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Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference1. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.
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Pueblos del Este de Asia , Etnicidad , Variación Genética , Genoma Humano , Genética Humana , Grupos Minoritarios , Humanos , Pueblos del Este de Asia/clasificación , Pueblos del Este de Asia/genética , Etnicidad/genética , Genoma Humano/genética , Análisis de Secuencia de ADN , Rayos Ultravioleta , Genética Humana/normas , Minorías Étnicas y Raciales , Estándares de Referencia , Haplotipos/genética , Eucromatina/genética , Alelos , Reparación del ADN/genética , Queratinas/genética , Queratinas/metabolismo , Longevidad/genética , Inmunidad/genéticaRESUMEN
The human leukocyte antigen (HLA) system, or the human version of the major histocompatibility complex (MHC), is known for its extreme polymorphic nature and high heterogeneity. Taking advantage of whole-genome and whole-exome sequencing data, we developed PGG.MHC to provide a platform to explore the diversity of the MHC in Asia as well as in global populations. PGG.MHC currently archives high-resolution HLA alleles of 53 254 samples representing 190 populations spanning 66 countries. PGG.MHC provides: (i) high-quality allele frequencies for eight classical HLA loci (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -DPA1 and -DPB1); (ii) visualization of population prevalence of HLA alleles on global, regional, and country-wide levels; (iii) haplotype structure of 134 populations; (iv) two online analysis tools including 'HLA imputation' for inferring HLA alleles from SNP genotyping data and 'HLA association' to perform case/control studies for HLA-related phenotypes and (v) East Asian-specific reference panels for HLA imputation. Equipped with high-quality frequency data and user-friendly computer tools, we expect that the PGG.MHC database can advance the understanding and facilitate applications of MHC genomic diversity in both evolutionary and medical studies. The PGG.MHC database is freely accessible via https://pog.fudan.edu.cn/pggmhc or https://www.pggmhc.org/pggmhc.
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Bases de Datos Genéticas , Complejo Mayor de Histocompatibilidad , Humanos , Alelos , Frecuencia de los Genes , Haplotipos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos HLA/genética , Complejo Mayor de Histocompatibilidad/genéticaRESUMEN
Structural variations (SVs) play important roles in human evolution and diseases, but there is a lack of data resources concerning representative samples, especially for East Asians. Taking advantage of both next-generation sequencing and third-generation sequencing data at the whole-genome level, we developed the database PGG.SV to provide a practical platform for both regionally and globally representative structural variants. In its current version, PGG.SV archives 584 277 SVs obtained from whole-genome sequencing data of 6048 samples, including 1030 long-read sequencing genomes representing 177 global populations. PGG.SV provides (i) high-quality SVs with fine-scale and precise genomic locations in both GRCh37 and GRCh38, covering underrepresented SVs in existing sequencing and microarray data; (ii) hierarchical estimation of SV prevalence in geographical populations; (iii) informative annotations of SV-related genes, potential functions and clinical effects; (iv) an analysis platform to facilitate SV-based case-control association studies and (v) various visualization tools for understanding the SV structures in the human genome. Taken together, PGG.SV provides a user-friendly online interface, easy-to-use analysis tools and a detailed presentation of results. PGG.SV is freely accessible via https://www.biosino.org/pggsv.
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Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Genómica/métodos , Secuenciación Completa del Genoma , Genoma Humano , Bases de Datos Genéticas , Variación Estructural del Genoma , Análisis de Secuencia de ADN/métodosRESUMEN
Gastric neuroendocrine neoplasms refer to a group of diseases that are relatively rare. They can be classified into three subtypes based on their clinical and histopathological features, and there are significant differences in diagnosis, treatment, and prognosis among the different subtypes. The incidence of gastric neuroendocrine neoplasms has been increasing globally in recent years with the localized disease being particularly evident. Gastrointestinal endoscopy is of irreplaceable importance for the diagnosis and management of g-NENs. Endoscopy with biopsy is the gold standard for the diagnosis of g-NENs. Ultrasound endoscopy can assess the depth of tumor invasion and the presence of lymphatic metastases, which is important for the development of treatment strategies. Meanwhile, for some small and low-risk lesions, endoscopic surveillance or endoscopic resection has satisfactory therapeutic results and prognosis. This means that even though the incidence has increased, advances in endoscopic techniques have allowed more patients to adopt a relatively conservative treatment strategy. However, the criteria for patients suitable for endoscopic surveillance or endoscopic resection remain controversial.
