plaques, neurofibrillary tangles composed of hyperphosphorylated tau, neuronal death, synapse loss, and brain atrophy. Many therapies have been tested to improve or at least effectively modify the course of AD. Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease. Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction, although certain weaknesses or limitations need to be overcome. This review recapitulates rodent models for AD, the therapeutic efficacy of stem cells, influencing factors, and the underlying mechanisms behind these changes. Stem cell therapy provides perspective and challenges for its clinical application in the future.

Abstract Background Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self‐renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low‐density lipoprotein, chylomicrons, and triglyceride‐rich lipoproteins. Methods The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence‐activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL+/− HSC microenvironment were detected by transplantation assays using red fluorescent protein (RFP) transgenic mice. Results To explore the function of LPL in HSC regulation, heterozygous LPL‐knockout mice (LPL+/−) were established and analyzed by FACS. LPL+/− mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single‐cell clonogenic assays and cell‐cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57KIP2 and p21WAF1/CIP1 in LPL+/− mice was upregulated. Conclusions LPL+/− mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.

Abstract Acute coronary syndrome (ACS) is a serious cardiovascular disease. The ACS risk prediction model is of great significance during the hospitalisation of ACS patients. However, traditional machine learning methods are not effective in predicting risk events in the ACS treatment process because of sample imbalance and noise. In this letter, the multilayer perceptron (MLP) and ensemble method are combined and then ensemble‐MLPs are proposed, which has made two innovations: 1) increase the diversity of the base MLP classifier at the data level, structure level, and parameter level and 2) improve the ensemble performance by proposing a new ensemble method using f1‐score weighted average. Experiments have shown that the proposed method outperforms conventional ensemble MLP method and other traditional machine learning methods on the task of predicting risk events in the ACS treatment process.

Artificial neurons are the fundamental elements in neuromorphic computing systems. Studies have revealed neuronal spike‐rate adaptation owing to intrinsic plasticity that neurons will adapt to the spiking patterns and store the events in the background spiking through clustered neuronal spiking. The event can be reactivated by specific retrieval clues instead of solely relying on synaptic plasticity. However, the neural adaptation, as well as the interactive adaptations of neuronal activity for information processing, have not been implemented. Herein, an artificial adaptive neuron via in materia modulation of the VO2/HfO2 based dual‐mode memristor is demonstrated. By changing the conductance of the HfO2 layer, the firing threshold can be modulated, thus the excitability and inhibition can be adjusted according to the previous stimuli without any complex peripherals, showing an adaptive firing rate even under the same stimuli. The artificial neuron clusters can emulate the concept of neuronal memory and neural adaptation, demonstrating spatiotemporal encoding capabilities via the correlated neural firing patterns. This conceptual work provides an alternative way to expand the computation power of spiking neural networks by exploiting the neural adaptation and could be enlightenment to maximize the synergy across both synapse and neuron in neuromorphic computing systems.

Early and accurate diagnosis of prostate cancer (PCa) is extremely important, as metastatic PCa remains hard to treat. EWI‐2, a member of the Ig protein subfamily, is known to inhibit PCa cell migration. In this study, we found that EWI‐2 localized on both the cell membrane and exosomes regulates the distribution of miR‐3934‐5p between cells and exosomes. Interestingly, we observed that EWI‐2 is localized not only on the plasma membrane but also on the nuclear envelope (nuclear membrane), where it regulates the nuclear translocation of signaling molecules and miRNA. Collectively, these functions of EWI‐2 found in lipid bilayers appear to regulate PCa cell metastasis through the epidermal growth factor receptor‐mitogen‐activated protein kinase‐extracellular‐signal‐regulated kinase (EGFR‐MAPK‐ERK) pathway. Our research provides new insights into the molecular function of EWI‐2 on PCa metastasis, and highlights EWI‐2 as a potential PCa biomarker.

In order to study the seepage failure mechanism of roadway filling medium consisting of cohesive soil under complex hydrogeological conditions, a large-scale triaxial stress-seepage test system was utilized to investigate the influence of kaolin content and seepage loading rate on the seepage characteristics of filling medium. Through the analysis on the variation rules of sand loss and particle size distribution, the seepage characteristics and whole process of seepage instability of filling medium were explored in depth. It is concluded that (1) The seepage instability process of filling medium can be categorized into three stages: the initiation loss of fine clay, the accelerating loss of soil, and the stable status of soil loss. (2) The seepage failure process rate is proportional to the seepage loading rate and inversely proportional to the content of kaolin. (3) The kaolin and sand content of remaining mixture presented initial>bottom>middle>top status. The research results have guidance value for exploring the instability evolution mechanism of filling medium in deep roadway.

Abstract Long noncoding RNAs (lncRNAs) are RNA molecules comprising more than 200 nucleotides, which are not translated into proteins. Many studies have shown that lncRNAs are involved in regulating a variety of biological processes, including immune, cancer, stress, development and differentiation at the transcriptional, epigenetic or post‐transcriptional levels. Here, we review the role of lncRNAs in the process of neurodevelopment, neural differentiation, synaptic function, and pathogenesis of Parkinson's disease (PD). These pathomechanisms include protein misfolding and aggregation, disordered protein degradation, mitochondrial dysfunction, oxidative stress, autophagy, apoptosis, and neuroinflammation. This information will provide the basis of lncRNA‐based disease diagnosis and drug treatment for PD.

Abstract DNA modifications, represented by 5‐methylcytosine (5mC), 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC), play important roles in epigenetic regulation of biological processes. The specific recognition of DNA modifications by the transcriptional protein machinery is thought to be a potential mechanism for epigenetic‐driven gene regulation, and many modified DNA‐specific binding proteins have been uncovered. However, the panoramic view of the roles of DNA modification readers at the proteome level remains largely unclear. Here, a recently developed concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) approach is employed to profile the binding activity of TFs at DNA modifications. Modified DNA‐binding activity is quantified for 1039 TFs, representing 70% of the TFs in the human genome. Additionally, the modified DNA‐binding activity of 600 TFs is monitored during the mouse brain development from the embryo to the adult stages. Readers of these DNA modifications are predicted, and the hierarchical networks between the transcriptional protein machinery and modified DNA are described. It is further demonstrated that ZNF24 and ZSCAN21 are potential readers of 5fC‐modified DNA. This study provides a landscape of TF–DNA modification interactions that can be used to elucidate the epigenetic‐related transcriptional regulation mechanisms under physiological conditions.

Abstract Coronary artery spasm (CAS) is considered an important mechanism of acute coronary syndrome but not very common in the clinical setting. We report a case of a 42‐year‐old woman with chest pain lasting for 4 h due to diffuse CAS, which led to widespread ST‐segment elevation in multiple leads of the electrocardiogram and elevated cardiac troponin T. Emergency coronary angiography at admission showed significantly different morphological results from the second angiography during hospitalization, indicating the patient's discomfort was due to CAS rather than stenosis. Our case illustrates that diffuse CAS can cause widespread ST‐segment elevation and severe ACS.