Expansion and differentiation of human neural stem cells on synthesized integrin binding peptide surfaces.

The extracellular matrix plays a crucial role in the growth of human neural stem cells (hNSCs) by forming a stem cell niche, both in vitro and in vivo. The demand for defined synthetic substrates has been increasing recently in stem cell research, reflecting the requirements for precise functions and safety concerns in potential clinical approaches. In this study, we tested the adhesion and expansion of one of the most representative hNSC lines, the ReNcell VM Human Neural Progenitor Cell Line, in a pure-synthesized short peptide-based in vitro niche using a previously established integrin-binding peptide array. Spontaneous cell differentiation was then induced using two different in vitro approaches to further confirm the multipotent features of cells treated with the peptides. Twelve different integrin-binding peptides were capable of supporting hNSC adhesion and expansion at varied proliferation rates. In the ReNcell medium-based differentiation approach, cells detached in almost all peptide-based groups, except integrin α5ß1 binding peptide. In an altered differentiation process induced by retinoic acid containing neural differentiation medium, cell adhesion was retained in all 12 peptide groups. These peptides also appeared to have varied effects on the differentiation potential of hNSCs towards neurons and astrocytes. Our findings provide abundant options for the development of in vitro neural stem cell niches and will help develop promising tools for disease modeling and future stem cell therapies for neurological diseases.

Leaf Traits Explain the Growth Variation and Nitrogen Response of Eucalyptus urophylla × Eucalyptus grandis and Dalbergia odorifera in Mixed Culture.

Mixed cultivation with legumes may alleviate the nitrogen (N) limitation of monoculture Eucalyptus. However, how leaf functional traits respond to N in mixed cultivation with legumes and how they affect tree growth are unclear. Thus, this study investigated the response of leaf functional traits of Eucalyptus urophylla × Eucalyptus grandis (E. urophylla × E. grandis) and Dalbergia odorifera (D. odorifera) to mixed culture and N application, as well as the regulatory pathways of key traits on seedling growth. In this study, a pot-controlled experiment was set up, and seedling growth indicators, leaf physiology, morphological parameters, and N content were collected and analyzed after 180 days of N application treatment. The results indicated that mixed culture improved the N absorption and photosynthetic rate of E. urophylla × E. grandis, further promoting seedling growth but inhibiting the photosynthetic process of D. odorifera, reducing its growth and biomass. Redundancy analysis and path analysis revealed that leaf nitrogen content, pigment content, and photosynthesis-related physiological indicators were the traits most directly related to seedling growth and biomass accumulation, with the net photosynthetic rate explaining 50.9% and 55.8% of the variation in growth indicators for E. urophylla × E. grandis and D. odorifera, respectively. Additionally, leaf morphological traits are related to the trade-off strategy exhibited by E. urophylla × E. grandis and D. odorifera based on N competition. This study demonstrated that physiological traits related to photosynthesis are reliable predictors of N nutrition and tree growth in mixed stands, while leaf morphological traits reflect the resource trade-off strategies of different tree species.

Asiatic acid and madecassic acid cause cardiotoxicity via inflammation and production of excessive reactive oxygen species in zebrafish.

Centella asiatica (L.) Urban is a famous Chinese traditional medicine, which is widely used for treating various chronic inflammatory diseases. Although there are reports that Centella total glycosides exhibit heart-protective properties, our previous experiment showed that it has cardiac toxic effects in zebrafish. The components of Centella total glycosides are complex, so we recommend further research to determine their key components and mechanisms. In this study, sample quantification was done using liquid chromatography-tandem mass spectrometry. The cardiotoxicity of Centella total glycosides, asiaticoside, madecassoside, asiatic acid, and madecassic acid was evaluated using zebrafish and cell models. The zebrafish oxidative stress model and myocarditis model were used to explore further the mechanisms through which cardiotoxicity is achieved. Asiatic acid and madecassic acid caused zebrafish cardiotoxicity and H9C2 cell death. However, no toxicity effects were observed for asiaticoside and madecassoside in zebrafish, until the solution was saturated. The results from the cell model study showed that asiatic acid and madecassic acid changed the expression of apoptosis-related genes in myocardial cells. In the zebrafish model, high concentrations of these components raised the levels of induced systemic inflammation, neutrophils gathered in the heart, and oxidative stress injury. Asiatic acid and madecassic acid are the main components causing cardiotoxicity in zebrafish. This may be due to enhanced inflammation and reactive oxygen species injury, which causes myocardial cell apoptosis, which further leads to cardiac toxicity.

