Generation of rat forebrain tissues in mice.

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.

A small-molecule approach to restore female sterility phenotype targeted by a homing suppression gene drive in the fruit pest Drosophila suzukii.

CRISPR-based gene drives offer promising prospects for controlling disease-transmitting vectors and agricultural pests. A significant challenge for successful suppression-type drive is the rapid evolution of resistance alleles. One approach to mitigate the development of resistance involves targeting functionally constrained regions using multiple gRNAs. In this study, we constructed a 3-gRNA homing gene drive system targeting the recessive female fertility gene Tyrosine decarboxylase 2 (Tdc2) in Drosophila suzukii, a notorious fruit pest. Our investigation revealed only a low level of homing in the germline, but feeding octopamine restored the egg-laying defects in Tdc2 mutant females, allowing easier line maintenance than for other suppression drive targets. We tested the effectiveness of a similar system in Drosophila melanogaster and constructed additional split drive systems by introducing promoter-Cas9 transgenes to improve homing efficiency. Our findings show that genetic polymorphisms in wild populations may limit the spread of gene drive alleles, and the position effect profoundly influences Cas9 activity. Furthermore, this study highlights the potential of conditionally rescuing the female infertility caused by the gene drive, offering a valuable tool for the industrial-scale production of gene drive transgenic insects.

Kinetic Promoters for Sulfur Cathodes in Lithium-Sulfur Batteries.

ConspectusLithium-sulfur (Li-S) batteries have attracted worldwide attention as promising next-generation rechargeable batteries due to their high theoretical energy density of 2600 Wh kg-1. The actual energy density of Li-S batteries at the pouch cell level has significantly exceeded that of state-of-the-art Li-ion batteries. However, the overall performances of Li-S batteries under practical working conditions are limited by the sluggish conversion kinetics of the sulfur cathodes. To overcome the above challenge, various kinetic promotion strategies have been proposed to accelerate the multiphase and multi-electron cathodic redox reactions between sulfur, lithium polysulfides (LiPSs), and lithium sulfide. Nowadays, kinetic promoters have been massively employed in sulfur cathodes to achieve Li-S batteries with high energy densities, high rates, and long lifespans. A comprehensive and timely summary of cutting-edge kinetic promoters for sulfur cathodes is of great essence to afford an in-depth understanding of the unique Li-S electrochemistry.In this Account, we outline the recent efforts on the design of sulfur cathode kinetic promoters for advanced Li-S batteries. The latest progress is discussed in detail regarding heterogeneous, homogeneous, and semi-immobilized kinetic promoters. Heterogeneous promoters, representatively known as electrocatalysts, function mainly by reducing the energy barriers of the interfacial electrochemical reactions. The working mechanism, activity regulation strategies, and reconstitution/deactivation processes of the heterogeneous promoters are reviewed to provide guiding principles for rational design. In comparison, homogeneous promoters are able to fully contact with the reaction interfaces and regulate the electron/ion-inaccessible reactants in working Li-S batteries. Redox mediators and redox comediators are typical homogeneous promoters. The former establishes extra chemical reaction pathways to circumvent the originally sluggish steps and boost the overall kinetics, while the latter fundamentally modifies the LiPS molecules to enhance their redox kinetics. For semi-immobilized promoters, the active units are generally anchored on the cathode substrate through flexible chains with mobile characteristics. Such a design endows the promoter with both heterogeneous and homogeneous characteristics to comprehensively regulate the multiphase sulfur redox reactions involving both mobile and immobile reactants.Overall, this Account summarizes the fundamental electrochemistry, design principles, and practical promotion effects of the various kinetic promoters used for the sulfur cathodes in Li-S batteries. We believe that this Account will provide an in-depth and cutting-edge understanding of the unique sulfur electrochemistry, thereby providing guidance for further development of high-performance Li-S batteries and analogous rechargeable battery systems.

Hepatocyte-specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity.

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases.

The landscape of nanoparticle-based siRNA delivery and therapeutic development.

Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions.

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway.

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

Nicotinic acetylcholine receptor modulator insecticides act on diverse receptor subtypes with distinct subunit compositions.

Insect nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of many insecticides, including neonicotinoids, which are the most widely used insecticides in the world. However, the development of resistance in pests and the negative impacts on bee pollinators affect the application of insecticides and have created a demand for alternatives. Thus, it is very important to understand the mode of action of these insecticides, which is not fully understood at the molecular level. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunit mutants to eleven insecticides acting on nAChRs. Our results showed that there are several subtypes of nAChRs with distinct subunit compositions that are responsible for the toxicity of different insecticides. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. Moreover, spinosyns may act exclusively on the α6 homomeric pentamers but not any other nAChRs. Behavioral assays using thermogenetic tools further confirmed the bioassay results and supported the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for the management of resistance and the development of novel insecticides targeting these important ion channels.

