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The rapid emergence of Extended-spectrum ß-lactamase producing Enterobacteriaceae (ESBL-E) is a major global public health concern. Previous studies have identified that intensive medical care of dogs and cats in veterinary hospitals have accelerated the infections and spread of ESBL-E. To investigate the spread of ESBL-E in a veterinary hospital, a total of 202 samples including hospitalized animals, veterinary healthcare workers and environment were collected from a veterinary hospital in Chengdu, China. ESBL-E were identified by antimicrobial susceptibility testing and 16 s rRNA sequencing and were further conducted on ESBL gene detection and multilocus sequence typing (MLST). At last, strains with transmission potential were analyzed by whole genome sequencing (WGS). Our results showed that the overall prevalence of ESBL-positive isolates was 34.7% (70/202), with 55.3% (26/47) in animals, 29.3% (12/41) in healthcare workers and 28.1% (32/114) in environment swabs. Twenty diverse MLST types were detected, with ST744, ST231 as the most prevalent ones. Transmission chains of two ESBL-E.coli (ST744 blaCTX-M-18, blaTEM-1) from cat_21 to cat_14, and two ESBL-Kp (ST231 blaCTX-M-27, blaTEM-1, blaSHV-1) from cat_20 to cat_37 were further confirmed by WGS. Furthermore, interdisciplinary investigation and cooperation of AMR are needed to better limit the transmissions of high-risk strains and to implement effective public health interventions.

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The human immunodeficiency virus type 1 (HIV-1) reservoir consists of latently infected cells which present a major obstacle to achieving a functional cure for HIV-1. The formation and maintenance of HIV-1 latency have been extensively studied, and latency-reversing agents (LRAs) that can reactivate latent HIV-1 by targeting the involved host factors are developed; however, their clinical efficacies remain unsatisfactory. Therefore, it is imperative to identify novel targets for more potential candidates or better combinations for LRAs. In this study, we utilized CRISPR affinity purification in situ of regulatory elements system to screen for host factors associated with the HIV-1 long terminal repeat region that could potentially be involved in HIV-1 latency. We successfully identified that origin recognition complex 1 (ORC1), the largest subunit of the origin recognition complex, contributes to HIV-1 latency in addition to its function in DNA replication initiation. Notably, ORC1 is enriched on the HIV-1 promoter and recruits a series of repressive epigenetic elements, including DNMT1 and HDAC1/2, and histone modifiers, such as H3K9me3 and H3K27me3, thereby facilitating the establishment and maintenance of HIV-1 latency. Moreover, the reactivation of latent HIV-1 through ORC1 depletion has been confirmed across various latency cell models and primary CD4+ T cells from people living with HIV-1. Additionally, we comprehensively validated the properties of liquid-liquid phase separation (LLPS) of ORC1 from multiple perspectives and identified the key regions that promote the formation of LLPS. This property is important for the recruitment of ORC1 to the HIV-1 promoter. Collectively, these findings highlight ORC1 as a potential novel target implicated in HIV-1 latency and position it as a promising candidate for the development of novel LRAs. IMPORTANCE: Identifying host factors involved in maintaining human immunodeficiency virus type 1 (HIV-1) latency and understanding their mechanisms prepares the groundwork to discover novel targets for HIV-1 latent infection and provides further options for the selection of latency-reversing agents in the "shock" strategy. In this study, we identified a novel role of the DNA replication factor origin recognition complex 1 (ORC1) in maintaining repressive chromatin structures surrounding the HIV-1 promoter region, thereby contributing to HIV-1 latency. This discovery expands our understanding of the non-replicative functions of the ORC complex and provides a potential therapeutic strategy for HIV-1 cure.

