Discovery of FO-4-15, a novel 1,2,4-oxadiazole derivative, ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKIIα pathway.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive impairments. Despite the limited efficacy of current treatments for AD, the 1,2,4-oxadiazole structure has garnered significant attention in medicinal chemistry due to its potential impact on mGluR1 and its association with AD therapy. In this study, a series of novel 1,2,4-oxadiazole derivatives were designed, synthesized, and evaluated for the neuroprotective effects in human neuroblastoma (SH-SY5Y) cells. Among all the derivatives tested, FO-4-15 (5f) existed the lowest cytotoxicity and the highest protective effect against H2O2. Based on these in vitro results, FO-4-15 was administered to 3×Tg mice and significantly improved the cognitive impairments of the AD mice. Pathological analysis showed that FO-4-15 significantly reduced Aß accumulation, Tau hyper-phosphorylation, and synaptic impairments in the 3×Tg mice. Dysfunction of the CaMKIIα/Fos signaling pathway in 3×Tg mice was found to be restored by FO-4-15 and the necessity of the CaMKIIα/Fos for FO-4-15 was subsequently confirmed by the use of a CaMKIIα inhibitor in vitro. Beyond that, mGluR1 was identified to be a potential target of FO-4-15, and the interaction of FO-4-15 and mGluR1 was displayed by Ca2+ flow increase, molecular docking, and interaction energy analysis. The target of FO-4-15 was further confirmed in vitro by JNJ16259685, a nonselective inhibitor of mGluR1. These findings suggest that FO-4-15 may hold promise as a potential treatment for Alzheimer's disease.

Discovery of palmatine derivatives as potent neuroprotective agents.

Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment.

Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.

Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are a type of toxic metabolite that are representative of multiple pathophysiological changes associated with T2DM. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by using a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by using hematoxylin-eosin (H&E), oil red O, myosin skeletal heavy chain (MHC), and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by using the dihydroethidium (DHE) stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored via the insulin tolerance test and the glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance, which was evidenced by reduced insulin tolerance and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and oil red O stains indicated increased intramuscular fibrosis and lipid deposits, respectively. Exposure to AGEs induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation, and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating the PERK/FOXO1 signaling pathway in skeletal muscle.NEW & NOTEWORTHY In this study, we proposed a molecular mechanism underlying the skeletal muscle atrophy-associated insulin resistance in type 2 diabetes mellitus (T2DM). Our investigation suggests that exposure to AGEs, which are characteristic metabolites of T2DM pathology, induces the activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, leading to the upregulation of the protein kinase RNA-like ER kinase (PERK)/forkhead box O1 (FOXO1)/muscle atrophy F-box pathway and subsequent skeletal muscle atrophy, ultimately resulting in insulin resistance.

Hydroxychloroquine Attenuates hERG Channel by Promoting the Membrane Channel Degradation: Computational Simulation and Experimental Evidence for QT-Interval Prolongation with Hydroxychloroquine Treatment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical trials, and full evaluation of their cardiotoxicity risks is in high demand. METHODS: We mainly focused on hydroxychloroquine (HCQ), one of the most concerned drugs for COVID-19 therapy, and investigated the effects and underlying mechanisms of HCQ on hERG channel via molecular docking simulations. We further applied the HEK293 cell line stably expressing hERG-wild-type channel (hERG-HEK) and HEK293 cells transiently expressing hERG-p.Y652A or hERG-p.F656A mutants to validate our predictions. Western blot analysis was used to determine the hERG channel, and the whole-cell patch clamp was utilized to record hERG current (IhERG). RESULTS: HCQ reduced the mature hERG protein in a time- and concentration-dependent manner. Correspondingly, chronic and acute treatment of HCQ decreased the hERG current. Treatment with brefeldin A (BFA) and HCQ combination reduced hERG protein to a greater extent than BFA alone. Moreover, disruption of the typical hERG binding site (hERG-p.Y652A or hERG-p.F656A) rescued HCQ-mediated hERG protein and IhERG reduction. CONCLUSION: HCQ can reduce the mature hERG channel expression and IhERG via enhancing channel degradation. The QT prolongation effect of HCQ is mediated by typical hERG binding sites involving residues Tyr652 and Phe656.

