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PANoptosis is a newly discovered type of cell death characterized by pyroptosis, apoptosis and/or necroptosis and has been implicated in the inflammatory response. Piezo1 is a mechanosensitive ion channel that plays important roles in physiological development and various diseases. However, whether cardiomyocytes undergo PANoptosis during myocardial ischaemia/reperfusion (I/R) injury and the role of Piezo1 in this process remain largely unexplored. In this study, our results revealed that the expression levels of the main components of the PANoptosome, including caspase-8, caspase-3, NLRP3, caspase-1, GSDMD, RIPK1, RIPK3 and MLKL, were significantly upregulated in I/R heart tissues over time, indicating the occurrence of PANoptosis in I/R hearts. Accordingly, Piezo1 expression was significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes. In contrast, pharmacological inhibition of Piezo1 by the inhibitor GsMTx4 in mice markedly attenuated the I/R-mediated decline in cardiac contractile function and increases in infarct size, apoptosis, oxidative stress and inflammation accompanied by the inhibition of PANoptosis-related mediators in I/R hearts. Consistently, the effects of Piezo1 on calcium influx and PANoptosis were further verified by GsMTx4 and Piezo1 activator Yoda1 in H/R-treated cardiomyocytes in vitro. Moreover, caspase-8 rather than calcium influx was required for H/R-induced PANoptosis in vitro. Mechanistically, Piezo1 interacts with caspase-8, a key initial activator of the PANoptosome complex, which subsequently activates cardiomyocyte PANoptosis, leading to cardiac dysfunction. In summary, these data suggest that Piezo1 is a new cardiac mechanosensor that promotes cardiac I/R injury possibly through the caspase-8-mediated activation of cardiomyocyte PANoptosis and highlight that Piezo1 may represent a new target for treating ischaemic heart disease., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The utilization of lignocellulosic substrates for microbial oil production by oleaginous yeasts has been evidenced as an economically viable process for industrial-scale biodiesel preparation. Efficient sugar utilization and tolerance to inhibitors are critical for lipid production from lignocellulosic substrates. This study investigated the lignocellulosic sugar utilization and inhibitor tolerance characteristics of Rhodotorula toruloides C23. The results demonstrated that C23 exhibited robust glucose and xylose assimilation irrespective of their ratios, yielding over 21 g/L of lipids and 11 mg/L of carotenoids. Furthermore, C23 exhibited high resistance and efficiently degradation towards toxic inhibitors commonly found in lignocellulosic hydrolysates. The potential molecular mechanism underlying xylose metabolism in C23 was explored, with several key enzymes and signal regulation pathways identified as potentially contributing to its superior lipid synthesis performance. The study highlights R. toruloides C23 as a promising candidate for robust biofuel and carotenoid production through direct utilization of non-detoxified lignocellulosic hydrolysates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Hypothyroidism and subclinical hypothyroidism were both characterized by elevated levels of thyroid stimulating hormone (TSH). Previous studies had found that high iodine or hyperlipidemia alone was associated with increased TSH level. However, their combined effects on TSH have not been elucidated. In this study, combination of high iodine and hyperlipidemia was established through the combined exposure of high-water iodine and high fat diet in Wistar rats. The results showed that combined exposure of high iodine and high fat can induce higher TSH level. The mRNA and protein levels of sodium iodide transporters (NIS) and type 1 deiodinase (D1) in thyroid tissues, which were crucial genes in the synthesis of thyroid hormones, decreased remarkably in combined exposure group. Mechanistically, down-regulated long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) may regulate the expression of NIS by increasing miR-339-5p, and regulating D1 by increasing miR-224-5p. Then, the above findings were explored in subjects exposed to high water iodine and hyperlipidemia. The results indicated that in population combined with high iodine and hyperlipidemia, TSH level increased to higher level and lncRNA MALAT1-miR-339-5p-NIS axis was obviously activated. Collectively, this study found that combined exposure of high iodine and hyperlipidemia induced a higher level of TSH, and lncRNA MALAT1-miR-339-5p-NIS axis may play important role., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is frequently located in the pharyngeal crypts. This is a highly aggressive malignant tumor that frequently leads to distant metastases in many cases and poses a significant public health challenge, particularly in certain geographic regions globally. This review discusses the epidemiology, risk factors, diagnosis, and treatment options for NPC, emphasizing the importance of early detection and comprehensive management strategies in improving patient outcomes. Moreover, the article explores the intricate mechanisms that cause NPC. Comprehending these fundamental principles can assist in creating specific prevention and therapy approaches for NPC. Recent advances in diagnostic methods, including imaging tests and molecular biomarkers, are emphasized to improve early diagnosis and individualized treatment strategies for individuals with NPC. The review also explores the most recent advancements in treating early-stage (stage I and II) NPC patients, highlighting the changing landscape of individualized therapy approaches for this particular set of patients., (© 2024. The Author(s).)

Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound ( 21o ) significantly inhibited the proliferation of MCF-7 cells with an IC 50 value of 2.0 μM, 1.5-fold more potent than pristimerin (IC 50 = 3.0 μM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o . Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.

Multiple myeloma (MM) is an incurable plasma cell malignancy that has prompted investigations into new potential therapeutic avenues. Epigallocatechin-3-gallate (EGCG), a major component of green tea, confers antioxidant, anti-inflammatory, and anti-tumor properties. Previous studies have shown that EGCG inhibits proliferation and induces apoptosis of multiple myeloma cells, however its underlying molecular mechanisms are largely unknown. In this study, we accordingly sought to examine the therapeutic effects and underlying mechanisms of EGCG on MM. Initially, using CCK8 (Cell Counting Kit-8) assays and Annexin V-FITC/PI staining, we demonstrated that EGCG dose-dependently reduced cell viability and induced apoptosis in the MM cell lines MM.1S and RPMI 8226. Subsequently, mRNA sequencing of EGCG-treated MM.1S cells revealed a significant upregulation of genes associated with endoplasmic reticulum stress (ERS), including P-eIF2α (phosphorylation-eukaryotic translation initiation factor 2 alpha), ATF4 (activating transcription factor 4), CHOP (C/EBP homologous protein, DDIT3), and PUMA (p53 upregulated modulator of apoptosis, BBC3), which were confirmed at the protein level by western blotting. Furthermore, treatment with the eIF2α inhibitor ISRIB reduced the rates of EGCG-induced apoptosis and promoted increases in the protein expression of all four ER stress-related molecules in MM cells. Additionally, mRNA-seq data revealed a downregulation of α-Tubulin 1b (TUBA1B) expression in EGCG-treated MM cells, which was confirmed by western blotting and immunofluorescence analyses. Moreover, we utilized a mouse model to show that EGCG inhibited myeloma tumor growth, which was inhibited by ISRIB. In summary, the findings of this novel study indicated that EGCG promotes apoptosis of MM cells, both via activation of the ER stress pathway and disruption of cytoskeletal integrity. These findings highlight the multi-faceted anti-tumor effects of EGCG and its potential clinical application in MM treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD., (© 2024. The Author(s).)