Combined analyses of RNA-sequence and Hi-C along with GWAS loci-A novel approach to dissect keloid disorder genetic mechanism.

Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.

Organic Synaptic Transistors with Environmentally Friendly Core/Shell Quantum Dots for Wavelength-Selective Memory and Neuromorphic Functions.

Organic transistors based on organic semiconductors together with quantum dots (QDs) are attracting more and more interest because both materials have excellent optoelectronic properties and solution processability. Electronics based on nontoxic QDs are highly desired considering the potential health risks but are limited by elevated surface defects, inadequate stability, and diminished luminescent efficiency. Herein, organic synaptic transistors based on environmentally friendly ZnSe/ZnS core/shell QDs with passivating surface defects are developed, exhibiting optically programmable and electrically erasable characteristics. The synaptic transistors feature linear multibit storage capability and wavelength-selective memory function with a retention time above 6000 s. Various neuromorphic applications, including memory enhancement, optical communication, and memory consolidation behaviors, are simulated. Utilizing an established neuromorphic model, accuracies of 92% and 91% are achieved in pattern recognition and complicated electrocardiogram signal processing, respectively. This research highlights the potential of environmentally friendly QDs in neuromorphic applications and health monitoring.

Synchronously Consolidating Li, Se, S, and C for Robust Li-SeS Batteries.

S-redox involving solvated polysulfides is accompanied by volumetric change and structural decay of the S-based cathodes. Here, we propose a synchronous construction strategy for consolidating Li, Se, S, and C elements within a composite cathode via a paradigm reaction of 8Li+2Se+CS2 = 2Li4SeS+C. The obtained composite features crystalline Li4SeS encapsulated in a carbon nanocage (Li4SeS@C), exhibiting ultrahigh electrical conductivity, ultralow activation barrier, and excellent structural integrity, accordingly enabling large specific capacity (615 mAh g-1) and high capacity retention (87.3% after 350 cycles) at 10 A g-1. TOF-SIMS demonstrates its superior volumetric efficiency to a similar derivative SeS@C (2Se+CS2 = 2SeS+C), and DFT reveals its lower activation barrier than Li2S@C and Li2Se@C. This consolidation design significantly improves the electrochemical performance of S-based cathodes, and the paradigm reaction guarantees structural diversity and flexibility. Moreover, employing a synchronous construction mechanism to maximize the synergistic effect between element consolidation and carbon encapsulation opens up a new approach for developing robust S or chalcogenide cathodes.

Revealing the Effect of the [CoO]6 Microstructure in Pseudocapacitance by Controlled Delithium of LiCoO2.

Revealing the in-depth structure-property relationship and designing specific capacity electrodes are particularly important for supercapacitors. Despite many efforts made to tune the composition and electronic structure of cobalt oxide for pseudocapacitance, insight into the [CoO]6 octahedron from the microstructure is still insufficient. Herein, we present a tunable [CoO]6 octahedron microstructure in LiCoO2 by a chemical delithiation process. The c-strained strain of the [CoO]6 octahedron is induced to form higher valence Co ions, and the (003) crystalline layer spacing increases to allow more rapid participation of OH- in the redox reaction. Interestingly, the specific capacity of L0.75CO2 is nearly four times higher than that of LiCoO2 at 10 mA g-1. The enhanced activity originated from the asymmetric strain [CoO]6 octahedra, resulting in enhanced electronic conductivity and Co-O hybridization for accelerated redox kinetics. This finding provides new insights into the modification strategy for pseudocapacitive transition metal oxides.

Predicting splicing patterns from the transcription factor binding sites in the promoter with deep learning.

BACKGROUND: Alternative splicing is a pivotal mechanism of post-transcriptional modification that contributes to the transcriptome plasticity and proteome diversity in metazoan cells. Although many splicing regulations around the exon/intron regions are known, the relationship between promoter-bound transcription factors and the downstream alternative splicing largely remains unexplored. RESULTS: In this study, we present computational approaches to unravel the regulatory relationship between promoter-bound transcription factor binding sites (TFBSs) and the splicing patterns. We curated a fine dataset that includes DNase I hypersensitive site sequencing and transcriptomes across fifteen human tissues from ENCODE. Specifically, we proposed different representations of TF binding context and splicing patterns to examine the associations between the promoter and downstream splicing events. While machine learning models demonstrated potential in predicting splicing patterns based on TFBS occupancies, the limitations in the generalization of predicting the splicing forms of singleton genes across diverse tissues was observed with carefully examination using different cross-validation methods. We further investigated the association between alterations in individual TFBS at promoters and shifts in exon splicing efficiency. Our results demonstrate that the convolutional neural network (CNN) models, trained on TF binding changes in the promoters, can predict the changes in splicing patterns. Furthermore, a systemic in silico substitutions analysis on the CNN models highlighted several potential splicing regulators. Notably, using empirical validation using K562 CTCFL shRNA knock-down data, we showed the significant role of CTCFL in splicing regulation. CONCLUSION: In conclusion, our finding highlights the potential role of promoter-bound TFBSs in influencing the regulation of downstream splicing patterns and provides insights for discovering alternative splicing regulations.

