The divergent effects of G3BP orthologs on human stress granule assembly imply a centric role for the core protein interaction network.

Liquid-liquid phase separation (LLPS) mediated by G3BP1/2 proteins and non-translating mRNAs mediates stress granule (SG) assembly. We investigated the phylogenetic evolution of G3BP orthologs from unicellular yeast to mammals and identified both conserved and divergent features. The modular domain organization of G3BP orthologs is generally conserved. However, invertebrate orthologs displayed reduced capacity for SG assembly in human cells compared to vertebrate orthologs. We demonstrated that the protein-interaction network facilitated by the NTF2L domain is a crucial determinant of this specificity. The evolution of the G3BP1 network coincided with its exploitation by certain viruses, as evident from the interaction between viral proteins and G3BP orthologs in insects and vertebrates. We revealed the importance and divergence of the G3BP interaction network in human SG formation. Leveraging this network, we established a 7-component in vitro SG reconstitution system for quantitative studies. These findings highlight the significance of G3BP network divergence in the evolution of biological processes.

Luoshi Neiyi Prescription inhibits estradiol synthesis and inflammation in endometriosis through the HIF1A/EZH2/SF-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Endometriosis (EMS) is a common gynecological disease that causes dysmenorrhea, chronic pelvic pain and infertility. Luoshi Neiyi Prescription (LSNYP), a traditional Chinese medicine (TCM) formula, is used to relieve EMS in the clinic. AIMS: This study aimed to examine the active components of LSNYP and the possible mechanism involved in its treatment of EMS. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify the chemical components of LSNYP. Human primary ectopic endometrial stromal cells (ecESCs) and eutopic endometrial stromal cells (euESCs) were isolated, and the expression levels of hypoxia inducible factor 1A (HIF1A), enhancer of zeste homolog 2 (EZH2) and steroidogenic factor 1 (SF-1) were detected by immunofluorescence and qPCR. Cobalt chloride (CoCl2) was utilized to construct an in vitro hypoxic environment, and lentiviruses were engineered to downregulate HIF1A and EZH2 and upregulate EZH2. Subsequently, the expression levels of HIF1A, EZH2, and SF-1 were measured using qPCR or western blotting. The binding of EZH2 to the SF-1 locus in ESCs was examined via ChIP. Furthermore, the effects of LSNYP on the HIF1A/EZH2/SF-1 pathway were evaluated both in vitro and in vivo. RESULTS: A total of 185 components were identified in LSNYP. The protein and gene expression levels of HIF1A and SF-1 were increased, whereas those of EZH2 were decreased in ecESCs. After treating euESCs with 50 µmol L-1 CoCl2 for 24 h, cell viability and estradiol (E2) production were enhanced. Hypoxia decreased EZH2 protein expression, while si-HIF1A increased it. SF-1 was increased when EZH2 was downregulated in normal and hypoxic environments, whereas the overexpression of EZH2 led to a decrease in SF-1 expression. ChIP revealed that hypoxia reduced EZH2 binding to the SF-1 locus in euESCs. In vitro, LSNYP-containing serum decreased E2 and prostaglandin E2 (PGE2) production, inhibited cell proliferation and invasion, and reduced the expression of HIF1A, SF-1, steroidogenic acute regulatory protein (StAR), and aromatase cytochrome P450 (P450arom). In vivo, LSNYP suppressed inflammation and adhesion and inhibited the HIF1A/EZH2/SF-1 pathway in endometriotic tissues. CONCLUSIONS: LSNYP may exert pharmacological effects on EMS by inhibiting E2 synthesis and inflammation through regulation of the HIF1A/EZH2/SF-1 pathway. These results suggest that LSNYP may be a promising candidate for the treatment of EMS.

Potential mechanism of Luoshi Neiyi prescription in endometriosis based on serum pharmacochemistry and network pharmacology.

