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Induced pluripotent stem cells (iPSCs) have the ability to differentiate into cardiomyocytes (CMs). They are not only widely used in cardiac pharmacology screening, human heart disease modeling, and cell transplantation-based treatments, but also the most promising source of CMs for experimental and clinical applications. However, their use is largely restricted by the immature phenotype of structure and function, which is similar to embryonic or fetal CMs and has certain differences from adult CMs. In order to overcome this critical issue, many studies have explored and revealed new strategies to induce the maturity of iPSC-CMs. Therefore, this article aims to review recent induction methods of mature iPSC-CMs, related mechanisms, and limitations.

High-entropy oxides (HEO) with entropic stabilization and compositional flexibility have great potential application in batteries and catalysis. In this work, HEO thin films were synthesized by pulsed laser deposition (PLD) from a rock-salt (Co 0.2 Ni 0.2 Cu 0.2 Mg 0.2 Zn 0.2 )O ceramic target. The films exhibited the target’s crystal structure, were chemically homogeneous, and possessed a three-dimensional (3D) island morphology with connected randomly shaped nanopores. The effects of varying PLD laser fluence on crystal structure and morphology were explored systematically. Increasing fluence facilitates film crystallization at low substrate temperature (300 °C) and increases film thickness (60–140 nm). The lateral size of columnar grains, islands (19 nm to 35 nm in average size), and nanopores (9.3 nm to 20 nm in average size) increased with increasing fluence (3.4 to 7.0 J/cm 2 ), explained by increased kinetic energy of adatoms and competition between deposition and diffusion. Additionally, increasing fluence reduces the number of undesirable droplets observed on the film surface. The nanoporous HEO films can potentially serve as electrochemical reaction interfaces with tunable surface area and excellent phase stability. Graphical abstract

Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

Verticillium wilt (VW), caused by the soil-borne phytopathogen Verticillium dahliae, is a devastating vascular disease that severely threatens global cotton production and causes substantial economic losses. Jasmonic acid (JA) signaling plays a crucial role in plant innate immunity; however, the molecular mechanisms governing JA biosynthesis during cotton defense responses to V. dahliae infection remain largely elusive. In this study, we identified that GhAOS1 (allene oxide synthase 1), a key rate-limiting enzyme-encoding gene in the JA biosynthetic pathway, was rapidly and significantly induced by V. dahliae infection and exclusively localized in chloroplasts. Functional analysis in GhAOS1-silenced cotton and overexpressing Arabidopsis plants demonstrated that GhAOS1 positively regulates resistance to V. dahliae. Transcriptome analysis of GhAOS1-silenced cotton plants showed that DEGs are significantly enriched in phenylpropanoid biosynthesis, flavonoid biosynthesis, and α-linolenic acid metabolism pathways. Consistent with these findings, silencing GhAOS1 significantly reduced endogenous JA levels and suppressed the expression of defense-related genes and JA biosynthetic genes in cotton. Furthermore, we identified that the transcription factor GhWRKY70 directly binds to the W-box cis-acting element in the GhAOS1 promoter through Y1H, LUC, and EMSA, which activated GhAOS1 transcription. Silencing GhWRKY70 in cotton significantly enhanced plant susceptibility to V. dahliae and suppressed the expression of JA signaling pathway-related genes. Collectively, our results elucidate that GhWRKY70 positively regulates cotton resistance to VW by activating GhAOS1-mediated JA biosynthesis, revealing a novel GhWRKY70-GhAOS1 regulatory module that integrates JA signaling to coordinate cotton immune responses against V. dahliae. This study provides new insights into the molecular mechanism of JA-mediated defense and offers potential targets for molecular breeding of VW-resistant cotton.

KEY MESSAGE : EaCHS1 functions in the tolerance of plantlets to salinity stress by maintaining ROS homeostasis. Chalcone synthase (CHS) is an essential enzyme in the biosynthesis of flavonoids. Expression of CHS is governed by a wide range of environmental stimuli, including UV light, pathogen attack, and circadian clocks. However, little research exists on the relationship between CHS and salinity stress. In this work, we constructed separate overexpression and RNA interference vectors of EaCHS1, and transferred them into tobacco. Overexpression of EaCHS1 increased the production of downstream flavonoids and the expressions of related genes in the phenylpropanoid pathway. It also improved resistance to salinity stress during seed germination and root development. In contrast, heterologous silencing of endogenous CHS in tobacco by a conserved EaCHS1 fragment had opposite effect. Together, our results indicated that changing the expression level of EaCHS1 in plants alters the accumulation of flavonoids and regulates plantlet tolerance to salinity stress by maintaining ROS homeostasis.

