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Background: To investigate the effects of Isoorientin on the apoptosis, proliferation, invasion, and migration of human gastric cancer cells (HGC27 cells)., Methods: We used network pharmacology to predict the targets of drugs and diseases. The CCK-8 assay was used to determine the effects of Isoorientin on the proliferation of HGC27 cells. Flow cytometry was employed to analyze the effects of Isoorientin on cell apoptosis and cell cycle distribution of HGC27 cells. Scratch test and transwell chamber test were conducted to assess the effects of Isoorientin on invasion and migration, respectively. Additionally, qPCR and western blot were performed to examine the impact of Isoorientin on apoptosis-related genes and protein expression, respectively., Results: The Isoorientin significantly inhibited the proliferation, migration, and invasion of HGC27 cells compared to the control group. Furthermore, Isoorientin induced apoptosis in HGC27 cells by upregulating the relative expression of Bax and caspase-3 while downregulating the relative expression of p-PI3K, p-AKT, and Bcl-2 proteins., Conclusion: The Isoorientin exhibits inhibitory effects on the proliferation, invasion, and migration of HGC27 cells, and induces apoptosis in gastric cancer cells., (© 2024. The Author(s).)

Submarine groundwater discharge (SGD) significantly impacts most coastal waters. However, its quantification, depending on chemical tracers/proxies, limits its parameterization in numerical models. This study explored the hydrographic proxies of SGD in the Jiulong River estuary (JRE) using 226 Ra and 228 Ra as SGD tracers. Our results showed significant monthly fluctuations in the flux of SGD, with a peak in June and a minimum in April. On average, the flux of SGD was equivalent to 10 ± 1.67 % of the concurrent river discharge, with the area-normalized rate of 0.007 ± 0.017 to 0.13 ± 0.04 m/day. Positive SGD response to river discharge implies a connection with the surface runoff of the shallow aquifers. Furthermore, the flux of SGD presented a significant negative correlation with the return flow factor and flushing time of the estuary. The radium activities in the estuary were positively correlated with water depth, indicating that SGD was not driven by tidal pumping. Instead, physical mixing in low to middle salinity regions predominated such behavior of radium. Our results indicate that river discharge, flushing time and return flow factor may serve as hydrographic proxies of SGD in the JRE and potentially be applicable in parameterization of SGD in numerical models in similar coastal ecosystems. Globally, a positive correlation between SGD flux and river discharge emphasizes the latter as a general proxy in estuaries., 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers., Competing Interests: Declaration of Competing Interest There are no missing disclosures or conflicts of interest associated with this work. 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Understanding the incidence and predictors of postpartum depression (PPD) among active-duty service members is critical given the importance of this population and its unique stressors. Methods: We conducted a retrospective cohort study of all active-duty U.S. Army soldiers with a record of at least one live-birth delivery between January 2012 and December 2013. Multivariate logistic regression models were used to estimate associations between demographic, health-related, and military-specific variables and diagnoses of PPD in the total population ( N = 4,178) as well as in a subpopulation without a record of depression before delivery ( N = 3,615). Results: The overall incidence of PPD diagnoses was 15.9% ( N = 664 cases) among the total population and 10.4% ( N = 376 cases) among those without prior depression. Statistically significant predictors of PPD in the adjusted model included lower pay grade, a higher number of prior deployments, a higher number of child dependents, tobacco use, and a history of depression or anxiety before or during pregnancy. For soldiers without a history of depression, lower pay grade, and a history of anxiety before or during pregnancy were significantly associated with PPD. Conclusions: Knowing the predictors of overall and novel onset PPD diagnoses in this population could help establish clearer guidelines on PPD prevention, screening, management, and return to duty.

Plants form two immune systems, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI), to combat Blumeria graminis f. sp. tritici (Bgt) infection during the evolutionary process. In PTI, receptor-like kinases (RLKs) play important roles during pathogen infections. Based on our previous reports, there were 280 TaRLKs identified in early response to powdery mildew infection, which were divided into 34 subfamilies in this study. Differences in gene structures, cis-acting elements, and expression levels implied the function diversity of TaRLKs. TaRLK2.4, a member of LRK10L-RLKs subfamily, contained 665 amino acids, and located on the cell membrane. The main objective of this study was to investigate the role of the receptor-like kinase gene TaRLK2.4 in conferring powdery mildew resistance in wheat. Real-time quantitative PCR results indicated that TaRLK2.4 expressed during Bgt infection process, and exhibited a transgressive expression characteristic in disease resistance NILs (BJ-1). To elucidate the function of TaRLK2.4 during Bgt infection, the comprehensive analysis of virus induced gene silence and over-expression demonstrated that TaRLK2.4 promoted powdery mildew resistance positively. In summary, these results contribute to a deeper understanding of the complex and diverse biological functions of RLKs, and provide new genetic resources for wheat molecular breeding., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain., Objectives: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure., Design: A longitudinal study., Setting and Participants: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included., Measurements: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied., Results: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume., Conclusions: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Visceral fat accumulation and obesity-induced chronic inflammation have been proposed as early markers for multiple disease states, especially in women. Nevertheless, the potential impact of fat distribution on α1-acid glycoprotein(AGP), a marker of inflammation, remains unclear. This research was conducted to investigate the relationships among obesity, fat distribution, and AGP levels., Methods: A cross-sectional observational study was performed using blood samples from adult females recruited through the National Health and Nutrition Examination Survey from 2015 to 2018. Serum levels of AGP were measured using the Tina-quant α-1-Acid Glycoprotein Gen.2 assay. Based on the fat distribution data obtained from dual-energy X-ray absorptiometry assessments, body mass index (BMI), total percent fat (TPF), android percent fat (APF), gynoid percent fat (GPF), android fat/gynoid fat ratio (AGR), visceral percent fat (VPF), subcutaneous percent fat (SPF), visceral fat/subcutaneous fat ratio (VSR) were used as dependent variables. To investigate the link between fat distribution and AGP, multivariate linear regression analysis was utilized. Furthermore, a sensitivity analysis was also performed., Results: The present study included 2,295 participants. After adjusting for covariates, BMI, TPF, APF, GPF, VPF, and SPF were found to be positively correlated with AGP levels (BMI: β = 23.65 95%CI:20.90-26.40; TPF: β = 25.91 95%CI:23.02-28.80; APF: β = 25.21 95%CI:22.49-27.93; GPF: β = 19.65 95%CI:16.96-22.34; VPF: β = 12.49 95%CI:9.08-15.90; SPF: β = 5.69, 95%CI:2.89-8.49; AGR: β = 21.14 95%CI:18.16-24.12; VSR: β = 9.35 95%CI:6.11-12.59, all P < 0.0001). All the above indicators exhibited a positive dose-response relationship with AGP. In terms of fat distribution, both AGR and VSR showed positive associations with AGP (P for trend < 0.0001). In particular, when compared to individuals in tertile 1 of AGR, participants in tertiles 2 and 3 had 13.42 mg/dL (95% CI 10.66-16.18) and 21.14 mg/dL (95% CI 18.16-24.12) higher AGP levels, respectively. Participants in the highest tertile of VSR were more likely to exhibit a 9.35 mg/dL increase in AGP compared to those in the lowest tertile (95% CI 6.11-12.59)., Conclusions: Overall, this study revealed a positive dose-dependent relationship between fat proportion/distribution and AGP levels in women. These findings suggest that physicians can associate abnormal serum AGP and obesity with allow timely interventions., (© 2024. The Author(s).)

