Corrigendum: Blood glucose to predict symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke with large infarct core: a prospective observational study.

[This corrects the article DOI: 10.3389/fneur.2024.1367177.].

Sedentary behaviour among elderly patients after total knee arthroplasty and its influencing factors.

To understand the status of sedentary behaviour in elderly patients after total knee arthroplasty and analyse its influencing factors so as to provide a reference for developing targeted interventions. Conveniently selected elderly patients undergoing total knee arthroplasty (> 6 months) in a tertiary hospital in Jiangsu Province were investigated using a general information questionnaire, the Charlson Comorbidity Index, patients' self-reported sedentary behaviour information, the WOMAC Score, The Groningen Orthopaedic Social Support Scale, and Lee's Fatigue. The median daily sedentary time was 5.5 h (4.5 h, 6.625 h) in 166 elderly patients after total knee arthroplasty, of whom 82 (49.40%) showed sedentary behaviour (≥ 6 h per day). Logistic regression analysis showed that being retired/unemployed (OR = 8.550, 95% CI 1.732-42.207, P = 0.0084), having a CCI score ≥ 3 (OR = 9.018, 95% CI 1.288-63.119, P < 0.0001), having high WOMAC scores (OR = 1.783, 95% CI 1.419-2.238, P < 0.0001), having a high social support score (OR = 1.155, 95% CI 1.031-1.294, P = 0.0130), and having a fatigue score ≥ 5 (OR = 4.848, 95% CI 1.084-21.682, P = 0.0389) made patients more likely to be sedentary. The sedentary time of elderly patients after total knee arthroplasty is long, and sedentary behaviour is common among them. Healthcare professionals should develop targeted sedentary behaviour interventions based on the influencing factors of sedentary behaviour in order to reduce the occurrence of sedentary behaviour in elderly patients after total knee arthroplasty.

Comprehensive analysis of distribution characteristics and horizontal gene transfer elements of blaNDM-1-carrying bacteria.

The worldwide dissemination of New Delhi metallo-ß-lactamase-1 (NDM-1), which mediates resistance to almost all clinical ß-lactam antibiotics, is a major public health problem. The global distribution, species, sources, and potential transfer risk of blaNDM-1-carrying bacteria are unclear. Results of a comprehensive analysis of literature in 2010-2022 showed that a total of 6002 blaNDM-1 carrying bacteria were widely distributed around 62 countries with a high trend in the coastal areas. Opportunistic pathogens or pathogens like Klebsiella sp., Escherichia sp., Acinetobacter sp. and Pseudomonas sp. were the four main species indicating the potential microbial risk. Source analysis showed that 86.45 % of target bacteria were isolated from the source of hospital (e.g., Hospital patients and wastewater) and little from surface water (5.07 %) and farms (3.98 %). A plasmid-encoded blaNDM-1Acinetobacter sp. with the resistance mechanisms of antibiotic efflux pump, antibiotic target change and antibiotic degradation was isolated from the wastewater of a typical tertiary hospital. Insertion sequences (IS3 and IS30) located in the adjacent 5 kbp of blaNDM-1-bleMBL gene cluster indicating the transposon-mediated horizontal gene transfer risk. These results showed that the worldwide spread of blaNDM-1-carrying bacteria and its potential horizontal gene transfer risk deserve good control.

Blood glucose to predict symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke with large infarct core: a prospective observational study.