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Tumores Neuroendocrinos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/terapia , Pronóstico , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/cirugía , Endoscopía Gastrointestinal/métodos , BiopsiaRESUMEN
Heterostructured materials integrate the advantages of adjustable electronic structure, fast electron/ions transfer kinetics, and robust architectures, which have attracted considerable interest in the fields of rechargeable batteries, photo/electrocatalysis, and supercapacitors. However, the construction of heterostructures still faces some severe problems, such as inferior random packing of components and serious agglomeration. Herein, a terminal group-oriented self-assembly strategy to controllably synthesize a homogeneous layer-by-layer SnSe2 and MXene heterostructure (LBL-SnSe2 @MXene) is designed. Benefitting from the abundant polar terminal groups on the MXene surface, Sn2+ is induced into the interlayer of MXene with large interlayer spacing, which is selenized in situ to obtain LBL-SnSe2 @MXene. In the heterostructure, SnSe2 layers and MXene layers are uniformly intercalated in each other, superior to other heterostructures formed by random stacking. As an anode for lithium-ion batteries, the LBL-SnSe2 @MXene is revealed to possess strong lithium adsorption ability, the small activation energy for lithium diffusion, and excellent structure stability, thus achieving outstanding electrochemical performance, especially with high specific capacities (1311 and 839 mAh g-1 for initial discharge and charge respectively) and ultralong cycling stability (410 mAh g-1 at 5C even after 16â¯000 cycles). This work conveys an inspiration for the controllable design and construction of homogeneous layered heterostructures.
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BACKGROUND: Determining drug-disease associations is an integral part in the process of drug development. However, the identification of drug-disease associations through wet experiments is costly and inefficient. Hence, the development of efficient and high-accuracy computational methods for predicting drug-disease associations is of great significance. RESULTS: In this paper, we propose a novel computational method named as layer attention graph convolutional network (LAGCN) for the drug-disease association prediction. Specifically, LAGCN first integrates the known drug-disease associations, drug-drug similarities and disease-disease similarities into a heterogeneous network, and applies the graph convolution operation to the network to learn the embeddings of drugs and diseases. Second, LAGCN combines the embeddings from multiple graph convolution layers using an attention mechanism. Third, the unobserved drug-disease associations are scored based on the integrated embeddings. Evaluated by 5-fold cross-validations, LAGCN achieves an area under the precision-recall curve of 0.3168 and an area under the receiver-operating characteristic curve of 0.8750, which are better than the results of existing state-of-the-art prediction methods and baseline methods. The case study shows that LAGCN can discover novel associations that are not curated in our dataset. CONCLUSION: LAGCN is a useful tool for predicting drug-disease associations. This study reveals that embeddings from different convolution layers can reflect the proximities of different orders, and combining the embeddings by the attention mechanism can improve the prediction performances.
