Effects of extracellular vesicles for ischemic stroke: A meta­analysis of preclinical studies.

Ischemic stroke is a common occurrence worldwide, posing a severe threat to human health and leading to negative financial impacts. Currently available treatments still have numerous limitations. As research progresses, extracellular vesicles are being found to have therapeutic potential in ischemic stroke. In the present study, the literature on extracellular vesicle therapy in animal studies of ischemic stroke was screened by searching databases, including PubMed, Embase, Medline, Web of Science and the Cochrane Library. The main outcomes of the present study were the neurological function score, apoptotic rate and infarct volumes. The secondary outcomes were pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6. The study quality was assessed using the CAMARADES Checklist. Subgroup analyses were performed to evaluate factors influencing extracellular vesicle therapy. Review Man3ager5.3 was used for data analysis. A total of 20 relevant articles were included in the present meta-analysis. The comprehensive analysis revealed that extracellular vesicles exerted a significant beneficial effect on neurobehavioral function, reducing the infarct volume and decreasing the apoptotic rate. Moreover, extracellular vesicles were found to promote nerve recovery by inhibiting pro-inflammatory factors (TNF-α, IL-1ß and IL-6). On the whole, the present meta-analysis examined the combined effects of extracellular vesicles on nerve function, infarct volume, apoptosis and inflammation, which provides a foundation for the clinical study of extracellular vesicles.

HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

Evidence supported by Mendelian randomization: impact on inflammatory factors in knee osteoarthritis.

Background: Prior investigations have indicated associations between Knee Osteoarthritis (KOA) and certain inflammatory cytokines, such as the interleukin series and tumor necrosis factor-alpha (TNFα). To further elaborate on these findings, our investigation utilizes Mendelian randomization to explore the causal relationships between KOA and 91 inflammatory cytokines. Methods: This two-sample Mendelian randomization utilized genetic variations associated with KOA from a large, publicly accessible Genome-Wide Association Study (GWAS), comprising 2,227 cases and 454,121 controls of European descent. The genetic data for inflammatory cytokines were obtained from a GWAS summary involving 14,824 individuals of European ancestry. Causal relationships between exposures and outcomes were primarily investigated using the inverse variance weighted method. To enhance the robustness of the research results, other methods were combined to assist, such as weighted median, weighted model and so on. Multiple sensitivity analysis, including MR-Egger, MR-PRESSO and leave one out, was also carried out. These different analytical methods are used to enhance the validity and reliability of the final results. Results: The results of Mendelian randomization indicated that Adenosine Deaminase (ADA), Fibroblast Growth Factor 5(FGF5), and Hepatocyte growth factor (HFG) proteins are protective factors for KOA (IVWADA: OR = 0.862, 95% CI: 0.771-0.963, p = 0.008; IVWFGF5: OR = 0.850, 95% CI: 0.764-0.946, p = 0.003; IVWHFG: OR = 0.798, 95% CI: 0.642-0.991, p = 0.042), while Tumor necrosis factor (TNFα), Colony-stimulating factor 1(CSF1), and Tumor necrosis factor ligand superfamily member 12(TWEAK) proteins are risk factors for KOA. (IVWTNFα: OR = 1.319, 95% CI: 1.067-1.631, p = 0.011; IVWCSF1: OR = 1.389, 95% CI: 1.125-1.714, p = 0.002; IVWTWEAK: OR = 1.206, 95% CI: 1.016-1.431, p = 0.032). Conclusion: The six proteins identified in this study demonstrate a close association with the onset of KOA, offering valuable insights for future therapeutic interventions. These findings contribute to the growing understanding of KOA at the microscopic protein level, paving the way for potential targeted therapeutic approaches.

Application value of MRI-guided wire localization to the non-palpable breast lesions only shown in Breast MRI.