Introduction: Symptomatic intracranial hemorrhage (sICH) is a serious complication of acute ischemic stroke (AIS) after endovascular treatment (EVT). Limited data exist regarding predictors and clinical implications of sICH after EVT, underscoring the significance of identifying risk factors to enhance prevention strategies. Therefore, the main objective of this study was to evaluate the incidence of sICH and identify its predictors after EVT in patients with large infarct core-AIS in the pre-circulation stage. Methods: Using data from the EVT for the Pre-circulation Large Infarct Core-AIS Study, we enrolled patients who were treated with EVT from the Prospective Multicenter Cohort Study of Early Treatment in Acute Stroke (MAGIC) registry. Baseline demographics, medical history, vascular risk factors, blood pressure, stroke severity, radiographic features, and EVT details were collected. The patients were classified into three groups: without intracranial hemorrhage (ICH), with asymptomatic intracranial hemorrhage (aICH), and sICH, based upon the occurrence of sICH. The main outcomes were the occurrence of sICH according to the Heidelberg Bleeding Classification and functional condition at 90 days. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to identify independent predictors of sICH after EVT. Results: The study recruited a total of 490 patients, of whom 13.3% (n = 65) developed sICH. Patients with sICH had less favorable outcomes than those without intracranial hemorrhage (ICH) and those with aICH (13.8% vs. 43.5% vs. 32.2%, respectively; p < 0.001). The overall mortality was 41.8% (n = 205) at 90 days post-EVT. The univariate analysis revealed significant differences among the three groups in terms of blood glucose levels at admission, probability of favorable outcomes, incidence of brain herniation, and 90-day mortality. The multifactorial logistic regression analysis revealed that the blood glucose level at admission [odds ratio (OR) 1.169, p < 0.001, confidence interval (CI) 1.076-1.269] was an independent predictor of sICH. A blood glucose level of 6.95 mmol/L at admission was the best predictor of sICH, with an area under the ROC curve (AUC) of 0.685 (95% CI: 0.616-0.754). Discussion: The study findings demonstrated that the probability of sICH after EVT was 13.3% in patients with pre-circulation large infarct core-AIS, and sICH increased the risk of an unfavorable prognosis. Higher blood glucose levels at admission were associated with sICH after EVT in patients with pre-circulation large infarct core AIS. These findings underscore the importance of early management strategies to mitigate this risk.

Isobavachalcone induces hepatotoxicity in zebrafish embryos and HepG2 cells via the System Xc--GSH-GPX4 signaling pathway in ferroptosis response.

Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH-Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin-1 could reverse the effect of IBC. Targeting the System Xc--GSH-GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC-induced hepatotoxicity.

Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy.

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

Development of a Perioperative Enteral Nutrition Program for Gastric Cancer Surgery.

Objective: This study aimed to summarize the current evidence-based approach to perioperative enteral nutritional (EN) program for gastric cancer (GC) surgery and to develop a staged and operable EN management scheme based on the evidence to provide clinical guidance for improving perioperative EN management in patients with GC.Methods: First, we synthesized expert consensuses, systematic reviews, and guidelines related to GC patients who had undergone surgery, based on a review of the literature and expert meetings. Subsequently, after carefully evaluating and selecting relevant EN management data, we created a preliminary draft of a perioperative EN program. Following Delphi expert consultations, the final version of the perioperative EN program was constructed after revision.Results: After two rounds of consultation, the expert opinions tended to be consistent. The expert positive coefficient was 1.00, and the expert authority coefficient was 0.90. After the second round of consultation, the coefficient of variation of the importance score ranged from 0.05 to 0.20, and the coefficient of variation of the feasibility score ranged from 0.09 to 0.23. The Kendall harmony coefficients were 0.338 and 0.392, and the difference between them was statistically significant (p < 0.001). The final practice plan includes 4 first-level, 16 s-level, and 64 third-level items.Conclusions: The perioperative EN program constructed in this study is comprehensive in content, feasible, and evidence-based, and can provide insights for clinical improvement.