A comparative study on the clinical efficacy of percutaneous endoscopic lumbar discectomy and conventional open surgery in the treatment of lumbar disc herniation.

Objective: To analyze the efficacy of single-channel percutaneous endoscopic lumbar discectomy (PELD) and conventional open surgery in the treatment of lumbar disc herniation (LDH). Methods: This is a retrospective study. A total of 66 patients with LDH admitted to Tianjin Medical University from June 2017 to June 2018 were divided into two groups: the observation group (single-channel PELD) and the control group (posterior lumbar interbody fusion), with 33 cases in each group. The two groups were compared in terms of visual analogue scale(VAS), oswestry disability index (ODI), Japanese Orthopaedic Association Score(JOA), perioperative indicators, clinical efficacy, postoperative complications, changes in inflammatory factors and serum T lymphocyte subsets. Results: The operation time, incision length, intraoperative blood loss, time in bed, hospital stay in the observation group were all lower than those in the control group. At 7d after treatment, the improvement of ODI, VAS and JOA in the observation group were better than that in the control group. At the last follow-up, there was no significant difference in Cobb angle and lumbar lordosis angle between the two groups. The levels of serum IL-1, IL-6 and TNF-α in the observation group were lower than those in the control group. The degree of reduction of serum CD3+ and CD4+ in the observation group were higher than those in the control group. And the level of elevation of CD8+ in the observation group was lower than that in the control group. Moreover, there was no significant difference in CD4+/CD8+ level between the two groups. The excellent rate of surgical results in the observation group was higher than that in the control group. Complications occurred in both groups, with no significant difference between the two groups. Conclusions: Single-channel PELD can achieve superior clinical efficacy over conventional open surgery in the treatment of LDH.

LINC01559 promotes lung adenocarcinoma metastasis by disrupting the ubiquitination of vimentin.

BACKGROUND: Distant metastasis is the major cause of lung adenocarcinoma (LUAD)-associated mortality. However, molecular mechanisms involved in LUAD metastasis remain to be fully understood. While the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance is being increasingly appreciated, the list of dysregulated lncRNAs that contribute to LUAD pathogenesis is also rapidly expanding. METHODS: Bioinformatics analysis was conducted to interrogate publicly available LUAD datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human LUAD tissues and cell lines, respectively. Wound healing as well as transwell migration and invasion assays were employed to examine LUAD cell migration and invasion in vitro. LUAD metastasis was examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were carried out to test RNA-protein associations. Cycloheximide-chase assays were performed to monitor protein turnover rates and Western blotting was employed to test protein expression. RESULTS: The expression of the lncRNA LINC01559 was commonly upregulated in LUADs, in particular, in those with distant metastasis. High LINC01559 expression was associated with poor outcome of LUAD patients and was potentially an independent prognostic factor. Knockdown of LINC01559 diminished the potential of LUAD cell migration and invasion in vitro and reduced the formation of LUAD metastatic lesions in vivo. Mechanistically, LINC01559 binds to vimentin and prevents its ubiquitination and proteasomal degradation, leading to promotion of LUAD cell migration, invasion, and metastasis. CONCLUSION: LINC01559 plays an important role in LUAD metastasis through stabilizing vimentin. The expression of LINC01559 is potentially an independent prognostic factor of LUAD patients, and LINC01559 targeting may represent a novel avenue for the treatment of late-stage LUAD.

Intracardiac echocardiography guided electrified J-wire trans-septal puncture: A prospective randomized controlled trial.

BACKGROUND: Application of electrocautery to a J-wire is used to perform transseptal puncture (TSP), but with limited evidence supporting safety and efficacy. We conducted a prospective randomized controlled trial to evaluate the safety and efficacy of this technique. METHODS: Two hundred consecutive patients were randomized in a 1:1 fashion to either the ICE-guided electrified J-wire TSP group or a conventional Brockenbrough (BRK) needle TSP group. The TSP was performed with a 0.032″ guidewire under 20 W, "coag" mode and was compared to TSP using the BRK needle. The primary safety endpoints were complications related to TSP. The primary efficacy endpoints included the TSP success rate, the total TSP time, and the total procedure time. RESULTS: All patients complete the procedure safely. The electrified J-wire TSP group had a significantly shorter TSP time than BRK needle TSP group. The total procedure time, number of TSP attempts required to achieve successful LA access, width of the intra-atrial shunt at the end of ablation were similar between the two groups. The incidence of new cerebral infarction detected by MRI were similar between the two groups (3/32 patients in the J-wire TSP group and 2/26 patients in conventional BRK TSP group, p = .82). And no difference in the incidence of residual intra-atrial shunt (4.3% vs. 6%, p = .654) during the 3-month's follow up. CONCLUSION: Using an electrified J-wire for TSP under the guidance of ICE appears to be as safe as and more efficient than conventional BRK needle TSP, which may be especially useful in the era of non-fluoroscopy AF ablation.