The efficient and complete extraction of uranium from aqueous solutions is crucial for safeguarding human health from potential radiotoxicity and chemotoxicity. Herein, an ultrathin 2D metal-organic framework (MOF) nanosheet with cavity structures was elaborately constructed, based on a calix[4]arene ligand. The large molecular skeleton and cup-shaped feature of the calix[4]arene enabled the as-prepared MOFs with large layer separations, which can be readily delaminated into ultrathin single-layer (∼1.25 nm) nanosheets. The incorporation of permanent cavity structures to the MOF nanosheets can fully utilize their structural features of readily accessible adsorption groups and exposed surface area in uranium removal, reaching ultrafast adsorption kinetics; the functionalized cavity structure endowed MOF nanosheets with the ability to preconcentrate and extract uranium from aqueous solutions with ultrahigh efficiencies, even at extremely low concentrations. As a result, relatively high removal ratios (>95%) can be achieved for uranium within 5 min, even in the ultralow concentration range of 75-250 ppb, and the residual uranium was reduced to below 4.9 ppb. The MOF nanosheets also exhibited extremely high anti-interference ability, which could efficiently remove the low-level uranium (∼150 ppb) from various real samples. The characterizations and density functional theory calculations demonstrated that the synergistic effects of multiple interactions between the carboxylate groups and cage-like cavities with uranyl ions can be responsible for the efficient and selective uranium extraction.

Denitrification driven by bacteria and fungi is the main source of nitrous oxide （N 2 O） emissions from paddy soil. It is generally believed that biochar reduces N 2 O emissions by influencing the bacterial denitrification process, but the relevant mechanism of its impact on fungal denitrification is still unclear. In this study, the long-term straw carbonization returning experimental field in Changshu Agricultural Ecological Experimental Base of the Chinese Academy of Sciences was taken as the object. Through indoor anaerobic culture and molecular biology technology, the relative contributions of bacteria and fungi to denitrifying N 2 O production in paddy soil and the related microorganism mechanism were studied under different long-term biochar application amounts （blank, 2.25 t·hm -2 , and 22.5 t·hm -2 , respectively, expressed by BC0, BC1, and BC10）. The results showed that compared with that in BC0, biochar treatment significantly reduced N 2 O emission rate, denitrification potential, and cumulative N 2 O emissions, and the contribution of bacterial denitrification was greater than that of fungal denitrification in all three treatments. Among them, the relative contribution rate of bacterial denitrification in BC10 （62.9%） was significantly increased compared to BC0 （50.8%）, whereas the relative contribution rate of fungal denitrification in BC10 （37.1%） was significantly lower than that in BC0 （49.2%）. The application of biochar significantly increased the abundance of bacterial denitrification functional genes （ nirK , nirS , and nosZ ） but reduced the abundance of fungal nirK genes. The contribution rate of fungal denitrification was significantly positively correlated with the N 2 O emission rate and negatively correlated with soil pH, TN, SOM, and DOC. Biochar may have inhibited the growth of denitrifying fungi by increasing pH and carbon and nitrogen content, reducing the abundance of related functional genes, thereby weakening the reduction ability of NO to N 2 O during fungal denitrification process. This significantly reduces the contribution rate of N 2 O production during the fungal denitrification process and the denitrification N 2 O emissions from paddy soil. This study helps to broaden our understanding of the denitrification process in paddy soil and provides a theoretical basis for further regulating fungal denitrification N 2 O emissions.

Background: Sepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment., Methods: Data related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines., Results: A total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia (P ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-β), hepatic growth factor (HGF) (P < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines (P < 0.05)., Conclusions: This comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis., (© 2024. The Author(s).)