Objective: To investigate the contribution of longitudinal mean arterial pressure (MAP) measurement during the first, second, and third trimesters of twin pregnancies to the prediction of pre-eclampsia., Methods: A retrospective cohort study was conducted on women with twin pregnancies. Historical data between 2019 and 2021 were analyzed, including maternal characteristics and mean artery pressure measurements were obtained at 11-13, 22-24, and 28-33 weeks of gestation. The outcome measures included pre-eclampsia with delivery <34 and ≥34 weeks of gestation. Models were developed using logistic regression, and predictive performance was evaluated using the area under the curve, detection rate at a given false-positive rate of 10%, and calibration plots. Internal validation was conducted via bootstrapping., Results: A total of 943 twin pregnancies, including 36 (3.82%) women who experienced early-onset pre-eclampsia and 93 (9.86%) who developed late-onset pre-eclampsia, were included in this study. To forecast pre-eclampsia during the third trimester, the most accurate prediction for early-onset pre-eclampsia resulted from a combination of maternal factors and MAP measured during this trimester. The optimal predictive model for late-onset pre-eclampsia includes maternal factors and MAP data collected during the second and third trimesters. The areas under the curve were 0.937 (95% confidence interval [CI] 0.894-0.981) and 0.887 (95% CI 0.852-0.921), respectively. The corresponding detection rates were 83.33% (95% CI 66.53%-93.04%) for early-onset pre-eclampsia and 68.82% (95% CI 58.26%-77.80%) for late-onset pre-eclampsia., Conclusion: Repeated measurements of MAP during pregnancy significantly improved the accuracy of late-onset pre-eclampsia prediction in twin pregnancies. The integration of longitudinal data into pre-eclampsia screening may be an effective and valuable strategy., (© 2024 International Federation of Gynecology and Obstetrics.)

Soybeans' isoflavone content increases with germination; nevertheless, their bioaccessibility in the gastrointestinal system is limited. This study evaluated the influence of germination time (1, 3, 5, and 7 days) and in vitro gastrointestinal conditions on the isoflavone profile of soybean sprouts. The total isoflavones (4.07 mg/g) and the malonyl genistin (1.37 mg/g) had the highest contents on day 5 in the gastric phase. The highest isoflavone bioaccessibility was observed in daidzein, genistein, and glycitin. An increase in antioxidant capacity was found during germination (day 7 > day 5 > day 3); however, the same trend was not observed during in vitro digestion. In summary, the results indicate that soybean sprouts germinated for 5 days may be more beneficial for consumption since they have the highest and most readily absorbed levels of isoflavones. These data suggest that soybean sprouts may be a functional food that provides bioavailable antioxidants., 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. The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

In this work, novel erythrocyte-shaped electrosprayed nanoparticles (EENPs) were designed and constructed by tri-axial electrospraying technique with PEG as the outer layer, PLGA as the middle drugs (paclitaxel [PTX] and osimertinib [OSI]) carrier layer and air as the inner layer. The prepared EENP were characterized and evaluated based on their spectral and morphological attributes. After the PTX/OSI ratio and process optimization, the EENP has inspiring features, including nanoscale size, erythrocyte morphology with a concave disk shape, and satisfactory drug loading (DL) and encapsulation efficiency (EE). In vitro drug release showed that PTX and OSI in the formulation were released in the same ratio, and the cumulative release percentage at 24 h was close to 80 %. Furthermore, the TGIR in the EENP formulation group exceeded 90 %, approximately 3.8-fold higher than that in the free drug group. In summary, we developed an erythrocyte three-core-shell nanoparticle for the co-delivery of PTX and OSI, providing a potential chemotherapeutic delivery system for the treatment of breast cancer., 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.)

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).)

Wheat powdery mildew is an important fungal disease that seriously jeopardizes wheat production, which poses a serious threat to food safety. SJ106 is a high-quality, disease-resistant spring wheat variety; this disease resistance is derived from Wheat-wheatgrass 33. In this study, the powdery mildew resistance genes in SJ106 were located at the end of chromosome 6DS, a new disease resistance locus tentatively named PmSJ106 locus . This interval was composed of a nucleotide-binding leucine-rich repeat (NLR) gene cluster containing 19 NLR genes. Five NLRs were tandem duplicated genes, and one of them (a coiled coil domain-nucleotide binding site-leucine-rich repeat (CC-NBS-LRR; CNL) type gene, TaRGA5-like ) expressed 69-836-fold in SJ106 compared with the susceptible control. The genome DNA and cDNA sequences of TaRGA5-like were amplified from SJ106, which contain several nucleotide polymorphisms in LRR regions compared with susceptible individuals and Chinese Spring. Overexpression of TaRGA5-like significantly increased resistance to powdery mildew in susceptible receptor wheat Jinqiang5. However, Virus induced gene silence (VIGS) of TaRGA5-like resulted in only a small decrease of SJ106 in disease resistance, presumably compensated by other NLR duplicated genes. The results suggested that TaRGA5-like confers partial powdery mildew resistance in SJ106. As a member of the PmSJ106 locus , TaRGA5-like functioned together with other NLR duplicated genes to improve wheat resistance to powdery mildew. Wheat variety SJ106 would become a novel and potentially valuable germplasm for powdery mildew resistance.

Purpose: N6-methyladenosine (m6A) methylation is a chemical modification that occurs on RNA molecules, where the hydrogen atom of adenine (A) nucleotides is replaced by a methyl group, forming N6-methyladenosine. This modification is a dynamic and reversible process that plays a crucial role in regulating various biological processes, including RNA stability, transport, translation, and degradation. Currently, there is a lack of research on the role of m6A modifications in maintaining the characteristics of RPE cells. m6A readers play a crucial role in executing the functions of m6A modifications, which prompted our investigation into their regulatory roles in the RPE., Methods: Phagocytosis assays, immunofluorescence staining, flow cytometry experiments, β-galactosidase staining, and RNA sequencing (RNA-seq) were conducted to assess the functional and cellular characteristics changes in retinal pigment epithelium (RPE) cells following short-hairpin RNA-mediated knockdown of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). RNA-seq and ultraviolet crosslinking immunoprecipitation with high-throughput sequencing (HITS-CLIP) were employed to identify the target genes regulated by IGF2BP2. adeno-associated virus (AAV) subretinal injection was performed in 6- to 8-week-old C57 mice to reduce IGF2BP2 expression in the RPE, and the impact of IGF2BP2 knockdown on mouse visual function was assessed using immunofluorescence, quantitative real-time PCR, optical coherence tomography, and electroretinography., Results: IGF2BP2 was found to have a pronounced effect on RPE phagocytosis. Subsequent in-depth exploration revealed that IGF2BP2 modulates the mRNA stability of PAX6 and OTX2, and the loss of IGF2BP2 induces inflammatory and aging phenotypes in RPE cells. IGF2BP2 knockdown impaired RPE function, leading to retinal dysfunction in vivo., Conclusions: Our data suggest a crucial role of IGF2BP2 as an m6A reader in maintaining RPE homeostasis by regulating the stability of PAX6 and OTX2, making it a potential target for preventing the occurrence of retinal diseases related to RPE malfunction.