Asunto(s)

Epigénesis Genética , Infecciones por VIH , Duplicado del Terminal Largo de VIH , VIH-1 , Complejo de Reconocimiento del Origen , Regiones Promotoras Genéticas , Latencia del Virus , Latencia del Virus/genética , Humanos , VIH-1/genética , VIH-1/fisiología , Duplicado del Terminal Largo de VIH/genética , Infecciones por VIH/virología , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Complejo de Reconocimiento del Origen/metabolismo , Complejo de Reconocimiento del Origen/genética , Linfocitos T CD4-Positivos/virología , Células HEK293 , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Regulación Viral de la Expresión Génica , Replicación Viral , Histonas/metabolismo , Histonas/genética

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Upon infection, naive CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodeling system in this process remains largely unknown. Here we show that BRD7, a component of the polybromo-associated BAF complex (PBAF), was required for naive CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7 deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicate that the expression of BRD7 significantly turned to high from naive CD8+ T cells to effector cells, which bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and upregulated its expression, leading to the maturation of effector T cells. Our research demonstrates that BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

Asunto(s)

Linfocitos T CD8-positivos , Diferenciación Celular , Proteínas Cromosómicas no Histona , Virus de la Coriomeningitis Linfocítica , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Diferenciación Celular/inmunología , Diferenciación Celular/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Virus de la Coriomeningitis Linfocítica/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ensamble y Desensamble de Cromatina , Proteínas que Contienen Bromodominio

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Protein binding to bile salts (BSs) reduces cholesterol levels, but the exact mechanism is unclear. In this study, we performed simulated gastrointestinal digestion of egg white protein hydrolysate (EWPHs) and included an unenzyme digestion group (CK) to investigate the changes in BSs binding capacity before and after digestion, as well as the relationship between egg white protein (EWP) structure and BSs binding capacity. In addition, peptidomics and molecular docking were used to clarify EWP's binding mechanism. We found that the BSs binding ability of EWPHs was slightly decreased after digestion, but significantly higher than that of the CK group and the digested CK group (D-CK). Particle size analysis and electrophoresis demonstrated that smaller particles and lower molecular weights exhibited enhanced binding capacity to BSs. Fourier Transform infrared spectroscopy (FTIR) results revealed that a disordered structure favored BS binding ability enhancement. Peptides FVLPM and GGGVW displayed hypocholesterolemic efficacy.

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One of the central focuses in self-assembly is precisely controlling the self-assembly pathway so that the target molecules can be produced exclusively. Trans-1,2-cyclohexanediamine contains two amino units that form a 60° angle when projected on a plane. This angle naturally favors the formation of triangular products in most cases when trans-1,2-cyclohexanediamine is used as a bisamino building block in the synthesis of macrocycles and tubes. Here, we synthesized a slightly bent tetraformyl precursor bearing a central dibenzothiophene moiety, whose 3,7-positions are functionalized with two m-phthalaldehyde units. We observed that combining this tetraformyl building block with trans-1,2-cyclohexanediamine yielded a quadrangular tube when the concentrations of the precursors were relatively high. Both experimental measurements and theoretical calculations indicate that the formation of this unlikely occurring quadrangular product was driven by the intramolecular C-H···π interactions between the dibenzothiophene building blocks within the tube framework. This driving force, however, was disturbed in the triangular tube, a smaller counterpart whose formation was considered previously much more thermodynamically favored. These results improved our fundamental understanding on how to create those products whose syntheses are considered difficult or impossible, by modulating the intramolecular driving forces.

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Skin aging is characterized by the disruption of skin homeostasis and impaired skin injury repair. Treatment of aging skin has long been limited by the unclear intervention targets and delivery techniques. Engineering extracellular vesicles (EVs) as an upgraded version of natural EVs holds great potential in regenerative medicine. In this study, we found that the expression of the critical antioxidant and detoxification gene Gstm2 was significantly reduced in aging skin. Thus, we constructed the skin primary fibroblasts-derived EVs encapsulating Gstm2 mRNA (EVsGstm2), and found that EVsGstm2 could significantly improve skin homeostasis and accelerate wound healing in aged mice. Mechanistically, we found that EVsGstm2 alleviated oxidative stress damage of aging dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promoted dermal fibroblasts to regulate skin epidermal cell function by paracrine secretion of Nascent Polypeptide-Associated Complex Alpha subunit (NACA). Furthermore, we confirmed that NACA is a novel skin epidermal cell protective molecule that regulates skin epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. Our findings demonstrate the feasibility and efficacy of EVs-mediated delivery of Gstm2 for aged skin treatment and unveil novel roles of GSTM2 and NACA for improving aging skin.