The role of monocytes in postmenopausal osteoporosis is widely recognized; however, the mechanisms underlying monocyte reprogramming remain unknown. In this study, single-cell RNA sequencing (scRNA-seq) was conducted on CD14+ bone marrow monocytes obtained from 3 postmenopausal women with normal BMD and 3 women with postmenopausal osteoporosis (PMOP). Monocle2 was used to classify the monocytes into 7 distinct clusters. The proportion of cluster 1 significantly decreased in PMOP patients, while the proportion of cluster 7 increased. Further analysis via GSEA, transcription factor activity analysis, and sc-metabolic analysis revealed significant differences between clusters 1 and 7. Cluster 7 exhibited upregulated pathways associated with inflammation, immunity, and osteoclast differentiation, whereas cluster 1 demonstrated the opposite results. Monocle2, TSCAN, VECTOR, and scVelo data indicated that cluster 1 represented the initial subset and that cluster 7 represents one of the terminal subsets. BayesPrism and ssGSEA were employed to analyze the bulk transcriptome data obtained from the GEO database. The observed alterations in the proportions of 1 and 7 were validated and found to have diagnostic significance. CD16 serves as the marker gene for cluster 7, thus leading to an increased proportion of CD16+ monocytes in women with PMOP. Flow cytometry was used to assess the consistency of outcomes with those of the bioinformatic analysis. Subsequently, an additional scRNA-seq analysis was conducted on bone marrow mononuclear cells obtained from 3 patients with PMOP and 3 postmenopausal women with normal BMD. The differential proportions of cluster 1 and cluster 7 were once again confirmed, with the pathological effect of cluster 7 may attribute to cell-cell communication. The scRNA-seq findings suggest that an imbalance in monocyte subsets is a characteristic feature of PMOP. These findings elucidate the limitations of utilizing bulk transcriptome data for detecting alterations in monocytes, which may influence novel research inquiries., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background/aim: As an antagonist of bone morphogenetic protein (BMP), Noggin facilitates osteolytic bone metastases from breast cancer. The present study aimed to further dissect its role in oestrogen receptor (ER) positive breast cancer., Materials and Methods: Noggin expression in ER positive breast cancer cell lines (MCF-7 and T-47D) was determined under conditions of oestrogen deprivation and treatment with 17-β-oestradiol (E 2 ). Activation of Smad1/5/8 in the oestrogen-regulated Noggin was examined using recombinant human BMP7 (rhBMP7) and a BMP receptor inhibitor (LDN-193189). The influence of Noggin on cellular functions was evaluated in MCF-7 and T-47D cell lines. Responses to tamoxifen and chemotherapy drugs were determined in MCF-7 and T-47D cells with Noggin over-expression using MTT assay., Results: Noggin expression was negatively correlated with ERα in breast cancers. Noggin was up-regulated upon oestrogen deprivation, an effect that was eliminated by E 2 Furthermore, increased levels of phosphorylated Smad1/5/8 were observed in the oestrogen-deprived MCF-7 and T-47D cells, which was prevented by E 2 and LDN-193189, respectively. BMP7-induced Noggin expression and activation of Smad1/5/8 was also prevented by E 2 and LDN-193189. Noggin over-expression resulted in an increase in the proliferation of both MCF-7 and T-47D cells. MCF-7 and T-47D cells over-expressing Noggin exhibited a good tolerance to tamoxifen (TAM), DTX, and 5-FU, but the percentage of viable cells was higher compared with the controls., Conclusion: Noggin expression can be repressed by oestrogen through inference with the BMP/Smad signalling. Over-expression of Noggin promotes the proliferation of MCF-7 and T-47D cells, contributing to drug resistance., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Isolated from intertidal sediment of the Yellow Sea, China, Bremerella sp. P1 putatively represents a novel species within the genus Bremerella of the family Pirellulaceae in the phylum Planctomycetota. The complete genome of strain P1 comprises a single circular chromosome with a size of 6,955,728 bp and a GC content of 55.26%. The genome contains 5772 protein-coding genes, 80 tRNA and 6 rRNA genes. A total of 147 CAZymes and 128 sulfatases have been identified from the genome of strain P1, indicating that the strain has the capability to degrade a wide range of polysaccharides. Moreover, a gene cluster related to bacterial microcompartments (BMCs) formation containing genes encoding the shell proteins and related enzymes to metabolize fucose or rhamnose is also found in the genome of strain P1. The genome of strain P1 represents the second complete one in the genus Bremerella, expanding the understanding of the physiological and metabolic characteristics, interspecies diversity, and ecological functions of the genus., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “The complete genome sequence of the planctomycetotal bacterium Bremerella sp. P1 with abundant genes involved in polysaccharide degradation”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the combined performance of orbital MRI and intracranial visual pathway diffusion kurtosis imaging (DKI) in diagnosing dysthyroid optic neuropathy (DON)., Methods: We retrospectively enrolled 61 thyroid-associated ophthalmopathy (TAO) patients, including 25 with DON (40 eyes) and 36 without DON (72 eyes). Orbital MRI-based apical muscle index (MI), diameter index (DI) of the optic nerve (ON), area index (AI) of the ON, apparent diffusion coefficient (ADC) and signal intensity ratio (SIR) of the ON, DKI-based kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) of the optic tract (OT), optic radiation (OR), and Brodmann areas (BAs) 17, 18, and 19 were measured and compared between groups. The diagnostic performances of models were evaluated using receiver operating characteristic curve analyses and compared using the DeLong test., Results: TAO patients with DON had significantly higher apical MI, apical AI, and SIR of the ON, but significantly lower ADC of the ON than those without DON (p < 0.05). Meanwhile, the DON group exhibited significantly lower KFA across the OT, OR, BA17, BA18, and BA19 and lower MK at the OT and OR than the non-DON group (p < 0.05). The model integrating orbital MRI and intracranial visual pathway DKI parameters performed the best in diagnosing DON (AUC = 0.926), with optimal diagnostic sensitivity (80%) and specificity (94.4%), followed by orbital MRI combination (AUC = 0.890), and then intracranial visual pathway DKI combination (AUC = 0.832)., Conclusion: Orbital MRI and intracranial visual pathway DKI can both assist in diagnosing DON. Combining orbital and intracranial imaging parameters could further optimize diagnostic efficiency., Clinical Relevance Statement: The novel finding could bring novel insights into the precise diagnosis and treatment of dysthyroid optic neuropathy, accordingly, contributing to the improvement of the patients' prognosis and quality of life in the future., Key Points: • Orbital MRI and intracranial visual pathway diffusion kurtosis imaging can both assist in diagnosing dysthyroid optic neuropathy. • Combining orbital MRI and intracranial visual pathway diffusion kurtosis imaging optimized the diagnostic efficiency of dysthyroid optic neuropathy., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 10 9 , 5 × 10 10 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objectives: Existing data regarding the risk of COVID-19 infection and its effects on seizure control in patients with epilepsy (PWE) are inconclusive. Our research aims to investigate the PWE who are susceptible to COVID-19 and what factors contribute to seizure exacerbation., Methods: From Dec 28, 2022 to Feb 19, 2023, a cross-sectional questionnaire survey among adult PWE was conducted. The demographics, epilepsy-related information, COVID-19-related variables, and seizure outcomes after COVID-19 infection were collected. Multivariate logistic analyses were performed to determine the risk factors associated with COVID-19 infection and exacerbated seizures., Results: Of 1557 PWE, 829 (53.2%) were infected with COVID-19 and 136 (16.4%) developed seizure exacerbation after COVID-19 infection. Overweight/obesity (OR 1.372, 95% CI 1.075-1.753, p = 0.011), immunocompromised (OR 3.301, 95% CI 1.093-9.974, p = 0.031), active epilepsy (OR 1.700, 95% CI 1.378-2.097, p < 0.001), and antiseizure medication (ASM) polytherapy (OR 1.314, 95% CI 1.065-1.621, p = 0.011) were associated with COVID-19 infection. Active epilepsy (OR 4.696, 95% CI 2.568-8.586, p < 0.001) and fever-associated seizures (OR 4.298, 95%CI 2.659-6.946, p < 0.001) were associated with seizure exacerbation., Significance: PWE with overweight/obesity, immunocompromised, active epilepsy, and ASM polytherapy were at higher risk of COVID-19 infection. Once infected with COVID-19, seizures were exacerbated in PWE with active epilepsy and fever-associated seizures., Plain Language Summary: Patients with epilepsy (PWE) do not appear to be more susceptible to COVID-19 infection than general population. Once infected with COVID-19, 16.4% of PWE had seizure exacerbation. The PWE who have experienced seizures within the past 12 months before infection tend to contract COVID-19 more often, and are more likely to experience seizure exacerbations following COVID-19 infection., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Purpose: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity., Experimental Approach: We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6 weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry., Key Results: Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP., Conclusions and Implications: These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: The present study aimed to investigate the incremental prognostic value of the right ventricular fractal dimension (FD), a novel marker of myocardial trabecular complexity by cardiac magnetic resonance (CMR) in patients with arrhythmogenic cardiomyopathy (ACM)., Methods: Consecutive patients with ACM undergoing CMR were followed up for major cardiac events, including sudden cardiac death, aborted cardiac arrest, and appropriate implantable cardioverter defibrillator intervention. Prognosis prediction was compared by Cox regression analysis. We established a multivariable model supplemented with RV FD and evaluated its discrimination by Harrell's C-statistic. We compared the category-free, continuous net reclassification improvement (cNRI) and integrated discrimination index (IDI) before and after the addition of FD., Results: A total of 105 patients were prospectively included from three centers and followed up for a median of 60 (48, 66) months; experienced 36 major cardiac events were recorded. Trabecular FD displayed a strong unadjusted association with major cardiac events (p < 0.05). In the multivariable Cox regression analysis, RV maximal apical FD maintained an independent association with major cardiac events (hazard ratio, 1.31 (1.11-1.55), p < 0.002). The Hosmer-Lemeshow goodness of fit test displayed good fit (X 2  = 0.68, p = 0.99). Diagnostic performance was significantly improved after the addition of RV maximal apical FD to the multivariable baseline model, and the continuous net reclassification improvement increased 21% (p = 0.001), and the integrated discrimination index improved 16% (p = 0.045)., Conclusions: In patients with ACM, CMR-assessed myocardial trabecular complexity was independently correlated with adverse cardiovascular events and provided incremental prognostic value., Clinical Relevance Statement: The application of FD values for assessing RV myocardial trabeculae may become an accessible and promising parameter in monitoring and early diagnosis of risk factors for adverse cardiovascular events in patients with ACM., Key Points: • Ventricular trabecular morphology, a novel quantitative marker by CMR, has been explored for the first time to determine the severity of ACM. • Patients with higher maximal apical fractal dimension of RV displayed significantly higher cumulative incidence of major cardiac events. • RV maximal apical FD was independently associated with major cardiac events and provided incremental prognostic value in patients with ACM., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: In recent decades, the occurrence of heart failure with preserved ejection fraction (HFpEF) has outweighed that of heart failure with reduced ejection fraction by degrees, but few drugs have been demonstrated to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, improves decompensated heart failure clinically. However, the anti-HFpEF activities of levosimendan and underlying molecular mechanisms are unclear., Methods: In this study, a double-hit HFpEF C57BL/6N mouse model was established, and levosimendan (3 mg/kg/week) was administered to HFpEF mice aged 13 to 17 weeks. Different biological experimental techniques were used to verify the protective effects of levosimendan against HFpEF., Results: After four weeks of drug treatment, left ventricular diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and exercise exhaustion were significantly alleviated. Junction proteins in the endothelial barrier and between cardiomyocytes were also improved by levosimendan. Among the gap junction channel proteins, connexin 43, which was especially highly expressed in cardiomyocytes, mediated mitochondrial protection. Furthermore, levosimendan reversed mitochondrial malfunction in HFpEF mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels., Conclusion: Regular long-term levosimendan administration can benefit cardiac function in a mouse model of HFpEF with metabolic syndromes (namely, obesity and hypertension) by activating connexin 43-mediated mitochondrial protection and sequential ferroptosis inhibition in cardiomyocytes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Iron-anchored nitrogen/doped carbon single-atom nanozymes (Fe-N/C), which possess homogeneous active sites and adjustable catalytic environment, represent an exemplary model for investigating the structure-function relationship and catalytic activity. However, the development of pyrolysis-free synthesis technique for Fe-N/C with adjustable enzyme-mimicking activity still presents a significant challenge. Herein, Fe-N/C anchored three carrier morphologies were created via a pyrolysis-free approach by covalent organic polymers. The peroxidase-like activity of these Fe-N/C nanozymes was regulated via the pores of the anchored carrier, resulting in varying electron transfer efficiency due to disparities in contact efficacy between substrates and catalytic sites within diverse microenvironments. Additionally, a colorimetric sensor array for identifying antioxidants was developed: (1) the Fe-N/C catalytically oxidized two substrates TMB and ABTS, respectively; (2) the development of a colorimetric sensor array utilizing oxTMB and oxABTS as sensing channels enabled accurate discrimination of antioxidants such as ascorbic acid (AsA), glutathione (GSH), cysteine (Cys), gallic acid (GA), and caffeic acid (CA). Subsequently, the sensor array underwent rigorous testing to validate its performance, including assessment of antioxidant mixtures and individual antioxidants at varying concentrations, as well as target antioxidants and interfering substances. In general, the present study offered valuable insights into the active origin and rational design of nanozyme materials, and highlighting their potential applications in food analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT)., Methods: In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III-IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin β1 (ITGB1) expression was analyzed as a biomarker for efficacy., Results: After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT., Conclusions: This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting., Trial Registration: www., Clinicaltrials: gov . NCT02923258 (date of registration: October 4, 2016)., (© 2024. The Author(s).)