Background: Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and succinate receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI)., Methods: The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 μg, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated., Result: The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1α (HIF-1α) expression, inhibitory κB-α (IκB-α) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1α expression and IκB-α phosphorylation., Conclusion: The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ke Wei reports financial support was provided by Chongqing Science and Technology Bureau. If there are other authors, they 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.)

Sulfonamides (SAs) is a class of antibiotics that extensively used for treating infectious diseases in livestock industries and aquaculture. Thus, it is urgent need to obtain the bio-receptor, which has excellent cross-reactivity and specificity to SAs, for developing high-throughput methods for the determination of multiple SAs even all commonly-used SAs, to realize the quick screening/detection of total SAs in animal-derived foods. We herein isolated several SAs-specific cross-reactive aptamers by using a library-immobilized SELEX with multi-SAs parallel selection strategy. Two of the isolated aptamers (Sul-01 and Sul-04) can specifically recognize and bind seven SAs respectively with higher binding affinity and no interference of non-sulfonamide antibiotics, and thus can be applied as bio-receptors for developing high-throughput aptasensors for the quick screening/detection of multiple SAs. By using the mixture of Sul-01 and Sul-04 as bio-receptor, a ratiometric fluorescent aptasensor was created for the quick detection of nine SAs including sulfamethoxydiazine (SMD), sulfapyridine (SPD), sulfaquinoxaline (SQ), sulfathiazole (ST), sulfamonomethoxine (SMM), sulfamerazine (SMR), sulfaguanidine (SG), sulfamethazine (SMZ) and sulfadiazine (SD) with a detection limit (LOD) of 0.10-0.50 μM, or total of above nine SAs with a LOD of 0.20 μM. The fluorescent aptasensor was successfully applied to detect each or total of SMD, SPD, SQ, ST, SMM, SMR, SG, SMZ and SD in fish samples with a recovery of 83 %-92 % and a relative standard deviation (RSD, n = 5) < 5 %. This study not only provided several promising bio-receptors for the development of diverse high-throughput aptasensors to achieve the quick screening of multiple SAs residues, but also provided a simple, stable and sensitive method for the quick screening of SMD, SPD, SQ, ST, SMM, SMR, SG, SMZ and SD in seafood., 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.)

The continual exposure of retinal tissues to oxidative stress leads to discernible anatomical and physiological alterations. Specifically, the onslaught of oxidative damage escalates the irreversible death of retinal pigmented epithelium (RPE) cells, pinpointed as the fundamental pathological event in dry age-related macular degeneration (AMD). There is a conspicuous lack of effective therapeutic strategies to counteract this degenerative process. This study screened a library of antioxidants for their ability to protect RPE cells against oxidative stress and identified L-ergothioneine (EGT) as a potent cytoprotective agent. L-ergothioneine provided efficient protection against oxidative stress-damaged RPE and maintained cell redox homeostasis and normal physiological functions. It maintained the normal structure of the retina in mice under oxidative stress conditions. Transcriptomic analysis revealed that EGT counteracted major gene expression changes induced by oxidative stress. It upregulated antioxidant gene expression and inhibited NRF2 translocation. The inhibition of NRF2 abolished EGT's protective effects, suggesting that NRF2 activation contributes to its mechanism of action. In conclusion, we identified EGT as a safe and effective small-molecule compound that is expected to be a novel antioxidative agent for treating AMD., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Postmenopausal women are prone to develop cardiovascular disorders. In addition, cardiovascular risk in women can be influenced by the long-term prescription of drugs that lead to estrogen deprivation, e.g., aromatase inhibitors, and that can cause dyslipidemia. Little is known about the impact of exemestane, an aromatase inhibitor, on serum lipids' concentration in women. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the influence of this pharmacological agent on the lipid profile in women., Methods: The Scopus, Web of Science, PubMed/Medline and EMBASE databases were searched by two surveyors for manuscripts published from the inception of these databases until April 3rd, 2023. No language restrictions were applied to the search. The random effects model was used to generate the combined results as weighted mean difference (WMD) and 95% confidence interval (CI)., Results: In total, 8 eligible RCTs were included in the meta-analysis. Overall results from the random effects model indicate that exemestane administration increases LDL-C (WMD: 4.42 mg/dL, 95 % CI: 0.44, 8.41, P = 0.02) and decreases HDL-C (WMD: -6.03 mg/dL, 95 % CI: -7.77, -4.29, P < 0.001) and TC (WMD: -5.40 mg/dL, 95 % CI: -9.95, -0.86, P = 0.02) levels, respectively. Moreover, exemestane prescription only lowered TG concentrations when it was administered for < 12 months (WMD: -14.60 mg/dL, 95 % CI: -23.57 to -5.62, P = 0.001)., Conclusion: Currently available evidence suggests that the administration of exemestane in females increases LDL-C values and reduces HDL-C, TC, and, when prescribed for less than 12 months, TG concentrations., 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.)

Competing Interests: Competing interests: None declared.

Background: Macrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity., Methods: Human lung tissues were obtained from obese patients (BMI ≥ 30.0 kg/m 2 ) and control patients (BMI 18.5-24.9 kg/m 2 ). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192., Results: In obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-κB inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge., Conclusions: Our study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI., (© 2024. The Author(s).)

Developing low-cost and high-performance n-type polymer semiconductors is essential to accelerate the application of organic thermoelectrics (OTEs). To achieve this objective, it is critical to design strong electron-deficient building blocks with simple structure and easy synthesis, which are essential for the development of n-type polymer semiconductors. Herein, we synthesized two cyano-functionalized highly electron-deficient building blocks, namely 3,6-dibromopyrazine-2-carbonitrile (CNPz) and 3,6-Dibromopyrazine-2,5-dicarbonitrile (DCNPz), which feature simple structures and facile synthesis. CNPz and DCNPz can be obtained via only one-step reaction and three-step reactions from cheap raw materials, respectively. Based on CNPz and DCNPz, two acceptor-acceptor (A-A) polymers, P(DPP-CNPz) and P(DPP-DCNPz) are successfully developed, featuring deep-positioned lowest unoccupied molecular orbital (LUMO) energy levels, which are beneficial to n-type organic thin-film transistors (OTFTs) and OTEs performance. An optimal unipolar electron mobility of 0.85 and 1.85 cm 2  V -1  s -1 is obtained for P(DPP-CNPz) and P(DPP-DCNPz), respectively. When doped with N-DMBI, P(DPP-CNPz) and P(DPP-DCNPz) show high n-type electrical conductivities/power factors of 25.3 S cm -1 /41.4 μW m -1  K -2 , and 33.9 S cm -1 /30.4 μW m -1  K -2 , respectively. Hence, the cyano-functionalized pyrazine CNPz and DCNPz represent a new class of structurally simple, low-cost and readily accessible electron-deficient building block for constructing n-type polymer semiconductors., (© 2024 Wiley-VCH GmbH.)