Fecal calprotectin: A novel predictor of ulcerated esophageal injury after atrial fibrillation catheter ablation.

BACKGROUND: Atrial esophageal fistula (AEF) is a lethal complication that can occur post atrial fibrillation (AF) ablation. Esophageal injury (EI) is likely to be the initial lesion leading to AEF. Endoscopic examination is the gold standard for a diagnosis of EI but extensive endoscopic screening is invasive and costly. This study was conducted to determine whether fecal calprotectin (Fcal), a marker of inflammation throughout the intestinal tract, may be associated with the existence of esophageal injury. METHODS: This diagnostic study was conducted in a cohort of 166 patients with symptomatic AF undergoing radiofrequency catheter ablation from May 2020 to June 2021. Fcal tests were performed 1-7 days after ablation. All patients underwent endoscopic ultrasonography 1 or 2 days after ablation. RESULTS: The levels of Fcal were significantly different between the EI and non-EI groups (404.9 µg/g (IQR 129.6-723.6) vs. 40.4 µg/g (IQR 15.0-246.2), p < .001). Analysis of ROC curves revealed that a Fcal level of 125 µg/g might be the optimal cut-off value for a diagnosis of EI, giving a 78.8% sensitivity and a 65.4% specificity. The negative predictive value of Fcal was 100% for ulcerated EI. CONCLUSIONS: The level of Fcal is associated with EI post AF catheter ablation. 125 µg/g might be the optimal cut-off value for a diagnosis of EI. Negative Fcal could predict the absence of ulcerated EI, which could be considered a precursor to AEF.

Use of intracardiac echocardiography in vein of Marshall ethanol infusion for ablation of persistent atrial fibrillation.

BACKGROUND: Few methods have been reported to demonstrate real-time effects during vein of Marshall (VOM) ethanol infusion in persistent atrial fibrillation (PeAF). OBJECTIVE: This study was to evaluate the impact of left atrial (LA) monitoring using intracardiac echocardiography (ICE) during VOM ethanol infusion. METHODS: Seventy-four consecutive patients with PeAF who underwent VOM ethanol infusion followed by radiofrequency (RF) ablation were included. Patients with findings on ICE consistent with echogenic streaming in the LA and with increased myocardial local echogenicity along the VOM area were placed into one group (group A) and those without into the other group (group B). Outcomes between the 2 groups were compared. RESULTS: Forty-six patients (62%) were placed into group A. A new ethanol-induced low-voltage area in group A was larger than that in group B (8.5 cm2 [5.5-10.2 cm2] and 4.0 cm2 (2.4-6.3 cm2]; P < .001). The RF ablation time required to achieve MI block was reduced in group A patients (263.0 seconds [196.0-351.0 seconds] vs 417.0 seconds [315.0-709.5 seconds] in group B patients; P < .001). MI block was achieved in 46 patients (100%) via an endocardial approach in group A and 27 patients (96.4%) in group B (extra coronary sinus ablation in 4 patients). One patient developed clinically significant pericardial effusions and required pericardiocentesis in group B. CONCLUSION: Presence of increased myocardial local echogenicity at the ridge and consistent echogenic streaming in the LA detected by ICE-based imaging during VOM ethanol infusion suggests increased ablated tissue in that region and lower RF ablation time during ablation for PeAF.

Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.

Left atrial appendage occlusion using the LAmbre device in atrial fibrillation patients with a history of ischemic stroke: 1-Year outcomes from a multicenter study in China.