The acute oral toxicity test of ethanol extract of salt-processed Psoraleae Fructus and its acute hepatotoxicity and nephrotoxicity risk assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoraleae Fructus is a well-known Traditional Chinese Medicine which has long been used to warm and tonify the kidney and treat diseases such as osteoporosis and diarrhea. However, it may cause multiorgan injury, which limited its use. AIM OF THE STUDY: The aim of this study was to identify the components of ethanol extract of salt-processed Psoraleae Fructus (EEPF) and systematically investigate its acute oral toxicity and the mechanism underlying its acute hepatotoxicity. MATERIALS AND METHODS: In this study, the UHPLC-HRMS analysis was carried out for components identification. Followed by acute oral toxicity test in Kunming mice, which received oral gavage of EEPF from 3.85 to 78.00 g/kg. Body weight, organ indexes, biochemical analysis, morphology, histopathology, oxidative stress state, TUNEL, mRNA and protein expression of NLRP3/ASC/Caspase-1/GSDMD signaling pathway were evaluated to study the EEPF-induced acute hepatotoxicity and its underlying mechanisms. RESULTS: The results showed that 107 compounds such as psoralen and isopsoralen were identified in EEPF. And the acute oral toxicity test demonstrated the LD50 of EEPF was 15.95 g/kg in Kunming mice. The survival mice displayed non-significant difference in body weight compared with Control at the end of the observation period. And the organ indexes of heart, liver, spleen, lung, and kidney showed no significant difference. However, the morphological and histopathological changes of these organs in high-dose-groups mice indicated that the liver and kidney might be the main target toxic organs of EEPF, which showed hepatocyte degeneration with lipid droplets and protein cast in kidney. It could be confirmed by the significant increases of liver and kidney function parameters such as AST, ALT, LDH, BUN, and Crea. In addition, the oxidative stress markers, MDA in the liver and kidney was significantly increased while SOD, CAT, GSH-Px (only liver), and GSH were significantly decreased. Furthermore, EEPF increased the TUNEL-positive cells and the mRNA and protein expression of NLRP3, Caspase-1, ASC and GSDMD in liver with increased protein expression of IL-1ß and IL-18. Notably, cell viability test showed that the specific inhibitor of Caspase-1 could reverse the Hep-G2 cell death induced by EEPF. CONCLUSION: To summarize, this study analyzed the 107 compounds of EEPF. The acute oral toxicity test demonstrated the LD50 value of EEPF was 15.95 g/kg in Kunming mice and the liver and kidney might be the main target toxic organs of EEPF. It caused liver injury through oxidative stress and pyroptotic damage via NLRP3/ASC/Caspase-1/GSDMD signaling pathway.

Sustained visual attentional load modulates audiovisual integration in older and younger adults.

Previous studies have shown that attention influences audiovisual integration (AVI) in multiple stages, but it remains unclear how AVI interacts with attentional load. In addition, while aging has been associated with sensory-functional decline, little is known about how older individuals integrate cross-modal information under attentional load. To investigate these issues twenty older adults and 20 younger adults were recruited to conduct a dual task including a multiple object tracking (MOT) task, which manipulated sustained visual attentional load, and an audiovisual discrimination task, which assesses AVI. The results showed that response times were shorter and hit rate was higher for audiovisual stimuli than for auditory or visual stimuli alone and in younger adults than in older adults. The race model analysis showed that AVI was higher under the load_3 condition (monitoring two targets of the MOT task) than under any other load condition (no-load [NL], one or three targets monitoring). This effect was found regardless of age. However, AVI was lower in older adults than younger adults under NL condition. Moreover, the peak latency was longer, and the time window of AVI was delayed in older adults compared to younger adults under all conditions. These results suggest that slight visual sustained attentional load increased AVI but that heavy visual sustained attentional load decreased AVI, which supports the claim that attention resource was limited, and we further proposed that AVI was positively modulated by attentional resource. Finally, there were substantial impacts of aging on AVI; AVI was delayed in older adults.

Cardiotoxicity of (-)-borneol, (+)-borneol, and isoborneol in zebrafish embryos is associated with Na+ /K+ -ATPase and Ca2+ -ATPase inhibition.

Borneol is an example of traditional Chinese medicine widely used in Asia. There are different isomers of chiral borneol in the market, but its toxicity and effects need further study. In this study, we used zebrafish embryos to examine the effects of exposure to three isomers of borneol [(-)-borneol, (+)-borneol, and isoborneol] on heart development and the association with Na+ /K+ -ATPase from 4 h post-fertilization (4 hpf). The results showed that the three isomers of borneol increased mortality and decreased hatching rate when the zebrafish embryo developed to 72 hpf. All three isomers of borneol (0.01-1.0 mM) significantly reduced heart rate from 48 to 120 hpf and reduced the expression of genes related to Ca2+ -ATPase (cacna1ab and cacna1da) and Na+ /K+ -ATPase (atp1b2b, atp1a3b, and atp1a2). At the same time, the three isomers of borneol significantly reduced the activities of Ca2+ -ATPase and Na+ /K+ -ATPase at 0.1 to 1.0 mM. (+)-Borneol caused the most significant reduction (p < 0.05), followed by isoborneol and (-)-borneol. Na+ /K+ -ATPase was mainly expressed in otic vesicles and protonephridium. All three isomers of borneol reduced Na+ /K+ -ATPase mRNA expression, but isoborneol was the most significant (p < 0.01). Our results indicated that (+)-borneol was the least toxic of the three isomers while the isoborneol showed the most substantial toxic effect, closely related to effects on Na+ /K+ -ATPase.