Asunto(s)

Vesículas Extracelulares , Fibroblastos , Glutatión Transferasa , ARN Mensajero , Envejecimiento de la Piel , Cicatrización de Heridas , Animales , Ratones , Fibroblastos/metabolismo , Glutatión Transferasa/metabolismo , Vesículas Extracelulares/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Epidermis/metabolismo , Ratones Endogámicos C57BL , Estrés Oxidativo , Piel/metabolismo , Masculino , Humanos , Células Epidérmicas/metabolismo , Células Cultivadas

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Objectives: To analyze the epidemiological characteristics and etiology of crayfish-related rhabdomyolysis. Methods: Cases of crayfish-related rhabdomyolysis in Wuhan were monitored, and professional training of city's surveillance personnel was conducted. Unified questionnaires were used to collect data. Results: The first case of crayfish-related rhabdomyolysis occurred on July 12, 2016. Subsequently, 423 patients were reported over the next 7 years, with muscle pain, weakness, and chest distress as main symptoms. In total, 64.54% (273/423) of patients were females, and young adults (aged 20-49 years) account for 86.22% (363/423) of patients. The primary clinical presentations were muscle pain, muscle weakness, and chest discomfort. The median incubation time was 6 h. And the number of cases may be related to water levels in Yangzi river. Laboratory tests revealed elevated creatine kinase and myoglobin levels. In total, 95.16% (236/248) of patients had consumed crayfish tail shrimp and 91.53% (227/248) had consumed crayfish liver and pancreas (Female crayfish also contain ovaries). Only 25.00% (62/248) of patients had a history of alcohol consumption. On average, 227 patients consumed 15 (3-50) crayfish, of whom 84.14% (191/227) consumed more than 10 crayfish. All patients had a favorable prognosis. Conclusion: Crayfish-related rhabdomyolysis is a kind of a case or cluster of patients present with severe myalgia or weakness of unknown etiology and mechanism disease in Wuhan, China, 2016-2022. Excessive consumption of crayfish may be a risk factor for the disease. The relationship between the specific parts of crayfish consumed and the onset of the disease is unclear, suggesting further research is needed to identify the relevant risk factors for the disease.

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Exosomes are increasingly recognized as important mediators of intercellular communication in cancer biology. Exosomes can be derived from cancer cells as well as cellular components in tumor microenvironment. After secretion, the exosomes carrying a wide range of bioactive cargos can be ingested by local or distant recipient cells. The released cargos act through a variety of mechanisms to elicit multiple biological effects and impact most if not all hallmarks of cancer. Moreover, owing to their excellent biocompatibility and capability of being easily engineered or modified, exosomes are currently exploited as a promising platform for cancer targeted therapy. In this review, we first summarize the current knowledge of roles of exosomes in risk and etiology, initiation and progression of cancer, as well as their underlying molecular mechanisms. The aptamer-modified exosome as a promising platform for cancer targeted therapy is then briefly introduced. We also discuss the future directions for emerging roles of exosome in tumor biology and perspective of aptamer-modified exosomes in cancer therapy.