Efficient Capture and Electroreduction of Dilute CO2 into Highly Pure and Concentrated Formic Acid Aqueous Solution.

High-purity CO2 rather than dilute CO2 (15 vol %, CO2/N2/O2 = 15:80:5, v/v/v) similar to the flue gas is currently used as the feedstock for the electroreduction of CO2, and the liquid products are usually mixed up with the cathode electrolyte, resulting in high product separation costs. In this work, we showed that a microporous conductive Bi-based metal-organic framework (Bi-HHTP, HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene) can not only efficiently capture CO2 from the dilute CO2 under high humidity but also catalyze the electroreduction of the adsorbed CO2 into formic acid with a high current density of 80 mA cm-2 and a Faradaic efficiency of 90% at a very low cell voltage of 2.6 V. Importantly, the performance in a dilute CO2 atmosphere was close to that under a high-purity CO2 atmosphere. This is the first catalyst that can maintain exceptional eCO2RR performance in the presence of both O2 and N2. Moreover, by using dilute CO2 as the feedstock, a 1 cm-2 working electrode coating with Bi-HHTP can continuously produce a 200 mM formic acid aqueous solution with a relative purity of 100% for at least 30 h in a membrane electrode assembly (MEA) electrolyzer. The product does not contain electrolytes, and such a highly concentrated and pure formic acid aqueous solution can be directly used as an electrolyte for formic acid fuel cells. Comprehensive studies revealed that such a high performance might be ascribed to the CO2 capture ability of the micropores on Bi-HHTP and the lower Gibbs free energy of formation of the key intermediate *OCHO on the open Bi sites.

Carborane-Cluster-Wrapped Copper Cluster with Cyclodextrin-like Cavities for Chiral Recognition.

Chiral atomically precise metal clusters, known for their remarkable chiroptical properties, hold great potential for applications in chirality recognition. However, advancements in this field have been constrained by the limited exploration of host-guest chemistry, involving metal clusters. This study reports the synthesis of a chiral Cu16(C2B10H10S2)8 (denoted as Cu16@CB8, where C2B10H12S2H2 = 9,12-(HS)2-1,2-closo-carborane) cluster by an achiral carboranylthiolate ligand. The chiral R-/S-Cu16@CB8 cluster features chiral cavities reminiscent of cyclodextrins, which are surrounded by carborane clusters, yet they crystallize in a racemate. These cyclodextrin-like cavities demonstrated the specific recognition of amino acids, as indicated by the responsive output of circular dichroism and circularly polarized luminescence signals of Cu16 moieties of the Cu16@CB8 cluster. Notably, a quantitative chiroptical analysis of amino acids in a short time and a concomitant deracemization of Cu16@CB8 were achieved. Density functional tight-binding molecular dynamics simulation and noncovalent interaction analysis further unraveled the great importance of the cavities and binding sites for chiral recognition. Dipeptide, tripeptide, and polypeptide containing the corresponding amino acids (Cys, Arg, or His residues) display the same chiral recognition, showing the generality of this approach. The functional synergy of dual clusters, comprising carborane and metal clusters, is for the first time demonstrated in the Cu16@CB8 cluster, resulting in the valuable quantification of the enantiomeric excess (ee) value of amino acids. This work opens a new avenue for chirality sensors based on chiral metal clusters with unique chiroptical properties and inspires the development of carborane clusters in host-guest chemistry.

Continuously Producing Highly Concentrated and Pure Acetic Acid Aqueous Solution via Direct Electroreduction of CO2.