BACKGROUND: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke have a significantly higher risk of stroke recurrence. This study aimed to examine the safety and efficacy of the LAmbre left atrial appendage occlusion device in NVAF patients with a history of stroke. METHODS: We examined 103 consecutive NVAF patients in 11 Chinese medical centers who had a history of stroke or transient ischemic attacks (TIA) and underwent placement of the LAmbre device. Follow-up was conducted 1, 3, 6, and 12 months after the procedure. The primary endpoints were the incidence of new ischemic or hemorrhagic stroke, TIA, systemic embolism, or cardiac death. Secondary endpoints were serious perioperative or device-related complications and cerebral, gastrointestinal, or other bleeding events requiring transfusion of at least 2 units of packed red blood cells. RESULTS: Mean patient age was 67.63 ± 7.14 years; mean CHA2DS2-VASc score was 4.72 ± 1.18 and mean HAS-BLED score was 1.90 ± 1.00. LAmbre device placement was successful in 101 patients (98.05%). Mean follow-up was 12.2 months. Five patients (4.95%) developed a new pericardial effusion after the procedure; none required treatment. Eighty-six patients (85.15%) exhibited no peri-device leak (PDL). However, 13 (12.8%) had a small (0-3 mm) PDL and two (2.3%) had a moderate PDL (3-5 mm). One recurrent stroke occurred during follow-up (1.1%). No other complications occurred. CONCLUSIONS: This multicenter study shows the safety and efficacy of LAmbre left atrial appendage occlusion for NVAF patients with a history of stroke or TIA.

SNHG3/WISP2 Axis Promotes Hela Cell Migration and Invasion via Activating Wnt/ß-Catenin Signaling.

BACKGROUND/AIM: Cervical cancer (CC) poses a significant threat to women's health and has a relatively poor prognosis due to local invasion and metastasis. It is, therefore, crucial to elucidate the molecular mechanisms of CC metastasis. SNHG3 has been implicated in various tumor metastasis processes, but its involvement in CC has not been thoroughly studied. Our study aimed to investigate the role of SNHG3 in metastasis and elucidate its underlying mechanisms in CC. MATERIALS AND METHODS: LncRNA SNHG3 expression in CC tissues was analyzed using TCGA and GSE27469 databases. Normal cervical epithelial cells and CC cell lines were used to detect mRNA expression of SNHG3 via quantitative reverse transcription polymerase chain reaction (qRT-PCR). With RNA interference (RNAi) technology, antisense oligonucleotides (ASO) can act on HeLa cells to knockdown target gene expression. The influence of SNHG3 on cell migration and invasion were determined by wound healing and transwell assays. Transcriptome sequencing (RNA-seq) was used to seek abnormally expressed genes between SNHG3 knockdown cells and control cells. The expressions of epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin signaling related proteins were detected using western blot. RESULTS: SNHG3 was obviously up-regulated in CC tissues and cell lines, and ectopic expression of SNHG3 was associated with lymph node metastasis of CC. Knockdown of SNHG3 significantly inhibited cell migration and invasion in CC. Further molecular mechanism studies showed that SNHG3 knockdown could down-regulate the expression of WNT1 Inducible Signaling Pathway Protein 2 (WISP2) so as to inhibit the activation of the Wnt/ß-catenin signaling pathway, and regulated the expression of EMT-related markers, that promoted the protein expression of E-cadherin, as well as decreased the expression of N-cadherin and vimentin. CONCLUSION: SNHG3 appears to exert a pro-metastatic effect in CC, as evidenced by inhibition of cell migration and invasion upon SNHG3 knockdown. EMT also appears to be attenuated. Of interest is the down-regulation of WISP2 following SNHG3 knockdown leads to the inactivation of the Wnt/ß-catenin signaling pathway.

Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/ß-catenin signaling in SCN5A-related Brugada syndrome.

BACKGROUND: Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/ß-catenin signaling has been recently established. However, the role of Wnt/ß-catenin signaling in BrS and underlying mechanisms remains unknown. METHODS: Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp. RESULTS: BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/ß-catenin signaling. Notably, inhibition of Wnt/ß-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with ß-catenin, and reduced expression of Nav1.5 leads to re-localization of ß-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/ß-catenin signaling to suppress SCN5A transcription. CONCLUSIONS: Our findings suggest that aberrant activation of Wnt/ß-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/ß-catenin as a potential therapeutic target.