Introduction: Endometriosis (EMs) is characterized by ectopic growth of active endometrial tissue outside the uterus. The Luoshi Neiyi prescription (LSNYP) has been extensively used for treating EMs in China. However, data on the active chemical components of LSNYP are insufficient, and its pharmacological mechanism in EMs treatment remains unclear. This study aimed to explore the potential mechanism of LSNYP for EMs through network pharmacology based on the components absorbed into the blood. Methods: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to analyze blood components, and a series of network pharmacology strategies were utilized to predict targets of these components and EMs. Protein-protein interaction (PPI) network analysis, component-target-disease network construction, gene ontology (GO) functional enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Additionally, molecular docking, molecular dynamics simulations, and in vitro and in vivo experiments were conducted to validate the HIF1A/EZH2/ANTXR2 pathway associated with hypoxic pathology in EMs. Results: Thirty-four absorbed components suitable for network pharmacology analysis were identified, and core targets, such as interleukin 6, EGFR, HIF1A, and EZH2, were founded. Enrichment results indicated that treatment of EMs with LSNYP may involve the regulation of hypoxia and inflammatory-related signaling pathways and response to oxidative stress and transcription factor activity. Experimental results demonstrated that LSNYP could decrease the expression of HIF1A, ANTXR2, YAP1, CD44, and ß-catenin, and increased EZH2 expression in ectopic endometrial stromal cells and endometriotic tissues. Molecular docking and molecular dynamics simulations manifested that there was stable combinatorial activity between core components and key targets of the HIF1A/EZH2/ANTXR2 pathway. Conclusion: LSNYP may exert pharmacological effects on EMs via the HIF1A/EZH2/ANTXR2 pathway; hence, it is a natural herb-related therapy for EMs.

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

Single-cell atlas of human gingiva unveils a NETs-related neutrophil subpopulation regulating periodontal immunity.

INTRODUCTION: Exaggerated neutrophil recruitment and activation are the major features of pathological alterations in periodontitis, in which neutrophil extracellular traps (NETs) are considered to be responsible for inflammatory periodontal lesions. Despite the critical role of NETs in the development and progression of periodontitis, their specific functions and mechanisms remain unclear. OBJECTIVES: To demonstrate the important functions and specific mechanisms of NETs involved in periodontal immunopathology. METHODS: We performed single-cell RNA sequencing on gingival tissues from both healthy individuals and patients diagnosed with periodontitis. High-dimensional weighted gene co-expression network analysis and pseudotime analysis were then applied to characterize the heterogeneity of neutrophils. Animal models of periodontitis were treated with NETs inhibitors to investigate the effects of NETs in severe periodontitis. Additionally, we established a periodontitis prediction model based on NETs-related genes using six types of machine learning methods. Cell-cell communication analysis was used to identify ligand-receptor pairs among the major cell groups within the immune microenvironment. RESULTS: We constructed a single-cell atlas of the periodontal microenvironment and obtained nine major cell populations. We further identified a NETs-related subgroup (NrNeu) in neutrophils. An in vivo inhibition experiment confirmed the involvement of NETs in gingival inflammatory infiltration and alveolar bone absorption in severe periodontitis. We further screened three key NETs-related genes (PTGS2, MME and SLC2A3) and verified that they have the potential to predict periodontitis. Moreover, our findings revealed that gingival fibroblasts had the most interactions with NrNeu and that they might facilitate the production of NETs through the MIF-CD74/CXCR4 axis in periodontitis. CONCLUSION: This study highlights the pathogenic role of NETs in periodontal immunity and elucidates the specific regulatory relationship by which gingival fibroblasts activate NETs, which provides new insights into the clinical diagnosis and treatment of periodontitis.

The Concentration of Benzo[a]pyrene in Food Cooked by Air Fryer and Oven: A Comparison Study.

The air fryer utilizes heated air rather than hot oil to achieve frying, eliminating the need for cooking oil, rendering it a healthier cooking method than traditional frying and baking. However, there is limited evidence supporting that the air fryer could effectively reduce the level of food-derived carcinogen. In this study, we compared the concentration of Benzo[a]pyrene (BaP), a typical carcinogen, in beef patties cooked using an air fryer and an oven, under different cooking conditions, including temperatures (140 °C, 160 °C, 180 °C, and 200 °C), times (9, 14, and 19 min), and oil added or not. The adjusted linear regression analysis revealed that the BaP concentration in beef cooked in the air fryer was 22.667 (95% CI: 15.984, 29.349) ng/kg lower than that in beef cooked in the oven. Regarding the air fryer, the BaP concentration in beef cooked without oil brushing was below the detection limit, and it was significantly lower than in beef cooked with oil brushing (p < 0.001). Therefore, cooking beef in the air fryer can effectively reduce BaP concentration, particularly due to the advantage of oil-free cooking, suggesting that the air fryer represents a superior option for individuals preparing meat at high temperatures.

Gonadal Transcriptomic Analysis Reveals Novel Sex-Related Genes in Bactrocera dorsalis.

Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) is one of the most devastating agricultural pests worldwide due to its high reproductive and invasive abilities. The elucidation of its gonadal developmental characteristics and the identification of sex-related genes will provide a useful genetic basis for reproductive-based pest control. Here, the gonadal transcriptome of B. dorsalis was sequenced, and novel gonad-specific expressed genes were analyzed. A total of 1338, 336, 35, and 479 differentially expressed genes (DEGs) were found in the testis (TE), ovary (OV), female accessory gland (FAG), and male accessory gland (MAG), respectively. Furthermore, 463 highly expressed gonad-specific genes were identified, with the TE having the highest number of specific highly expressed genes, at 402, followed by 51 in the OV, 9 in the MAG, and only 1 in the FAG. Strikingly, approximately half of highly expressed gonad-specific genes were uncharacterized. Then, it was found that 35, 17, 3, 2, and 1 of 202 uncharacterized highly expressed TE-specific genes encoded proteins that contained transmembrane domains, signal peptides, high-mobility group boxes, the zinc finger domain, and the BTB/POZ domain, respectively. Interestingly, approximately 40% of uncharacterized highly expressed gonad-specific genes encoding proteins were not predicted to possess functional motifs or domains. Finally, the spatiotemporal expression and sequence characterization of six novel highly expressed gonad-specific genes were analyzed. Altogether, our findings provide a valuable dataset for future functional analyses of sex-related genes and potential target sites for pest control.

Bisphenol A sorption on commercial polyvinyl chloride microplastics: Effects of UV-aging, biofilm colonization and additives on plastic behaviour in the environment.

Chemical additives are important components in commercial microplastics and their leaching behaviour has been widely studied. However, little is known about the potential effect of additives on the adsorption/desorption behaviour of pollutants on microplastics and their subsequent role as vectors for pollutant transport in the environment. In this study, two types of commercial polyvinyl chloride (PVC1 and PVC2) microplastics were aged by UV irradiation and biotic modification via biofilm colonization to investigate the adsorption and desorption behaviour of bisphenol A (BPA). Surface cracks and new functional groups (e.g., O-H) were found on PVC1 after UV irradiation, which increased available adsorption sites and enhanced H‒bonding interaction, resulting in an adsorption capacity increase from 1.28 µg/L to 1.85 µg/L. However, the adsorption and desorption capacity not showed significant changes for PVC2, which might be related to the few characteristic changes after UV aging with the protection of light stabilizers and antioxidants. The adsorption capacity ranged from 1.28 µg/L to 2.06 µg/L for PVC1 and PVC2 microplastics, and increased to 1.62 µg/L-2.95 µg/L after colonization by biofilms. The increased adsorption ability might be related to the N-H functional group, amide groups generated by microorganisms enhancing the affinity for BPA. The opposite effect was observed for desorption. Plasticizers can be metabolized during biofilm formation processes and might play an important role in microorganism colonization. In addition, antioxidants and UV stabilizers might also indirectly influence the colonization of microorganisms' on microplastics by controlling the degree to which PVC microplastics age under UV. The amount of biomass loading on the microplastics would further alter the adsorption/desorption behaviour of contaminants. This study provides important new insights into the evaluation of the fate of plastic particles in natural environments.

Dose finding for ZSP1601 in patients with nonalcoholic steatohepatitis using population pharmacokinetics and exposure-response approach.

INTRODUCTION: ZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD). AIM: The aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure-response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials. METHODS: Analysis of pooled concentration-time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored. RESULTS: A two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601's pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure-response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUCss) on the 29th day. ZSP1601 exposure levels (Cmax1) exhibited a significant exposure-response relationship with headaches (p < 0.001). CONCLUSION: The PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601's pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations.

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation.

Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.

Serum SERCA2a levels in heart failure patients are associated with adverse events after discharge.