It is crucial to achieve continuous production of highly concentrated and pure C2 chemicals through the electrochemical CO2 reduction reaction (eCO2RR) for artificial carbon cycling, yet it has remained unattainable until now. Despite one-pot tandem catalysis (dividing the eCO2RR to C2 into two catalytical reactions of CO2 to CO and CO to C2) offering the potential for significantly enhancing reaction efficiency, its mechanism remains unclear and its performance is unsatisfactory. Herein, we selected different CO2-to-CO catalysts and CO-to-acetate catalysts to construct several tandem catalytic systems for the eCO2RR to acetic acid. Among them, a tandem catalytic system comprising a covalent organic framework (PcNi-DMTP) and a metal-organic framework (MAF-2) as CO2-to-CO and CO-to-acetate catalysts, respectively, exhibited a faradaic efficiency of 51.2% with a current density of 410 mA cm-2 and an ultrahigh acetate yield rate of 2.72 mmol m-2 s-1 under neutral conditions. After electrolysis for 200 h, 1 cm-2 working electrode can continuously produce 20 mM acetic acid aqueous solution with a relative purity of 95+%. Comprehensive studies revealed that the performance of tandem catalysts is influenced not only by the CO supply-demand relationship and electron competition between the two catalytic processes in the one-pot tandem system but also by the performance of the CO-to-C2 catalyst under diluted CO conditions.

Kinetic Evaluation on Lithium Polysulfide in Weakly Solvating Electrolyte toward Practical Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are highly considered as next-generation energy storage techniques. Weakly solvating electrolyte with low lithium polysulfide (LiPS) solvating power promises Li anode protection and improved cycling stability. However, the cathodic LiPS kinetics is inevitably deteriorated, resulting in severe cathodic polarization and limited energy density. Herein, the LiPS kinetic degradation mechanism in weakly solvating electrolytes is disclosed to construct high-energy-density Li-S batteries. Activation polarization instead of concentration or ohmic polarization is identified as the dominant kinetic limitation, which originates from higher charge-transfer activation energy and a changed rate-determining step. To solve the kinetic issue, a titanium nitride (TiN) electrocatalyst is introduced and corresponding Li-S batteries exhibit reduced polarization, prolonged cycling lifespan, and high actual energy density of 381 Wh kg-1 in 2.5 Ah-level pouch cells. This work clarifies the LiPS reaction mechanism in protective weakly solvating electrolytes and highlights the electrocatalytic regulation strategy toward high-energy-density and long-cycling Li-S batteries.

Biosynthesis of fungal terpenoids.

Covering: up to August 2023Terpenoids, which are widely distributed in animals, plants, and microorganisms, are a large group of natural products with diverse structures and various biological activities. They have made great contributions to human health as therapeutic agents, such as the anti-cancer drug paclitaxel and anti-malarial agent artemisinin. Accordingly, the biosynthesis of this important class of natural products has been extensively studied, which generally involves two major steps: hydrocarbon skeleton construction by terpenoid cyclases and skeleton modification by tailoring enzymes. Additionally, fungi (Ascomycota and Basidiomycota) serve as an important source for the discovery of terpenoids. With the rapid development of sequencing technology and bioinformatics approaches, genome mining has emerged as one of the most effective strategies to discover novel terpenoids from fungi. To date, numerous terpenoid cyclases, including typical class I and class II terpenoid cyclases as well as emerging UbiA-type terpenoid cyclases, have been identified, together with a variety of tailoring enzymes, including cytochrome P450 enzymes, flavin-dependent monooxygenases, and acyltransferases. In this review, our aim is to comprehensively present all fungal terpenoid cyclases identified up to August 2023, with a focus on newly discovered terpenoid cyclases, especially the emerging UbiA-type terpenoid cyclases, and their related tailoring enzymes from 2015 to August 2023.

FTO-Mediated m6A Modification of FTH1 Inhibits Ferroptosis of Neurons in Neonatal Cerebral Hypoxic Ischemia.

FTO alpha-ketoglutarate dependent dioxygenase (FTO) is aberrantly expressed in brain disorders. However, the roles of FTO in neonatal hypoxic-ischemic brain injury (HIE) are still unclear. This study aims to investigate the potential of FTO in neonatal HIE. Oxygen-glucose deprivation (OGD) was used to establish HIE in vitro. mRNA levels were detected by real-time reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Protein expression was detected by Western blot. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), ferrous iron (Fe2+) and glutathione (GSH) was detected by specific kit. m6A sites were analyzed using SRAMP and further verify by methylated RNA immunoprecipitation (MeRIP) assay. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay. Cell death was determined by propidium iodide (PI) staining. FTO was downregulated in patients with neonatal HIE and OGD-treated neurons. Moreover, FTO mRNA expression was decreased in ferroptosis inducer, especially ferric ammonium citrate (FAC). However, overexpression of FTO inhibited the ferroptosis of neurons. Moreover, FTO-mediated N6-methyladenosine (m6A) modification of ferritin heavy chain 1 (FTH1) suppressed its mRNA expression and stability, inhibiting its protein expression. However, overexpression of FTH1 abrogated the effects of FTO and promoted the ferroptosis of neurons. In summary, FTO functions as a protective role in neonatal HIE via inhibiting FTH1 signaling. Thence, targeting may be a promising strategy for FTO neonatal HIE.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.