Coxsackievirus group B3 regulates ASS1-mediated metabolic reprogramming and promotes macrophage inflammatory polarization in viral myocarditis.

Coxsackievirus group B3 (CVB3) belongs to the genus Enteroviruses of the family Picornaviridae and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, and then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for treating this disease. IMPORTANCE: Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3, and discovered the therapeutic potential of citrulline for VMC.

DRONet: effectiveness-driven drug repositioning framework using network embedding and ranking learning.

As one of the most vital methods in drug development, drug repositioning emphasizes further analysis and research of approved drugs based on the existing large amount of clinical and experimental data to identify new indications of drugs. However, the existing drug repositioning methods didn't achieve enough prediction performance, and these methods do not consider the effectiveness information of drugs, which make it difficult to obtain reliable and valuable results. In this study, we proposed a drug repositioning framework termed DRONet, which make full use of effectiveness comparative relationships (ECR) among drugs as prior information by combining network embedding and ranking learning. We utilized network embedding methods to learn the deep features of drugs from a heterogeneous drug-disease network, and constructed a high-quality drug-indication data set including effectiveness-based drug contrast relationships. The embedding features and ECR of drugs are combined effectively through a designed ranking learning model to prioritize candidate drugs. Comprehensive experiments show that DRONet has higher prediction accuracy (improving 87.4% on Hit@1 and 37.9% on mean reciprocal rank) than state of the art. The case analysis also demonstrates high reliability of predicted results, which has potential to guide clinical drug development.

A high heterozygosity genome assembly of Aedes albopictus enables the discovery of the association of PGANT3 with blood-feeding behavior.

The Asian tiger mosquito, Aedes albopictus, is a global invasive species, notorious for its role in transmitting dangerous human arboviruses such as dengue and Chikungunya. Although hematophagous behavior is repulsive, it is an effective strategy for mosquitoes like Aedes albopictus to transmit viruses, posing a significant risk to human health. However, the fragmented nature of the Ae. albopictus genome assembly has been a significant challenge, hindering in-depth biological and genetic studies of this mosquito. In this research, we have harnessed a variety of technologies and implemented a novel strategy to create a significantly improved genome assembly for Ae. albopictus, designated as AealbF3. This assembly boasts a completeness rate of up to 98.1%, and the duplication rate has been minimized to 1.2%. Furthermore, the fragmented contigs or scaffolds of AealbF3 have been organized into three distinct chromosomes, an arrangement corroborated through syntenic plot analysis, which compared the genetic structure of Ae. albopictus with that of Ae. aegypti. Additionally, the study has revealed a phylogenetic relationship suggesting that the PGANT3 gene is implicated in the hematophagous behavior of Ae. albopictus. This involvement was preliminarily substantiated through RNA interference (RNAi) techniques and behavioral experiment. In summary, the AealbF3 genome assembly will facilitate new biological insights and intervention strategies for combating this formidable vector of disease. The innovative assembly process employed in this study could also serve as a valuable template for the assembly of genomes in other insects characterized by high levels of heterozygosity.

Species sensitivities to artificial light at night: A phylogenetically controlled multilevel meta-analysis on melatonin suppression.

The rapid urbanization of our world has led to a surge in artificial lighting at night (ALAN), with profound effects on wildlife. Previous research on wildlife's melatonin, a crucial mechanistic indicator and mediator, has yielded inconclusive evidence due to a lack of comparative analysis. We compiled and analysed an evidence base including 127 experiments with 437 observations across 31 wild vertebrates using phylogenetically controlled multilevel meta-analytic models. The evidence comes mainly from the effects of white light on melatonin suppression in birds and mammals. We show a 36% average decrease in melatonin secretion in response to ALAN across a diverse range of species. This effect was observed for central and peripheral melatonin, diurnal and nocturnal species, and captive and free-living populations. We also reveal intensity-, wavelength-, and timing-dependent patterns of ALAN effects. Exposure to ALAN led to a 23% rise in inter-individual variability in melatonin suppression, with important implications for natural selection in wild vertebrates, as some individuals may display higher tolerance to ALAN. The cross-species evidence has strong implications for conservation of wild populations that are subject to natural selection of ALAN. We recommend measures to mitigate harmful impacts of ALAN, such as using 'smart' lighting systems to tune the spectra to less harmful compositions.