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Biología Computacional , Bases de Datos Factuales , Modelos Químicos , Redes Neurales de la Computación , Preparaciones Farmacéuticas/química , FarmacocinéticaRESUMEN
Chronic tissue fibrosis is a common pathological feature of connective tissue diseases and malignant tumors, and its prevention has been a major focus of relevant research.However, the details of the mechanism of action of tissue-colonizing immune cells in fibroblast migration are unclear. In this study, connective tissue disease tissue specimens and solid tumor specimens were selected to observe the relationship between mast cells and interstitial fibrosis and the expression characteristics of mast cells. Our findings suggest that the number of mast cells in the tissue correlates with the degree of pathological fibrosis and that mast cells specifically express the chemokines CCL19 and CCL21, especially CCL19. CCR7+ fibroblasts are highly expressed in mast cell clusters. The mast cell line HMC-1 regulates CD14+ monocyte-derived fibroblasts via CCL19. In disease tissue fibrosis, mast cell activation may increase the expression of chemokines, especially CCL19, in the tissue, thereby inducing a large number of CCR7-positive fibroblasts to migrate to specific tissues. This study lays a foundation for the mechanism of tissue fibrosis and provides evidence for the mechanism by which mast cells induce fibroblast migration.Through the experimental results of this paper, we can combine the induction factors of chronic tissue fibrosis and put forward targeted health prevention strategies.
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Quimiocinas , Mastocitos , Humanos , Mastocitos/metabolismo , Receptores CCR7/metabolismo , Quimiocinas/metabolismo , Movimiento Celular , Fibrosis , Quimiocina CCL19RESUMEN
Protein tyrosine phosphatases non-receptor 13 (PTPN13) could be a potential biomarker in breast cancer (BRCA), but its genetic variation and biological significance in BRCA remain undefined. Hereon, we comprehensively investigated the clinical implication of PTPN13 expression/gene mutation in BRCA. In our study, a total of 14 cases of triple-negative breast cancers (TNBC) treated with neoadjuvant therapy were enrolled, and post-operation TNBC tissues were collected for next-generation sequencing (NGS) analysis (422 genes including PTPN13). According to the disease-free survival (DFS) time, 14 TNBC patients were divided into Group A (long-DFS) and Group B (short-DFS). The NGS data displayed that the overall mutation rate of PTPN13 was 28.57% as the third highest mutated gene, and PTPN13 mutations appeared only in Group B with short-DFS. In addition, The Cancer Genome Atlas (TCGA) database demonstrated that PTPN13 was lower expressed in BRCA than in normal breast tissues. However, PTPN13 high expression was identified to be related to a favorable prognosis in BRCA using data from the Kaplan-Meier plotter. Moreover, Gene Set Enrichment Analysis (GSEA) revealed that PTPN13 is potentially involved in interferon signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, PTEN pathway, and MAPK6/MAPK4 signaling in BRCA. This study provided evidence that PTPN13 might be a tumor suppressor gene and a potential molecular target for BRCA, and genetic mutation and/or low expression of PTPN13 predicted an unfavorable prognosis in BRCA. The anticancer effect and molecular mechanism of PTPN13 in BRCA may be associated with some tumor-related signaling pathways.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Mutación , Transducción de Señal , Pronóstico , Proteínas Quinasas Activadas por Mitógenos , Proteína Tirosina Fosfatasa no Receptora Tipo 13/genéticaRESUMEN