Automatic pavement texture recognition using lightweight few-shot learning.

Texture is a crucial characteristic of roads, closely related to their performance. The recognition of pavement texture is of great significance for road maintenance professionals to detect potential safety hazards and carry out necessary countermeasures. Although deep learning models have been applied for recognition, the scarcity of data has always been a limitation. To address this issue, this paper proposes a few-shot learning model based on the Siamese network for pavement texture recognition with a limited dataset. The model achieved 89.8% accuracy in a four-way five-shot task classifying the pavement textures of dense asphalt concrete, micro surface, open-graded friction course and stone matrix asphalt. To align with engineering practice, global average pooling (GAP) and one-dimensional convolution are implemented, creating lightweight models that save storage and training time. Comparative experiments show that the lightweight model with GAP implemented on dense layers and one-dimensional convolution on convolutional layers reduced storage volume by 94% and training time by 99%, despite a 2.9% decrease in classification accuracy. Moreover, the model with only GAP implemented on dense layers achieved the highest accuracy at 93.5%, while reducing storage volume and training time by 83% and 6%, respectively. This article is part of the theme issue 'Artificial intelligence in failure analysis of transportation infrastructure and materials'.

Neutrophilic granulocyte percentage is associated with anxiety in Chinese hospitalized heart failure patients.

BACKGROUND: In patients with heart failure, anxiety disorder is common and associated with adverse prognosis. This study intended to find more confounding factors of Chinese heart failure patients. METHODS: We enrolled 284 hospitalized heart failure patients, whose New York Heart Association (NYHA) classed as II-IV and left ventricular ejection fraction (LVEF) ≤ 45%. All the patients were scaled in Hamilton Rating Scale for Anxiety (14-items) (HAM-A14). Ordinal logistic regression analysis was performed to examine the association of correlated factors with anxiety disorder. RESULTS: There were 184 patients had anxiety accounting for 64.8% of all 284 hospitalized heart failure patients. The neutrophilic granulocyte percentage, urea nitrogen, total bilirubin and brain natriuretic peptide were positively associated with HAM-A14 score, meanwhile, the hemoglobin, red blood cells counts, albumin and LVEF were negatively associated with HAM-A14 score (All P < 0.05). After the adjustments of sex, hemoglobin, urea nitrogen, total bilirubin, albumin and brain natriuretic peptide, the neutrophilic granulocyte percentage was significantly associated with anxiety (OR = 43.265, P = 0.012). The neutrophilic granulocyte percentage was 0.616 ± 0.111, 0.640 ± 0.102, 0.681 ± 0.106 and 0.683 ± 0.113 in heart failure patients with no anxiety, possible anxiety, confirmed anxiety and obvious anxiety, respectively. CONCLUSIONS: Neutrophilic granulocyte percentage as well as the traditional risk factors such as sex, urea nitrogen and brain natriuretic peptide is associated with anxiety in hospitalized heart failure patients.

A Retrospective Study to Evaluate the Effect of Dynamic Fracture Mobility on Cement Leakage in Percutaneous Vertebroplasty and Percutaneous Kyphoplasty in 286 Patients with Osteoporotic Vertebral Compression Fractures.