ITGAM-macrophage modulation as a potential strategy for treating neutrophilic Asthma: insights from bioinformatics analysis and in vivo experiments.

Identification of molecular biomarkers associated with neutrophilic asthma (NA) phenotype may inform the discovery of novel pathobiological mechanisms and the development of diagnostic markers. Three mRNA transcriptome datasets extracted from induced sputum of asthma patients with various inflammatory types were used to screen for macrophage-related molecular mechanisms and targets in NA. Furthermore, the predicted targets were also validated on an independent dataset (N = 3) and animal model (N = 5). A significant increase in total cells, neutrophils and macrophages was observed in bronchoalveolar lavage (BAL) fluid of NA mice induced by ovalbumin/freund's adjuvant, complete (OVA/CFA). And we also found elevated levels of neutrophil and macrophage infiltration in NA subtype in external datasets. NA mice had increased secretion of IgE, IL-1ß, TNF-α and IL-6 in serum and BAL fluid. MPO, an enzyme present in neutrophils, was also highly expressed in NA mice. Then, weighted gene co-expression network analysis (WGCNA) identified 684 targets with the strongest correlation with NA, and we obtained 609 macrophage-related specific differentially expressed genes (DEGs) in NA by integrating macrophage-related genes. The top 10 genes with high degree values were obtained and their mRNA levels and diagnostic performance were then determined by RT-qPCR and receiver operator characteristic (ROC) analysis. Statistically significant correlations were found between macrophages and all key targets, with the strongest correlation between ITGAM and macrophages in NA. Double-Immunofluorescence staining further confirmed the co-localization of ITGAM and F4/80 in NA. ITGAM was identified as a critical target to distinguish NA from healthy/non-NA individuals, which may provide a novel avenue to further uncover the mechanisms and therapy of NA.

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

Comparison of downsizing strategy (HANGZHOU Solution) and standard annulus sizing strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a downsizing strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of downsizing strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

Damage-associated molecular patterns in viral infection: potential therapeutic targets.

Frequent viral infections leading to infectious disease outbreaks have become a significant global health concern. Fully elucidating the molecular mechanisms of the immune response against viral infections is crucial for epidemic prevention and control. The innate immune response, the host's primary defense against viral infection, plays a pivotal role and has become a breakthrough in research mechanisms. A component of the innate immune system, damage-associated molecular patterns (DAMPs) are involved in inducing inflammatory responses to viral infections. Numerous DAMPs are released from virally infected cells, activating downstream signaling pathways via internal and external receptors on immune cells. This activation triggers immune responses and helps regulate viral host invasion. This review examines the immune regulatory mechanisms of various DAMPs, such as the S100 protein family, high mobility group box 1 (HMGB1), and heat shock proteins, in various viral infections to provide a theoretical basis for designing novel antiviral drugs.

See farther and more: a master-slave UAVs based synthetic optical aperture imaging system with wide and dynamic baseline.

An open challenge remained in designing an optical system to capture the aerial image with a wide field of view (FoV) and high resolution. The optical system of one camera from a single unmanned aerial vehicle (UAV) can hardly promise the FoV and resolution. The conventional swarm UAVs can form the camera array with a short or fixed baseline. They can capture the images with a wide FoV and high resolution, but the cost is the requirement of many UAVs. We aim to design a camera array with a wide and dynamic baseline to reduce the demand for UAVs to organize a synthetic optical aperture. In this thought, we propose a master-slave UAVs-based synthetic optical aperture imaging system with a wide and dynamic baseline. The system consists of one master UAV and multiple slave UAVs. Master and slave UAVs provide the global and local FoVs, respectively, and improve the efficiency of image acquisition. In such a system, fusing UAV images becomes a new challenge due to two factors: (i) the small FoV overlap of slave UAVs and (ii) the gap in resolution scale from slave to master UAV images. To deal with it, a coarse-to-fine stitching method is proposed to stitch up the multi-view images into one to obtain a wide FoV with high resolution. A video stabilization method has also been designed for the proposed imaging system. Challenges caused by wide and dynamic baselines can thus be solved by the above methods. Actual data experiments demonstrate that the proposed imaging system achieves high-quality imaging results.

Multifocal multiview imaging and data compression based on angular-focal-spatial representation.