The probiotic E. coli Nissle 1917 (EcN) plays an important role in regulating the microbial components of the gut and preventing inflammation of the gastrointestinal tract. Currently, the long-term use of antibiotics for the treatment of lethal white diarrhea in chicks caused by Salmonella has led to increased morbidity and mutation rates. Therefore, we want to use EcN as an antibiotic alternative as an alternative approach to prevent Salmonella-induced white diarrhea in chickens. To date, there are no reports of EcN being used for the prevention and control of Salmonella pullorum (S. pullorum) in chickens. In vitro, pretreatment with EcN significantly decreased the cellular invasion of S. pullorum CVCC533 in a chicken fibroblast (DF-1) cell model. Then, 0-day-old egg-laying chickens were orally inoculated with EcN at a dose of 109 CFU/100 µL at either Day 1 (EcN1) or both Day 1 and Day 4 (EcN2). Then, S. pullorum CVCC533 was used to challenge the cells at a dose of 1.0 × 107 CFU/100 µL on Day 8. Next, the body weights and survival rates were recorded for 14 consecutive days, and the colonization of S. pullorum in the spleen and liver at 7 days post-challenge (dpc) was determined. Chicken feces were also collected at 2, 4, 6 and 8 dpc to evaluate the excretion of pathogenic bacteria in feces. The liver, duodenum and rectum samples were collected and analyzed by pathological histology at 7 dpc to evaluate the protective effect of EcN on the mucosa, villi and crypts of the small intestine. The spleen and bursa were collected, and the immune organ index was calculated. In addition, the contents of the cecum of chicks were collected at 7 dpc for 16S rRNA sequencing to detect the distribution of microbial communities in the intestine. The results showed that EcN was able to protect against CVCC533 challenge, as shown by decreased body weight loss, mortality and shedding of pathogenic bacteria in fecal samples in the EcN1 plus Salmonella challenge group (EcN1S) but not the EcN2 plus Salmonella challenge group (EcN2S). The pathogenic changes in the liver, duodenum and rectum also demonstrated that one dose but not two doses of EcN effectively prolonged the length of the pilus with decreased crypt depth, indicating its protective effects against S. pullorum. In addition, the 16S rRNA sequencing results suggested that EcN could enlarge the diversity of intestinal flora, decrease the abundance of pathogenic bacteria and increase the abundance of beneficial bacteria, such as Lactobacillus. In conclusion, EcN has shown moderate protection against S. pullorum challenge in chickens.
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Enfermedades de las Aves de Corral , Salmonelosis Animal , Animales , Antibacterianos , Pollos , Diarrea/prevención & control , Diarrea/veterinaria , Escherichia coli , Enfermedades de las Aves de Corral/prevención & control , Enfermedades de las Aves de Corral/microbiología , ARN Ribosómico 16S , Salmonella/genética , Salmonelosis Animal/prevención & control , Salmonelosis Animal/microbiologíaRESUMEN
BACKGROUND: Molluscan shellfish, including oysters, often cause allergic reactions in sensitive people throughout the world. It has been demonstrated that arginine kinase (AK) is one of the major allergens of oyster. The present study aimed to evaluate the immunoreactivity and structure of oyster AK as affected by heat treatment, pH change, and in vitro digestion. What is more, the immunoglobulin E-binding epitopes of this allergen were also predicted and validated. RESULTS: Thermal and pH assays revealed that AK was unstable at temperature >40 °C or pH ≤5.0 by sodium dodecyl sulfate polyacrylamide gel electrophoresis and circular dichroism, and the digestibility assays suggested that AK was more easily digested by pepsin than by trypsin and chymotrypsin. The potential epitopes were predicted through immunoinformatics tools, and seven linear epitopes were identified by indirect competition enzyme-linked immunosorbent assay with pooled sera and individual serum from oyster-allergic patients. The critical amino acids in each epitope were also confirmed using mutant peptides. These linear epitopes and critical amino acids were apt to distribute on the outer surface of homology-based AK model. Moreover, the three denaturants (sodium dodecyl sulfate, ß-mercaptoethanol, and urea) can destroy the spatial structure of AK and increase or reduce its allergenicity by denaturation treatments. CONCLUSION: Processing conditions lay the foundation for the variation of allergenicity. Seven linear epitopes and their critical amino acids were identified by indirect competitive enzyme-linked immunosorbent assay. These findings will be helpful in allergy diagnosis and development of hypoallergenic products in the near future. © 2021 Society of Chemical Industry.