BACKGROUND Cement leakage is the most common complication following percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures (OVCFs). Dynamic fracture mobility was determined by comparing preoperative standing lateral radiographs with intraoperative prone lateral radiographs. This retrospective study from a single center aimed to evaluate the effect of dynamic fracture mobility on cement leakage in PVP and PKP in 286 patients with OVCFs. MATERIAL AND METHODS Records of patients who underwent PVP or PKP in our department between January 2016 and December 2019 were retrospectively analyzed, showing that 156 patients received PVP and 130 patients received PKP. Variables that were significantly related to presence of cement leakage in the univariate analysis were subsequently included in a multivariate logistic regression analysis for determining the independent risk factors for cement leakage. RESULTS The univariate analysis showed that dynamic fracture mobility (P<0.001), operative approach (P=0.026), peripheral vertebrae wall damage (P<0.001), intravertebral cleft (P<0.001), and cement volume injected (P<0.001) were correlated with cement leakage. Factors that showed differences by univariate analysis underwent multivariate logistic regression analysis, showing that peripheral vertebrae wall damage (OR=11.774,95% CI 4.384-31.619, P=0.000), dynamic fracture mobility (OR=5.884, 95% CI 2.295-15.087, P=0.000), operative approach (OR=3.143, 95% CI 1.136-8.698, P=0.027), and cement volume injected (OR=1.486, 95% CI 1.119-1.973, P=0.006) were independent risk factors for postoperative cement leakage. CONCLUSIONS This retrospective study showed that dynamic fracture mobility, peripheral vertebrae wall damage, operative approach, and cement volume injected were risk factors for cement leak following PVP and PKP.

Activation of RAGE-dependent endoplasmic reticulum stress associates with exacerbated postmyocardial infarction ventricular arrhythmias in diabetes.

Association between receptor for advanced glycation end products (RAGE) and postmyocardial infarction (MI) ventricular arrhythmias (VAs) in diabetes was investigated. Correlation between premature ventricular contractions (PVCs) and serum advanced glycation end products (AGEs) content was analyzed in a cohort consisting of 101 patients with ST-segment elevated MI (STEMI). MI diabetic rats were treated with anti-receptor for AGE (RAGE) antibody. Electrocardiography was used to record VAs. Myocytes were isolated from adjacent area around infracted region. Immunofluorescent stains were used to evaluate the association between FKBP12.6 (FK506-bindingprotein 12.6) and ryanodine receptor 2 (RyR2). Calcium sparks were evaluated by confocal microscope. Protein expression and phosphorylation were assessed by Western blotting. Calcineurin (CaN) enzymatic activity and RyR2 channel activity were also determined. In the cohort study, significantly increased amount of PVC was found in STEMI patients with diabetes (P < 0.05). Serum AGE concentration was significantly positively correlated with PVC amount in patients with STEMI (r = 0.416, P < 0.001). Multivariate analysis showed that serum AGE concentration was independently and positively related to frequent PVCs (adjusted hazard ratio, 1.86; 95% CI, 1.09-3.18, P = 0.022). In the animal study, increased glucose-regulated protein 78 (GRP78) expression, protein kinase RNA-like ER kinase (PERK) phosphorylation, CaN enzymatic activity, FKBP12.6-RyR2 disassociation, RyR2 channel opening, and endoplasmic reticulum (ER) calcium releasing were found in diabetic MI animals, which were attenuated by anti-RAGE antibody treatment. This RAGE blocking also significantly lowered the VA amount in diabetic MI animals. Activation of RAGE-dependent ER stress-mediated PERK/CaN/RyR2 signaling participated in post-MI VAs in diabetes.NEW & NOTEWORTHY In this study, we proposed a possible mechanism interpreting the clinical scenario that after myocardial infarction (MI) patients were more vulnerable to ventricular arrhythmias (VAs) when complicated with diabetes. A cohort study revealed that advanced glycation end products (AGEs) accumulated in patients with diabetes and closely associated post-MI VAs. In vivo and in vitro studies indicated that receptor for AGEs (RAGE)-dependent endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK) pathway triggered VAs, via ER calcium releasing, through calcineurin/RyR2 mechanism.

CATHER: a novel threading algorithm with predicted contacts.