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Exopolysaccharide produced by lactic acid bacteria has various functions. In the present study, one anti-oxidant polysaccharide fraction, namely S1-EPS, was extracted and purified from Pediococcus acidilactici S1, and its structure and its potential effect on the gel properties of fat substitute meat mince were investigated. The results showed that S1-EPS, one of homogeneous polysaccharides, was mainly composed of Gal, Glc, and Man in molar ratio of 7.61: 15.25: 77.13 and molecular weight of 46.975 kDa. The backbone of EPS-S1 contained →2,6)-α-D-Manp-(1→，→2)-α-D-Manp-(1→,→3)-α-D-Glcp-(1 → and a small amount of→6)-ß-D-Manp-(1→. The linkages of branches in EPS-S1 were mainly composed of α-D-Manp-(1→ attached to a sugar residue →2,6)-α-D-Manp-(1→O-2 or ß-D-Galp-(1→ attached to a sugar residue →2,6)-α-D-Manp-(1→O-6. Furthermore, as S1-EPS increased, the meat minced gel pores decreased, and the surface became smooth. A remarkable inhibitory effect on the lipid oxidation of meat minced gel was found as S1-EPS concentration increased. Overall, S1-EPS was found to have substantial potential in low-fat meat products by serving as a natural, anti-oxidant, and functional additive.

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Sustitutos de Grasa , Pediococcus acidilactici , Polisacáridos Bacterianos , Polisacáridos Bacterianos/química , Pediococcus acidilactici/metabolismo , Pediococcus acidilactici/química , Sustitutos de Grasa/química , Peso Molecular , Antioxidantes/química , Antioxidantes/farmacología , Geles/química , Productos de la Carne/microbiología

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Here, we successfully synthesized four structurally analogous, self-assembled chiral molecular tubes with relatively high yields. This achievement involved the condensation of six equivalents of enantiomerically pure trans-cyclohexane-1,2-diamine (trans-CHDA) and three equivalents of the corresponding tetraformyl precursor. Each precursor was equipped with a luminescent linker terminated by two m-phthalaldehyde units. Even though these tetraformyl precursors are barely soluble in almost all organic solvents, the molecular tubes are highly soluble in nonpolar solvents such as chloroform, allowing us to fully characterize them in solution. The stereo-chirality of the chiral bisamino building blocks endows the frameworks of molecular tubes with planar chirality. As a consequence, all of these molecular tubes exhibit circularly polarized luminescence (CPL) with relatively large dissymmetry values |glum| up to 7×10-3, providing an efficient method for synthesizing CPL-active materials.

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PURPOSE: The purpose of this study was to analyze the intracerebral abnormalities of hemodynamics in patients with Parkinson's disease (PD) through arterial spin labelling (ASL) technique with multi-delay ASL (MDASL) and conventional single-delay ASL (SDASL) protocols and to verify the potential clinical application of these features for the diagnosis of PD. MATERIALS AND METHODS: Perfusion data of the brain obtained using MDASL and SDASL in patients with PD were compared to those obtained in healthy control (HC) subjects. Intergroup comparisons of z-scored cerebral blood flow (zCBF), arterial transit time (zATT) and cerebral blood volume (zCBV) were performed via voxel-based analysis. Performance of these perfusion metrics were estimated using area under the receiver operating characteristic curve (AUC) and compared using Delong test. RESULTS: A total of 47 patients with PD (29 men; 18 women; mean age, 69.0 ± 7.6 (standard deviation, [SD]) years; range: 50.0-84.0 years) and 50 HC subjects (28 men; 22 women; mean age, 70.1 ± 6.2 [SD] years; range: 50.0-93.0 years) were included. Relative to the uncorrected-zCBF map, the corrected-zCBF map further refined the distributed brain regions in the PD group versus the HC group, manifested as the extension of motor-related regions (PFWE < 0.001). Compared to the HC subjects, patients with PD had elevated zATT and zCBV in the right putamen, a shortened zATT in the superior frontal gyrus, and specific zCBV variations in the left precuneus and the right supplementary motor area (PFWE < 0.001). The corrected-zCBF (AUC, 0.90; 95% confidence interval [CI]: 0.84-0.96) showed better classification performance than uncorrected-zCBF (AUC, 0.84; 95% CI: 0.75-0.92) (P = 0.035). zCBV achieved an AUC of 0.89 (95% CI: 0.82-0.96) and zATT achieved an AUC of 0.66 (95% CI: 0.55-0.77). The integration model of hemodynamic features from MDASL provided improved performance (AUC, 0.97; 95% CI: 0.95-0.98) for the diagnosis of PD by comparison with each perfusion model (P < 0.001). CONCLUSION: ASL identifies impaired hemodynamics in patients with PD including regional abnormalities of CBF, CBV and ATT, which can better be mapped with MDASL compared to SDASL. These findings provide complementary depictions of perfusion abnormalities in patients with PD and highlight the clinical feasibility of MDASL.