Importance: Recently passed legislation aimed at improving access to care has considerably expanded options for veterans to receive emergency care in community, or non-Veterans Affairs (VA) settings. However, national trends in community emergency department (ED) use by veterans are unknown., Objective: To examine national, temporal trends in the frequencies and types of ED visits provided in community settings and explore the association between facilities' purchase of community care with facility and regional characteristics., Design, Setting, and Participants: Retrospective, observational cross-sectional study of ED visits over fiscal years (FY) 2016 to 2022. VA and community ED encounter data were obtained from the VA Corporate Data Warehouse and the Office of Integrated Veteran Care. Participants were veterans receiving ED care at VA facilities or paid for by the VA in the community. Data were analyzed from June to September 2023., Main Outcomes and Measures: The primary outcome measures included community ED visit volume, disposition, and payments over time. Also, the most common and costly ED visits were assessed. Negative binomial regression analysis examined associations between facility and regional characteristics and the rate of ED visits purchased in community settings relative to all ED visits., Results: There were 19 787 056 ED visits, predominantly at VA facilities (14 532 261 visits [73.4%]), made by 3 972 503 unique veterans from FY 2016 to 2022. The majority of ED users were male (3 576 120 individuals [90.0%]), and the median (IQR) age was 63 (48-73) years. The proportion of community ED visits increased in absolute terms from 18% in FY 2016 to 37% in FY 2022. Total community ED payments, adjusted to 2021 dollars, were $1.18 billion in FY 2016 and over $6.14 billion in FY 2022. The most common reasons for ED visits in the community were for nonspecific chest pain (305 082 visits [6%]), abdominal pain (174 836 visits [3%]), and septicemia (149 968 visits [3%]). The average proportion of ED visits purchased by a VA facility increased from 14% in FY 2016 to 32% by FY 2022. In multivariable analyses, facilities with greater ED volume and low-complexity facilities had higher expected rates of community emergency care than lower volume and high-complexity facilities, respectively., Conclusions and Relevance: As veterans increasingly use community EDs for acute, unscheduled needs, attention to factors associated with veterans' use of acute care services in different settings are important to identify access barriers and to ensure veterans' health care needs are met.

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-β1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate., 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.)

Objective: To prospectively evaluate the prognosis of fetuses diagnosed with micrognathia using prenatal ultrasound screening., Methods: Between January 2019 and December 2022, a normal range of IFA to evaluate the facial profile in fetuses with micrognathia in a Chinese population between 11 and 20 gestational weeks was established, and the pregnancy outcomes of fetal micrognathia were described. The medical records of these pregnancies were collected, including family history, maternal demographics, sonographic findings, genetic testing results, and pregnancy outcomes., Results: Ultrasound identified 25 patients with fetal micrognathia, with a mean IFA value of 43.6°. All cases of isolated fetal micrognathia in the initial scans were non-isolated in the following scans. A total of 78.9% (15/19) cases had a genetic cause confirmed, including 12 with chromosomal abnormalities and 3 with monogenic disorders. Monogenic disorders were all known causes of micrognathia, including two cases of campomelic dysplasia affected by SOX9 mutations and one case of mandibulofacial dysostosis with an EFTUD2 mutation. In the end, 19 cases were terminated, 1 live birth was diagnosed as Pierre Robin syndrome, and 5 cases were lost to follow-up., Conclusion: IFA is a useful indicator and three-dimensional ultrasound is a significant support technique for fetal micrognathia prenatal diagnosis. Repeat ultrasound monitoring and genetic testing are crucial, with CMA recommended and Whole exome sequencing performed when normal arrays are reported. Isolated fetal micrognathia may be an early manifestation of monogenic disorders., (© 2024 American Institute of Ultrasound in Medicine.)

Ethnopharmacological Relevance: Jinfu'an Decoction (JFAD) is a traditional Chinese decoction used in lung cancer treatment to improve patient quality of life and survival. Previous research has established that JFAD has a significant therapeutic effect on non-small cell lung cancer (NSCLC), although the underlying molecular mechanisms have not been largely underexplored., Aim of the Study: We used network pharmacology to identify the putative active ingredients of JFAD and conducted experimental studies to determine the potential molecular mechanism of JFAD in NSCLC treatment., Materials and Methods: The herbal components in JFAD-containing serum were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), and targets associated with the anti-lung cancer metastasis effects of JFAD were retrieved from various databases. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Next, the protein-protein interactions network and the "JFAD-Chemical Component-Target-KEGG Pathway" network were constructed. The network pharmacology findings were confirmed by in vitro and in vivo experiments. In vitro experiments were conducted to assess cell viability by CCK8 assay, cell cycle analysis by propidium iodide (PI) assay, and migration and invasion ability of cells by the transwell assay. In vivo experiments were performed to assess the efficacy of JFAD on the tumor by observing the growth of transplanted tumor models in nude mice and evaluated by in vivo bioluminescence imaging. Moreover, we assessed the effect of JFAD on the PI3K/Akt signaling pathway and proteins of Lumican, p120ctn, and specific RhoGTP enzyme family members (RhoA, Rac1, and RhoC) by Western Blot and immunohistochemistry., Results: 32 herbal components were identified in the JFAD-containing serum, which potentially acted on 229 targets related to lung cancer metastasis. Network pharmacology results suggested that JFAD may treat lung cancer metastasis by targeting the PI3K/Akt pathway via regulating multiple core targets. Our experiments showed that JFAD suppressed the proliferation of A549 cells in vitro, induced cell cycle arrest, and reduced the migration and invasion ability of A549 cells. Our in vivo study revealed that JFAD inhibited tumor growth in a nude mouse model. Additionally, we found that JFAD could downregulate the expression of the PI3K/Akt pathway and affect the expression of Lumican, p120ctn, and specific RhoGTPase family members., Conclusions: In conclusion, through network pharmacology, we have unveiled the underlying mechanisms that link the various components, targets, and pathways influenced by JFAD in the context of lung cancer metastasis. Our experimental results suggest that the oncostatic effects of JFAD may be achieved by upregulating the expression of Lumican/p120ctn and downregulating the levels of specific RhoGTPase family members, which in turn block the PI3K/Akt signaling pathway., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The inflammatory response in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is heightened in obesity. The aim of this study was to investigate whether lncRNAs are involved in the effects of obesity on acute lung injury and to find possible effector lncRNAs., Main Methods: Microarray analysis was used to assess the transcriptional profiles of lncRNAs and mRNAs in lung tissues from normal (CON), high-fat diet induced obese (DIO), and obese ALI mice (DIO-ALI). GO and KEGG analyses were employed to explore the biological functions of differentially expressed genes. A lncRNA-mRNA co-expression network was constructed to identify specific lncRNA. Lung tissues and peripheral blood samples from patients with obesity and healthy lean donors were utilized to confirm the expression characteristics of lncFirre through qRT-PCR. lncFirre was knocked down in MH-S macrophages to explore its function. ELISA and Griess reagent kit were used to detect PGE2 and NO. Flow cytometry was used to detect macrophages polarization., Key Findings: There were 475 lncRNAs and 404 mRNAs differentially expressed between DIO and CON, while 1348 lncRNAs and 1349 mRNAs between DIO-ALI and DIO. Obesity increased lncFirre expression in both mice and patients, and PA elevated lncFirre in MH-S. PA exacerbated the inflammation and proinflammatory polarization of MH-S induced by LPS. LncFirre knockdown inhibited the secretion of PGE2 and NO, M1 differentiation while promoted the M2 differentiation in PA and LPS co-challenged MH-S., Significance: Interfering with lncFirre effectively inhibit inflammation in MH-S, lncFirre can serve as a promising target for treating obesity-related ALI., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure in society. Symptomatically, both DLU and CLE exhibit delayed healing and excessive inflammation; however, there is little evidence to support a molecular and cellular connection between these two diseases. In this study, we investigated potential common characteristics between DFU and CLE at the molecular level to provide new insights into skin diseases and regeneration, and identify potential targets for the development of new therapies. The gene expression profiles of DFU and CLE were obtained from the Gene Expression Omnibus (GEO) database and used for analysis. A total of 41 common differentially expressed genes (DEGs), 16 upregulated genes and 25 downregulated genes, were identified between DFU and CLE. GO and KEGG analysis showed that abnormalities in epidermal cells and the activation of inflammatory factors were both involved in the occurrence and development of DFU and CLE. Protein-protein interaction network (PPI) and sub-module analysis identified enrichment in seven common key genes which is KRT16 , S100A7 , KRT77, OASL, S100A9, EPGN and SAMD9 . Based on these seven key genes, we further identified five miRNAs(has-mir-532-5p, has-mir-324-3p,has-mir-106a-5p,has-mir-20a-5p,has-mir-93-5p) and7 transcription factors including CEBPA, CEBPB, GLI1, EP30D, JUN,SP1, NFE2L2 as potential upstream molecules. Functional immune infiltration assays showed that these genes were related to immune cells. The CIBERSORT algorithm and Pearson method were used to determine the correlations between key genes and immune cells, and reverse key gene-immune cell correlations were found between DFU and CLE. Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions., 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 Wu, Wang, Duan, Teng, Wang and Qi.)