MOTIVATION: Threading is one of the most effective methods for protein structure prediction. In recent years, the increasing accuracy in protein contact map prediction opens a new avenue to improve the performance of threading algorithms. Several preliminary studies suggest that with predicted contacts, the performance of threading algorithms can be improved greatly. There is still much room to explore to make better use of predicted contacts. RESULTS: We have developed a new contact-assisted threading algorithm named CATHER using both conventional sequential profiles and contact map predicted by a deep learning-based algorithm. Benchmark tests on an independent test set and the CASP12 targets demonstrated that CATHER made significant improvement over other methods which only use either sequential profile or predicted contact map. Our method was ranked at the Top 10 among all 39 participated server groups on the 32 free modeling targets in the blind tests of the CASP13 experiment. These data suggest that it is promising to push forward the threading algorithms by using predicted contacts. AVAILABILITY AND IMPLEMENTATION: http://yanglab.nankai.edu.cn/CATHER/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Three-dimensional vectorcardiographic characteristics of breast cancer patients treated with chemotherapy.

BACKGROUND: Patients receiving chemotherapy for breast cancer (breast cancer) may develop cardiac electrophysiological abnormalities. The aim of this study is to examined possible alterations in cardiac electrophysiological parameters detected by three-dimensional vectorcardiograms (3D-VCGs) in breast cancer patients who received chemotherapy. METHODS: This was a prospective single-center cohort study conducted in Fourth Hospital of Hebei Medical University, China. Patients with breast cancer referred for chemotherapy from May 1, 2019, to October 1, 2019 were invited to participate in the study. 3D-VCGs and echocardiography were recorded at rest four times (baseline, after the first cycle, after third cycles and at the end of the regimen, respectively). RESULTS: A total of 63 patients were included. Compared with baseline, decreases in 3D maximum T vector magnitude (TVM) (0.29 ± 0.10 vs. 0.25 ± 0.10 mV; p < 0.05) and 3D T/QRS ratio (0.26 ± 0.11 vs. 0.21 ± 0.11; p < 0.05) were observed by the end of chemotherapy regimen, while echocardiographic parameters showed no significant variation before and after chemotherapy (all P > 0.05). Furthermore, after third cycles, maximum TVM were correlated with LVEF except in horizontal plane (3D: r = 0.33, p < 0.01; frontal plane: r = 0.34, p < 0.01; horizontal plane: r = 0.24, p = 0.06; right side plane: r = 0.30, p = 0.02). After completion of chemotherapy, maximum TVM were also positive correlated with LVEF (3D: r = 0.33, P < 0.01; frontal plane: r = 0.32, P = 0.01; horizontal plane: r = 0.27, P = 0.03, right side plane: r = 0.38, P < 0.01). CONCLUSIONS: Along with chemotherapy, maximum TVM and T/QRS is lower in patients with breast cancer. After third cycles and after completion of chemotherapy, there is a positive correlation between maximum TVM and LVEF. 3D-VCGs can be used to detect electrophysiological abnormalities in breast cancer patients receiving chemotherapy.

Analysis of medial tibial plateau fracture injury patterns using quantitative 3D measurements.

BACKGROUND: The Wahlquist system classifies tibial medial plateau fractures into three types based on the sagittal fracture line location, with type C at highest risk of complications. However, the injury mechanism of tibial medial plateau fractures, especially tibial rotation movement, remains unclear. The purpose of the present study was to determine the injury patterns of medial tibial plateau fractures using 3D model simulation and quantitative 3D measurements. METHODS: Seventy-eight consecutive AO/OTA type 41-B tibial plateau fractures were retrospectively analyzed using CT-based 3D models and quantitative 3D measurements. The knee posture at the moment of fracture occurrence was simulated, and various knee angles in the sagittal, coronal, and axial planes were measured to evaluate the mechanism of medial tibial plateau fracture. The mean valgus-varus, hyperextension-flexion, and internal-external rotation angles were determined, and the chi-square test was used for comparisons of categorical varus and valgus force data to determine the main force direction in Wahlquist type C fractures. RESULTS: Angle measurements in the coronal planes showed that 28 (35.9%) medial tibial plateau fractures resulted from a varus injury pattern, while 50 fractures (64.1%) resulted from a valgus pattern. Valgus force produced significantly more Wahlquist type C fractures (37 of 50 fractures) than varus force (2 of 28 fractures) (p < 0.05). There was no significant difference in the cases of patients with type C fractures between the tibial internal and external rotation injury patterns(P > 0.05). CONCLUSIONS: Valgus force was the cause of 64.1% of the medial tibia plateau fractures in the present cohort. Furthermore, valgus force produced more Wahlquist type C fractures than varus force. The present findings will help orthopedists understand the injury mechanism of the Wahlquist classification system, and will facilitate the identification of the common features of medial tibial plateau fractures induced by specific injury patterns.