Background and Purpose: Some patients with intracerebral hemorrhage show lesions on diffusion-weighted magnetic resonance imaging (MRI), and such lesions have been associated with greater risk of worse prognosis. Here we meta-analyzed the available evidence for such an association., Methods: Studies that reported presence or absence of lesions on diffusion-weighted imaging (DWI) after intracerebral hemorrhage as well as clinical or radiological outcomes were systematically reviewed and meta-analyzed. Clinical outcome was defined as score of modified Rankin scale (mRS) at admission to 90 days., Results: Ten studies involving 3575 patients were included in the meta-analysis, and the incidence of DWI lesions ranged from 11.1% to 49.6%. Lesions were associated with significantly higher risk of poor outcome (mRS scores 3-6) across six studies (OR 2.91, 95%CI 1.62-5.23, P < 0.001). In subgroup analysis, mRS scores 4-6 were associated with the presence of lesions on DWI (OR 2.18, 95%CI 1.31-3.60, P =0.003). We observed similar results using three different definitions of lesions on DWI. Some studies have reported that recurrence of intracerebral hemorrhage was also related with DWI lesions. But there was controversy on the relationship between mortality, ischemic stroke, and hematoma volume and DWI lesions., Conclusion: Lesions on DWI after intracerebral hemorrhage were associated with higher risk of poor outcome, but large longitudinal studies are needed to verify this association., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The study aimed to investigate the correlation between the change of sex hormone levels and ocular surface parameters in girls with idiopathic central precocious puberty(ICPP)., Methods: Eighteen girls with ICPP and 18 age-matched normal girls participated in this study, all of the participants had undergone physical measurements, laboratory tests, imaging examination and ocular surface assessments., Results: The Objective Scatter Index (OSI) in the ICPP group was significantly higher than in the control group ( P = 0.031), girls with ICPP showed slightly lower MNITBUT compared to the normal control group, although this difference was not statistically significant. Bivariate analysis revealed a positive association between estradiol and OSI (r=0.383, P =0.021), Additionally, in the study population, both Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were negatively correlated with Mean noninvasive tear breakup time (MNITBUT) (r=-0.359, P =0.031)(r=-0.357, P =0.032)., Conclusion: In comparison with the normal control group, alterations in the OSI were observed in girls with ICPP. This alteration may be associated with an elevation in estrogen levels. Although there was a slight non-significant decrease in NITBUT in ICPP girls, the negative correlation between LH and FSH with MNITBUT suggests new perspective for further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Yang and Liang.)