Multifocal multiview (MFMV) is an emerging high-dimensional optical data that allows to record richer scene information but yields huge volumes of data. To unveil its imaging mechanism, we present an angular-focal-spatial representation model, which decomposes high-dimensional MFMV data into angular, spatial, and focal dimensions. To construct a comprehensive MFMV dataset, we leverage representative imaging prototypes, including digital camera imaging, emerging plenoptic refocusing, and synthesized Blender 3D creation. It is believed to be the first-of-its-kind MFMV dataset in multiple acquisition ways. To efficiently compress MFMV data, we propose the first, to our knowledge, MFMV data compression scheme based on angular-focal-spatial representation. It exploits inter-view, inter-stack, and intra-frame predictions to eliminate data redundancy in angular, focal, and spatial dimensions, respectively. Experiments demonstrate the proposed scheme outperforms the standard HEVC and MV-HEVC coding methods. As high as 3.693 dB PSNR gains and 64.22% bitrate savings can be achieved.

Microfluidic bead-based biosensor: Ultrasensitive ctDNA detection based on duplex-functional split-DNAzyme and dendritic enzyme-free signal amplification.

Circulating tumor DNA (ctDNA) is a crucial cancer biomarker for early or noninvasive monitoring, which is essential for developing ultrasensitive and selective assays in cancer diagnosis and treatment. Herein, a cascade signal amplification of duplex-functional split-DNAzyme and dendritic probes was proposed for ultrasensitive and specific detection of nasopharyngeal carcinoma-associated Epstein-Barr virus (EBV) DNA on microfluidic microbead array chips. With the assistance of Pb2+, the duplex-functional split-DNAzyme recognizes EBV DNA and then rapidly cleaves the substrate strand. Subsequently, the released target could be recycled, and its exposed capture probe, triggered the dendritic enzyme-free signal amplification. As the enhanced mass transfer capability, target recycling, and dendritic DNA structure signal amplification inherent to microfluidic bead arrays were integrated, it achieved an excellent detection limit of 0.36 fM and a wide linear range of 1 fM∼103 fM. Further, it was applied to content detect simulated samples of EBV DNA, recovery ranged from 97.2 % to 108.1 %, and relative standard deviation (RSD) from 3.3 % to 5.9 %, exhibiting satisfactory recovery results. The developed microfluidic biosensor was a high-sensitivity and anti-interference system for ctDNA analysis, with minimal reagent volumes (microlitres) required. Thus, it is a promising platform for ctDNA at the lowest level at their earliest incidence.

CX3C chemokine: Hallmarks of fibrosis and ageing.

Fibrosis refers to the progressive tissue lesion process characterized by excessive secretion and deposition of extracellular matrix (ECM). Abnormal fibrous tissue deposition distorts tissue architecture and leads to the progressive loss of organ function. Notably, fibrosis is one of the primary pathological appearances of many end stage illnesses, and is considered as a lethal threat to human health, especially in the elderly with ageing-related diseases. CX3C ligand 1 (CX3CL1) is the only member of chemokine CX3C and binds specifically to CX3C receptor 1 (CX3CR1). Different from other chemokines, CX3CL1 possesses both chemotactic and adhesive activity. CX3CL1/CX3CR1 axis involves in various physiological and pathological processes, and exerts a critical role in cells from the immune system, vascular system, and nervous system etc. Notably, increasing evidence has demonstrated that CX3CL1/CX3CR1 signaling pathway is closely related to the pathological process of fibrosis in multiple tissue and organs. We reviewed the crucial role of CX3CL1/CX3CR1 axis in fibrosis and ageing and systematically summarized the underlying mechanism, which offers prospective strategies of targeting CX3C for the therapy of fibrosis and ageing-related diseases.

High CO2 adaptation mechanisms revealed in the miR156-regulated flowering time pathway.