Asunto(s)

Circulación Cerebrovascular , Hemodinámica , Enfermedad de Parkinson , Marcadores de Spin , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Circulación Cerebrovascular/fisiología , Hemodinámica/fisiología , Anciano de 80 o más Años , Estudios de Casos y Controles , Encéfalo/diagnóstico por imagen , Encéfalo/irrigación sanguínea , Imagen por Resonancia Magnética/métodos

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Cuticular waxes play important roles in plant development and the interaction between plants and their environment. Researches on wax biosynthetic pathways have been reported in several plant species. Also, wax formation is closely related to environmental condition. However, the regulatory mechanism between wax and environmental factors, especially essential mineral elements, is less studied. Here we found that nitrogen (N) played a negative role in the regulation of wax synthesis in apple. We therefore analysed wax content, composition and crystals in BTB-TAZ domain protein 2 (MdBT2) overexpressing and antisense transgenic apple seedlings and found that MdBT2 could downregulate wax biosynthesis. Furthermore, R2R3-MYB transcription factor 16-like protein (MdMYB106) interacted with MdBT2, and MdBT2 mediated its ubiquitination and degradation through the 26S proteasome pathway. Finally, HXXXD-type acyl-transferase ECERIFERUM 2-like1 (MdCER2L1) was confirmed as a downstream target gene of MdMYB106. Our findings reveal an N-mediated apple wax biosynthesis pathway and lay a foundation for further study of the environmental factors associated with wax regulatory networks in apple.

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Arabidopsis , Malus , Arabidopsis/genética , Malus/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Aciltransferasas/metabolismo , Ceras/metabolismo , Regulación de la Expresión Génica de las Plantas

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Highly sensitive and facile detection of low levels of protein markers is of great significance for the early diagnosis and efficacy monitoring of diseases. Herein, aided by an efficient tyramine-signal amplification (TSA) mechanism, we wish to report a simple but ultrasensitive immunoassay with signal readout on a portable personal glucose meter (PGM). In this study, the bioconjugates of tyramine and invertase (Tyr-inv), which act as the critical bridge to convert and amplify the protein concentration information into glucose, are prepared following a click chemistry reaction. Then, in the presence of a target protein, the sandwich immunoreaction between the immobilized capture antibody, the target protein, and the horseradish peroxidase (HRP)-conjugated detection antibody is specifically performed in a 96-well microplate. Subsequently, the specifically loaded HRP-conjugated detection antibodies will catalyze the amplified deposition of a large number of Tyr-inv molecules onto adjacent proteins through highly efficient TSA. Then, the deposited invertase, whose dosage can faithfully reflect the original concentration of the target protein, can efficiently convert sucrose to glucose. The amount of finally produced glucose is simply quantified by the PGM, realizing the highly sensitive detection of trace protein markers such as the carcinoembryonic antigen and alpha fetoprotein antigen at the fg/mL level. This method is simple, cost-effective, and ultrasensitive without the requirement of sophisticated instruments or specialized laboratory equipment, which may provide a universal and promising technology for highly sensitive immunoassay for in vitro diagnosis of diseases.