Background: The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear., Aim: To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients., Methods: A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted., Results: A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols ( P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded., Conclusion: TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens., Competing Interests: Conflict-of-interest statement: The authors deny any conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: This study aims to investigate the potential of preoperative blood supply condition measured by dynamic susceptibility contract (DSC) MRI in prediction of postoperative outcomes for patients with cervical spondylotic myelopathy (CSM)., Materials and Method: Thirty-nine patients (Age: 61 ± 7, male: 23, female: 16) with CSM who underwent laminoplasty were enrolled. All patients received DSC MRI before the operation. Five parameters include Enhance, rEnhance, full width at half maxima (FWHM), Slope1 and Slope2 in DSC MRI, were calculated at all the compressed spinal cord segments. Clinical outcomes were evaluated by modified Japanese Orthopaedic Association (mJOA) scores. Patients were divided into two groups based on mJOA recovery rate of 5 years: good recovery (> 50%) or poor recovery (≤ 50%). The difference between two groups were compared. The value of DSC MRI to CSM was evaluated by logistic and receiver operating characteristic (ROC) curve analysis., Results: There were 26 patients in good recovery group and 13 patients in poor recovery group. The baseline characteristics, including age, gender, preoperative mJOA score, and smoking status showed no significant difference between the two groups (all p > 0.05). The FWHM was significantly higher in the poor recovery group (9.77 ± 2.78) compared to the good recovery group (6.64 ± 1.65) (p = 0.002). Logistic regression analysis indicated that an increased FWHM was a significant risk factor for poor prognosis recovery (p = 0.013, OR = 0.392, 95%CI: 0.187-0.822). The AUC of FWHM for ROC was 0.843 (95% CI: 0.710-0.975) with a p value of 0.001. In addition, an FWHM greater than 5.87, with a sensitivity of 92.3% and specificity of 69.2%, was found to be an independent risk factor for poor postoperative recovery in patients with CSM., Conclusion: In this study, we successfully quantified the spinal cord blood supply condition by DSC MRI technique. We found that an increase in FWHM was an independent risk factor for poor postoperative recovery in CSM patients. Specifically, patients with FWHM > 5.87 have a poor postoperative recovery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to investigate the clinical features, pathogenic gene variants, and potential genotype-phenotype correlations in Chinese patients with hereditary spherocytosis (HS)., Methods: Retrospective analysis of clinical data and molecular genetic characteristics was conducted on patients diagnosed with HS at Jiangxi Provincial Children's Hospital, the Second Affiliated Hospital of Nanchang University, Pingxiang People's Hospital and The Third People's Hospital of Jingdezhen between November 2017 and June 2023. Statistical analyses were performed to compare and analyze the red blood cell (RBC), hemoglobin (HB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) data between and within groups based on different mutations and age groups (< 14 and ≥ 14 years)., Results: A total of 34 HS patients were included in this study, comprising 22 children (64.70%) and 12 adults (35.30%). The probands who underwent genetic testing were derived from 34 unrelated families. Thirty-two variants were tested and 9 of them are novel. Eighteen cases had ANK1 variants, 15 had SPTB variants, and 1 had SLC4A1 variant. 25 patients performed core family members underwent genetic testing, 17 (68.0%, 17/25) were de novo, 5 (20.0%, 5/25) were maternally inherited, and 3 (12.0%, 3/25) were paternally inherited. ANK1-HS patients exhibited more severe anemia compared to cases with SPTB-HS, showing lower levels of RBC and HB (P < 0.05). Anemia was more severe in patients diagnosed in childhood than in those diagnosed in adulthood. Within the ANK1-HS group, MCH levels in adult patients was significantly higher than those in children (P < 0.05), while there were no significant differences in RBC, HB, MCV, and MCHC levels between two groups. Adult patients with SPTB-HS had significantly higher levels of RBC, HB, and MCH than pediatric patients (P < 0.05), while MCV and MCHC levels showed no significant statistical differences., Conclusion: This study conducted a comparative analysis of phenotypic characteristics and molecular genetics in adult and pediatric patients diagnosed with HS, confirming that pediatric ANK1-HS patients exhibit a more severe anemic phenotype compared to SPTB-HS patients, while the severity of HS in adults does not significantly differ between different causative genes., (© 2024. The Author(s).)

Hybrid N 2 -CO 2 huff-n-puff (HnP) has been experimentally demonstrated to be a promising approach for improving oil recovery from tight/ultratight shale oil reservoirs. Despite this, the detailed soaking process and interaction mechanisms remain unclear. Adopting molecular dynamic simulations, the soaking behavior of hybrid N 2 -CO 2 HnP was investigated at the molecular and atomic levels. Initially, the soaking process of fluid pressure equilibrium after injection pressure decays in a single matrix nanopore connected to a shale oil reservoir is studied. The study revealed that counter-current and cocurrent displacement processes exist during the CO 2 and hybrid N 2 -CO 2 soaking, but cocurrent displacement occurs much later than counter-current displacement. Although the total displacement efficiency of the hybrid N 2 -CO 2 soaking system is lower than that of the CO 2 soaking system, the cocurrent displacement initiates earlier in the hybrid N 2 -CO 2 soaking system than in the CO 2 soaking system. Moreover, the N 2 soaking process is characterized by only counter-current displacement. Next, the soaking process of fluid pressure nonequilibrium before the injection pressure decays is investigated. It was discovered that counter-current and cocurrent displacement processes initiate simultaneously during the CO 2 , N 2 , and hybrid N 2 -CO 2 soaking process, but cocurrent displacement exerts a dominant influence. During the CO 2 soaking process, many hydrocarbon molecules in the nanopore are dissolved in CO 2 while simultaneously exhibiting a substantial retention effect in the nanopore. After pure N 2 injection, there is a tendency to form a favorable path of N 2 through the oil phase. The injection of hybrid CO 2 -N 2 facilitates the most significant cocurrent displacement effect and the reduction in residual oil retained in the nanopore during the soaking process, thus resulting in the best oil recovery. However, the increase rate in total displacement efficiencies of the different soaking systems over time (especially the hybrid N 2 -CO 2 soaking system) was significantly larger before than after injection pressure decays. Additionally, the displacement effect induced by oil volume swelling is significantly restricted before the injection pressure decays compared to the soaking process after the injection pressure decays. This study explains the role of CO 2 -induced oil swelling and N 2 -induced elastic energy played by hybrid N 2 and CO 2 at different stages of the hybrid N 2 -CO 2 soaking process before and after pressure decays and provides theoretical insights for hybrid gas HnP-enhanced recovery. These pore-scale results highlight the importance of injection pressure and medium composition during the soaking process in unconventional oil reservoirs.

