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Abstract Hepatic polypeptide nutrient solution (HP) is a mixture of hepatoprotective peptides derived from fresh porcine liver with various effects. However, the role and mechanisms of HP in nonalcoholic fatty liver disease (NAFLD) are still not well understood. We investigated the effects of HP NAFLD rats induced by high‐cholesterol diet (HCD) and its underlying mechanisms. Rats were provided with HCD for 4 weeks and then received HP or metformin after 2 weeks of HCD feeding. The study found that HP reduced cholesterol and triglyceride levels in rats with NAFLD (all p

The tyrosine kinase inhibitors (TKIs) have improved overall survival of CML (chronic myeloid leukemia) patients and allow them to experience normal life expectancy. However, relapse and drug resistance remain the main challenges in the clinical treatment of CML. The B-cell lymphoma 6 (BCL6) is essential to regulation of multiple function such as immune response and lymphomagenesis in lymph node germinal cells. Recent studies have shown that BCL6 is required for the maintenance of leukemia stem cells in CML, but the expression of Bcl-6 in response to Imatinib and the underlying mechanism are still unclear. Here, we found that BCL6 is expressed at high levels in primary CML bone marrow samples and CML TKI-resistance cell lines. CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML.

This paper proposes a meta-model-based parametric Historic Building Information Modelling (HBIM) approach to preserving and renewing traditional timber dwellings, specifically focusing on traditional Bai ethnic residential architecture. The study integrates traditional architectural principles with contemporary digital construction techniques. Traditional Bai dwellings have complex timber structural and spatial characteristics with various components. Results from the application of HBIM demonstrate improved efficiency in documenting and managing structural information, facilitating the maintenance and preservation of heritage buildings. The study concludes that HBIM, supported by parametric and generative design approaches, offers significant advantages in the digital preservation of architectural heritage. This approach not only ensures the structural integrity and historical accuracy of the models but also provides a scalable solution for managing and preserving traditional dwellings in the face of modernization pressures. This research broadens the scope of parametric design within digital construction theory, particularly concerning ancient timber structures. It offers a crucial framework that can inform both future studies and practical efforts in the preservation of heritage buildings.

Abstract Objectives Pulmonary vein stenosis (PVS), one of the most challenging clinical problems in congenital heart disease, leads to secondary pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy. Due to the lack of a rodent model, the mechanisms underlying PVS and its associated secondary effects are largely unknown, and treatments are minimally successful. This study developed a neonatal rat PVS model with the aim of increasing our understanding of the mechanisms and developing possible treatments for PVS. Methods PVS was created at postnatal day 1 (P1) by banding pulmonary veins that receive blood from the right anterior and mid lobes. The condition was confirmed using echocardiography, computed tomography (CT), gross anatomic examination, hematoxylin and eosin (H&E) staining, fibrosis staining, and immunofluorescence. Lung and RV remodeling under the condition of PVS were evaluated using H&E staining, fibrosis staining, and immunofluorescence. Results At P21, echocardiography revealed a change in wave form and a decrease in pulmonary artery acceleration time—indicators of PAH—at the transpulmonary valve site in the PVS group. CT at P21 showed a decrease in pulmonary vein diameter in the PVS group. At P30 in the PVS group, gross anatomic examination showed pulmonary congestion, H&E staining showed wall thickening and lumen narrowing in the upstream pulmonary veins, and immunofluorescence showed an increase in the smooth muscle layers in the upstream pulmonary veins. In addition, at P30 in the PVS group, lung remodeling was evidenced by hyperemia, thickening of pulmonary small vessel walls and smooth muscle layers, and reduction of the number of alveoli. RV remodeling was evidenced by an increase in RV free wall thickness. Conclusions A neonatal rat model of PVS was successfully established, showing secondary lung and RV remodeling. This model may serve as a useful platform for understanding the mechanisms and treatments for PVS.