Calcium homeostasis imbalance is one of the important pathological mechanisms in heart failure. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a calcium ATPase on the sarcoplasmic reticulum in cardiac myocytes, is a myocardial systolic-diastolic Ca2 + homeostasis regulating enzyme that is not only involved in cardiac diastole but also indirectly affects cardiac myocyte contraction. SERCA2a expression was found to be decreased in myocardial tissue in heart failure, however, there are few reports on serum SERCA2a expression in patients with heart failure, and this study was designed to investigate whether serum SERCA2a levels are associated with the occurrence of adverse events after discharge in patients hospitalized with heart failure. Patients with heart failure hospitalized in the cardiovascular department of the Second Affiliated Hospital of Guangdong Medical University, China, from July 2018 to July 2019 were included in this study, and serum SERCA2a concentrations were measured; each enrolled patient was followed up by telephone after 6 months (6 ±â€…1 months) for general post-discharge patient status. The correlation between serum SERCA2a levels and the occurrence of adverse events (death or readmission due to heart failure) after hospital discharge was assessed using multiple analysis and trend analysis. Seventy-one patients with heart failure were finally included in this study, of whom 38 (53.5%) were men and 33 (46.5%) were women (All were postmenopausal women). Multiple analysis revealed no correlation between serum SERCA2a levels and the occurrence of adverse events in the total study population and in male patients, but serum SERCA2a levels were associated with the occurrence of adverse outcome events after hospital discharge in female patients (OR = 1.02, P = .047). Further analysis using a trend analysis yielded a 4.0% increase in the risk of adverse outcomes after hospital discharge for each unit increase in SERCA2a in female patients (OR = 1.04; P = .02), while no significant difference was seen in men. This study suggests that serum SERCA2a levels at admission are associated with the occurrence of post-discharge adverse events in postmenopausal female patients hospitalized with heart failure.

Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

Alpha-lipoic acid improves cryopreservation of rooster semen by reducing oxidative stress.

Inhibiting oxidative stress is key for ensuring sperm motility during semen cryopreservation. The aim of this study was to investigate the effect of adding alpha-lipoic acid (ALA) as an extender in rooster semen cryopreservation. Different concentrations of ALA were added to the frozen diluent of rooster semen; subsequently, computer-aided semen analysis was used to determine membrane functional integrity, acrosome integrity, antioxidant capacity (based on T-AOC, GSH-Px, SOD, CAT, and MDA contents), and mitochondrial integrity. The frozen sperm ultrastructure was observed using transmission electron microscopy. The results showed that the addition of different concentrations of ALA partially to greatly improved the quality of frozen sperm; in particular, 8 µg/mL ALA significantly improved multiple parameters of sperm quality, including sperm motility and antioxidant enzyme activity, after freeze-thaw. The results of this study provide empirical and theoretical support for effective rooster semen cryopreservation and can inform the development of new protective agents in the field of livestock reproduction.

Bismuth Ferrite-Based Lead-Free High-Entropy Piezoelectric Ceramics.

Piezoelectric ceramics, as essential components of actuators and transducers, have captured significant attention in both industrial and scientific research. The "entropy engineering" approach has been demonstrated to achieve excellent performance in lead-based materials. In this study, the "entropy engineering" approach was employed to introduce the morphotropic phase boundary (MPB) into the bismuth ferrite (BF)-based lead-free system. By employing this strategy, a serial of novel "medium to high entropy" lead-free piezoelectric ceramics were successfully synthesized, namely (1-x)BiFeO3-x(Ba0.2Sr0.2Ca0.2Bi0.2Na0.2)TiO3 (BF-xBSCBNT, x = 0.15-0.5). Our investigation systematically examined the phase structure, domain configuration, and ferroelectric/piezoelectric properties as a function of conformational entropy. Remarkable performances with a largest strain of 0.50% at 100 kV/cm, remanent polarization ∼40.07 µC/cm2, coercive field ∼74.72 kV/cm, piezoelectric coefficient ∼80 pC/N, and d33* ∼500 pm/V were achieved in BF-0.4BSCBNT ceramics. This exceptional performance can be attributed to the presence of MPB, coexisting rhombohedral and cubic phases, along with localized nanodomains. The concept of high-entropy lead-free piezoelectric ceramics in this study provides a promising strategy for the exploration and development of the next generation of lead-free piezoelectric materials.

Constructing green superhydrophilic and superoleophobic COFs-MOFs hybrid-based membrane for efficiently emulsion separation and synchronous removal of microplastics, dyes, and pesticides.