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate the expression of a wide range of target genes in response to endogenous and exogenous ligands, including steroid hormones, thyroid hormone, vitamin D, retinoic acid, fatty acids, and oxidative steroids. Upon ligand binding, nuclear receptors form dimer complexes with transcriptional cofactors, which interact with specific DNA sequences in the promoter or enhancer regions of target genes to modulate gene expression. This process plays a crucial role in many physiological processes such as reproduction, development, immune responses, metabolism, and homeostasis. Dysregulation of nuclear receptor signaling is implicated in the pathogenesis of numerous diseases, including cancers, metabolic disorders, cardiovascular diseases, and autoimmune conditions. Therefore, understanding the molecular mechanisms underlying nuclear receptor functions is essential for the development of novel therapeutic strategies. This review summarizes the current understanding of nuclear receptors in both physiological and pathological contexts, providing insights into the signaling pathways they regulate. Additionally, we discuss recent advances in drug development targeting nuclear receptors, with a focus on preclinical and clinical studies aimed at improving therapeutic efficacy. By exploring these therapeutic avenues, this article highlights the potential of nuclear receptors as promising targets for future treatments of a variety of human diseases, paving the way for more personalized and effective therapies in clinical medicine.

Objective To investigate the prognostic relevance of specific measurement parameters such as tumor diameter, tumor volume, tumor volume reduction rate (TVRR), and changes in the squamous cell carcinoma antigen (SCC-Ag) level in patients with locally-advanced cervical cancer (LACC) undergoing concurrent radiotherapy and chemotherapy. Methods This was a retrospective study of 203 patients with stage IIA–IVA cervical squamous cell carcinoma who were newly diagnosed at our hospital between January 2011 and March 2015. Clinical data and pre-and post-treatment imaging information were collected and each parameter was calculated using 3DSlicer software. The pre/post-treatment tumor diameter (TD pre/post ), tumor volume (TV pre/post ), SCC-Ag (SCC pre/post ), and TVRR, SCC-Ag reduction rate (SCCRR) were analyzed and their prognostic relevance evaluated. Results The median follow-up was 69 months. The 5-year overall survival (OS) and disease progression-free survival (PFS) rates were 69.5% and 64.5%, respectively. On univariate analysis, TD pre/post , TV pre/post , TVRR, SCC pre/post and SCCRR showed significant association with OS and PFS ( P  < 0.05). On multivariate analysis, TD pre [Hazard ratio ( HR)  = 0.373, P  = 0.028], TD post ( HR  = 0.376, P  = 0.003) and SCC post ( HR  = 0.374, P  = 0.001) were independent predictors of OS. TVRR ( HR  = 2.998, P  < 0.001), SCC pre ( HR  = 0.563, P  = 0.041), and SCC post ( HR  = 0.253, P  < 0.001) were independent predictors of PFS. Tumor measurement parameters showed a positive correlation with SCC-Ag ( P  < 0.05). Conclusion TD pre/post , TV pre/post , TVRR, SCC pre/post , and SCCRR were prognostic factors in LACC. TD pre/post and SCC post showed the most significant prognostic value. TVRR and SCC pre/post were closely related to disease progression. Further studies should investigate the correlation between measurement parameters of tumor and SCC-Ag.

AbstractObjectivesTo evaluate the efficacy of dual antiplatelet therapy (DAPT) for three months versus 12 months in saphenous vein graft occlusion while reducing bleeding risk.DesignMulticentre, non-inferiority, double blind, randomised controlled trial.Setting13 cardiac surgery centres in China, with enrolment between February 2023 and July 2024.Participants2300 participants aged 18 to 80 years who underwent elective primary coronary artery bypass grafting with ≥1 saphenous vein graft.InterventionsParticipants were randomly assigned (1:1) to receive DAPT (ticagrelor 90 mg twice daily plus aspirin 100 mg once daily) for 12 months or the same dual antiplatelet regimen for the first three months, followed by placebo plus aspirin for nine months.Main outcome measuresThe primary outcomes were saphenous vein graft occlusion at one year (non-inferiority) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (superiority). Secondary outcomes were major adverse cardiovascular events (MACCE), saphenous vein graft failure, venous or arterial graft stenosis, and venous or arterial graft occlusion.Results2290 patients (mean age 61.5 (standard deviation (SD) 8.4) years, 20.6% (n=472) women) were included in the modified intention-to-treat set. The mean number of saphenous vein graft segments was 2.5 (SD 0.8). 2070 patients (90.4%) with a total of 5125 saphenous vein graft segments were assessed at one year. Saphenous vein graft occlusion occurred in 280 of 2596 (10.8%) in the three month DAPT group and 283 of 2529 (11.2%) in the 12 month DAPT group (absolute difference −0.31%, 95% confidence interval (CI) −3.13% to 2.52%; P=0.008 for non-inferiority). During a median follow-up of 368 (interquartile range 358-382) days, BARC type 2, 3, or 5 bleeding occurred in 95 patients (8.3%) in the three month DAPT group and 149 patients (13.2%) in the 12 month DAPT group (absolute difference −4.67%, 95% CI −7.18% to −2.16%; P<0.001). The number needed to treat to prevent one bleeding event was 21 (95% CI 13 to 46). MACCE occurred in 26 (2.3%) patients in the three month DAPT group and 27 (2.7%) in the 12 month DAPT group (absolute difference −0.11%, 95% CI −1.48% to 1.26%). The findings for other secondary outcomes were also similar between the two groups.ConclusionsA three month DAPT strategy was non-inferior to the 12 month DAPT strategy in saphenous vein graft occlusion and was superior in reducing bleeding risk.Trial registrationClinicalTrials.gov NCT05380063.