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Técnicas Biosensibles , Glucosa , beta-Fructofuranosidasa/química , Técnicas Biosensibles/métodos , Inmunoensayo/métodos , Anticuerpos , Peroxidasa de Rábano Silvestre/química , Tiramina/química , Oro/química

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Introduction: Streptococcus agalactiae (S. agalactiae) is a pathogen causing bovine mastitis that results in considerable economic losses in the livestock sector. To understand the distribution and drug resistance characteristics of S. agalactiae from dairy cow mastitis cases in China, multilocus sequence typing (MLST) was carried out and the serotypes and drug resistance characteristics of the bacteria in the region were analysed. Material and Methods: A total of 21 strains of bovine S. agalactiae were characterised based on MLST, molecular serotyping, antimicrobial susceptibility testing, and the presence of drug resistance genes. Results: The serotypes were mainly Ia and II, accounting for 47.6% and 42.9% of all serotypes, respectively. Five sequence types (STs) were identified through MLST. The ST103 and ST1878 strains were predominant, with rates of 52.4% and 28.6%, respectively. The latter is a novel, previously uncharacterised sequence type. More than 90% of S. agalactiae strains were susceptible to penicillin, oxacillin, cephalothin, ceftiofur, gentamicin, florfenicol and sulfamethoxazole. The bacteria showed high resistance to tetracycline (85.7%), clindamycin (52.1%) and erythromycin (47.6%). Resistant genes were detected by PCR, the result of which showed that 47.6%, 33.3% and 38.1% of isolates carried the tet(M), tet(O) and erm(B) genes, respectively. Conclusion: The results of this study indicate that S. agalactiae show a high level of antimicrobial resistance. It is necessary to monitor the pathogens of mastitis to prevent the transmission of these bacteria.

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Background: Escin is the main active component in Aesculus hippocastanum. It has been demonstrated that escin has anti-inflammatory properties. This study combined the methods of network pharmacology, molecular docking, and molecular dynamics to explore the molecular mechanism of escin against neuropathic pain (NP). Methods: The Swiss Target Prediction and the Pharm Mapper database were employed for predicting the targets of escin. Also, the candidate targets of NP were gathered via the databases including Therapeutic Targets, DisGeNet, GeneCards, DrugBank, and OMIM. Subsequently, the network of protein-protein interaction was screened for the key targets by the software Cytoscape 3.8.0. Then, the intersection of these targets was analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Additionally, we further investigated the ligand-target interactions by molecular docking and molecular dynamics simulations. Results: In total, 94 escin targets were predicted by network pharmacology. Among them, SRC, MMP9, PTGS2, and MAPK1 were the core candidate targets. Subsequently, the analysis of GO and KEGG enrichment revealed that escin affected NP by regulating protein kinase C, MAP kinase, TRP channels, the T-cell receptors signaling pathway, and the TNF signaling pathway. The results of molecular docking and molecular dynamics simulation confirmed that escin not only had a strong binding activity with the four core target proteins but also stably combined in 50 ns. Conclusions: Our study revealed that escin acts on the core targets SRC, MMP9, PTGS2, MAPK1, and associated enrichment pathways to alleviate neuronal inflammation and regulate the immune response, thus exerting anti-NP efficacy. This study provided innovative ideas and methods for the promising treatment of escin in relieving NP.

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Zhalajiao, a traditional Chinese fermented food, is popular due to its unique flavor. Traditional Zhalajiao fermentation is closely related to flavor compounds production. However, the mechanisms underlying the formation of these crucial flavor components in Zhalajiao remain unclear. Here, we explored the dynamic changes in physical and chemical properties, microbial diversity, and flavor components of Zhalajiao at various fermentation times. In total, 6 organic acids, 17 amino acids, and 21 key volatile compounds were determined as flavor components. In Zhalajiao, Lactobacillus and Cyanobacterium were the main bacteria that were involved in the formation of crucial flavor compounds. Candida showed a significant correlation with 14 key flavor compounds during fermentation (p < 0.05) and was the main fungal genus associated with flavor formation in Zhalajiao. This research offers a theoretical foundation for the flavor regulation and quality assurance of Zhalajiao.