Introduction: Magnetic resonance imaging (MRI)-guided wire localization can be applied to assist to remove suspected breast lesions accurately. This study aimed to evaluate the clinical application value of this technique in Chinese women. Methods: A total of 126 patients (131 lesions) who had underwent such technique in our hospital from April 2017 to June 2023 were enrolled. 1.5T MRI system and a wire localization device were used. Image characteristics, clinical features and postoperative pathology were collected and analyzed. Results: All of 126 patients (131 lesions) were successfully localized by MRI and excised for biopsy. There were 39 malignant lesions (29.77%) and 92 benign lesions (70.23%). There was no significant correlation between the morphology of DCE-MRI and the ratio of malignant lesions (P=0.763), while there was a statistical correlation between the BPE, TIC curve and the malignancy rate (P<0.05). All the lesions were assessed according to BI-RADS category of MRI (C4A=77, C4B=40, C4C=12, C5=2). The malignancy rates were as follows: 16.88% for 4A lesions (13/77), 37.50% for 4B lesions (15/40), 75.00% for 4C lesions (9/12) and 100% for 5 lesions (2/2). There was a significant correlation between the BI-RADS category and the incidence of benign-to-malignant lesions (P<0.001). Conclusion: MRI-guided wire localization can assist to remove suspected breast lesions early, safely and accurately. This technique makes up for the deficiency of X-ray and ultrasound, improves the accuracy of diagnosis and resection therapy in intraductal carcinoma and early invasive carcinoma, and helps to improve the the prognosis of breast cancer.

Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant PIK3CA and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide's first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding. The more rigid neoantigen is insusceptible to this limiting dynamic, and with the gate open, is able to transit its central tryptophan residue underneath the peptide backbone to the contralateral side of the HLA-A3 peptide binding groove, facilitating TCR binding. Our findings reveal a novel mechanism driving TCR specificity for a cancer neoantigen that is rooted in the dynamic and allosteric nature of peptide/MHC-I complexes, with implications for resolving long-standing and often confounding questions about the determinants of T cell specificity.

Ultrasonic cavitation induced Vibrio parahaemolyticus entering an apoptosis-like death process through SOS response.

As an effective non-thermal sterilization method, ultrasound remains at the level of passive bacterial death despite the initial understanding of its sterilization mechanism. Here, we present the perspective that bacteria can choose to actively enter an apoptosis-like death state in response to external ultrasonic stress. In this study, Vibrio parahaemolyticus exhibited apoptotic markers such as phosphatidylserine ectropion and activated caspases when subjected to ultrasound stress. Additionally, the accumulation of reactive oxygen species (ROS) and enhanced calcium signaling were observed. Further transcriptomic analysis was conducted to investigate the regulatory mechanism of the SOS response in Vibrio parahaemolyticus during an apoptosis-like state. The results showed that the genes encoding the citrate cycle were down-regulated in Vibrio parahaemolyticus cells adapted to ultrasonic stress, leading to an apoptosis-like state and a decrease in production capacity and ability to catabolize carbon dioxide. Furthermore, the level of oxidized glutathione increased, suggesting that the bacteria were engaged in various anti-oxidative stress responses, ultimately leading to apoptosis. Moreover, the ultrasound field activated the regulatory factor CsrA, which facilitates stress survival as cells transition from rapid growth to an apoptotic state through a stringent response and catabolic inhibition system. Parallel reaction monitoring (PRM) revealed that the expression of certain key SOS proteins in Vibrio parahaemolyticus was up-regulated following ultrasound treatment, resulting in a gradual adaptation of the cells to external stress and ultimately leading to active cell death. In conclusion, the biological lethal effect of ultrasound treatment is not solely a mechanical cell necrosis process as traditionally viewed, but also a programmed cell death process regulated by cellular adaptation. This enriched the biological effect pathway of ultrasound sterilization.

Utility of the triglyceride-glucose index for predicting restenosis following revascularization surgery for extracranial carotid artery stenosis: A retrospective cohort study.

BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are effective interventions for treating extracranial carotid artery stenosis (ECAS), but long-term prognosis is limited by postoperative restenosis. Carotid restenosis is defined as carotid stenosis >50% by various examination methods in patients after carotid revascularization. This retrospective cohort study examined the value of the triglyceride-glucose (TyG) index for predicting vascular restenosis after carotid revascularization. METHODS: A total of 830 patients receiving CEA (408 cases, 49.2%) or CAS (422 cases, 50.8%) were included in this study. Patients were stratified into three subgroups according to TyG index tertile (high, intermediate, and low), and predictive value for restenosis was evaluated by constructing multivariate Cox proportional hazard regression models. RESULTS: Incidence of postoperative restenosis was significantly greater among patients with a high TyG index according to univariate analysis. Kaplan-Meier survival curve analysis revealed a progressive increase in restenosis prevalence with rising TyG index. Multivariate Cox regression models also identified TyG index as an independent predictor of restenosis, while receiver operating characteristic (ROC) curve analysis showed that TyG index predicted restenosis with moderate sensitivity (57.24%) and specificity (67.99%) (AUC: 0.619, 95% CI 0.585-0.652, z-statistic=4.745, p<0.001). Addition of the TyG index to an established risk factor model incrementally improved restenosis prediction (AUC: 0.684 (0.651-0.715) vs 0.661 (0.628-0.694), z-statistic =2.027, p = 0.043) with statistical differences. CONCLUSION: The TyG index is positively correlated with vascular restenosis risk after revascularization, which can be used for incremental prediction and has certain predictive value.

California's zero-emission vehicle adoption brings air quality benefits yet equity gaps persist.

Zero-emission vehicle (ZEV) adoption is a key climate mitigation tool, but its environmental justice implications remain unclear. Here, we quantify ZEV adoption at the census tract level in California from 2015 to 2020 and project it to 2035 when all new passenger vehicles sold are expected to be ZEVs. We then apply an integrated traffic model together with a dispersion model to simulate air quality changes near roads in the Greater Los Angeles. We found that per capita ZEV ownership in non-disadvantaged communities (non-DACs) as defined by the state of California is 3.8 times of that in DACs. Racial and ethnic minorities owned fewer ZEVs regardless of DAC designation. While DAC residents receive 40% more pollutant reduction than non-DACs due to intercommunity ZEV trips in 2020, they remain disproportionately exposed to higher levels of traffic-related air pollution. With more ZEVs in 2035, the exposure disparity narrows. However, to further reduce disparities, the focus must include trucks, emphasizing the need for targeted ZEV policies that address persistent pollution burdens among DAC and racial and ethnic minority residents.

Chronologic evolution and prognostic implications of impaired coronary flow after chronic total occlusion angioplasty.

Background: Although vessels have the potential to recover following successful recanalization of chronic total occlusion (CTO), evidence is limited about the clinical significance of slow flow (SF) phenomenon after recanalization. The aim of this study was to evaluate the determinants, development and prognostic impact of SF after percutaneous coronary intervention (PCI) for CTO. Methods: This was a retrospective cohort study, 500 patients were consecutively enrolled undergoing CTO PCI and consecutive follow-up angiography in Zhongshan Hospital, Fudan University, between 2015 and 2020. Coronary flow was assessed by corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC). The association between SF and outcomes of CTO PCI was evaluated by analyzing the clinical, angiographic, and procedural characteristics. Results: SF was observed in 29 (5.8%) patients immediately after CTO PCI. Prior myocardial infraction, right coronary artery (RCA) revascularization and lack of bilateral collaterals were independent predictors of SF. SF was associated with increased risks of periprocedural myocardial infarction (PMI) [adjusted odds ratio (adOR): 4.12; 95% confidence interval (CI): 1.68-10.07; P=0.002] and target lesion restenosis (adOR: 2.50; 95% CI: 1.10-5.72; P=0.030). In patients with baseline left ventricular ejection fraction (LVEF) ≤60%, systolic improvement was compromised in the SF group (LVEF: 55.4%±9.6% in follow up vs. 52.1%±9.4% before CTO PCI, P=0.147) compared with that of the normal group (LVEF: 55.7%±9.3% vs. 51.6%±8.5%, P<0.001). Conclusions: SF has a significant influence on the prognosis of patients undergoing CTO PCI. Achieving normal coronary flow is essential in CTO revascularization.