Background Large efforts have focused on screening for genes involved in the virulence and pathogenicity of Verticillium dahliae , a destructive fungal pathogen of numerous plant species that is difficult to control once the plant is infected. Although Agrobacterium tumefaciens -mediated transformation (ATMT) has been widely used for gene screening, a quick and easy method has been needed to facilitate transformation. Results High-quality protoplasts, with excellent regeneration efficiency (65 %) in TB3 broth (yeast extract 30 g, casamino acids 30 g and 200g sucrose in 1L H 2 0), were generated using driselase (Sigma D-9515) and transformed with the GFP plasmid or linear GFP cassette using PEG or electroporation. PEG-mediated transformation yielded 600 transformants per microgram DNA for the linear GFP cassette and 250 for the GFP plasmid; electroporation resulted in 29 transformants per microgram DNA for the linear GFP cassette and 24 for the GFP plasmid. To determine whether short interfering RNAs (siRNAs) can be delivered to the protoplasts and used for silencing genes, we targeted the GFP gene of Vd-GFP ( V. dahliae GFP strain obtained in this study) by delivering one of four different siRNAs—19-nt duplex with 2-nt 3′ overhangs (siRNA-gfp1, siRNA-gfp2, siRNA-gfp3 and siRNA-gfp4)—into the Vd-GFP protoplasts using PEG-mediated transformation. Up to 100 % silencing of GFP was obtained with siRNA-gfp4; the other siRNAs were less effective (up to 10 % silencing). Verticillium transcription activator of adhesion ( Vta2 ) gene of V. dahliae was also silenced with four siRNAs (siRNA-vta1, siRNA-vta2, siRNA-vta3 and siRNA-vta4) independently and together using the same approach; siRNA-vta1 had the highest silencing efficiency as assessed by colony diameter and quantitative real time PCR (qRT-PCR) analysis. Conclusion Our quick, easy transformation method can be used to investigate the function of genes involved in growth, virulence and pathogenicity of V. dahliae .

Verticillium dahliae , a soil-borne fungus, can invade plant vascular tissue and cause Verticillium wilt. The enzyme α-oxoglutarate dehydrogenase (OGDH), catalyzing the oxidation of α-oxoglutarate in the tricarboxylic acid cycle (TCA), is vital for energy metabolism in the fungi. Here, we identified the OGDH gene in V. dahliae ( VdOGDH , VDAG_10018) and investigated its function in virulence by generating gene deletion mutants ( ΔVdOGDH ) and complementary mutants ( ΔVdOGDH - C ). When the ΔVdOGDH mutants were supplemented with different carbon sources, vegetative growth on Czapek Dox medium was significantly impaired, suggesting that VdOGDH is crucial for vegetative growth and carbon utilization. Conidia of the ΔVdOGDH mutants were atypically rounded or spherical, and hyphae were irregularly branched and lacked typical whorled branches. Mutants ΔVdOGDH - 1 and ΔVdOGDH - 2 were highly sensitive to H 2 O 2 in the medium plates and had higher intracellular ROS levels. ΔVdOGDH mutants also had elevated expression of oxidative response-related genes, indicating that VdOGDH is involved in response to oxidative stress. In addition, the disruption of VdOGDH caused a significant increase in the expression of energy metabolism-related genes VdICL , VdICDH , VdMDH , and VdPDH and melanin-related genes Vayg1 , VdSCD , VdLAC , VT4HR , and VaflM in the ΔVdOGDH mutants; thus, VdOGDH is also important for energy metabolism and melanin accumulation. Cotton plants inoculated with ΔVdOGDH mutants exhibited mild leaf chlorosis and the disease index was lower compared with wild type and ΔVdOGDH - C strains. These results together show that VdOGDH involved in energy metabolism of V. dahliae , is also essential for full virulence by regulating multiple fungal developmental factors.