ABSTRACT: In this study, 2 types of drinking water were provided to broiler chicks to evaluate the relationship between the bacterial load of drinking water and cecal microbiota. One type of drinking water was untreated, while the other type was daily treated with sodium dichlorocyanurate (50 mg/L). A total of 240 broiler chicks were divided into 2 groups based on their initial body weight. There were 6 replicates in each group, and each replicate cage contained 20 birds. Each cage was assigned to a different floor of the battery cage. On the final day, water samples were collected from each replicate cage at the opening of the drinking cup height, and one bird was selected from each replicate cage to obtain cecal content samples for measuring microbiota composition using the 16S rRNA technique. We found that drinking water treated with sodium dichlorocyanurate significantly reduced the richness and diversity of microbiota and diminished/disappeared most gram-negative bacteria. Broiler chicks that consumed chlorinated drinking water exhibited changes in the composition of cecal microbiota, with Alistipes serving as the marker species in the cecal content of broiler chicks that consumed untreated water, whereas AF12 served as the marker species in the cecal content of broiler chicks that consumed chlorinated drinking water. Functional prediction using the MetaCyc database and species composition analysis of metabolic pathways showed that changes in 7 metabolic pathways were related to the abundance of Providencia. Therefore, we concluded that chlorinated drinking water reduced the bacterial load in drinking water, thereby altering the cecal microbiota composition and regulating the metabolic activity of broiler chicks.

Introduction: Adult patients with atrial septal defects (ASD), the most common form of adult congenital heart disease, often die of arrhythmias, and the immaturity of cardiomyocytes contributes significantly to arrhythmias. ASD typically induces a left-to-right shunt, which then leads to the right atrium (RA) volume overload (VO). Whether or not VO contributes to RA cardiomyocyte immaturity and thereby causes arrhythmias in adult patients with ASD remains unclear.Methods: Here, we developed the first neonatal RA VO mouse model by creating a fistula between the inferior vena cava and abdominal aorta on postnatal day 7. RA VO was confirmed by increases in the mean flow velocity, mean pressure gradient, and velocity time integral across the tricuspid valve, and an increase in the RA diameter and RA area middle section.Results: We found that VO decreased the regularity and length of sarcomeres, and decreased the T-element density, regularity, and index of integrity of T-tubules in RA cardiomyocytes, suggesting that the two most important maturation hallmarks (sarcomere and T-tubules) of RA cardiomyocytes were impaired by VO. Accordingly, the calcium handling capacity of cardiomyocytes from postnatal day 21 (P21) RA was decreased by VO. VO caused a significant elongation of the PR interval. The expression of connexin 43 (Cx43) was decreased in RA VO. Moreover, gene ontology (GO) analysis of the downregulated genes in RA demonstrated that there was an abundance of enriched terms associated with sarcomeres and T-tubules exposed to VO. The results were further verified by qRT-PCR.Conclusions: In conclusion, the first neonatal RA VO mouse model was developed; furthermore, using this neonatal RA VO mouse model, we revealed that VO impeded RA sarcomere and T-tubule maturation, which may be the underlying causes of atrial arrhythmias in adult patients with ASD.

Abstract Background Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. Methods and results We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell–cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. Conclusions This study suggested that promoting cell–cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion–induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion. Graphical Abstract

ABSTRACT: Environmental exposures during early life are important for animals’ intestinal microbiota composition and their production performance. This experiment investigated the growth performance, hematology parameters, jejunal morphology, and cecal microbiota of broiler chicks as affected by exogenous factors from the aspects of drinking water quality and dietary manipulation. A total of 480-day-old broiler chicks (Arbor acre; 41.59 ± 0.88 g) were randomly assigned into 4 groups (CON, HWGM, CA, CAHWGM). Each group had 6 replicates with 20 birds per replicate. Broiler chicks in CON group were fed with basal diet and drank normal drinking water; in HWGM group were fed with basal diet supplemented with 1.5g/kg herbal extract blend (hops, grape seed, and wheat germ) and drank normal drinking water; in CA group were fed with basal diet and drank sodium dichlorocyanurate (50 mg/L) treated-drinking water; in CAHWGM group were fed with basal diet supplemented with 1.5 g/kg herbal extract blend and drank chlorinated drinking water. The experimental period was 42 d. We found that broiler chicks drank chlorinated drinking water led to an increase in body weight gain and feed efficiency during d 22 to 42 and 1 to 42, as well as a decrease in cecal Dysgonomonas and Providencia abundance. Dietary supplementation of herbal extract blend increased cecal Lactobacillus and Enterococcus abundance, whereas decreased Dysgonomonas abundance. Moreover, we observed that cecal Dysgonomonas abundance synergistically decreased by treating drinking water with sodium dichlorocyanurate and supplementing herbal extract blend to the diet. Therefore, results obtained in this study indicated that providing chlorinated drinking water is an effective strategy to improve the growth performance of broiler chicks by regulating intestinal microbiota. Additionally, dietary supplementation of herbal extract blend alone or combined with chlorinated drinking water is able to regulate cecal microbiota.