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Arginina Quinasa , Crassostrea , Alérgenos/química , Secuencia de Aminoácidos , Aminoácidos , Animales , Arginina Quinasa/química , Arginina Quinasa/metabolismo , Epítopos/química , Humanos , Dodecil Sulfato de SodioRESUMEN
BACKGROUND: Food allergy is a serious public nutritional health problem that has attracted extensive worldwide attention. Shellfish allergy is a long-lasting disorder that has a lifelong impact on health. Sarcoplasmic calcium-binding protein (SCP) plays a vital role in cell and muscle functions and has been identified as an allergen in oyster. RESULTS: In this study, recombinant SCP (rSCP) with a molecular mass of 21 kDa was produced and identified based on SCP amino acid sequencing of Pacific oyster (Crassostrea gigas), and was used as a follow-up experimental material. Its physicochemical characterization showed that purified rSCP is highly stable to heat and acid-alkali and trypsin digestion but less resistant to pepsin digestion. We established an animal sensitization model and rSCP displayed stronger Immunoglobulin E (IgE)-binding activity with rat serum in the rSCP + cholera toxin (CT) group compared with the CT group and a control group. Five epitope peptides were identified as linear immunodominant epitopes by indirect competitive enzyme-linked immunosorbent assay (icELISA) for the first time. We also found that conformational epitopes may play a major role in the immunoreactivity of SCP. CONCLUSION: These results are significant for understanding hypersensitization of humans to oyster and offer available preventive measures and treatment programs in further research. © 2021 Society of Chemical Industry.
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Alérgenos , Crassostrea , Alérgenos/química , Alérgenos/genética , Secuencia de Aminoácidos , Animales , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Crassostrea/genética , Epítopos/química , RatasRESUMEN
The anticancer therapy strategy mediated by tumor-targeting bacteria needs better visualization tools for imaging and monitoring bacteria in vivo. The probiotic strain Escherichia coli Nissle 1917 (EcN), one of the tumor-targeting bacteria, leads to the potential application for cancer therapy. Here, we report the development and application of a live, EcN-based imageable vehicle for noninvasive in vivo bioluminescence imaging in live mice. Firefly luciferase (Fluc) and luciferin-regenerating enzyme (LRE), an enzyme that contributes to stable bioluminescence, were functionally coexpressed in EcN. The recombinant EcN strain expressing the genomically integrated Fluc-LRE cassette was demonstrated to be a valuable tool for generating robust, continuous, and red-shifted bioluminescence for bacterial tracking in vitro and in vivo, thus providing an optical tumor-targeting system for the in vivo study of bacteria-assisted cancer therapy. Additionally, in vivo imaging of the recombinant EcN strain in the mouse intestinal tract indicated the potential of this strain to be used as a tool in the study of gut.
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Infecciones por Escherichia coli , Probióticos , Animales , Escherichia coli , Luciferasas de Luciérnaga/genética , RatonesRESUMEN
BACKGROUND: Many transcripts have been generated due to the development of sequencing technologies, and lncRNA is an important type of transcript. Predicting lncRNAs from transcripts is a challenging and important task. Traditional experimental lncRNA prediction methods are time-consuming and labor-intensive. Efficient computational methods for lncRNA prediction are in demand. RESULTS: In this paper, we propose two lncRNA prediction methods based on feature ensemble learning strategies named LncPred-IEL and LncPred-ANEL. Specifically, we encode sequences into six different types of features including transcript-specified features and general sequence-derived features. Then we consider two feature ensemble strategies to utilize and integrate the information in different feature types, the iterative ensemble learning (IEL) and the attention network ensemble learning (ANEL). IEL employs a supervised iterative way to ensemble base predictors built on six different types of features. ANEL introduces an attention mechanism-based deep learning model to ensemble features by adaptively learning the weight of individual feature types. Experiments demonstrate that both LncPred-IEL and LncPred-ANEL can effectively separate lncRNAs and other transcripts in feature space. Moreover, comparison experiments demonstrate that LncPred-IEL and LncPred-ANEL outperform several state-of-the-art methods when evaluated by 5-fold cross-validation. Both methods have good performances in cross-species lncRNA prediction. CONCLUSIONS: LncPred-IEL and LncPred-ANEL are promising lncRNA prediction tools that can effectively utilize and integrate the information in different types of features.