The same class of environmental steroid estrogens (SEs) with the highest estrogenic activity share the same chemical core structure and are often found together in the environment, posing significant risks to organismal health and environmental safety due to toxicity accumulation. In this study, a novel method for constructing the group-targeting aptasensor was developed to comprehensively analyze SEs. Through artificial intervention base substitution mutagenesis of adjacent bases T13 and C20 of the aptamer-binding domain recognizing 17β-estradiol, combined with docking calculations, the group-targeting SEs-aptamer for class-specific recognition SEs, such as estrone, estradiol, estriol, and ethinylestradiol were obtained. The binding constant of the SEs-aptamer to the SEs was 10 8 M -1 . The established group-targeting SEs aptasensor exhibited high sensitivity within a concentration range from 0.1 to 10 nM and demonstrated strong interference resistance, as well as high stability and wide pH water applicability. It was further applied to analyze real water samples and monitor changes in SEs concentrations during the removal process by Chlorella pyrenoidosa. These successful applications have demonstrated the excellent ability of this aptasensor to monitor SE in the environment. The method offered a new approach and idea for recognizing and detecting the same class of environmental pollutants in complex systems., 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 © 2023 Elsevier B.V. All rights reserved.)

Proper differentiation of corneal epithelial cells (CECs) from limbal stem/progenitor cells (LSCs) is required for maintenance of ocular homeostasis and clear vision. Here, using a single-cell transcriptomic atlas, we delineate the comprehensive and refined molecular regulatory dynamics during human CEC development and differentiation. We find that RORA is a CEC-specific molecular switch that initiates and drives LSCs to differentiate into mature CECs by activating PITX1. RORA dictates CEC differentiation by establishing CEC-specific enhancers and chromatin interactions between CEC gene promoters and distal regulatory elements. Conversely, RORA silences LSC-specific promoters and disrupts promoter-anchored chromatin loops to turn off LSC genes. Collectively, our work provides detailed and comprehensive insights into the transcriptional dynamics and RORA-mediated epigenetic remodeling underlying human corneal epithelial differentiation., (© 2024. The Author(s).)

Electric double layers are crucial to energy storage and electrocatalytic device performance. While double layer formation originates in electrostatic interactions, electric double layer properties are governed by a balance of both electrostatic and entropic driving forces. Favorable ion-surface electrostatic interactions attract counterions to charged surfaces to compensate, or "screen," potentials, but the confinement of these same ions from a bulk reservoir to the interface incurs an entropic penalty. Here, we use a dicationic imidazolium ionic liquid and its monovalent analogue to explore how cation valence and entropy influence double layer formation and electrochemical reactivity using CO 2 electroreduction as a model reaction. We find that divalent and monovalent cations display similar CO 2 reduction kinetics but differ vastly in steady-state reactivity due to rapid electrochemically induced precipitation of insulating dicationic (bi)carbonate films. Using in situ surface-enhanced Raman scattering spectroscopy, we find that potential-dependent cation reorientation occurs at similar potentials between the two ionic liquids, but the introduction of a covalent link in the divalent cation imparts a more ordered double layer structure that favors (bi)carbonate precipitation. In mixed monovalent-divalent electrolytes, we find that the divalent cations dominate interfacial properties by preferentially accumulating at surfaces even at very low relative concentrations. Our findings confirm that ion entropy plays a key role in modulating local electrochemical environments. Furthermore, we highlight how double layer properties are sensitive to the properties of counterions that pay the lowest entropic penalty to accumulate at interfaces. Overall, we illustrate that ion entropy provides a new knob to tune reaction microenvironments and unveil how entropy plays a major role in modulating electrochemical reactivity in mixed ion electrolytes.

We challenge the prevailing view that the end-Permian extinction impeded the Triassic evolution of sponges. Here, we report a deep-water community dominated by abundant keratose sponges in the lowest Triassic strata from Southwest China. The sponge fossils occur as dark elliptical imprints in mudstone with distinct oscula on their tops. The structure of preserved fibers suggests closest affinity with the extant Dictyoceratida, an aspiculate demosponge. The exceptional preservation plays a crucial role in retaining their exquisite structures. Sedimentary, taphonomic, pyrite framboid, and trace elemental analyses indicate that the sponges proliferated in an oxygen-poor habitat, demonstrating the high tolerance of sponges to severe conditions. Sponge proliferation is a signal of environmental upheaval but they also stabilized the ecosystem, driving the first phase of biotic recovery after the end-Permian extinction., (© 2023 John Wiley & Sons Ltd.)

Biological springs can be used in nature for energy conservation and ultra-fast motion. The loading and unloading rates of elastic materials can play an important role in determining how the properties of these springs affect movements. We investigate the mechanical energy efficiency of biological springs (American bullfrog plantaris tendons and guinea fowl lateral gastrocnemius tendons) and synthetic elastomers. We measure these materials under symmetric rates (equal loading and unloading durations) and asymmetric rates (unequal loading and unloading durations) using novel dynamic mechanical analysis measurements. We find that mechanical efficiency is highest at symmetric rates and significantly decreases with a larger degree of asymmetry. A generalized one-dimensional Maxwell model with no fitting parameters captures the experimental results based on the independently characterized linear viscoelastic properties of the materials. The model further shows that a broader viscoelastic relaxation spectrum enhances the effect of rate-asymmetry on efficiency. Overall, our study provides valuable insights into the interplay between material properties and unloading dynamics in both biological and synthetic elastic systems.