IFITM3 restricts RABV infection through inhibiting viral entry and mTORC1- dependent autophagy.

Rabies, which caused by rabies virus (RABV), is a zoonotic and life-threatening disease with 100% mortality, and there is no effective treatment thus far due to the unclear pathogenesis and less of treatment targets. Interferon-induced transmembrane protein 3 (IFITM3) has recently been identified as an important anti-viral host effector induced by type I interferon. However, the role of IFITM3 in RABV infection has not been elucidated. In this study, we demonstrated that IFITM3 is a crucial restriction factor for RABV, the viral-induced IFITM3 significantly inhibited RABV replication, while knockdown of IFITM3 had the opposite effect. We then identified that IFNß induces the upregulation of IFITM3 in the absence or presence of RABV infection, meanwhile, IFITM3 positively regulates RABV-triggered production of IFNß in a feedback manner. In-depth research we found that IFITM3 not only inhibits the virus absorb and entry, but also inhibits viral replication through mTORC1-dependent autophagy. All these findings broaden our understanding of IFITM3 function and uncover a novel mechanism against RABV infection.

Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy.

Mitochondrial fission has been noted in the pathogenesis of dilated cardiomyopathy (DCM), but the underlying specific regulatory mechanism, especially in the development of doxorubicin (DOX)-induced cardiomyopathy remains unclear. In the present study, we explore whether the aspartate-glutamate carrier1 (AGC1) interacts with the fission protein dynamin-related protein 1 (Drp1) and reveal the functional and molecular mechanisms contributing to DOX-induced cardiomyopathy. Results of co-immunoprecipitation mass spectrometry (CO-IP MS) analysis based on heart tissue of DCM patients revealed that AGC1 expression was significantly upregulated in DCM-induced injury and AGC1 level was closely correlated with mitochondrial morphogenesis and function. We showed that AGC1 knockdown protected mice from DOX-induced cardiomyopathy by preventing mitochondrial fission, while the overexpression of AGC1 in the mouse heart led to impairment of cardiac function. Mechanistically, AGC1 overexpression could upregulate Drp1 expression and contribute to subsequent excessive mitochondrial fission. Specifically, AGC1 knockdown or the use of Drp1-specific inhibitor Mdivi-1 alleviated cardiomyocyte apoptosis and inhibited impairment of mitochondrial function induced by DOX exposure. In summary, our data illustrate that AGC1, as a novel contributor to DCM, regulates cardiac function via Drp1-mediated mitochondrial fission, indicating that targeting AGC1-Drp1 axis could be a potential therapeutic strategy for DOX-induced cardiomyopathy.

Aicardi-Goutières syndrome type 7 in a Chinese child: A case report.

BACKGROUND: IFIH1 is a protein-coding gene. Disorders associated with IFIH1 include Aicardi-Goutières syndrome (AGS) type 7 and Singleton-Merten syndrome type 1. Related pathways include RIG-I/MDA5-mediated induction of the interferon (IFN)-α/ß pathway and the innate immune system. AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. In infancy, most patients present with psychomotor retardation, axial hypotonia, spasticity, and brain imaging changes Laboratory assessments showed increased IFN-α activity with upregulation of IFN signaling and IFN-stimulated gene expression. Some patients develop normally in the early stage, and then have episodic neurological deficits. CASE SUMMARY: The 5-year-old girl presented with postpartum height and weight growth retardation, language retardation, brain atrophy, convulsions, and growth hormone deficiency. DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation. Heterozygous mutations in the IFIH1 gene were found. Physical examination at admission found that language development was delayed, the reaction to name calling was average, there was no communication with people, but there was eye contact, no social smile, and no autonomous language. However, the child had rich gesture language and body language, could understand instructions, had bad temper. When she wants to achieve something, she starts crying or shouting. Cardiopulmonary examination showed no obvious abnormality, and abdominal examination was normal. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes exist, but pathological reflexes were not elicited. CONCLUSION: We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7, which expanded the mutational spectrum of the IFIH1 gene.