Digitalisation of birth registration system in Malaysia: Boon or bane for the hard-to-reach and marginalised?

Access to birth registration among the refugees, migrants, and undocumented or stateless individuals in Sabah and Peninsular Malaysia remains hindered largely due to their lack of legal status. This study identifies the barriers to birth registration faced by these communities, including during the COVID-19 pandemic, and explores the extent to which digital technologies may overcome or amplify these barriers. Findings are reported from a review of literature, websites, and media articles and semi-structured interviews with community-based organisations and community leaders representing the communities. The themes for the questions were structured based on Plan International's (2015) Step-by-step Guide for Identifying and Addressing the Risks to Children in Digitised birth registration systems. We identified that the digitalisation of birth registration poses more risks of exclusion than benefits to the marginalised communities without a secure and inclusive operating environment. Subject to an inequality assessment to evaluate and address the existing inequalities, a hybrid system that factors in the role of citizen facilitation hubs would be ideal for ensuring no one gets "left behind".

Pseudoephedrine hydrochloride causes hyperactivity in zebrafish via modulation of the serotonin pathway.

This study aimed to explore behavioral changes of embryonic and larval zebrafish caused by pseudoephedrine hydrochloride (PSE) and its underlying mechanism. Zebrafish embryos were exposed to 0.5 µM, 2 µM, and 8 µM PSE at 4 h post-fertilization (4 hpf) or 22-23 hpf. Mortality, hatching rate, coiling frequency, heart rate, behavior changes, and related gene expression were observed at different developmental stages. PSE below 8 µM did not affect zebrafish mortality, hatching rate, and heart rate compared with the control group. For embryos, PSE caused an increase at 16-32 hpf in zebrafish coiling frequency which could be rescued by serotonin antagonist WAY100635. Similarly, PSE caused an increase in the swimming distance of zebrafish larvae at 120 hpf. PSE also elevated the expression of serotonin (5-HT)-related genes 5-htr1ab and tph2 and dopamine-related gene dbh. Behavioral changes in zebrafish embryos and larvae caused by PSE may be closely associated with increased expression of 5-HT and dopamine-related genes. This may be reflected that the behavioral changes in zebrafish are a possible PSE monitoring indicator.

Retinoic acid inhibits the angiogenesis of human embryonic stem cell-derived endothelial cells by activating FBP1-mediated gluconeogenesis.

BACKGROUND: Endothelial cells are located in the inner lumen of blood and lymphatic vessels and exhibit the capacity to form new vessel branches from existing vessels through a process called angiogenesis. This process is energy intensive and tightly regulated. Glycolysis is the main energy source for angiogenesis. Retinoic acid (RA) is an active metabolite of vitamin A and exerts biological effects through its receptor retinoic acid receptor (RAR). In the clinic, RA is used to treat acne vulgaris and acute promyelocytic leukemia. Emerging evidence suggests that RA is involved in the formation of the vasculature; however, its effect on endothelial cell angiogenesis and metabolism is unclear. METHODS: Our study was designed to clarify the abovementioned effect with human embryonic stem cell-derived endothelial cells (hESC-ECs) employed as a cell model. RESULTS: We found that RA inhibits angiogenesis, as manifested by decreased proliferation, migration and sprouting activity. RNA sequencing revealed general suppression of glycometabolism in hESC-ECs in response to RA, consistent with the decreased glycolytic activity and glucose uptake. After screening glycometabolism-related genes, we found that fructose-1,6-bisphosphatase 1 (FBP1), a key rate-limiting enzyme in gluconeogenesis, was significantly upregulated after RA treatment. After silencing or pharmacological inhibition of FBP1 in hESC-ECs, the capacity for angiogenesis was enhanced, and the inhibitory effect of RA was reversed. ChIP-PCR demonstrated that FBP1 is a target gene of RAR. When hESC-ECs were treated with the RAR inhibitor BMS493, FBP1 expression was decreased and the effect of RA on angiogenesis was partially blocked. CONCLUSIONS: The inhibitory role of RA in glycometabolism and angiogenesis is RAR/FBP1 dependent, and FBP1 may be a novel therapeutic target for pathological angiogenesis.