The dominant bacteria in the hindgut of calves play an important role in their growth and health, which could even lead to lifelong consequences. However, the identification of core probiotics in the hindgut and its mechanism regulating host growth remain unclear. Here, a total of 1045 fecal samples were analyzed by 16S rRNA gene sequencing from the 408 Holstein dairy calves at the age of 0, 14, 28, 42, 56, and 70 days to characterize the dynamic changes of core taxa. Moreover, the mechanisms of nutrient metabolism of calf growth regulated by core bacteria were investigated using multi-omics analyses. Finally, fecal microbiota transplantation (FMT) in mice were conducted to illustrate the potential beneficial effects of core bacteria. Four calf enterotypes were identified and enterotypes dominated by Bifidobacterium and Oscillospiraceae&#95;UCG-005 were representative. The frequency of enterotype conversion shifted from variable to stable. The close relationship observed between phenotype and enterotype, revealing a potential pro-growth effect of Bifidobacterium, might be implemented by promoting the use of carbohydrate, activating the synthesis of volatile fatty acids, amino acids and vitamin B6, and inhibiting methane production in the hindgut. The FMT results indicated the beneficial effect of Bifidobacterium on host growth and hindgut development. These results support the notion that the Bifidobacterium-dominated fecal microbiome would be an important driving force for promoting the host growth in the early life. Our findings provide new insights into the potential probiotic mining and application strategies to promote the growth of young animals or improve their growth retardation., (© 2024. The Author(s).)

Objective: The present study aimed to investigate the involvement of aberrant BMP8A expression in TNBC and bone metastasis., Methods: Aberrant expression of BMP8A in breast cancer was first determined by analyzing The Cancer Genome Atlas breast cancer cohort (TCGA-BRCA) and an immunohistochemical (IHC) staining of BMP8A in a breast cancer tissue microarray (TMA). Clinical relevance of deregulated BMP8A in breast cancer was assessed using Kaplan-Meier online analysis. The influence of BMP8A on cellular functions of two TNBC cell lines was assessed using in vitro assays. Conditional medium (CM) collected from the supernatant of hFOB cells and bone matrix extract (BME) was applied to mimic the bone micro-environment to evaluate the role played by BMP8A in bone metastasis. Correlations with both osteolytic and osteoblastic markers were evaluated in the TCGA-BRCA cohort. Expression of certain responsive genes was quantified in the BMP8A overexpression cell lines. Additionally, signal transduction through both Smad-dependent and independent pathways was evaluated using Western blot assay., Results: Compared to the adjacent normal tissues, BMP8A expression was significantly increased in primary tumors ( p < 0.05) which was associated with shorter distant metastasis free survival (DMFS) in TNBC ( p < 0.05). BMP8A was observed to enhance cell invasion and migration within TNBC cells. In the simulated bone milieu, both MDA-MB-231 BMP8Aexp and BT549 BMP8Aexp cells presented enhanced invasiveness. BMP8A level was strongly correlated with most osteolytic and osteoblastic markers, suggesting the potential involvement of BMP8A in bone metastasis in TNBC. Receptor activator of nuclear factor kappa-B ligand (RANKL) expression was significantly increased in BMP8A overexpressed triple-negative cell lines (MDA-MB-231 and BT549). Furthermore, enhanced phosphorylation of Smad3 and increased expression of epidermal growth factor receptor (EGFR) were observed in MDA-MB-231 cells overexpressing BMP8A., Conclusion: BMP8A was upregulated in TNBC which was associated with poorer DMFS. BMP8A overexpression enhanced the invasion and migration of TNBC cells. With a putative role in osteolytic bone metastasis in TNBC, BMP8A represents a promising candidate for further investigation into its therapeutic potential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sui, Cong, Liu, Liu, Xu, Jiang and Ye.)

Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD.

Assisted reproduction technology (ART) procedures are often impacted by post-ovulatory aging (POA), which can lead to reduced fertilization rates and impaired embryo development. This study used RNA sequencing analysis and experimental validation to study the similarities and differences between in vivo- and vitro-matured porcine oocytes before and after POA. Differentially expressed genes (DEGs) between fresh in vivo-matured oocyte (F&#95;vivo) and aged in vivo-matured oocyte (A&#95;vivo) and DEGs between fresh in vitro-matured oocyte (F&#95;vitro) and aged in vitro-matured oocyte (A&#95;vitro) were intersected to explore the co-effects of POA. It was found that "organelles", especially "mitochondria", were significantly enriched Gene Ontology (GO) terms. The expression of genes related to the "electron transport chain" and "cell redox homeostasis" pathways related to mitochondrial function significantly showed low expression patterns in both A&#95;vivo and A&#95;vitro groups. Weighted correlation network analysis was carried out to explore gene expression modules specific to A&#95;vivo. Trait-module association analysis showed that the red modules were most associated with in vivo aging. There are 959 genes in the red module, mainly enriched in "RNA binding", "mRNA metabolic process", etc., as well as in GO terms, and "spliceosome" and "nucleotide excision repair" pathways. DNAJC7 , IK , and DDX18 were at the hub of the gene regulatory network. Subsequently, the functions of DDX18 and DNAJC7 were verified by knocking down their expression at the germinal vesicle (GV) and Metaphase II (MII) stages, respectively. Knockdown at the GV stage caused cell cycle disorders and increase the rate of abnormal spindle. Knockdown at the MII stage resulted in the inefficiency of the antioxidant melatonin, increasing the level of intracellular oxidative stress, and in mitochondrial dysfunction. In summary, POA affects the organelle function of oocytes. A&#95;vivo oocytes have some unique gene expression patterns. These genes may be potential anti-aging targets. This study provides a better understanding of the detailed mechanism of POA and potential strategies for improving the success rates of assisted reproductive technologies in pigs and other mammalian species.

Background: Multiple high doses of 131 I therapy in patients with differentiated thyroid cancer (DTC) might disrupt the balance of gut microbiota and metabolites. This study aimed to investigate the alterations of intestinal bacteria and metabolism over two courses of 131 I therapy, explore the interactions, and construct diagnostic models reflecting enteric microecology based on 131 I therapy., Methods: A total of 81 patients were recruited for the first 131 I therapy ( 131 I-1st), among whom 16 received a second course ( 131 I-2nd) after half a year. Fecal samples were collected 1 day before (Pre- 131 I-1st/2nd) and 3 days after (Post- 131 I-1st/2nd) 131 I therapy for microbiome (16S rRNA gene sequencing) and metabolomic (LC-MS/MS) analyses., Results: A total of six microbial genera and 11 fecal metabolites enriched in three pathways were identified to show significant differences between Pre- 131 I-1st and other groups throughout the two courses of 131 I treatment. In the Post- 131 I-1st group, the beneficial bacteria Bifidobacterium, Lachnoclostridium, uncultured&#95;bacterium&#95;f&#95;Lachnospiraceae, and Lachnospiraceae&#95;UCG004 were abundant and the radiation-sensitive pathways of linoleic acid (LA), arachidonic acid, and tryptophan metabolism were inhibited compared with the Pre- 131 I-1st group. Compared with the Pre- 131 I-1st group, the Pre- 131 I-2nd group exhibited a reduced diversity of flora and differentially expressed metabolites, with a low abundance of beneficial bacteria and dysregulated radiation-sensitive pathways. However, less significant differences in microbiota and metabolites were found between the Pre/Post- 131 I-2nd groups compared with those between the Pre/Post- 131 I-1st groups. A complex co-occurrence was observed between 6 genera and 11 metabolites, with Lachnoclostridium, Lachnospiraceae&#95;UCG004, Escherichia-Shigella, and LA-related metabolites contributing the most. Furthermore, combined diagnostic models of charactered bacteria and metabolites answered well in the early, long-term, and dose-dependent responses for 131 I therapy., Conclusions: Different stages of 131 I therapy exert various effects on gut microecology, which play an essential role in regulating radiotoxicity and predicting the therapeutic response., (© 2024. The Author(s).)