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ARN Largo no Codificante , Biología Computacional , Aprendizaje Automático , ARN Largo no Codificante/genéticaAsunto(s)
Carcinoma Hepatocelular , Enteroscopía de Doble Balón , Hemorragia Gastrointestinal , Neoplasias Hepáticas , Humanos , Persona de Mediana Edad , Carcinoma Hepatocelular/secundario , Carcinoma Hepatocelular/patología , Hemorragia Gastrointestinal/etiología , Neoplasias Intestinales/complicaciones , Neoplasias Intestinales/patología , Neoplasias Intestinales/secundario , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , FemeninoRESUMEN
Tripterygium wilfordii Hook F (TwHF) is a promising Chinese traditional medicine used to significantly reduce proteinuria and improve renal function. However, its efficacy and safety in treatment of chronic kidney disease need to be further explored in order to promote its application in clinics. This review compared the efficacy and safety of TwHF with the placebo, conventional Western medicine and other immunosuppressive medicine in a range of kidney disorders. One hundred three randomized controlled trials were included. TwHF therapy decreased 24-hr proteinuria by 0.59 g/day (95% confidence interval [CI; -0.68, -0.50]), serum creatinine level by 1.93 µmol/L (95% CI [-3.69, -0.17]), and blood urea nitrogen level by 0.24 mmol/L (95% CI [-0.41, -0.07]); increased the total effective rate by 27% (95% CI [1.24, 1.30]); and decreased the incidence of adverse reactions by 19% (95% CI [0.68, 0.96]) overall. Meta regression results showed that the duration of therapy and mean age of participants were the major sources of high heterogeneity. Sensitivity analysis demonstrated that our statistic results were relatively stable and credible. The present findings suggested that TwHF possibly has nephroprotective effects by decreasing proteinuria, serum creatinine level, and blood urea nitrogen level and no more adverse reactions compared with control group in most kidney disorders. However, these findings still need to be further confirmed by high-quality trials.
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Medicina Tradicional China/métodos , Insuficiencia Renal Crónica/tratamiento farmacológico , Tripterygium/metabolismo , Adulto , Anciano , China , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disrupted in mammals. We here investigated the roles of cul4a and cul4b during zebrafish embryogenesis by using the morpholino knockdown approach. We found that cul4a is essential for cardiac development as well as for pectoral fin development. Whereas cul4a morphants appeared to be unperturbed in chamber specification, they failed to undergo heart looping. The failures in heart looping and pectoral fin formation in cul4a morphants were accompanied by greatly reduced proliferation of cardiac cells and pectoral fin-forming cells. We demonstrated that tbx5a, a transcription factor essential for heart and limb development, is transcriptionally upregulated by cul4a and mediates the function of cul4a in cardiac and pectoral fin development. In contrast to the critical importance of cul4a, cul4b appeared to be dispensable for zebrafish development and was incapable of compensating for the loss of cul4a. This work provides the first demonstration of an essential role of cul4a, but not cul4b, in cardiac development and in the regulation of tbx5a in zebrafish. These findings justify exploring the functional role of CUL4A in human cardiac development.
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Proteínas Cullin/metabolismo , Miembro Anterior/crecimiento & desarrollo , Corazón/crecimiento & desarrollo , Proteínas de Dominio T Box/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Animales , Proliferación Celular , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Cardiopatías Congénitas/metabolismo , Miocitos Cardíacos/metabolismo , Pez Cebra/metabolismoRESUMEN
Autosomal-recessive nonsyndromic hearing loss (ARNSHL) features a high degree of genetic heterogeneity. Many genes responsible for ARNSHL have been identified or mapped. We previously mapped an ARNSHL locus at 17q12, herein designated DFNB99, in a consanguineous Chinese family. In this study, whole-exome sequencing revealed a homozygous missense mutation (c.1259G>A, p.Arg420Gln) in the gene-encoding transmembrane protein 132E (TMEM132E) as the causative variant. Immunofluorescence staining of the Organ of Corti showed Tmem132e highly expressed in murine inner hair cells. Furthermore, knockdown of the tmem132e ortholog in zebrafish affected the mechanotransduction of hair cells. Finally, wild-type human TMEM132E mRNA, but not the mRNA carrying the c.1259G>A mutation rescued the Tmem132e knockdown phenotype. We conclude that the variant in TMEM132E is the most likely cause of DFNB99.