Elevated CO2 concentrations have been observed to accelerate flowering time in Arabidopsis through the action of a highly conserved regulatory network controlled by miR156 and miR172. However, the network's robustness to the impact of increasing CO2 concentrations on flowering time remains poorly understood. In this study, we investigate this question by conducting a comprehensive analysis of the global landscape of network dynamics, including quantifying the probabilities associated with juvenile and flowering states and assessing the speed of the transition between them. Our findings reveal that a CO2 concentration range of 400-800ppm only mildly advances flowering time, contrasting with the dramatic changes from 200 to 300ppm. Notably, the feedback regulation of miR156 by squamosal promoter binding protein-like proteins (SPLs) plays a substantial role in mitigating the effects of increasing CO2 on flowering time. Intriguingly, we consistently observe a correlation between delayed flowering time and increased variance in flowering time, and vice versa, suggesting that this might be an intrinsic adaptation mechanism embedded within the network. To gain a deeper understanding of this network's dynamics, we identified the sensitive features within the feedback loops of miR156 SPLs and miR172-APETALA2 family proteins (AP2s), with the latter proving to be the most sensitive. Strikingly, our study underscores the indispensability of all feedback regulations in maintaining both juvenile and adult states as well as the transition time between them. Together, our research provides the first physical basis in plant species, aiding in the elucidation of novel regulatory mechanisms and the robustness of the miRNAs-regulated network in response to increasing CO2, therefore influencing the control of flowering time. Moreover, this study provides a promising strategy for engineering plant flowering time to enhance their adaptation and resilience.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

Animal Models of Helicobacter pylori Infection and Vaccines: Current Status and Future Prospects.

Helicobacter pylori infection causes chronic gastritis, ulcers, and gastric cancer, making it a threat to human health. Despite the use of antibiotic therapy, the global prevalence of H. pylori infection remains high, necessitating early eradication measures. Immunotherapy, especially vaccine development, is a promising solution in this direction, albeit the selection of an appropriate animal model is critical in efficient vaccine production. Accordingly, we conducted a literature, search and summarized the commonly used H. pylori strains, H. pylori infection-related animal models, and models for evaluating H. pylori vaccines. Based on factors such as the ability to replicate human diseases, strain compatibility, vaccine types, and eliciting of immune responses, we systematically compared the advantages and disadvantages of different animal models, to obtain the informed recommendations. In addition, we have proposed novel perspectives on H. pylori-related animal models to advance research and vaccine evaluation for the prevention and treatment of diseases such as gastric cancer.

Electrochemical Na+/K+ Ion Exchange in Zeolitic Vanadium(IV) Borophosphate K1.33Na0.67[VO(B2O)(PO4)2(HPO4)]·1.63H2O as Cathode Material for Sodium-Ion Batteries.

Electrochemical ion exchange has recently been demonstrated to be a unique method for the preparation of novel cathode materials, which cannot be accessible by traditional direct synthesis routes. In this study, the vanadium borophosphate compound K1.33Na0.67[VO(B2O)(PO4)2(HPO4)]·1.63H2O (KNVBP) with zeolitic framework exhibits fast electrochemical Na+/K+ ion exchange when used as cathode material in sodium-ion batteries (SIBs). Ex situ structural analyses and electrochemical measurements confirm that most of the K+ ions in the parent KNVBP can be extracted and exchanged by Na+ ions after the first charge/discharge cycle. The in situ-generated Na-rich phase shows reversible electrochemical activity at approximately 3.9 V versus Na+/Na with a specific capacity of 52.9 mAh g-1, comparable to 96.2% of the theoretical capacity. Moreover, enhanced ionic diffusion kinetics can be achieved after the Na+/K+ exchange. This study provides a valuable insight into the electrochemical ion exchange in polyanion compounds toward application in metal-ion batteries.

Insights into the regulatory role of bacterial sncRNA and its extracellular delivery via OMVs.

Small noncoding RNAs (sncRNAs) play important regulatory roles in bacterial physiological processes and host-pathogen interactions. Meanwhile, bacterial outer membrane vesicles (OMVs), as naturally secreted outer membrane structures, play a vital role in the interaction between bacteria and their living environment, including the host environment. However, most current studies focus on the biological functions of sncRNAs in bacteria or hosts, while neglecting the roles and regulatory mechanisms of the OMVs that encapsulate these sncRNAs. Therefore, this review aims to summarize the intracellular regulatory roles of bacterial sncRNAs in promoting pathogen survival by regulating virulence, modulating bacterial drug resistance, and regulating iron metabolism, and their extracellular regulatory function for influencing host immunity through host-pathogen interactions. Additionally, we introduce the key role played by OMVs, which serve as important cargoes in bacterial sncRNA-host interactions. We propose emerging pathways of sncRNA action to further discuss the mode of host-pathogen interactions, highlighting that the inhibition of sncRNA delivery by OMVs may prevent the occurrence of infection to some extent. Hence, this review lays the foundation for future prophylactic treatments against bacterial infections and strategies for addressing bacterial drug resistance. KEY POINTS: •sncRNAs have intracellular and extracellular regulatory functions in bacterial physiological processes and host-pathogen interactions. •OMVs are potential mediators between bacterial sncRNAs and host cells. •OMVs encapsulating sncRNAs have more potential biological functions.