BackgroundCopy number variations (CNVs) have been shown to be overrepresented in children with congenital heart disease (CHD). Genetic evaluation of CHD is currently underperformed in China. We sought to determine the occurrence of CNVs in CNV regions with disease-causing potential among a large cohort of Chinese pediatric CHD patients and investigate whether these CNVs could be the important critical modifiers of surgical intervention.MethodsCNVs screenings were performed in 1,762 Chinese children who underwent at least one cardiac surgery. CNV status at over 200 CNV locus with disease-causing potential was analyzed with a high-throughput ligation-dependent probe amplification (HLPA) assay.ResultsWe found 378 out of 1,762 samples (21.45%) to have at least one CNV and 2.38% of them were carrying multiple CNVs. The detection rates of ppCNVs (pathogenic and likely pathogenic CNVs) were 9.19% (162/1,762), significantly higher than that of the healthy Han Chinese individuals from The Database of Genomic Variants archive (9.19% vs. 3.63%; P = 0.0012). CHD cases with ppCNVs had a significantly higher proportion of complex surgeries compared to CHD patients with no ppCNVs (62.35% vs. 37.63%, P

In this paper, we introduce the complex valued $ C^{p} $-class function, a type of Geraghty contraction and a type of JS contraction in complete partially ordered complex valued $ G_b $-metric spaces, prove three fixed point theorems in this space, and also we give some examples to support our results.

In this paper, we are concerned with the following modified Schrödinger equation $ \begin{array}{l} -\Delta u+V(|x|)u-\kappa u\Delta(u^2)+ \\ \qquad\qquad\qquad q\frac{h^2(|x|)}{|x|^2}(1+\kappa u^2)u\ + q\left(\int_{|x|}^{+\infty}\frac{h(s)}{s}(2+\kappa u^2(s))u^2(s){\rm{d}}s\right) u = (I_\alpha\ast F(u))f(u), \, \, x\in {\mathbb R}^2, \end{array} $ where $ \kappa $, $ q > 0 $, $ I_\alpha $ is a Riesz potential, $ \alpha\in (0, 2) $ and $ V \in \mathcal{C}({\mathbb R}^2, {\mathbb R}) $, $ F(t) = \int^t_0f(s){\rm{d}}s $. Under appropriate assumptions on $ f $ and $ V(x) $, by using the variational methods, we establish the existence of ground state solutions of the above equation.

Abstract Background Primary care doctors in Shenzhen, China are increasingly expected to identify and prevent depressive disorder; however, they have received limited mental health training and community healthcare centres (CHC) do not provide standardised protocols for the diagnosis and care of depressive disorder. The World Health Organization’s mental health gap intervention guide, version 2 (mhGAP-IG.v2) is a decision support tool for non-specialists for the assessment, management and follow-up of mental, neurological and substance use disorders (including depressive disorder). Given that mhGAP-IG.v2 is a generic tool, it requires adaptation to take account of cultural differences in depression presentation and unique characteristics of China’s emergent mental health system. Methods A two-round, web-based, Delphi survey was conducted. A panel of primary care doctors from Shenzhen, were invited to score their level of agreement with 199 statements (arranged across 10 domains) proposing changes to the content and structure of mhGAP-IG.v2 for use in Shenzhen. Consensus was predefined as 80% panelists providing a rating of either “somewhat agree/definitely agree”, or “definitely disagree/somewhat disagree” on a five-point scale for agreement. Results 79% of statements received consensus with a mean score of 4.26 (i.e. “somewhat agree”). Agreed adaptations for mhGAP-IG.v2 included:- an assessment approach which considers a broader spectrum of depression symptoms and reflects the life course of disease; incorporating guidance for screening tool usage; clarifying physicians’ roles and including referral pathways for intersectorial care with strong family involvement; aligning drug treatment with national formularies; stronger emphasis of suicide prevention throughout all sections of the guide; contextualizing health education; reflecting a person-centred approach to care. Panelists chose to maintain diagnostic and treatment advice for bipolar patients experiencing a depressive episode as in the current guide. Conclusions An adapted mhGAP-IG.v2 for depression recognises China’s cultural and contextual needs for assessment guidance; unique primary healthcare system organization, priorities and treatment availability; and diverse psychosocial educational needs. An adapted mhGAP-IG.v2 could both inform the future training programs for primary care in Shenzhen and also offer an additional mental health resource for non-specialists in other countries.