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Clear cell renal cell carcinoma (ccRCC) constitutes the most prevalent histopathologic subtype of renal cell carcinoma. The interplay between aging and cancer is complicated, and we provide a relatively new set of senescence genes that has not yet been used in the study of clear cell renal cell carcinoma. Our objective is to investigate the involvement of senescence in the development and diagnosis of ccRCC. RNA-seq and clinical data for ccRCC was obtained from the cancer genome atlas and gene expression omnibus databases. Consensus clustering analysis was performed to identify novel molecular subgroups. Tumor immune status was assessed using estimating stromal and immune cells in malignancy using expression data, microenvironment cell populations, and single-sample gene set enrichment analysis analyses. Functional analysis, including gene ontology, gene set variation analysis, and gene set enrichment analysis, was conducted to explore potential mechanisms. A prognostic risk model was constructed using the LASSO algorithm and multivariate Cox regression analysis. Decision trees and nomograms were developed for survival prediction. SenMayo classified ccRCC patients into 2 molecular subtypes with significantly different survival rates, and significant differences in their immune status, characterized by poor prognosis with relatively high immune status. Besides, the differentially expressed genes between the 2 subgroups were mainly enriched in immune-related pathways. The burden of aging tissues and cells may lead to immune dysregulation and drug resistance, which could contribute to poor prognosis in ccRCC patients. Risk models, decision trees, and nomogram for ccRCC survival prediction have great potential applications. In conclusion, our study establishes a clear association between aging in ccRCC and the immune microenvironment, demonstrating the predictive potential of senescence genes for ccRCC prognosis.

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Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Envejecimiento , Neoplasias Renales/genética , Expresión Génica , Pronóstico , Microambiente Tumoral/genética

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Objectives: The potential role of shear wave elastography (SWE) and superb microvascular imaging (SMI) for early assessment of treatment response to neoadjuvant chemotherapy (NAC) in breast cancer remains unexplored. This study aimed to identify potential factors associated with the pathological response to NAC using these advanced ultrasound techniques. Methods: Between August 2021 and October 2022, 68 patients with breast cancer undergoing NAC were recruited. Patients underwent conventional ultrasonography, SMI, and SWE examinations at baseline and post-2nd cycle of NAC. Maximum tumor diameter (Dmax), maximum elastic value (Emax), peak systolic velocity (PSV), and resistance index (RI) at baseline and the rate of change of these parameters post-2nd cycle were recorded. After chemotherapy, all patients underwent surgery. Using the Miller-Payne's grade, patients were categorized into response (grades 3, 4, or 5) and non-response (grades 1 or 2) group. Parameters were compared using t-tests at baseline and post-2nd cycle. Binary logistic regression analysis was used to identify variables and their odds ratios (ORs) related to responses and a prediction model was established. ROC curves were drawn to analyze the efficacy of each parameter and their combined model for early NAC response prediction. Results: Among the 68 patients, 15(22.06%) were categorized into the non-response group, whereas 53(77.94%) were categorized into the response group. At baseline, no significant differences were observed between the two groups (p>0.05). Post-2nd cycle of NAC, rates of change of Emax, PSV and RI (ΔEmax, ΔPSV and ΔRI) were higher in responders than non-responders (p<0.05). Binary logistic regression analysis revealed that ΔEmax (OR 0.797 95% CI, 0.683-0.929), ΔPSV (OR 0.926, 95%CI, 0.860-0.998), and ΔRI (OR 0.841, 95%CI, 0.736-0.960) were independently associated with the pathological response of breast cancer after NAC. The combined prediction model exhibited higher accuracy in the early evaluation of the response to NAC (AUC 0.945, 95%CI, 0.873-1.000). Conclusion: SWE and SMI techniques enable early identification of tumor characteristics associated with the pathological response to NAC and may be potentially indicative of an effective response. These factors may eventually be used for the early assessment of NAC treatment for clinical management.