Developmental disorders caused by cefixime in the otic vesicles of zebrafish embryos or larvae.

To explore the developmental toxicity of cefixime (CE) in the developmental disorder and toxicity mechanism of CE on otic vesicles, zebrafish embryos were used as an animal model. The results showed that CE increased mortality in a dose-dependent manner and decreased the hatching rate of zebrafish larva at 96 hpf. Interestingly, CE significantly reduced the area of the saccule and utricle, as well as the area of otic vesicles in zebrafish larvae (p < 0.001). Fibroblast growth factor 8a (Fgf8a) inhibitors and bone morphogenetic protein (BMP) inhibitors caused similar morphological changes. CE decreased the lateral hair cells of zebrafish larvae in a dose-dependent manner. Furthermore, CE caused the downregulation of cartilage and bone-related genes and Na+/K+-ATPase-related genes of zebrafish larvae at 72 hpf and 120 hpf according to RT-qPCR. A comparison with the control group revealed that 100 µg/mL CE also caused a decrease in Na+/K+-ATPase activity (p < 0.01). In addition, antibody staining verified that CE inhibited the expression of Na+/K+-ATPase in the otic vesicles and the nephridium of zebrafish larvae. The data obtained in this study suggested that CE has significant ototoxicity during embryonic development of zebrafish, which is closely related to Na+/K+-ATPase and the regulation of the Fgf8a/BMP signaling pathways. The effects and toxicity of CE on ear development in other animal models need to be further explored.

Establishment of an in vitro safety assessment model for lipid-lowering drugs using same-origin human pluripotent stem cell-derived cardiomyocytes and endothelial cells.

Cardiovascular safety assessment is vital for drug development, yet human cardiovascular cell models are lacking. In vitro mass-generated human pluripotent stem cell (hPSC)-derived cardiovascular cells are a suitable cell model for preclinical cardiovascular safety evaluations. In this study, we established a preclinical toxicology model using same-origin hPSC-differentiated cardiomyocytes (hPSC-CMs) and endothelial cells (hPSC-ECs). For validation of this cell model, alirocumab, a human antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), was selected as an emerging safe lipid-lowering drug; atorvastatin, a common statin (the most effective type of lipid-lowering drug), was used as a drug with reported side effects at high concentrations, while doxorubicin was chosen as a positive cardiotoxic drug. The cytotoxicity of these drugs was assessed using CCK8, ATP, and lactate dehydrogenase release assays at 24, 48, and 72 h. The influences of these drugs on cardiomyocyte electrophysiology were detected using the patch-clamp technique, while their effects on endothelial function were determined by tube formation and Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake assays. We showed that alirocumab did not affect the cell viability or cardiomyocyte electrophysiology in agreement with the clinical results. Atorvastatin (5-50 µM) dose-dependently decreased cardiovascular cell viability over time, and at a high concentration (50 µM, ~100 times the normal peak serum concentration in clinic), it affected the action potentials of hPSC-CMs and damaged tube formation and Dil-Ac-LDL uptake of hPSC-ECs. The results demonstrate that the established same-origin hPSC-derived cardiovascular cell model can be used to evaluate lipid-lowering drug safety in cardiovascular cells and allow highly accurate preclinical assessment of potential drugs.

Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect.

AIMS: Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD. METHODS AND RESULTS: Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time. CONCLUSIONS: In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.

Intermittent Starvation Promotes Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent an infinite cell source for cardiovascular disease modeling, drug screening and cell therapy. Despite extensive efforts, current approaches have failed to generate hPSC-CMs with fully adult-like phenotypes in vitro, and the immature properties of hPSC-CMs in structure, metabolism and electrophysiology have long been impeding their basic and clinical applications. The prenatal-to-postnatal transition, accompanied by severe nutrient starvation and autophagosome formation in the heart, is believed to be a critical window for cardiomyocyte maturation. In this study, we developed a new strategy, mimicking the in vivo starvation event by Earle's balanced salt solution (EBSS) treatment, to promote hPSC-CM maturation in vitro. We found that EBSS-induced starvation obviously activated autophagy and mitophagy in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Intermittent starvation, via 2-h EBSS treatment per day for 10 days, significantly promoted the structural, metabolic and electrophysiological maturation of hESC-CMs. Structurally, the EBSS-treated hESC-CMs showed a larger cell size, more organized contractile cytoskeleton, higher ratio of multinucleation, and significantly increased expression of structure makers of cardiomyocytes. Metabolically, EBSS-induced starvation increased the mitochondrial content in hESC-CMs and promoted their capability of oxidative phosphorylation. Functionally, EBSS-induced starvation strengthened electrophysiological maturation, as indicated by the increased action potential duration at 90% and 50% repolarization and the calcium handling capacity. In conclusion, our data indicate that EBSS intermittent starvation is a simple and efficient approach to promote hESC-CM maturation in structure, metabolism and electrophysiology at an affordable time and cost.