Ear Crease Features Are Associated with Complexity of Coronary Lesions.

BACKGROUND The presence of a Frank's sign ear crease is closely correlated with coronary artery disease (CAD). The SYNTAX score indicates the complexity of coronary lesions. This present investigation sought to identify the correlation between SYNTAX score and several specific ear creases. MATERIAL AND METHODS Four specific types of ear creases - crossing crease not originated from ear hole (CC-NEH), crossing crease originated from ear hole (CC-EH), vertical creases on the face side (VC-F), and vertical creases dividing earlobe and face (VC-EF) - were investigated in patients undergoing coronary angiography. A Frank's sign score system was introduced based on the 4 creases. Demographic data, clinical data, and SYNTAX score were also documented. The association between ear creases and SYNTAX score, as well as the correlation between Frank's score and SYNTAX score, were statistically analyzed. RESULTS CC-NEH had the highest positive predictive value (positive predictive value=0.439), and VC-F had the highest negative predictive value for the detection of intermediate and high SYNTAX score (negative predictive value=1.000). VC-EF and CC-NEH were associated with intermediate and high SYNTAX scores (OR=2.913-7.694, all P<0.05). Only 2.9% of patients with Frank's score=0 had intermediate or high SYNTAX scores, and 52.2% and 50.0% of patients with Frank's sign score=3 and 4 had intermediate or high SYNTAX scores, respectively. The Frank's sign score was significantly and positively correlated with SYNTAX score (r=0.457, P<0.001). CONCLUSIONS Features of specific ear creases and Frank's sign scores were associated with intermediate and high complexity of coronary lesions.

mTM-align: a server for fast protein structure database search and multiple protein structure alignment.

With the rapid increase of the number of protein structures in the Protein Data Bank, it becomes urgent to develop algorithms for efficient protein structure comparisons. In this article, we present the mTM-align server, which consists of two closely related modules: one for structure database search and the other for multiple structure alignment. The database search is speeded up based on a heuristic algorithm and a hierarchical organization of the structures in the database. The multiple structure alignment is performed using the recently developed algorithm mTM-align. Benchmark tests demonstrate that our algorithms outperform other peering methods for both modules, in terms of speed and accuracy. One of the unique features for the server is the interplay between database search and multiple structure alignment. The server provides service not only for performing fast database search, but also for making accurate multiple structure alignment with the structures found by the search. For the database search, it takes about 2-5 min for a structure of a medium size (∼300 residues). For the multiple structure alignment, it takes a few seconds for ∼10 structures of medium sizes. The server is freely available at: http://yanglab.nankai.edu.cn/mTM-align/.

Platelets-released insulin-like growth factor 1 is correlated with anxiety in myocardial infarction.