Patient-specific iPSC-derived cardiomyocytes reveal variable phenotypic severity of Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the genotype-phenotype correlations are not completely matched. Clinical phenotypes of a particular SCN5A variant may range from asymptomatic to SCD. Here, we used comparison of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from a SCN5A mutation-positive (D356Y) BrS family with severely affected proband, asymptomatic mutation carriers (AMCs) and healthy controls to investigate this variation. METHODS: 26 iPSC lines were generated from skin fibroblasts using nonintegrated Sendai virus. The generated iPSCs were differentiated into cardiomyocytes using a monolayer-based differentiation protocol. FINDINGS: D356Y iPSC-CMs exhibited increased beat interval variability, slower depolarization, cardiac arrhythmias, defects of Na+ channel function and irregular Ca2+ signaling, when compared to controls. Importantly, the phenotype severity observed in AMC iPSC-CMs was milder than that of proband iPSC-CMs, an observation exacerbated by flecainide. Interestingly, the iPSC-CMs of the proband exhibited markedly decreased Ca2+ currents in comparison with control and AMC iPSC-CMs. CRISPR/Cas9-mediated genome editing to correct D356Y in proband iPSC-CMs effectively rescued the arrhythmic phenotype and restored Na+ and Ca2+ currents. Moreover, drug screening using established BrS iPSC-CM models demonstrated that quinidine and sotalol possessed antiarrhythmic effects in an individual-dependent manner. Clinically, venous and oral administration of calcium partially reduced the malignant arrhythmic events of the proband in mid-term follow-up. INTERPRETATION: Patient-specific and genome-edited iPSC-CMs can recapitulate the varying phenotypic severity of BrS. Our findings suggest that preservation of the Ca2+ currents might be a compensatory mechanism to resist arrhythmogenesis in BrS AMCs. FUNDING: National Key R&D Program of China (2017YFA0103700), National Natural Science Foundation of China (81922006, 81870175), Natural Science Foundation of Zhejiang Province (LD21H020001, LR15H020001), National Natural Science Foundation of China (81970269), Key Research and Development Program of Zhejiang Province (2019C03022) and Natural Science Foundation of Zhejiang Province (LY16H020002).

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Chinese expert consensus on the construction of the fluoroless cardiac electrophysiology laboratory and related techniques.

Transcatheter radiofrequency ablation has been widely introduced for the treatment of tachyarrhythmias. The demand for catheter ablation continues to grow rapidly as the level of recommendation for catheter ablation. Traditional catheter ablation is performed under the guidance of X-rays. X-rays can help display the heart contour and catheter position, but the radiobiological effects caused by ionizing radiation and the occupational injuries worn caused by medical staff wearing heavy protective equipment cannot be ignored. Three-dimensional mapping system and intracardiac echocardiography can provide detailed anatomical and electrical information during cardiac electrophysiological study and ablation procedure, and can also greatly reduce or avoid the use of X-rays. In recent years, fluoroless catheter ablation technique has been well demonstrated for most arrhythmic diseases. Several centers have reported performing procedures in a purposefully designed fluoroless electrophysiology catheterization laboratory (EP Lab) without fixed digital subtraction angiography equipment. In view of the lack of relevant standardized configurations and operating procedures, this expert task force has written this consensus statement in combination with relevant research and experience from China and abroad, with the aim of providing guidance for hospitals (institutions) and physicians intending to build a fluoroless cardiac EP Lab, implement relevant technologies, promote the standardized construction of the fluoroless cardiac EP Lab.

False Tendons in the Left Ventricle: Implications for Successful Ablation of Left Posterior Fascicular Tachycardias.

BACKGROUND: The anatomical substrate for left posterior fascicular ventricular tachycardia (LPF-VT) is still unclear. OBJECTIVES: The purpose of this study is to describe the endocavitary substrate of the re-entrant loop of LPF-VT. METHODS: A total of 26 consecutive patients with LPF-VT underwent an electrophysiology study and radiofrequency ablation. RESULTS: Intracardiac echocardiography imaging observed a 100% prevalence of false tendons (FTs) at the left posterior septal region in all patients, and 3 different types of FTs could be classified according to their location. In 22 patients, a P1 potential could be recorded via the multielectrode catheter from a FT. In 4 patients without a recorded P1 during LPF-VT, the earliest P2 potentials were recorded from a FT in 3 patients, and from a muscular connection between 2 posteromedial papillary muscles in 1 patient. Catheter ablation focused on the FTs with P1 or earliest P2 (in patients without P1) was successful in all 26 patients. After 19 ± 8.5 months of follow-up, no patients had recurrence of LPF-VT. CONCLUSIONS: FTs provide an electroanatomical substrate for LPF-VT and a "culprit FT" may be identified as the critical structure bridging the macro-re-entrant loop. Targeting the "culprit FT" is a novel anatomical ablation strategy that results in long-term arrhythmia-free survival.