Effect of long-term use of antipsychotics on the ventricular repolarization index.

BACKGROUND: The risk of arrhythmia is usually assessed by the length of the corrected QT interval (QTc) when patients use antipsychotics. Prolonged QTc intervals are thought to increase the probability of malignant ventricular arrhythmias, and if we focus only on the QTc interval, we may be influenced by a single factor and make decisions that are not conducive to effective treatment. The index of cardiac electrophysiological balance (iCEB) is considered more valuable than the QTc for predicting drug-induced arrhythmias. It has been used in clinical practice, but no studies have observed changes in this index after the use of antipsychotics. OBJECTIVE: To investigate the changes in ventricular repolarization indices and the occurrence of arrhythmias in patients who have been using antipsychotic drugs for a long time, to compare the changes in iCEBc and QTc and to predict abnormal iCEBc values. METHODS: Patients with schizophrenia who had been hospitalized for more than 4 years and who were receiving atypical antipsychotics underwent a 12-lead synchronized electrocardiogram (ECG) every 2-4 weeks. The baseline data were measured at admission, defined as the baseline (time0), and the most obvious abnormal changes in ventricular depolarization and repolarization measured every 12 months were one-year follow-up (time1), two-year follow-up (time2), three-year follow-up (time3), and four-year follow-up (time4). Repeated measures analysis of variance was used for comparisons. The types and doses of drugs taken at 5 time points were recorded and converted into chlorpromazine equivalents for comparison. The incidence of arrhythmia during the observation cycle was recorded. RESULTS: The patients had been treated with antipsychotic medication for 4 years, and the duration of the QRS wave was longer in males than in females. TpTe, TpTe/QRS, TpTe/QT, TpTe/QTc, iCEB, and iCEBc increased significantly with hospital stay, while TpTe, TpTe/QRS, TpTe/QT, and TpTe/QTc exhibited more obvious changes in these indicators in female patients (P < 0.01). The changes in iCEB and iCEBc were more significant in males (P < 0.01). The incidences of arrhythmia (arrhythmic events included premature ventricular beats and premature atrial beats) within 5 time points were 2.5%, 6.25%, 6.25%, 6.25% and 5%, respectively. More than 90% of patients treated with antipsychotics did not have any arrhythmias. No TdP syncope or other cardiovascular symptoms were found in any of the patients. CONCLUSION: After long-term use of antipsychotics, the ventricular repolarization index gradually increased with time. The new ventricular repolarization indices iCEB and iCEBc were more sensitive than the QTc at predicting arrhythmia. According to the abnormal QTc values in men and women, we predict that the abnormal value of the iCEBc in males is 4.528 and that in females is 5.315.

Association of antenatal corticosteroids with mortality and morbidities in very preterm infants born to women with hypertensive disorders of pregnancy: a multicenter prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS. METHODS: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge. RESULTS: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference. CONCLUSIONS: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples.

LncRNA H19 Participates in Leukemia Inhibitory Factor Mediated Stemness Promotion in Colorectal Cancer Cells.

Colorectal cancer (CRC) is a common human malignancy and the third leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) were considered to play important roles in the genesis and development of many tumors. In recent years, it has been observed that leukemia inhibitory factor (LIF) might be involved in the regulation of stemness in cancer cells. In this study, we observed that LIF could increase the spheroid formation and stemness marker expression (inculding Nanog and SOX2) in CRC cell lines, such as HCT116 and Caco2 cells. Meanwhile, we also observed that LIF could upregulate LncRNA H19 expression via PI3K/AKT pathway. Knockdown of the expression of LncRNA H19 could decrease the spheroid formation and SOX2 expression in LIF-treated HCT116 and Caco2 cells, and thereby LncRNA H19 knockdown could compensate for the stemness enhancement effects induced by LIF. Our results indicated that LncRNA H19 might participate in the stemness promotion of LIF in CRC cells.