OBJECTIVE: The aim of this study is to investigate the role of platelets in anxiety in myocardial infarction (MI). METHODS: A protein kinase D (PKD) inhibitor CRT0066101 was administrated to MI rat models. Open-field (OF) test, dark-light transfer (DLT) test and elevated plus maze (EPM) test were used to assess anxiety of animals. Platelets granule releasing was evaluated by ATP releasing assay and flow cytometry detecting CD62P. ELISA was used to measure the levels of vWF, soluble tissue factor (sTF) and IGF1 in serum. Protein phosphorylations were evaluated with western blotting. 171 patients with MI, 189 patients with stable CAD (SCAD) and 200 healthy volunteers (HV) were included in the population study. HAM-A was used to evaluate the anxiety. RESULTS: In the animal study, PKD inhibitor significantly suppressed platelets granule releasing and serum IGF1 levels (P < 0.05) in MI rats without affecting serum levels of vWF and sTF. MI rats exhibited significantly promoted anxiety-like behaviors (P < 0.05) which was attenuated by PKD inhibitor administration (P < 0.05). In the cross-sectional population study, aggravated anxiety, endothelial damage and platelets granule releasing were found in MI patients. Serum vWF (r = 0.790, P < 0.001) and sTF (r = 0.510, P < 0.001) were significantly correlated with platelets granule releasing. Platelets granule releasing was correlated with serum IGF1 level (r = 0.872, P < 0.001). Anxiety was significantly and positively correlated with platelet granule releasing (r = 0.752, P < 0.001), serum vWF (r = 0.790, P < 0.001), serum sTF (r = 0.510, P < 0.001) and serum IGF1 (r = 0.774, P < 0.001) levels. Multivariate analysis identified platelet activation (OR = 1.58, 95% CI 1.07-2.32, P = 0.022) and IGF1 serum level (OR = 1.05 95% CI 1.04-1.06, P < 0.001) were significantly and positively correlated with anxiety in MI patients after adjustments. CONCLUSIONS: Anxiety is exacerbated in MI via endothelial damage-induced platelets granule releasing-mediated IGF1.

Association Between the Lipid Profile and Renal Dysfunction in the Heart Failure Patients.

BACKGROUND/AIMS: In heart failure patients with high prevalence of chronic renal disease (CKD), hospitalization and mortality, whether the lipid profile was associated with renal dysfunction remained unknown. The present study intended to clarify the association between the lipid profile and renal dysfunction in the heart failure patients. METHODS: 336 hospitalized heart failure patients with left ventricle ejection fraction (LVEF) ≤45% and New York Heart Association (NYHA) class II-IV were enrolled. The estimated glomerular filtration rate (eGFR) < 90 mL/min·1.73 m2 was defined as renal dysfunction. The demographic, clinical data, blood samples and echocardiography were documented. The Pearson simple linear correlation was performed to evaluate the confounding factors correlated with eGFR. The significantly correlated factors were enrolled in Logistic regression as confounding factors to determine the association between the lipid profile and renal dysfunction in the heart failure patients. RESULTS: 182 patients (54.2%) had renal dysfunction and 154 patients (45.8%) did not have renal dysfunction. The waist circumference, platelet counts, platelet distribution width (PDW), high density lipoprotein-cholesterol (HDL-C), apolipoprotein A1 (apoA1), albumin and left ventricular ejection fraction (LVEF) are positively correlated with eGFR (all P< 0.05). Meanwhile, the age, mean platelet volume (MPV), neutrophilic granulocyte percentage (NEUT%), urea nitrogen (BUN), creatinine and total bilirubin (TBIL) are negatively correlated with eGFR (all P< 0.05). The total cholesterol (TC), triglyceride, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) show no correlation with eGFR. After the adjustment of sex, hypertension, diabetes mellitus, age, waist circumference, platelet counts, MPV, PDW, NEUT%, TBIL, albumin and LVEF, HDL-C is the only lipid factor still significantly associated with renal dysfunction in hospitalized heart failure patients (OR=0.119, P=0.003). CONCLUSION: Among the lipid profile of TC, triglyceride, LDL-C, HDL-C, apo A1 and apo B, the HDL-C is the only lipid factor significantly associated with renal dysfunction in hospitalized heart failure patients.

Apolipoprotein A1 is associated with SYNTAX score in patients with a non-ST segment elevation myocardial infarction.