Lipidome, central carbon metabolites, and sleep rhythm in coronary heart disease with nontraditional risks: An exploratory pilot study.

Aims: Altered lipid, energy metabolism and sleep disorders had been linked with coronary heart disease (CHD), however, the metabolic signatures and sleep rhythm in non-obstructive coronary atherosclerosis-CHD remain unclear. This pilot study aims to investigate the lipidome and central carbon metabolites profiles and associated sleep characteristics among CHD patients without traditional risk factors. Methods: From January to July 2021, 15 CHD patients and 15 healthy controls were randomly selected from the cardiology unit of Zhongshan Hospital, Shanghai. A total of 464 lipids and 45 central carbon metabolites (CCM) were quantified in blood plasma. Metabolic signatures were selected through orthogonal projections to latent structures discriminant analysis (OPLS-DA) and principal component analysis (PCA) was conducted to link the profiles of identified metabolites with CHD risk, sleep patterns, cardiometabolic traits and cardiac electrophysiologic parameters. Results: Using OPLS-DA, we identified 40 metabolites (variable influence on projection >1) that were altered in CHD patients, with 38 lipids, including 25 triacylglycerols (TAGs), 8 diacylglycerols (DAGs), being elevated and two CCM metabolites (i.e., succinic acid and glycolic acid) being reduced. Using PCA, four principal components (PCs) were identified and associated with increased risk of CHD. Specifically, one standard unit increasement in the PC that was characterized by high levels of DAG (18:1) and low succinic acid and the PC that was characterized by high levels of two sphingomyelins [SM (26:0) and SM (24:0)] was associated with 21% [odds ratio (OR) = 1.21, 95% CI: 1.02,1.43] and 14% (OR = 1.14,1.02,1.29) increased risk of CHD, respectively. Further regression analyses confirmed that the identified metabolites and the four PCs were positively associated with TG and ALT. Interestingly, glycolic acid was negatively associated with sleep quality and PSQI. Participants with night sleep mode tended to have a high level of the identified lipids, especially FFA (20:4). Conclusion: In the present pilot study, our findings provide clues on alterations of lipid and energy metabolism in CHD patients without traditional risk factors, with multiple triacylglycerols and diacylglycerols metabolites seemingly elevated and certain nonlipids metabolites (e.g., succinic acid and glycolic acid) decreased in cases. Considering the limit sample size, further studies are warranted to confirm our results.

Inactivation of Vibrio parahaemolyticus and retardation of quality loss in oyster (Crassostrea gigas) by ultrasound processing during storage.

The health problems caused by foodborne pathogens of raw oysters have been widely concerned. Traditional heating methods tend to lead the loss of the original nutrients and flavors, in this study, the nonthermal ultrasound technology was applied to inactivate Vibrio parahaemolyticus on raw oysters, and the retardation effects on microbial growth and quality loss of oysters stored at 4 ℃ after ultrasonic treatment were also investigated. After treated by 7.5 W/mL ultrasound for 12.5 min, the Vibrio parahaemolyticus in oysters was reduced by 3.13 log CFU/g. By measuring total aerobic bacteria and total volatile base nitrogen, the growth trend after ultrasonic treatment was delayed compared with heat treatment, and the shelf life of oysters was prolonged. At the same time, ultrasonic treatment delayed the changes of color difference and lipid oxidation of oysters during cold storage. Texture analysis showed that ultrasonic treatment helped maintain the good textural structure of oysters. Histological section analysis also demonstrated that muscle fibers were still tightly packed after ultrasonic treatment. Low-field nuclear magnetic resonance (LF-NMR) illustrated that the water in the oysters was well maintained after ultrasonic treatment. In addition, gas chromatograph - ion mobility spectrometer (GC-IMS) showed that ultrasound treatment could better preserve the flavor of oysters during cold storage. Therefore, it is believed that ultrasound can inactivate foodborne pathogens of raw oysters and keep its freshness and original taste better during storage.