In carbon allotropes, a series of topological semi-metals have been predicted, but both novel electronic properties and mechanical characteristics, e.g. , a negative Poisson's ratio (NPR), are rarely discovered in the same sp 2 type system. Here, a new three-dimensional carbon network, named WZGN, constructed from distorted one-dimensional zigzag graphene nanoribbons is proposed. The stability of the system is fully ensured by the phonon dispersion, AIMD simulation, and binding energy calculations. Besides, it is found that the system holds both topologically protected nodal line semi-metal properties together with an NPR property. Especially, the value of the NPR can exceed -0.36 when 21% uniaxial tensile strain along the c '-direction is applied. Our findings point out that nodal line semi-metals can be compatible with intrinsic NPR properties in a wide strain range in carbon systems with sp 2 hybridization, suggesting possible applications in mechanical and electronics fields.

Background: Acupuncture has been shown for the treatment of allergic rhinitis in previous studies. Nevertheless, relevant evidence was lacked for paediatric patients with allergic rhinitis. We aim to validate the efficacy of acupuncture for allergic rhinitis in children by meta-analysis and trial sequence analysis., Method: Comprehensive search of eight databases were conducted until August 27, 2023. Randomized controlled trials comparing acupuncture alone or in combination with drugs versus medication in children with AR were included. The primary outcome was total nasal symptom score (TNSS). The secondary outcomes were serum immunoglobulin E levels, and relapse rates., Results: Thirteen studies involving 1186 participants were included. In results, acupuncture group (AC group) versus medication group (Med group) shows no significant difference in the treatment of AR in children (risk ratio [RR] = 1.10, 95% CI = 0.97 to 1.24, p = 0.13), while TSA suggested the included sample size did not exceed required information size (RIS). Significant differences were found between the AC + Med group versus the Med group (RR = 1.29, 95% CI = 1.17 to 1.42, p < 0.00001), with sufficient sample size. Results in serum IgE after treatment which favored the Med group (MD = 51.94, 95% CI [22.24, 81.65], p = 0.0006). In terms of relapse rate, The AC group had a lower relapse rate than the Med group (RR = 0.40, 95% CI = 0.26-0.63, p < 0.0001)., Conclusions: Acupuncture is an efficacious treatment for allergic rhinitis in children, but this conclusion might be limited by the generally low quality of evidence. TSA suggested additional high-quality trials with larger sample sizes and longer treatment durations were needed., (© 2024 ARS‐AAOA, LLC.)

Bronchopulmonary dysplasia (BPD) is a serious disease that occurs in premature and low-birth-weight infants. In recent years, the incidence of BPD has not decreased, and there is no effective treatment for it. Oridonin (Ori) is a traditional Chinese medicine with a wide range of biological activities, especially pharmacological and anti-inflammatory. It is well known that inflammation plays a key role in BPD. However, the therapeutic effect of Ori on BPD has not been studied. Therefore, in the present study, we will observe the anti-inflammatory activity of Ori in an experimental animal model of BPD. Here, we showed that Ori could significantly decrease hyperoxia-induced alveolar injury, inhibit neutrophil recruitment, myeloperoxidase concentrations, and release inflammatory factors in BPD neonatal rats. Taken together, the experimental results suggested that Ori can significantly improve BPD in neonatal rats by inhibiting inflammatory response., (© 2024 Wiley Periodicals LLC.)

Background: As a key substance for intercellular communication, exosomes could be a potential strategy for stroke treatment. Activated microglia disrupt the integrity of blood-brain barrier (BBB) to facilitate the stroke process. Hence, this study was designed to investigate the effect of microglia-derived exosomes on BBB cell model injury and to explore the underlying molecular mechanisms., Methods: M1 polarization of BV2 cells was induced with LPS and their derived exosomes were isolated. Astrocytes were cultured in primary culture and constructed with End3 cells as a BBB cell model. After co-culture with exosomes, the BBB cell model was examined for changes in TEER, permeability, and expression of BBB-related proteins (Claudin-1, Occludin, ZO-1 and JAM). Resting and M1-type BV2 cell-derived exosomes perform small RNA sequences and differentially expressed miRNAs (DE-miRNAs) are identified by bioinformatics., Results: M1-type BV2 cell-derived exosomes decreased End3 cell viability, and increased their apoptotic ratio. Moreover, M1 type BV2 cell-derived exosomes dramatically enhanced the permeability of BBB cell model, and diminished the TEER and BBB-related protein (Claudin-1, Occludin, ZO-1) expression. Notably, resting BV2 cell-derived exosomes had no effect on the integrity of BBB cell model. Sequencing results indicated that 71 DE-miRNAs were present in M1 BV2 cell-derived exosomes, and their targets mediated neurological development and signaling pathways such as MAPK and cAMP. RT-qPCR confirmed the differential expression of mmu-miR-125a-5p, mmu-miR-122b-3p, mmu-miR-139-3p, mmu-miR-330-3p, mmu-miR-3057-5p and mmu-miR-342-3p consistent with the small RNA sequence. Furthermore, Creb1, Jun, Mtor, Frk, Pabpc1 and Sdc1 are the most well-connected proteins in the PPI network., Conclusion: M1-type microglia-derived exosomes contribute to the injury of BBB cell model, which has the involvement of miRNAs. Our findings provide new perspectives and potential mechanisms for future M1 microglia-derived exosomes as therapeutic targets in stroke., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) represents the most widespread neurodegenerative disorder, distinguished by a gradual onset and slow progression, presenting a substantial challenge to global public health. The mitochondrial-associated membrane (MAMs) functions as a crucial center for signal transduction and material transport between mitochondria and the endoplasmic reticulum, playing a pivotal role in various pathological mechanisms of AD. The dysregulation of mitochondrial quality control systems is considered a fundamental factor in the development of AD, leading to mitochondrial dysfunction and subsequent neurodegenerative events. Recent studies have emphasized the role of MAMs in regulating mitochondrial quality control. This review will delve into the molecular mechanisms underlying the imbalance in mitochondrial quality control in AD and provide a comprehensive overview of the role of MAMs in regulating mitochondrial quality control., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Minisci-type dehydrogenative coupling of C(sp 3 )-H and N-heteroaromatics was performed with N -hydroxysuccinimide as a hydrogen atom transfer catalyst in a photoelectrochemical cell composed of a mesoporous BiVO 4 photoanode and a Pt electrode. In the absence of metal catalysts and chemical oxidants, a range of N -heteroarenes (e.g., quinolines, isoquinolines, and quinoxaline) can undergo coupling with various C(sp 3 )-H partners to form the corresponding products in excellent yields.