BACKGROUND: The study was designed to investigate lipid profile and SYNTAX score in patients with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: 311 patients with NSTEMI were enrolled. The demographic, clinical data, blood samples and SYNTAX score were documented. The Pearson linear correlation was used to detect confounding factors linearly correlated with SYNTAX score. The significantly correlated confounding factors were put into the multiple linear regressions. RESULTS: The Pearson linear correlation showed that high-density lipoprotein- cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) were significantly correlated with Syntax Score (r = - 0.119, P = 0.044 and r = - 0.182, P = 0.002, respectively). The multiple linear regressions for Syntax Score were built using HDL-C and ApoA1, respectively. After the adjustment of other significantly correlated confounding factors such as white blood cell count (WBC), myohemoglobin (MB), glutamic-oxalacetic transaminase (AST) and creatinine, the ApoA1 still showed significant association with Syntax Score (ß = - 0.151, P = 0.028). The area under curve was (AUC) 0.624 and the optimal cutoff value is 1.07 g/L when using ApoA1 to predict moderate and severe coronary artery lesions. The patients with ApoA1 ≥ 1.07 g/L and < 1.07 g/L have the Syntax Scores of 12.21 ± 11.58 and 16.33 ± 11.53, respectively (P = 0.001). CONCLUSIONS: The ApoA1 is the only lipid factor significantly associated with complexity of coronary artery lesion in patients with NSTEMI, the patients with ApoA1 < 1.07 g/L may have more complex coronary artery lesions.

Sfrp1 attenuates TAC-induced cardiac dysfunction by inhibiting Wnt signaling pathway- mediated myocardial apoptosis in mice.

BACKGROUND: Hemodynamic overload causes cardiac hypertrophy leading to heart failure. Wnt signaling pathway was reported activated in heart failure. Secreted frizzled related protein 1 (Sfrp1) is a suppressor of Wnt signaling activation. The aim of the present study was to investigate the protective effect of Sfrp1 on hemodynamic overload- induced cardiac dysfunction. METHODS: A mice transverse aortic constriction (TAC)- induced heart failure model was established. A recombinant adeno-associated virus 9 (AAV9) vector was used to deliver Sfrp1 gene into myocardium. Fluorescence and immunohistochemistry staining was used to evaluate the effectiveness of viral vector delivery. Invasive hemodynamic examination was used to evaluate cardiac systolic and diastolic functions. Myocardium apoptosis was detected by TUNEL assay. The expression levels of Sfrp1, ß-catenin, caspase3, Bax, Bcl-2 and c-Myc were measured by Western blotting. RESULTS: Increased mean arterial pressure and impaired cardiac function confirmed the establishment of TAC model. Sfrp1 protein expression was effectively increased in myocardium of mice treated with AAV9-Sfrp1 viral vector. The viral vector administration improved both systolic and diastolic cardiac functions by reducing myocardial apoptosis in TAC mice. The expression levels of ß-catenin, caspase3 and Bax were significantly reduced while the expression levels of Bcl-2 and c-Myc were dramatically increased in myocardium by the viral vector treatment in TAC mice. CONCLUSIONS: AAV9 viral vector delivered sfrp1 expression gene into myocardium, which attenuated TAC-induced cardiac dysfunction by inhibiting Wnt signaling pathway activation- mediated apoptosis.

Influence of different great trochanteric entry points on the outcome of intertrochanteric fractures: a retrospective cohort study.