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition., Competing Interests: Declaration of interests M.T.L. is a founder and limited partner in StemMed, Ltd., and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics, Inc. Some PDXs are exclusively licensed to StemMed, Ltd., resulting in royalty income to M.T.L. L.E.D. is a compensated employee of StemMed, Ltd. Some PDXs are exclusively licensed to StemMed, Ltd., resulting in royalty income to L.E.D. A.K.S. discloses the following competing interests: consulting (Merck, GSK, ImmunoGen, Iylon, Kiyatec, Astra Zeneca, Onxeo), shareholder (BioPath), and patent (EGFL6 antibody)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Limbal epithelial stem/progenitor cells (LESCs) proliferate, migrate and differentiate into mature corneal epithelium cells (CECs) that cover the ocular surface. LESCs play a crucial role in the maintenance and regeneration of the corneal epithelium, and their dysfunction can lead to various corneal diseases. Neuregulin 1 (NRG1) is a member of the epidermal growth factor family that regulates the growth and differentiation of epithelial tissues. Here, we depicted the dynamic transcriptomic profiles during human CEC differentiation, identifying six gene co-expression modules that were specific to different differentiation stages. We found that the expression of NRG1 was high in human LESCs and decreased dramatically upon differentiation. Knockdown of NRG1 significantly inhibited LESC proliferation and upregulated the expression of the terminal differentiation marker genes KRT3 , KRT12 and CLU . In addition, the scratch wound closure assay showed that knockdown of NRG1 attenuated wound closure of LESCs over 24 h. Together, we dissected the transcriptional regulatory dynamics during CEC differentiation and identified NRG1 as a key regulator that promoted LESC proliferation and migration and maintained the undifferentiated state.

Human lysyl-tRNA synthetase (LysRS) was previously shown to be re-localized from its normal cytoplasmic location in a multi-aminoacyl-tRNA synthetase complex (MSC) to the nucleus of HIV-1 infected cells. Nuclear localization depends on S207 phosphorylation but the nuclear function of pS207-LysRS in the HIV-1 lifecycle is unknown. Here, we show that HIV-1 replication was severely reduced in a S207A-LysRS knock-in cell line generated by CRISPR/Cas9; this effect was rescued by S207D-LysRS. LysRS phosphorylation up-regulated HIV-1 transcription, as did direct transfection of Ap4A, an upstream transcription factor 2 (USF2) activator that is synthesized by pS207-LysRS. Overexpressing an MSC-derived peptide known to stabilize LysRS MSC binding inhibited HIV-1 replication. Transcription of HIV-1 proviral DNA and other USF2 target genes was reduced in peptide-expressing cells. We propose that nuclear pS207-LysRS generates Ap4A, leading to activation of HIV-1 transcription. Our results suggest a new role for nuclear LysRS in facilitating HIV-1 replication and new avenues for antiviral therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Pentraxin 3 (PTX3) is a soluble pattern recognition molecule in the innate immune system that has multiple functions. It is involved in resisting pathogen infection. However, the functions of PTX3 in teleost fish are not well understood. In this study, we identified and characterized PTX3 in Nile tilapia (Oreochromis niloticus) (OnPTX3). The open reading frame of OnPTX3 was found to be 1305 bp, encoding 434 aa. We conducted spatial mRNA expression analysis and found that the expression of OnPTX3 was significantly increased after infection with Streptococcus agalactiae and Aeromonas hydrophila, both in vivo and in vitro. We also observed that recombinant OnPTX3 protein could bind and agglutinate bacterial pathogen. Furthermore, OnPTX3 enhanced the phagocytosis of bacteria (S. agalactiae and A. hydrophila) by head kidney macrophages. Additionally, OnPTX3 was found to influence the expression of inflammatory cytokines, suggesting its involvement in the regulation of the inflammatory response. Moreover, OnPTX3 was shown to promote complement-mediated hemolysis and possess antibacterial activity. In conclusion, our research demonstrates that OnPTX3 has bacterial binding and agglutination activities, enhances phagocytosis, and regulates inflammation. It plays a crucial role in the defense of Nile tilapia against pathogenic bacteria, providing valuable insights for the prevention and control of aquatic diseases in the future., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interests with respect to the research, authorship or publication of this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether expanded access to Veterans Affairs (VA)-purchased care increased overall utilization or induced a shift from other payers to VA for emergency care among VA enrollees., Data Sources and Study Setting: This study included all emergency department (ED) encounters in 2019 from hospitals in the state of New York., Study Design: We conducted a difference-in-differences analysis comparing VA enrollees to the general population before and after the implementation of the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act in June 2019., Data Collection/extraction Methods: We included all ED visits with individuals aged 30 or older at the time of the encounter. Individuals were considered eligible for the policy change if they were enrolled with VA at the beginning of 2019., Principal Findings: Of the 5,577,199 ED visits in the sample, 4.9% (n = 253,799) were made by VA enrollees. Of these, 44.9% of visits were paid by Medicare, 32.8% occurred in VA facilities, and 7% were paid by private health insurance. There was a 6.4% (2.91 percentage points; std. error = 0.18; p < 0.01) decrease in the proportion of ED visits paid by Medicare among VA enrollees relative to the general population after the implementation of the MISSION Act in June 2019. This decrease was larger for ED visits with a subsequent inpatient admission (-8.4%; 4.87 percentage points; std. error = 0.33; p < 0.01). There was no statistically significant change in the total volume of ED visits (0.06%; std. error = 0.08; p = 0.45)., Conclusions: Leveraging a novel dataset, we demonstrate that MISSION Act implementation coincided with a shift in the financing of non-VA ED visits from Medicare to VA without any increase in overall ED utilization. These findings have important implications for VA health care financing and delivery., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Previous studies have demonstrated that tumor-associated macrophages (TAMs) exhibiting an M2 phenotype contribute significantly to the pathogenesis of various cancer types, including lung cancer. Therapeutic approaches targeting TAMs have the potential to complement and synergize with conventional chemotherapy and immunotherapy. Through database analysis, it has become evident that the expression of CTNNB1 (β-catenin) is predominantly localized in macrophages, and its presence is associated with unfavorable outcomes in the absence of CD8+ cells. Jin-Fu-An decoction (JFAD) has been utilized as an adjunct to augment current clinical interventions. By conducting a network pharmacological analysis, we discovered that CTNNB1 is a significant target of JFAD. Experiments were conducted to examine the impact of JFAD on macrophage polarization both in vitro and in vivo. Furthermore, the study investigated the combined effect of JFAD and cisplatin (CDDP) on mitigating adverse reactions and prolonging survival in subcutaneously transplanted tumor models and orthotopic lung cancer models. The percentage of M1 and M2 macrophages in the tumor and spleen were measured using flow cytometry. Additionally, the levels of β-catenin, M1, and M2 macrophage markers were measured by Western blotting and qPCR, while CD8 and iNOS protein expression was analyzed via immunohistochemistry. Our research findings indicate that JFAD has the ability to modulate the transformation of M2 macrophages into M1 macrophages, augment the anticancer efficacy of CDDP, and diminish the expression of cell-related markers in M2 cells. This regulatory effect may potentially be associated with the downregulation of β-catenin expression., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Prostate cancer is the most prevalent type of cancer among men worldwide. The importance of circular RNA (circRNA) in prostate cancer and its connection to malignancy has been steadily recognized. circRNA expression was obtained by circRNA sequencing of prostate cancer. circRNA and its function were further analysed. The results were verified by qRT-PCR, RIP assay, FISH, RNA pulldown, WB, CCK-8, colony formation assay and wound-healing assay. BALB/c Nude mice were used for xenograft hosts. Low expression of circDHRS3 was assessed in prostate cancer. Overexpression of circDHRS3 inhibited prostate cancer growth and migration in vitro . Additionally, miR-421 was shown to be the downstream target of circDHRS3, as shown by fluorescence in situ hybridization and dual-luciferase experiments. The rescue assay results for the PC3 and Du145 cell lines demonstrated that circDHRS3 inhibits prostate cancer cell lines' ability to proliferate and metastasize by modulating MEIS2 expression through the circDHRS3/miR-421/MEIS2 axis. In vivo investigations confirmed that the overexpression of circDHRS3 could inhibit both the lung and bone metastasis of prostate cancer cells. circDHRS3 has the potential to become a biomarker and a targeted therapeutic site for prostate cancer, particularly in the malignant stage. Our study indicates that circDHRS3 inhibits prostate cancer cell proliferation and metastasis through the circDHRS3/miR-421/MEIS2 axis.