In this paper, we study the following quasilinear Schrödinger equation \begin{equation*} \begin{split} -\Delta u&+V(x)u-\kappa u\Delta(u^2)+\mu\frac{h^2(|x|)}{|x|^2}(1+\kappa u^2)u\\ &+\mu\left(\int_{|x|}^{+\infty}\frac{h(s)}{s}(2+\kappa u^2(s))u^2(s)\text{d}s\right)u=f(u)\quad\text{in}~\mathbb{R}^2, \end{split} \end{equation*} where $\kappa>0$, $\mu>0$, $V \in \mathcal{C}^1(\mathbb{R}^2,\mathbb{R})$ and $f \in \mathcal{C}(\mathbb{R},\mathbb{R})$. By using a constraint minimization of Pohožaev–Nehari type and analytic techniques, we obtain the existence of ground state solutions.

Abstract The molecular atlas of postnatal mouse ventricular development has been made available and cardiac regeneration is documented to be a downregulated process. The right ventricle (RV) differs from the left ventricle. How volume overload (VO), a common pathologic state in children with congenital heart disease, affects the downregulated processes of the RV is currently unclear. We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 7 (P7) using a mouse model to induce a prepubertal RV VO. RNAseq analysis of RV (from postnatal day 14 to 21) demonstrated that angiogenesis was the most enriched gene ontology (GO) term in both the sham and VO groups. Regulation of the mitotic cell cycle was the second-most enriched GO term in the VO group but it was not in the list of enriched GO terms in the sham group. In addition, the number of Ki67-positive cardiomyocytes increased approximately 20-fold in the VO group compared to the sham group. The intensity of the vascular endothelial cells also changed dramatically over time in both groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the downregulated transcriptome revealed that the peroxisome proliferators-activated receptor (PPAR) signaling pathway was replaced by the cell cycle in the top-20 enriched KEGG terms because of the VO. Angiogenesis was one of the primary downregulated processes in postnatal RV development, and the cell cycle was reactivated under the influence of VO. The mechanism underlying the effects we observed may be associated with the replacement of the PPAR-signaling pathway with the cell-cycle pathway.

BackgroundLeft ventricular (LV) volume overload (VO), commonly found in patients with chronic aortic regurgitation (AR), leads to a series of left ventricular (LV) pathological responses and eventually irreversible LV dysfunction. Recently, questions about the applicability of the guideline for the optimal timing of valvular surgery to correct chronic AR have been raised in regard to both adult and pediatric patients. Understanding how VO regulates postnatal LV development may shed light on the best timing of surgical or drug intervention.Methods and ResultsPrepubertal LV VO was induced by aortocaval fistula (ACF) on postnatal day 7 (P7) in mice. LV free walls were analyzed on P14 and P21. RNA-sequencing analysis demonstrated that normal (P21_Sham vs.P14_Sham) and VO-influenced (P21_VO vs. P14_VO) LV development shared common terms of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) in the downregulation of cell cycle activities and the upregulation of metabolic and sarcomere maturation. The enriched GO terms associated with cardiac condition were only observed in normal LV development, while the enriched GO terms associated with immune responses were only observed in VO-influenced LV development. These results were further validated by the examination of the markers of cell cycle, maturation, and immune responses. When normal and VO-influenced LVs of P21 were compared, they were different in terms of immune responses, angiogenesis, percentage of Ki67-positive cardiomyocytes, mitochondria number, T-tubule regularity, and sarcomere regularity and length.ConclusionsA prepubertal LV VO mouse model was first established. VO has an important influence on LV maturation and development, especially in cardiac conduction, suggesting the requirement of an early correction of AR in pediatric patients. The underlying mechanism may be associated with the activation of immune responses.