The updated view on induced pluripotent stem cells for cardiovascular precision medicine.

Cardiovascular diseases have consistently been one of the leading causes of mortality, despite investigations by many scientists and clinicians. Animal models are versatile platforms to illustrate various mechanisms of different diseases, but are lacking in accurately portraying cardiovascular disease phenotypes. The advent of human pluripotent stem cells (PSCs) has led to much development in the construction of cardiovascular disease models. In this review, we provide a brief overview of the history and utilization of PSCs for cardiovascular precision medicine, including disease modeling, drug screening, and gene editing, and elaborate on the current updated research status of patient-specific induced pluripotent stem cell (iPSC)-based disease models for cardiac channelopathies, cardiomyopathies, and other cardiovascular diseases. Furthermore, we highlight the development of novel human iPSC-derived engineered heart tissues for cardiovascular disease modeling. Finally, we put forward our own views on the existing advantages and difficulties for moving forward in this field.

Aconitine disrupts serotonin neurotransmission via 5-hydroxytryptamine receptor in zebrafish embryo.

Medicinal plants of the genus Aconitum are one of the most commonly used herbs in traditional medicine in East Asia to treat conditions related to the heart, pain, or inflammation. However, these herbs are also dangerous as accidental poisoning due to misuse is a recurring issue. These plants contain a number of diester-diterpenoid alkaloid compounds and aconitine is the most abundant and active one. This study investigated neurotoxicity of aconitine to zebrafish embryos in early development in relation to serotonin regulation. Experimental results showed that aconitine exposure (1, 10, and 100 µM) increased frequency of coiling behavior in zebrafish embryos in a dose-dependent manner and this effect can be triggered by either exposure to 5-hydroxytryptamine 1A (5-HT1A) receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) or overexpression of serotonin receptor 5-htr1ab. At the same time, coiling behavior caused by aconitine exposure could be rescued by co-exposure to 5-HT1A receptor antagonist WAY-100635 Maleate (WAY100635) and knockdown of 5-htr1ab using morpholino. Exposure to aconitine also significantly increased serotonin receptor 5-htr1ab and 5-htr1bd gene expression at 24 h post fertilization (hpf), but decreased their expression and protein expression of the serotonin receptor at 96 hpf with the high dose. These results suggest that neurotoxicity caused by aconitine is mediated through the 5-HT receptor.

Bifurcation and oscillatory dynamics of delayed CDK1-APC feedback loop.

Extensive experimental evidence has been demonstrated that the dynamics of CDK1-APC feedback loop play crucial roles in regulating cell cycle processes, but the dynamical mechanisms underlying the regulation of this loop are still not completely understood. Here, the authors systematically investigated the stability and bifurcation criteria for a delayed CDK1-APC feedback loop. They showed that the maximum reaction rate of CDK1 inactivation by APC can drive sustained oscillations of CDK1 activity ([inline-formula removed]) and APC activity ([inline-formula removed]), and the amplitude of these oscillations is increasing with the increase of the reaction rate over a wide range; a certain range of the self-activation rate for CDK1 is also significant for generating these oscillations, for too high or too low rates the oscillations cannot be generated. Moreover, they derived the sufficient conditions to determine the stability and Hopf bifurcations, and found that the sum of time delays required for activating CDK1 and APC can induce [inline-formula removed] and [inline-formula removed] to be oscillatory, even when the [inline-formula removed] and [inline-formula removed] settle in a definite stable steady state. Furthermore, they presented an explicit algorithm for the properties of periodic oscillations. Finally, numerical simulations have been presented to justify the validity of theoretical analysis.