Epithelial-mesenchymal transition (EMT) is crucial to metastasis by increasing cancer cell migration and invasion. At the cellular level, EMT-related morphological and functional changes are well established. At the molecular level, critical signaling pathways able to drive EMT have been described. Yet, the translation of EMT into efficient diagnostic methods and anti-metastatic therapies is still missing. This highlights a gap in our understanding of the precise mechanisms governing EMT. Here, we discuss evidence suggesting that overcoming this limitation requires the integration of multiple omics, a hitherto neglected strategy in the EMT field. More specifically, this work summarizes results that were independently obtained through epigenomics/transcriptomics while comprehensively reviewing the achievements of proteomics in cancer research. Additionally, we prospect gains to be obtained by applying spatio-temporal multiomics in the investigation of EMT-driven metastasis. Along with the development of more sensitive technologies, the integration of currently available omics, and a look at dynamic alterations that regulate EMT at the subcellular level will lead to a deeper understanding of this process. Further, considering the significance of EMT to cancer progression, this integrative strategy may enable the development of new and improved biomarkers and therapeutics capable of increasing the survival and quality of life of cancer patients.

Immunomodulation therapies have attracted immense interest recently for the treatment of immune-related diseases, such as cancer and viral infections. This new wave of enthusiasm for immunomodulators, predominantly revolving around cytokines, has spurred emerging needs and opportunities for novel immune monitoring and diagnostic tools. Considering the highly dynamic immune status and limited window for therapeutic intervention, precise real-time detection of cytokines is critical to effectively monitor and manage the immune system and optimize the therapeutic outcome. The clinical success of such a rapid, sensitive, multiplex immunoanalytical platform further requires the system to have ease of integration and fabrication for sample sparing and large-scale production toward massive parallel analysis. In this article, we developed a nanoplasmonic bioink-based, label-free, multiplex immunosensor that can be readily "written" onto a glass substrate via one-step calligraphy patterning. This facile nanolithography technique allows programmable patterning of a minimum of 3 μL of nanoplasmonic bioink in 1 min and thus enables fabrication of a nanoplasmonic microarray immunosensor with 2 h simple incubation. The developed immunosensor was successfully applied for real-time, parallel detection of multiple cytokines (e.g., interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β)) in immunomodulated macrophage samples. This integrated platform synergistically incorporates the concepts of nanosynthesis, nanofabrication, and nanobiosensing, showing great potential in the scalable production of label-free multiplex immunosensing devices with superior analytical performance for clinical applications in immunodiagnostics and immunotherapy.

Bisphenol analogues (BPs) are typical environmental hormones with endocrine-disrupting effects and reproductive toxicity requiring analysis and monitoring in complex aquatic environments. However, the presence of various co-existing contaminants makes the accurate determination of total BPs difficult. To address this challenge, there is a strong need to obtain a group-targeting binder to specifically detect a class of BPs. In this work, for the first time we have identified the group-targeting BPs-aptamer with similar affinities for multiple structurally and qualitatively similar BPs. Base mutations were introduced into an aptamer specific to bisphenol A (BPA) and utilized molecular docking calculations to identify a group-targeting aptamer capable of binding BPs, including BPA, bisphenol B (BPB), bisphenol E (BPE) and bisphenol F (BPF) with binding constants in the range of 2.0 × 10 6 ∼ 2.7 × 10 6 / M. In addition, an electrochemical aptamer-based sensor (aptasensor) was constructed for highly sensitive and comprehensive analysis of a class of BPs. This aptasensor demonstrated remarkable anti-interference performance against co-existing contaminants at concentrations up to 100-fold and achieved an impressive detection limit of 6.7 pM. This innovative approach of engineering a group-targeting BPs-aptamer is important for the comprehensive analysis of BPs, providing insights into identification and monitoring a class of pollutants., 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 © 2023. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers., Aim of the Review: We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer., Materials and Methods: Relevant studies about BSAT were collected from PubMed and Web of science., Results: Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors., Conclusions: BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy., Competing Interests: Declaration of competing interest The authors declare that the study was conducted in the absence of any business or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC., Implications: This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC., (©2023 American Association for Cancer Research.)

Purpose: This study aimed to investigate the effect of epidural analgesia (EA) on maternal and fetal hemodynamics., Methods: A prospective single-center observational study was conducted from March 2022 to May 2022 on low-risk singleton pregnancies who received prenatal care at 37-40 weeks and delivered at our hospital. Pre- and post-EA, maternal and fetal hemodynamics, including maternal parameters of mean arterial pressure (MAP), heart rate (HR) and saturation of pulse oxygen (SPO 2 ), fetal heart rate (FHR), Doppler flow parameters of umbilical artery (UA), middle cerebral artery (MCA), and uterine artery (UtA) during labor were measured before epidural insertion (T0), and 15 (T1), 30 (T2), and 60 (T3) minutes after. Computational analysis was performed using a one-way ANOVA test., Results: In total, 100 singleton pregnant women were enrolled. After EA, maternal MAP, HR, and SPO 2 were significantly lower than baseline values at all times except for HR in T3 and remained lower for the study's duration (P < .05). As for FHR, there was no significant difference between pre- and post-epidural. The mean UtA-PI (pulsatility index), UA-PI, UA-RI (resistance index), and UA-S/D (systolic/diastolic ratio) were not significantly modified after EA. Nevertheless, MCA-PI and RI significantly decreased in 15 minutes after initiating EA compared with T0 values (P < .05), and MCA-PSV (resistance index and peak systolic velocities) was significantly increased compared with T0 at all times (P < .05). The above changes were all within the normal range., Conclusion: Although maternal MAP, HR, and SPO 2 significantly decreased after EA, fetal hemodynamics remained relatively stable., (© 2023 American Institute of Ultrasound in Medicine.)