Deep learning-derived 12-lead electrocardiogram-based genotype prediction for hypertrophic cardiomyopathy: a pilot study.

Objective: Given the psychosocial and ethical burden, patients with hypertrophic cardiomyopathy (HCMs) could benefit from the establishment of genetic probability prior to the test. This study aimed to develop a simple tool to provide genotype prediction for HCMs.Methods: A convolutional neural network (CNN) was built with the 12-lead electrocardiogram (ECG) of 124 HCMs who underwent genetic testing (GT), externally tested by predicting the genotype on another HCMs cohort (n = 54), and compared with the conventional methods (the Mayo and Toronto score). Using a third cohort of HCMs (n = 76), the role of the network in risk stratification was explored by calculating the sudden cardiac death (SCD) risk scorers (HCM risk-SCD) across the predicted genotypes. Score-CAM was employed to provide a visual explanation of the network.Results: Overall, 80 of 178 HCMs (45%) were genotype-positive. Using the 12-lead ECG as input, the network showed an area under the curve (AUC) of 0.89 (95% CI, 0.83-0.96) on the test set, outperforming the Mayo score (0.69 [95% CI, 0.65-0.78], p < 0.001) and the Toronto score (0.69 [95% CI, 0.64-0.75], p < 0.001). The network classified the third cohort into two groups (predicted genotype-negative vs. predicted genotype-positive). Compared with the former, patients predicted genotype-positive had a significantly higher HCM risk-SCD (0.04 ± 0.03 vs. 0.03 ± 0.02, p <0.01). Visualization indicated that the prediction was heavily influenced by the limb lead.Conclusions: The network demonstrated a promising ability in genotype prediction and risk assessment in HCM.

Patients with genotype-positive hypertrophic cardiomyopathy (HCM) have a higher risk of severe heart failure and sudden cardiac death (SCD). A deep learning-derived 12-lead electrocardiogram was developed, outperformed the conventional methods in genotype prediction, and showed a promising future in SCD risk assessment in HCM.

ArhGAP11A mediates amyloid-ß generation and neuropathology in an Alzheimer's disease-like mouse model.

Amyloid-ß (Aß) plays an important role in the neuropathology of Alzheimer's disease (AD), but some factors promoting Aß generation and Aß oligomer (Aßo) neurotoxicity remain unclear. We here find that the levels of ArhGAP11A, a Ras homology GTPase-activating protein, significantly increase in patients with AD and amyloid precursor protein (APP)/presenilin-1 (PS1) mice. Reducing the ArhGAP11A level in neurons not only inhibits Aß generation by decreasing the expression of APP, PS1, and ß-secretase (BACE1) through the RhoA/ROCK/Erk signaling pathway but also reduces Aßo neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of the ArhGAP11A level in neurons significantly reduces Aß production and plaque deposition and ameliorates neuronal damage, neuroinflammation, and cognitive deficits. Moreover, Aßos enhance ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle. Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis and that decreasing ArhGAP11A expression may be a promising therapeutic strategy for AD treatment.

MiR-138-5p inhibits prostate cancer cell proliferation and chemoresistance by targeting APOBEC3B.

Docetaxel is one of the most commonly used drugs in prostate cancer (PCa) chemotherapy, but its therapeutic effect in PCa is usually limited due to its drug resistance. APOBEC3B is a DNA cytosine deaminase that can alter biological processes, including chemoresistance. APOBEC3B is upregulated in various cancers. However, the biological function and underlying regulation of APOBEC3B in PCa remain unclear. In this study, we explored the role of APOBEC3B in PCa chemoresistance and the molecular mechanism of its dysregulated expression. Our results revealed that APOBEC3B was upregulated in PCa docetaxel-resistant cells, while its knockdown significantly repressed cell proliferation and docetaxel resistance of PCa cells. Bioinformatics and luciferase report analysis showed that miR-138-5p targeted APOBEC3B. In addition, miR-138-5p overexpression impeded cell proliferation and docetaxel resistance in PCa, while miR-138-5p inhibitors reversed this process. Further studies showed that upregulation of APOBEC3B expression in docetaxel-resistant cells overexpressing miR-138-5p could desensitize PCa cells to docetaxel treatment. Taken together, miR-138-5p regulates PCa cell proliferation and chemoresistance by targeting the 3'-UTR of APOBEC3B, which may provide novel insights and therapeutic targets for the treatment of PCa.