Background: Pulmonary regurgitation caused by the correction or palliation of pediatric tetralogy of Fallot (TOF) leads to chronic right ventricular (RV) volume overload (VO), which induces adolescent RV dysfunction. A better understanding of the molecular mechanism by which VO initiates neonatal RV remodeling may bring new insights into the post-surgical management of pediatric TOF.Methods and Results: We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 1 (P1) using a rat model to induce neonatal VO. Echocardiography revealed that the velocity and velocity- time-integral of the pulmonary artery (PA) were significantly elevated, and hematoxylin and eosin (H&E) staining showed that the diameter of the RV significantly increased. RNA-seq analysis of the RV on P7 indicated that the top 10 enriched Gene Ontology (GO) terms and the top 20 enriched terms in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were associated with immune responses. Flow-cytometric analysis demonstrated that the number of CD4+and CD8+ immune cells were significantly augmented in the VO group compared with the sham group.Conclusions: A neonatal cardiac VO rat model on P1 was successfully created, providing a platform for studying the molecular biology of neonatal RV under the influence of VO. VO - induces an immune response at the neonatal stage (from P1 to P7), suggesting that immune responses may be an initiating factor for neonatal RV remodeling under the influence of VO and that immunosuppressants may be used to prevent pediatric RV remodeling caused by VO.

Background: In children with hypoplastic left heart syndrome (HLHS), volume overload (VO) is inevitable, and the right ventricle (RV) pumps blood into the systemic circulation. Understanding the molecular differences and their different responses to VO between the RV and left ventricle (LV) at the neonatal and highly plastic stages may improve the long-term management of children with HLHS. Methods and Results: A neonatal rat ventricular VO model was established by the creation of a fistula between the inferior vena cava and the abdominal aorta on postnatal day 1 (P1) and confirmed by echocardiographic and histopathological analyses. Transcriptomic analysis demonstrated that some of the major differences between a normal neonatal RV and LV were associated with the thyroid hormone and insulin signaling pathways. Under the influence of VO, the levels of insulin receptors and thyroid hormone receptors were significantly increased in the LV but decreased in the RV. The transcriptomic analysis also demonstrated that under the influence of VO, the top two common enriched pathways between the RV and LV were the insulin and thyroid hormone signaling pathways, whereas the RV-specific enriched pathways were primarily associated with lipid metabolism and arrhythmogenic right ventricular cardiomyopathy (ARVC); further, the LV-specific enriched pathways were primarily associated with nucleic acid metabolism and microRNAs in cancer. Conclusions: Insulin and thyroid hormones may play critical roles in the differences between a neonatal RV and LV as well as their common responses to VO. Regarding the isolated responses to VO, the RV favors an ARVC change and the LV favors a reduction in microRNAs in cancer. The current study suggests that insulin, thyroid hormone, and cancer-associated microRNAs are potential therapeutic targets that should be explored by basic science studies to improve the function of the RV to match that of the LV.

Background Current right ventricular (RV) volume overload (VO) is established in adult mice. There are no neonatal mouse VO models and how VO affects postnatal RV development is largely unknown. Methods and Results Neonatal VO was induced by the fistula between abdominal aorta and inferior vena cava on postnatal day 7 and confirmed by abdominal ultrasound, echocardiography, and hematoxylin and eosin staining. The RNA‐sequencing results showed that the top 5 most enriched gene ontology terms in normal RV development were energy derivation by oxidation of organic compounds, generation of precursor metabolites and energy, cellular respiration, striated muscle tissue development, and muscle organ development. Under the influence of VO, the top 5 most enriched gene ontology terms were angiogenesis, regulation of cytoskeleton organization, regulation of vasculature development, regulation of mitotic cell cycle, and regulation of the actin filament‐based process. The top 3 enriched signaling pathways for the normal RV development were PPAR signaling pathway, citrate cycle (Tricarboxylic acid cycle), and fatty acid degradation. VO changed the signaling pathways to focal adhesion, the PI3K‐Akt signaling pathway, and pathways in cancer. The RNA sequencing results were confirmed by the examination of the markers of metabolic and cardiac muscle maturation and the markers of cell cycle and angiogenesis. Conclusions A neonatal mouse VO model was successfully established, and the main processes of postnatal RV development were metabolic and cardiac muscle maturation, and VO changed that to angiogenesis and cell cycle regulation.