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Objective: The physiological process of wound healing is dynamic, continuous, and intricate. Nowadays, full-thickness burn wounds are treated by autologous skin transplantation. Unfortunately, when substantial burns develop, there are fewer donor sites accessible, making it difficult to satisfy the requirement for large-scale skin transplants and increasing the risk of patient mortality. This study investigated the possibility of using a newly created hypoimmunogenic epidermal cell sheet to heal skin wounds. Methods: Transfection with lentivirus was used to generate Keratinocytes (KCs) that overexpress Indoleamine 2,3-Dioxygenase (IDO). Western blotting and quantitative polymerase chain reaction were used to measure IDO levels. To evaluate the function of IDO+ keratinocytes, CCK-8 and Transwell assays were performed. In cell sheet induction media, KCs and Fibroblasts (FBs) were cultured to yield epidermal cell sheets. The full-thickness skin excisions of BALB/c mice were transplanted with epidermal cell sheets. To assess the tumorigenicity of IDO+ keratinocytes, BALB/c nude mouse xenograft models were also used. CD3 and CD31 immunofluorescence labeling of wound tissue on day 12 to identify T lymphocyte infiltration and capillary development. ELISA measurement of IL-1 and TNF-α concentrations. Results: IDO + keratinocytes dramatically enhanced the expression levels of IDO mRNA and protein, as well as the amount of kynurenine in the conditioned media of IDO+ keratinocytes, compared to the Control and NC groups. CD8+ T cell apoptosis was considerably greater in the IDO group than in the Control and NC groups. Nevertheless, the proliferation and migratory capabilities of IDO+ keratinocytes were not substantially different from those of the Control and NC groups. In vitro cultivation of the hypoimmunogenic epidermal cell sheet was effective. In vivo transplantation experiments demonstrated that IDO+ epidermal cell sheets can effectively promote wound healing without tumorigenicity, and IDO+ epidermal cell sheets may promote wound healing by decreasing the expression levels of inflammatory factors (TNF and IL-1) in wound tissue, decreasing CD3+ T lymphocytes, and increasing infiltration and new capillaries in wound tissue. Conclusion: In this study, we successfully constructed the hypoimmunogenic epidermal cell sheet and demonstrated that the hypoimmunogenic epidermal cell sheet could accelerate wound healing.

RESUMEN

BACKGROUND: The traditional Sichuan Sun-dried vinegar (SSV) with unique flavor and taste is believed to be generated by the solid-state fermentation craft. However, how microorganisms and their metabolites change along with fermentation has not yet been explored. RESULTS: In this study, our results demonstrated that the middle and late stages of SSV fermentation were the periods showing the largest accumulation of organic acids and amino acids. Furthermore, in the bacterial community, the highest average relative abundance was Lactobacillus (ranging from 37.55 to 92.50%) in all fermentation stages, while Acetobacters ranked second position (ranging from 20.15 to 0.55%). The number of culturable lactic acid bacteria is also increased during fermentation process (ranging from 3.93 to 8.31 CFU/g). In fungal community, Alternaria (29.42%), Issatchenkia (37.56%) and Zygosaccharomyces (69.24%) were most abundant in different fermentation stages, respectively. Interestingly, Zygosaccharomyces, Schwanniomyces and Issatchenkia were first noticed as the dominant yeast genera in vinegar fermentation process. Additionally, spearman correlation coefficients exhibited that Lactobacillus, Zygosaccharomyces and Schwanniomyces were significant correlation with most metabolites during the fermentation, implying that these microorganisms might make a significant contribution to the flavor formation of SSV. CONCLUSION: The unique flavor of SSV is mainly produced by the core microorganisms (Lactobacillus, Zygosaccharomyces and Schwanniomyces) during fermentation. This study will provide detailed information related to the structure of microorganism and correlation between changes in metabolites and microbial succession in SSV. And it will be very helpful for proposing a potential approach to monitor the traditional fermentation process.

Asunto(s)

Ácido Acético , Alimentos Fermentados , Fermentación , Ácido Acético/química , Lactobacillus/metabolismo , Zygosaccharomyces/metabolismo , Saccharomycetales/metabolismo , Aminoácidos/metabolismo , Fenoles/análisis , Flavonoides/análisis , Alimentos Fermentados/microbiología