Oil spills and micropollutants have become thorny environmental issues, posing serious threat to ecosystem and human health. To settle such dilemma, this study successfully constructed a robust and environmentally-friendly MOFs-COFs hybrid-based membrane (FS-50/COF(MATPA)-MOF(Zr)/PDA@PVDF) for the first time through solution synthesis and solvothermal method, combined with surface modification of FS-50 molecule. Importantly, we employed a simple two-step strategy to obtain the high-aspect-ratio MOFs fibers: (1) solvent regulation to generate smaller needle-like whiskers during the in-situ growth of MOFs on COFs; (2) high pressure induced directional crystallization in filtration process. The introduction of polydopamine (PDA) greatly improved the adhesion between coating and PVDF membrane. The in-situ growth of high length-diameter ratio MOFs fibers on blocky COFs greatly enhanced the specific surface area of MOFs-COFs hybrid, thus provided sufficient absorption sites. The functional groups of FS-50 endowed the hybrid membrane with superhydrophilicity and superoleophobicity, which facilitated to selectively penetrate water molecules and repel non-polar pollutants. The separation efficiency and decontamination mechanism of hybrid membrane to the simulated oily wastewater (containing various MPs, dyes, and pesticides) were investigated through experiments and theoretical calculations. The hybrid membrane could selectively and synchronously adsorb various dyes (20 mg/L-120 mg/L, almost 100% removal) and pesticides (10 mg/L for DIF and TET, adsorption rates 93.2% and 90.9%, respectively) from oil-water emulsion (50 mL). The large-scale coated sponge (6 cm × 4.5 cm × 3 cm) could quickly achieve separation of oil-water mixture (almost 100%) with a water permeability of more than 162 L m-2·h-1·bar-1, and simultaneously remove various MPs (PP-2000, PP-100, PE-2000, PS-100, 0.2 g/300 mL for each), Sudan Ⅲ (C0 = 200 mg/L), and DIF (C0 = 10 mg/L) from a simulant oily wastewater (300 mL), with the removal rates of almost 100% for MPs, 99.7% for Sudan Ⅲ, and 95.8% for DIF. Furthermore, we elucidated the removal mechanism of pesticide and dyes through simulating the theoretical adsorption energy and potential adsorption sites. The hybrid membrane not only provides a promising candidate for the removal of multiple pollutants from oil-water emulsion, but also opens a new strategy for achieving efficient and clean aquatic environment restoration.

An injury-responsive mmp14b enhancer is required for heart regeneration.

Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent mmp14b endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of mmp14b. Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.

ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial.

Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.

Prevalence of propionic acidemia in China.

Propionic acidemia (PA) is a rare autosomal recessive congenital disease caused by mutations in the PCCA or PCCB genes. Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA. Early-onset PA can lead to acute deterioration, metabolic acidosis, and hyperammonemia shortly after birth, which can result in high mortality and disability. Late-onset cases of PA have a more heterogeneous clinical spectra, including growth retardation, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease. Timely and accurate diagnosis and appropriate treatment are crucial to saving patients' lives and improving their prognosis. Recently, the number of reported PA cases in China has increased due to advanced diagnostic techniques and increased research attention. However, an overview of PA prevalence in China is lacking. Therefore, this review provides an overview of recent advances in the pathogenesis, diagnostic strategies, and treatment of PA, including epidemiological data on PA in China. The most frequent variants among Chinese PA patients are c.2002G > A in PCCA and c.1301C > T in PCCB, which are often associated with severe clinical symptoms. At present, liver transplantation from a living (heterozygous parental) donor is a better option for treating PA in China, especially for those exhibiting a severe metabolic phenotype and/or end-organ dysfunction. However, a comprehensive risk-benefit analysis should be conducted as an integral part of the decision-making process. This review will provide valuable information for the medical care of Chinese patients with PA.

Low-grade wind-driven directional flow in anchored droplets.

Low-grade wind with airspeed Vwind < 5 m/s, while distributed far more abundantly, is still challenging to extract because current turbine-based technologies require particular geography (e.g., wide-open land or off-shore regions) with year-round Vwind > 5 m/s to effectively rotate the blades. Here, we report that low-speed airflow can sensitively enable directional flow within nanowire-anchored ionic liquid (IL) drops. Specifically, wind-induced air/liquid friction continuously raises directional leeward fluid transport in the upper portion, whereas three-phase contact line (TCL) pinning blocks further movement of IL. To remove excessive accumulation of IL near TCL, fluid dives, and headwind flow forms in the lower portion, as confirmed by microscope observation. Such stratified circulating flow within single drop can generate voltage output up to ~0.84 V, which we further scale up to ~60 V using drop "wind farms". Our results demonstrate a technology to tap the widespread low-grade wind as a reliable energy resource.

Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia.

OBJECTIVE: NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. DESIGN: We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays. RESULTS: Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30 mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity. CONCLUSION: We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic for NRF2high ESCC.