Restoration and enhancement on low exposure raw images by joint demosaicing and denoising.

Restoring high quality images from raw data in low light is challenging due to various noises caused by limited photon count and complicated Image Signal Process (ISP). Although several restoration and enhancement approaches are proposed, they may fail in extreme conditions, such as imaging short exposure raw data. The first path-breaking attempt is to utilize the connection between a pair of short and long exposure raw data and outputs RGB images as the final results. However, the whole pipeline still suffers from some blurs and color distortion. To overcome those difficulties, we propose an end-to-end network that contains two effective subnets to joint demosaic and denoise low exposure raw images. While traditional ISP are difficult to image them in acceptable conditions, the short exposure raw images can be better restored and enhanced by our model. For denoising, the proposed Short2Long raw restoration subnet outputs pseudo long exposure raw data with little noisy points. Then for demosaicing, the proposed Color consistent RGB enhancement subnet generates corresponding RGB images with the desired attributes: sharpness, color vividness, good contrast and little noise. By training the network in an end-to-end manner, our method avoids additional tuning by experts. We conduct experiments to reveal good results on three raw data datasets. We also illustrate the effectiveness of each module and the well generalization ability of this model.

Joint-detection of Salmonella typhimurium and Escherichia coli O157:H7 by an immersible amplification dip-stick immunoassay.

To explore the superiority of multifunctional nanocomposites and realize the joint-detection of foodborne pathogens, an immersible amplification dip-stick immunoassay (DSIA) was exploited for the sensitive detection of Salmonella typhimurium (S. typhi) and Escherichia coli O157:H7 (E. coli O157:H7). Saving for the basic colorimetric performance, the reporter molecule of CoFe2O4 (CFO) possesses multivalent elements (Co2+/3+, Fe2+/3+) as well as multifunction of superior catalase-like activity and magnetic properties. By dint of the catalytic activity of CFO, a directly immersible amplification can be simply achieved to endure the DSIA with an intensive signal and a dual-visible mode for the determination of S. typhi and E. coli O157:H7. In virtue of the magnetic separation and enrichment capability of the CFO, the DSIA can perform a matrix-interference-free detection and obtain a dynamic detection range of 102-108 CFU/mL and a low assay limit of 102 CFU/mL. Moreover, the DSIA has reasonable recovery rates for contamination monitoring of two target bacteria in milk and beef samples. Our research provides a persuasive supplement for the application of multifunctional nanocomposites in the ongoing dip-stick immunoassay and an alternative strategy for the efficient detection of foodborne pathogens.

Transmembrane kinase 1-mediated auxin signal regulates membrane-associated clathrin in Arabidopsis roots.

Clathrin-mediated endocytosis (CME) is the major endocytic pathway in eukaryotic cells that directly regulates abundance of plasma membrane proteins. Clathrin triskelia are composed of clathrin heavy chains (CHCs) and light chains (CLCs), and the phytohormone auxin differentially regulates membrane-associated CLCs and CHCs, modulating the endocytosis and therefore the distribution of auxin efflux transporter PIN-FORMED2 (PIN2). However, the molecular mechanisms by which auxin regulates clathrin are still poorly understood. Transmembrane kinase (TMKs) family proteins are considered to contribute to auxin signaling and plant development; it remains unclear whether they are involved in PIN transport by CME. We assessed TMKs involvement in the regulation of clathrin by auxin, using genetic, pharmacological, and cytological approaches including live-cell imaging and immunofluorescence. In tmk1 mutant seedlings, auxin failed to rapidly regulate abundance of both CHC and CLC and to inhibit PIN2 endocytosis, leading to an impaired asymmetric distribution of PIN2 and therefore auxin. Furthermore, TMK3 and TMK4 were shown not to be involved in regulation of clathrin by auxin. In summary, TMK1 is essential for auxin-regulated clathrin recruitment and CME. TMK1 therefore plays a critical role in the establishment of an asymmetric distribution of PIN2 and an auxin gradient during root gravitropism.