In recent years, optoelectronics and related industries have developed rapidly. As typical optoelectronics devices, photodetectors (PDs) are widely applied in various fields. The functional materials in traditional PDs exhibit high hardness, and the performance of these rigid detectors is thus greatly reduced upon their stretching or bending. Therefore, the development of new flexible PDs with bendable and foldable functions is of great significance and has much interest in wearable, implantable optoelectronic devices. Graphene with excellent electrical and optical performance constructed on various flexible and rigid substrates has great potential in PDs. In this review, recent research progress on graphene-based flexible PDs is outlined. The research states of graphene conductive films are summarized, focusing on PDs based on single-component graphene and mixed-structure graphene, with a systematic analysis of their optical and mechanical performance, and the techniques for optimizing the PDs are also discussed. Finally, a summary of the current applications of graphene flexible PDs and perspectives is provided, and the remaining challenges are discussed.

Background: Ischemia-reperfusion injury (I/R) strongly affects the prognosis of children with complicated congenital heart diseases (CHDs) who undergo long-term cardiac surgical processes. Recently, the α2-adrenergic receptor agonist Dexmedetomidine (Dex) has been reported to protect cardiomyocytes (CMs) from I/R in cellular models and adult rodent models. However, whether and how Dex may protect human CMs in young children remains largely unknown.Methods and Results: Human ventricular tissue from tetralogy of Fallot (TOF) patients and CMs derived from human-induced pluripotent stem cells (iPSC-CMs) were used to assess whether and how Dex protects human CMs from I/R. The results showed that when pretreated with Dex, the apoptosis marker-TUNEL and cleaved caspase 3 in the ventricular tissue were significantly reduced. In addition, the autophagy marker LC3II was significantly increased compared with that of the control group. When exposed to the hypoxia/reoxygenation process, iPSC-CMs pretreated with Dex also showed reduced TUNEL and cleaved caspase 3 and increased LC3II. When the autophagy inhibitor (3-methyladenine, 3-MA) was applied to the iPSC-CMs, the protective effect of Dex on the CMs was largely blocked. In addition, when the fusion of autophagosomes with lysosomes was blocked by Bafilomycin A1, the degradation of p62 induced by Dex during the autophagy process was suspended. Moreover, when pretreated with Dex, both the human ventricle and the iPSC-CMs expressed more AMP-activated protein kinase (AMPK) and phospho AMPK (pAMPK) during the I/R process. After AMPK knockout or the use of an α2-adrenergic receptor antagonist-yohimbine, the protection of Dex and its enhancement of autophagy were inhibited.Conclusion: Dex protects young human CMs from I/R injury, and α2-adrenergic receptor/AMPK-dependent autophagy plays an important role during this process. Dex may have a therapeutic effect for children with CHD who undergo long-term cardiac surgical processes.

HIV-1 envelope glycoprotein (Env) interacts with cellular receptors and mediates virus entry into target cells. Blocking Env-receptor interactions represents an effective interventional strategy for developing HIV-1 entry inhibitors. We previously designed a panel of CD4-linker-DC-SIGN (CLD) constructs by fusing the extracellular CD4 and DC-SIGN domains with various linkers. Such CLDs produced by the prokaryotic system efficiently inhibited HIV-1 infection and dissemination in vitro and ex vivo. In this study, following the construction and identification of the most promising candidate with a linker of 8 Gly4Ser repeats (named CLD), we further designed an improved form (named CLDmut) by back mutating Cys to Ser at amino acid 60 of CD4. Both CLD and CLDmut were produced in mammalian (293F) cells for better protein translation and modification. The anti-HIV-1 activity of CLD and CLDmut was assessed against the infection of a range of HIV-1 isolates, including transmitted and founder (T/F) viruses. While both CLD and CLDmut efficiently neutralized the tested HIV-1 isolates, CLDmut demonstrated much higher neutralizing activity than CLD, with an IC50 up to one log lower. The neutralizing activity of CLDmut was close to or more potent than those of the highly effective HIV-1 broadly neutralizing antibodies (bNAbs) reported to date. Findings in this study indicate that mammalian cell-expressed CLDmut may have the potential to be used as prophylaxis or/and therapeutics against HIV-1 infection.