Context: Dysthyroid optic neuropathy (DON) is a serious vision-threatening complication of thyroid-associated ophthalmopathy (TAO). Exploration of the underlying mechanisms of DON is critical for its timely clinical diagnosis., Objective: We hypothesized that TAO patients with DON may have altered brain functional networks. We aimed to explore the alterations of static and dynamic functional connectomes in patients with and without DON using resting-state functional magnetic resonance imaging with the graph theory method., Methods: A cross-sectional study was conducted at a grade A tertiary hospital with 66 TAO patients (28 DON and 38 non-DON) and 30 healthy controls (HCs). Main outcome measures included topological properties of functional networks., Results: For static properties, DON patients exhibited lower global efficiency (Eg), local efficiency, normalized clustering coefficient, small-worldness (σ), and higher characteristic path length (Lp) than HCs. DON and non-DON patients both exhibited varying degrees of abnormalities in nodal properties. Meanwhile, compared with non-DON, DON patients exhibited abnormalities in nodal properties in the orbitofrontal cortex and visual network (VN). For dynamic properties, the DON group exhibited higher variance in Eg and Lp than non-DON and HC groups. A strengthened subnetwork with VN as the core was identified in the DON cohort. Significant correlations were found between network properties and clinical variables. For distinguishing DON, the combination of static and dynamic network properties exhibited optimal diagnostic performance., Conclusion: Functional network alterations were observed both in DON and non-DON patients, providing novel insights into the underlying neural mechanisms of disease. Functional network properties may be potential biomarkers for reflecting the progression of TAO from non-DON to DON., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Microglia, as resident macrophages in the central nervous system, play a multifunctional role in the pathogenesis of Alzheimer's disease (AD). Their clustering around amyloid-β (Aβ) deposits is a core pathological feature of AD. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have revealed dynamic changes in microglial phenotypes over time and across different brain regions during aging and AD progression. As AD advances, microglia primarily exhibit impaired phagocytosis of Aβ and tau, along with the release of pro-inflammatory cytokines that damage synapses and neurons. Targeting microglia has emerged as a potential therapeutic approach for AD. Treatment strategies involving microglia can be broadly categorized into two aspects: (1) enhancing microglial function: This involves augmenting their phagocytic ability against Aβ and cellular debris and (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce the neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches for AD treatment have garnered attention. Additionally, natural products show promise in enhancing beneficial effects and suppressing inflammatory responses. Clarifying microglial dynamics, understanding their roles, and exploring novel therapeutic approaches will advance our fight against AD.

Two bis-cyclometalated heteroleptic iridium complexes incorporating 1-phenylisoquinoline (piq) as the main cyclometalating ligand and 3-hydroxy-2-methyl-4-pyrone (ma) or 2-ethyl-3-hydroxy-4H-pyran-4-one (ema) as the auxiliary ligand, namely Ir(piq) 2 (ma) (Ir-1) and Ir(piq) 2 (ema) (Ir-2), were developed and applied as deep-red phosphors in organic light-emitting diodes (OLEDs). The two auxiliary ligands had similar influences on the photophysical, electrochemical, and electroluminescent properties of the iridium complexes. Ir(piq) 2 (ma) (Ir-1) showed better luminescence performance in a simple phosphorescent OLED compared to the traditional red iridium complex Ir(piq) 2 (acac) and exhibited a current efficiency of 9.39 cd A -1 (EQE of 12.09%). In contrast, Ir(piq) 2 (ema) exhibited an efficiency of 8.6 cd A -1 (EQE of 10.19%).

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

In recent years, with the global warming getting worse and increasing demand for energy, countries around the world are trying to develop new energy storage technologies to solve this problem. Currently, potassium-ion batteries (PIBs) have attracted tremendous attention from researchers as low-cost and high-performance energy storage devices. However, due to the huge ionic radius of K + , PIBs face significant volume expansion during cycling, which can easily lead to the collapse of electrode structures. In addition, the poor diffusion kinetics of K + seriously affect the electrochemical performance of the battery. Carbon nanofibers (CNFs)-based materials (including CNFs, metal/CNFs composites, chalcogenide/CNFs composites, and other CNFs-based materials) are widely used as PIBs electrode anode materials due to their three-dimensional conductive network, heteroatom doping and excellent mechanical properties. This review discusses in detail the research progress of CNFs-based materials in PIBs, including material preparation, structural design, and performance optimization. On this basis, this article explores the key issues faced by CNFs-based materials and future development directions, and proposes improvement suggestions for providing new ideas for the development of CNFs-based materials., (© 2023 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

This study aimed to investigate the effects of male hepatitis B virus (HBV) infection on male fertility, embryonic development, and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes. We performed a retrospective cohort study that included 3965 infertile couples who received fresh embryo transfer cycles for the first time at the Fujian Maternity and Child Health Hospital (Fuzhou, China) from January 2018 to January 2021. Infertile couples were categorized based on their HBV infection status into the HBV group (HBV-positive men and HBV-negative women) and the control group (HBV-negative couples). A 1:1 propensity score matching was performed with relatively balanced covariates. Baseline characteristics, semen parameters, laboratory outcomes, clinical outcomes, and obstetric and neonatal outcomes were compared between groups. After propensity score matching, 821 couples were included in each group. Both groups had similar semen parameters and obstetric and neonatal outcomes. The HBV group showed a significantly lower live birth rate than the control group ( P < 0.05). The HBV group had a significantly higher abortion rate than the control group ( P < 0.05). The rates of high-quality embryos and blastocyst formation were significantly lower in the HBV group than those in the control group (both P < 0.05). In conclusion, in couples who undergo IVF/ICSI, male HBV infection reduces the live birth rate and increases the risk of miscarriage. However, the incidence of low birth weight in women with IVF/ICSI does not increase with male HBV infection., (Copyright © 2024 Copyright: ©The Author(s)(2024).)

Background: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131 I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131 I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment., Methods: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131 I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses., Results: 131 I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131 I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1., Conclusion: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects., (© 2024. The Author(s).)

Objectives: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss., Methods: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes., Results: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis., Discussion: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance., (© 2024. The Author(s).)

Multisubstituted furans occupy a pivotal position within the realms of synthetic chemistry and pharmacological science due to their distinctive chemical configurations and inherent properties. We herein introduce a tandem difunctionalization protocol of alcohols for the efficient synthesis of multisubstituted 2,3-dihydrofurans and γ-butyrolactones through the combination of photocatalysis and iron catalysis under mild conditions. Photoredox alcohol α-C(sp 3 )-H activation and Pinner-type intramolecular cyclization are two key processes. This method features significant convenience, economic benefits, and environmental friendliness.