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Células Ciliadas Auditivas Internas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Análisis de Secuencia de ADN/métodos , Animales , China , Cromosomas Humanos Par 15/genética , Sordera/genética , Exoma , Técnicas de Silenciamiento del Gen , Genes Recesivos , Humanos , Masculino , Ratones , Mutación Missense , Linaje , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.
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Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Curcumina/farmacología , Compuestos Organoplatinos/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Masculino , Ratones , Ratones Desnudos , Oxaliplatino , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Renal clear cell carcinoma (RCC) is a type of malignant tumor, which, in addition to surgical resection, radiotherapy, and chemotherapy, has been widely treated through immunotherapy recently. However, the influence of the tumor microenvironment and the infiltrating immune cells within it on immunotherapy remains unclear. It is imperative to study the interactions between various immune cells of RCC. The scRNA-seq dataset from GEO's database was used to analyze the immune cells present in tumor tissue and peripheral blood samples. Through quality control, clustering, and identification, the types and proportions of infiltrating immune cells were determined. The cellular differences were determined, and gene expression levels of the differentially present cells were investigated. A protein-protein interaction network analysis was performed using string. KEGG and GO analyses were performed to investigate abnormal activities. The microglia marker CD68 and CD1C+ B dendritic cells marker CD11C were detected using multiplex immunofluorescence staining. Many depleted CD8+ T cells (exhausted CD8+ T cells) appeared in tumor tissues as well as microglia. CD1C+ B dendritic cells did not infiltrate tumor tissues. HSPA1A was correlated with DNAJB1 in microglia. Compared with Paracancer tissues, microglia increased while CD1C+ B dendritic cells decreased in pathological stages I and I-II in cancerous tissues. An altered tumor microenvironment caused by increases in microglia in RCC in the early stage resulted in an inability of CD1C+ B dendritic cells to infiltrate, resulting in CD8+ T cells being unable to receive the antigens presented by them, and in turn being depleted in large quantities.
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Antígenos CD1 , Linfocitos T CD8-positivos , Carcinoma de Células Renales , Células Dendríticas , Neoplasias Renales , Microglía , Microambiente Tumoral , Humanos , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Microambiente Tumoral/inmunología , Microglía/inmunología , Microglía/metabolismo , Antígenos CD1/metabolismo , Masculino , Estadificación de Neoplasias , Femenino , GlicoproteínasRESUMEN
The purpose of this study is to explore the relationship between appearance anxiety and social media use among Chinese adolescents. Using a grounded theory approach, the study conducted two-round online interviews with ten Chinese university students and subsequently constructed a theoretical model of social media appearance anxiety among Chinese young people. The results of the study indicate that social media has a dual impact on appearance anxiety. On one hand, increased social media engagement amplifies appearance anxiety by shaping aesthetic standards and fostering comparative environments. On the other hand, diverse aesthetic perspectives and authentic presentations on social media partially alleviate appearance anxiety by promoting acceptance of unique appearances and boosting self-confidence. It is emphasized in this study that there should be an in-depth understanding of the dual impact and complicated relationship of social media on the daily lives of Chinese adolescents to further develop relevant strategies that promote healthy social media behavior among youth. Furthermore, this study calls for efforts to actively promote the healthy image and psychological well-being of adolescents while alleviating the negative impact of appearance anxiety and overall mental health. Such efforts are needed to ensure a positive and healthy development for the younger generation.