BACKGROUND: The Proximal Femoral Nail Antirotation (PFNA) system for treatment of intertrochanteric fractures is currently widely applied worldwide. However, even though the PFNA has produced good clinical outcomes, a poor introduction technique with an inappropriate entry point can cause surgical complications. Some researchers suggest improving clinical outcomes by modifying the entry point, but no research has focused on this issue. The purpose of the present study is to compare the clinical and radiological outcomes of two different trochanteric entry points for the treatment of intertrochanteric fractures using the PFNA system. METHODS: From May 2010 to October 2015, a total of 212 elderly patients with intertrochanteric fractures who were treated with the PFNA-II system were included into this retrospective cohort study. Group LA (98 patients) was treated using a lateral anterior trochanteric entry point, and group MP (114 patients) was treated using a medial posterior trochanteric entry point. All patients underwent follow-up assessments at 1, 3, 6, and 12 months after surgery. Radiographic evaluation was based on the impingement, tip-apex distance (TAD) and the position of the helical blade within the femoral head. Clinical evaluation was based on the surgical time, fluoroscopy time, blood loss, hospital stay, visual analogue scale (VAS), thigh pain, and Harris hip score. RESULTS: The impingement was significantly reduced (P = 0.011) in group MP. The helical blade positions were significantly lower (P = 0.001) in group MP. The TADs in group LA (22.40 ± 4.43) and group MP (23.39 ± 3.60) were not significantly different (P = 0.075). The fluoroscopy time of group LA (53.26 ± 14.44) was shorter than that of group MP (63.29 ± 11.12, P = 0.000). Five iatrogenic lateral proximal fractures and 3 helical blade cutouts occurred in group LA, but none occurred in group MP. At 1 and 3 months postoperation, the Harris hip scores were significantly higher in group MP (P = 0.001 and P = 0.000, respectively), and the VAS scores were lower (P < 0.05). CONCLUSIONS: The medial posterior trochanteric entry point achieved excellent nail and helical blade position, reduced surgical complications, and enabled early hip function recovery but required longer fluoroscopy time than the lateral anterior trochanteric entry point.

Increasing the efficiency of CRISPR/Cas9-mediated precise genome editing in rats by inhibiting NHEJ and using Cas9 protein.

Precise modifications such as site mutation, codon replacement, insertion or precise targeted deletion are needed for studies of accurate gene function. The CRISPR/Cas9 system has been proved as a powerful tool to generate gene knockout and knockin animals. But the homologous recombination (HR)-directed precise genetic modification mediated by CRISPR/Cas9 is relatively lower compared with nonhomologous end-joining (NHEJ) pathway and extremely expected to be improved. Here, in this study 2 strategies were used to increase the precise genetic modification in rats. Scr7, a DNA ligase IV inhibitor, first identified as an anti-cancer compound, and considered as a potential NHEJ inhibitor, was used to increase the HR-mediated precise genetic modification. Meanwhile, the Cas9 protein instead of mRNA was used to save the mRNA to protein translation step to improve the precise modification efficiency. The Fabp2 and Dbndd1 loci were selected to knockin Cre and CreER(T2), respectively. Our result showed that both Scr7 and Cas9 protein can increase the precise modification.

Effects of Salt Loading on Plasma Osteoprotegerin Levels and Protective Role of Potassium Supplement in Normotensive Subjects.

BACKGROUND: Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects on cardiovascular disorders. In epidemiological studies, increased plasma osteoprotegerin (OPG) concentrations are associated with atherosclerosis and vascular deaths. Our study was designed to examine the effects of salt intake and potassium supplementation on plasma OPG levels in normotensive subjects.Methods and Results:The 18 normotensive subjects were selected from a rural community in China. They were sequentially maintained on low-salt diet for 7 days (3 g/day, NaCl), high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for 7 days (18 g/day of NaCl+4.5 g/day of KCl). High-salt intake enhanced plasma OPG levels (252.7±13.9 vs. 293.4±16.1 pg/mL). This phenomenon was abolished through potassium supplementation (293.4±16.1 vs. 235.1±11.3 pg/mL). Further analyses revealed that the OPG concentration positively correlated with 24-h urinary sodium excretion (r=0.497, P<0.01). By contrast, OPG concentration negatively correlated with 24-h urinary potassium excretion (r=0.594, P<0.01). CONCLUSIONS: Salt loading can enhance the production of circulating OPG. Potassium supplementation can reverse the effects of excessive OPG. Our study results may improve our understanding of the roles of salt and potassium in the risk of cardiovascular disorders.