Objective: We aim to evaluate the effect of right lateral position on fetal hemodynamics (including umbilical artery [UA] and middle cerebral artery (MCA) blood flow-velocity waveform)., Methods: In total, 150 low-risk singleton full-term pregnant women were included in the study from November 2021 to January 2022. Doppler flow velocity waveforms of the fetal UA and MCA tested by ultrasound were collected in gestation of 37-40 weeks. Computational analysis was performed using the one-way ANOVA test., Results: Compared with the maternal left lateral position, there was a significant increase in Doppler indices of UA-RI (P = .033), UA-S/D (P = .019) and MCA-PSV (P = .021) and a significant decrease in MCA-RI (P = .030) in the supine position group. There was no statistical significance in all Doppler indices between the left and right lateral position (P > .05). Among the Doppler indices of three different maternal positions, there was no significance in both UA-PI and MCA-PI (P > .05)., Conclusion: There were no significant differences on changes of the fetal hemodynamics between left and right lateral positions. Pregnant women could adopt to lie in the left or right lateral position alternately to relieve the discomfort in late pregnancy., (© 2023 American Institute of Ultrasound in Medicine.)

The aim of this evaluation was to assess caregiver experience and burden during their first year in a geriatric home-based primary care (HBPC) program with qualitative interviews and surveys. HBPC included in-home visits for homebound, older adult patients. Seventeen caregivers, with varied amount of experience with HBPC, participated in semi-structured interviews. Change in caregiver burden from baseline was captured for 44 caregivers at 3 months post-enrollment, 27 caregivers at 6 months, and 22 caregivers at 12 months. Satisfaction survey was administered at these timepoints, but the last response of 48 caregivers was analyzed. Caregiver interviews revealed three themes: caregiving stressors, reliance on HBPC in relation to other medical care, and healthcare in the home. Surveyed caregivers were highly satisfied, but burden did not change substantially over the 1 year intervention. Caregivers appreciated HBPC reduced patient transportation and provided satisfactory primary care, but additional research is needed to tailor this care to reduce caregiver burden.

Transforming growth factor β (TGFβ) is a multifunctional cytokine, and its signalling responses are exerted via integrated intracellular pathways and complex regulatory mechanisms. Due to its high potency, TGFβ signalling is tightly controlled under normal circumstances, while its dysregulation in cancer favours metastasis. The recognised potential of TGFβ as a therapeutic target led to emerging development of anti-TGFβ reagents with preclinical success, yet these therapeutics failed to recapitulate their efficacy in experimental settings. In this review, possible reasons for this inconsistency are discussed, addressing the knowledge gap between theoretical and actual behaviours of TGFβ signalling. Previous studies on oncogenic cells have demonstrated the spatiotemporal heterogeneity of TGFβ signalling intensity. Under feedback mechanisms and exosomal ligand recycling, cancer cells may achieve cyclic TGFβ signalling to facilitate dissemination and colonisation. This challenges the current presumption of persistently high TGFβ signalling in cancer, pointing to a new direction of research on TGFβ-targeted therapeutics.

In recent decades, China's rapid urbanization has produced numerous economic benefits while simultaneously creating substantial risks to ecological security. China's 14th Five-Year Plan and the United Nations Sustainable Development Goals (SDGs) have recently explicitly called for the coordinated development of ecological security and urbanization. Given this context, it is important to explore the mechanism by which ecological security and urbanization are coupled and coordinated to promote sustainable development. In this study, an index of the relationship between ecological security and urbanization was established via high-resolution data, and a "Computation-Verification-Coupling" (CVC) framework was constructed. The accuracy of the ecological security index was verified using a linear regression model, and the coordination level between ecological security and urbanization was analyzed via a coupled coordination model (CCM). The results revealed a steady increase in the ecological security index from 2010 to 2020; the proportion of the area above the medium level increased from 63.1 % to 74.1 %. The urbanization index in core counties exhibited rapid growth, with level V urbanized areas expanding from 5.5 % to 9.9 %. The ecological security verification model produced a coefficient of determination (R²) of 0.75685, indicating a satisfactory degree of predictive capability. From 2010-2020, the coupled coordination improved, with the high coordination area accounting for 48.8 % and the extreme discoordination area decreasing from 1.8 % to 1.0 %. Coordinated development exhibited a stable progression, characterized by a cyclical evolution from initial coupling to antagonistic coupling and finally to coordinated development. This framework can be used not only to investigate the relationship between ecological security and urbanization but also to provide a quantifiable measure of progress toward achieving the SDGs., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteosarcoma, a rare malignant tumor, has a poor prognosis. This study aimed to find the best prognostic model for osteosarcoma. There were 2912 patients included from the SEER database and 225 patients from Hebei Province. Patients from the SEER database (2008-2015) were included in the development dataset. Patients from the SEER database (2004-2007) and Hebei Province cohort were included in the external test datasets. The Cox model and three tree-based machine learning algorithms (survival tree [ST], random survival forest [RSF] and gradient boosting machine [GBM]) were used to develop the prognostic models by 10-fold cross-validation with 200 iterations. Additionally, performance of models in the multivariable group was compared with the TNM group. The 3-year and 5-year cancer specific survival (CSS) were 72.71% and 65.92% in the development dataset, respectively. The predictive ability in the multivariable group was superior to that in the TNM group. The calibration curves and consistency in the multivariable group were superior to those in the TNM group. The Cox and RSF models performed better than the ST and GBM models. A nomogram was constructed to predict the 3-year and 5-year CSS of osteosarcoma patients. The RSF model can be used as a nonparametric alternative to the Cox model. The constructed nomogram based on the Cox model can provide reference for clinicians to formulate specific therapeutic decisions both in America and China.

Striatin-interacting phosphatases and kinases (STRIPAKs) are evolutionarily conserved supramolecular complexes that control various important cellular processes such as signal transduction and development. However, the role of the STRIPAK complex in pathogenic fungi remains elusive. In this study, the components and function of the STRIPAK complex were investigated in Fusarium graminearum, an important plant-pathogenic fungus. The results obtained from bioinformatic analyses and the protein-protein interactome suggested that the fungal STRIPAK complex consisted of six proteins: Ham2, Ham3, Ham4, PP2Aa, Ppg1, and Mob3. Deletion mutations of individual components of the STRIPAK complex were created, and observed to cause a significant reduction in fungal vegetative growth and sexual development, and dramatically attenuae virulence, excluding the essential gene PP2Aa. Further results revealed that the STRIPAK complex interacted with the mitogen-activated protein kinase Mgv1, a key component in the cell wall integrity pathway, subsequently regulating the phosphorylation level and nuclear accumulation of Mgv1 to control the fungal stress response and virulence. Our results also suggested that the STRIPAK complex was interconnected with the target of rapamycin pathway through Tap42-PP2A cascade. Taken together, our findings revealed that the STRIPAK complex orchestrates cell wall integrity signalling to govern the fungal development and virulence of F. graminearum and highlighted the importance of the STRIPAK complex in fungal virulence., (© 2023 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)