Background Current mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial. RNAseq has demonstrated a very limited set of differentially expressed genes between sham and operated hearts in myocardial infarction models. Here, we investigated in rats whether pressure overload in the right ventricle, a common phenomenon in children with congenital heart disease, could be used as a better animal model for heart regeneration studies when considering cardiomyocyte proliferation as the most important index. Methods and Results In the rat model, pressure overload was induced by pulmonary artery banding on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7. RNA sequencing analyses of purified right ventricular cardiomyocytes at postnatal day 7 from pulmonary artery banding and sham‐operated rats revealed that there were 5469 differentially expressed genes between these 2 groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous overproliferation of cardiomyocytes in the right ventricle after pulmonary artery banding, in particular for the first 3 postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately 2‐fold increase of Ki67/pHH3/aurora B‐positive cardiomyocytes in human‐overloaded right ventricles compared with nonoverloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis. Conclusions Pressure overload profoundly promotes cardiomyocyte proliferation in the neonatal stage in both rats and human beings. This activates a regeneration‐specific gene program and may offer an alternative animal model for heart regeneration research.

All human activity is associated with the generation of electrical signals. These signals are collectively referred to as electrical physiology (EP) signals (e.g., electrocardiogram, electroencephalogram, electromyography, electrooculography, etc.), which can be recorded by electrodes. EP electrodes are not only widely used in the study of primary diseases and clinical practice, but also have potential applications in wearable electronics, human–computer interface, and intelligent robots. Various technologies are required to achieve such goals. Among these technologies, adhesion and stretchable electrode technology is a key component for rapid development of high-performance sensors. In last decade, remarkable efforts have been made in the development of flexible and high-adhesive EP recording systems and preparation technologies. Regarding these advancements, this review outlines the design strategies and related materials for flexible and adhesive EP electrodes, and briefly summarizes their related manufacturing techniques.

For multidimensional dependent cases with incomplete probability information of random variables, global sensitivity analysis (GSA) theory is not yet mature. The joint probability density function (PDF) of multidimensional variables is usually unknown, meaning that the samples of multivariate variables cannot be easily obtained. Vine copula can decompose the joint PDF of multidimensional variables into the continuous product of marginal PDF and several bivariate copula functions. Based on Vine copula, multidimensional dependent problems can be transformed into two-dimensional dependent problems. A novel Vine copula-based approach for analyzing variance-based sensitivity measures is proposed, which can estimate the main and total sensitivity indices of dependent input variables. Five considered test cases and engineering examples show that the proposed methods are accurate and applicable.

Abstract Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin’s anti-coagulation assessed by INR and rat thrombosis model. The interactions between ginsenosides and warfarin on thrombosis, pharmacokinetics, activities of coagulation factors and liver cytochrome P450 isomers are determined by using thrombosis analyzer, UPLC/MS/MS, ELISA and real-time PCR, respectively. The antagonism correlates well with the related pharmacokinetic interaction showing that the blood plateaus of warfarin reached by one-week warfarin administration are significantly reduced after three-week co-administration of warfarin with ginsenosides while 7-hydroxywarfarin is increased. The one-week warfarin and three-week warfarin-ginsenosides regimen result in restoring the suppressed levels by warfarin of the coagulating factors II, VII and protein Z, and significantly enhance activities of P450 3A4 and 2C9 that metabolize warfarin. The present study, for the first time, provides the solid evidence to demonstrate the warfarin-ginsenoside interaction, and warns the warfarin users and regulation authorities of the dangerous interaction.

Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.

The degree of paraxiality (DOP) of a diffracted multi-Gaussian beam is discussed. It is shown that the DOP of the multi-Gaussian beam will decrease as it is diffracted by a circular aperture, and the DOP of the diffracted multi-Gaussian beam is influenced by both the aperture radius and the characteristics of beam source. As an example, the dependence of the DOP on the aperture radius, the boundary characteristic, and the beam waist width is investigated. [ABSTRACT FROM AUTHOR]