Microbiological analysis and characterization of Salmonella and ciprofloxacin-resistant Escherichia coli isolates recovered from retail fresh vegetables in Shaanxi Province, China.

Fresh vegetables are closely associated with foodborne disease outbreaks; however, systematic analysis of the microbiological quality of fresh vegetables and molecular information on foodborne pathogens in fresh produce are poorly reported in China. Here, we evaluated the epidemiological prevalence of coliforms via the most probable number method and characterized Salmonella and ciprofloxacin-resistant (CIPR) Escherichia coli isolates recovered from retail fresh vegetables in Shaanxi Province, China. Antimicrobial susceptibility testing, serotype determination, multilocus sequence typing (MLST), core genome multilocus sequence typing (cgMLST), antibiotic resistance encoding gene (ARG) annotation, virulence factor prediction, and functional classification were performed. Between October 2020 and September 2021, 576 samples (i.e., tomatoes, lettuces, spinaches, and cabbages) were found to be positive for coliforms, and the prevalence of coliforms showed a seasonal trend. Coliform counts of vegetables in supermarkets in Xi'an were significantly lower (P < 0.01) than that in other cities. The detection rates of Salmonella and CIPRE. coli-positive vegetables were 1 % (6/576) and 0.7 % (4/576), respectively. All isolates exhibited resistance to ≥1 antibiotics, and 92.9 % (13/14) were multidrug-resistant. One extended spectrum ß-lactamase (ESBL)-producing CIPRE. coli isolate in spinach was resistant to not only three third-generation cephalosporins but also to two polymyxins. Among nine Salmonella isolates, five different serovars (S. Enteritidis, S. Indiana, monophasic variant of S. Typhimurium, S. Agona, and S. Gallinarum), four sequence types (STs; ST11, ST13, ST17, and ST34), and seven core genome STs (cgSTs) were identified. Five CIPRE. coli strains were assigned to three serovars (O101:H4, O8:H18, and O11:H25), three STs (ST44, ST48, and ST457), and four cgSTs. Coexisting amino acid mutations of Thr57Ser/Ser80Arg in ParC and Ser83Phe/Asp87Gly in GyrA in quinolone resistance-determining regions (QRDRs) might be causes for nalidixic acid resistance. Eight definite virulence profiles in eight serovars were identified. Notably, cdtB and pltA only encoded typhoid toxins and were just detected from S. Typhoid isolates were also detected from S. Indiana and monophasic S. Typhimurium, which are closely associated with swine food chain were first detected in fresh vegetables. In conclusion, our findings suggest that coliform contamination on fresh vegetables is prevalent in this province. Most Salmonella and CIPRE. coli isolates were phenotypically and genetically diverse and could resist multiple antibiotics by carrying multiple ARGs and virulence genes.

Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

A natural strategy for astaxanthin stabilization and color regulation: Interaction with proteins.

The pigment astaxanthin, one of the carotenoids, is regarded as a functional factor with various biological activities, widely applied in feed, nutraceutical, and cosmetic industries. However, its low stability and poor water solubility limit its application. Examples in nature suggest that binding to proteins is a simple and effective method to improve the stability and bioavailability of astaxanthin. Proteins from algae, fish, and crustaceans have all been demonstrated to have astaxanthin-binding capacity. Inspired by nature, artificial astaxanthin-protein systems have been established in foods. Binding to proteins could bring aquatic species various colors, and changes in the conformation of astaxanthin after binding to proteins leads to color changes. The review innovatively summarizes multiple examples of proteins as means of protecting astaxanthin, giving a reference for exploring and analyzing pigment-protein interactions and providing a strategy for carotenoids stabilization and color regulation, which is beneficial to the broader and deeper applications of carotenoids.