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Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for promoting the immunosuppressive capacity of TIMs.
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Metiltransferasas , Neoplasias , Adenosina/metabolismo , Animales , Humanos , Terapia de Inmunosupresión , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Células Mieloides/metabolismo , ARN , Microambiente TumoralRESUMEN
The flower-infecting fungus Ustilaginoidea virens causes rice false smut, which is a severe emerging disease threatening rice (Oryza sativa) production worldwide. False smut not only reduces yield, but more importantly produces toxins on grains, posing a great threat to food safety. U. virens invades spikelets via the gap between the 2 bracts (lemma and palea) enclosing the floret and specifically infects the stamen and pistil. Molecular mechanisms for the U. virens-rice interaction are largely unknown. Here, we demonstrate that rice flowers predominantly employ chitin-triggered immunity against U. virens in the lemma and palea, rather than in the stamen and pistil. We identify a crucial U. virens virulence factor, named UvGH18.1, which carries glycoside hydrolase activity. Mechanistically, UvGH18.1 functions by binding to and hydrolyzing immune elicitor chitin and interacting with the chitin receptor CHITIN ELICITOR BINDING PROTEIN (OsCEBiP) and co-receptor CHITIN ELICITOR RECEPTOR KINASE1 (OsCERK1) to impair their chitin-induced dimerization, suppressing host immunity exerted at the lemma and palea for gaining access to the stamen and pistil. Conversely, pretreatment on spikelets with chitin induces a defense response in the lemma and palea, promoting resistance against U. virens. Collectively, our data uncover a mechanism for a U. virens virulence factor and the critical location of the host-pathogen interaction in flowers and provide a potential strategy to control rice false smut disease.
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Quitina , Flores , Hypocreales , Oryza , Enfermedades de las Plantas , Oryza/microbiología , Oryza/metabolismo , Oryza/genética , Enfermedades de las Plantas/microbiología , Quitina/metabolismo , Flores/microbiología , Hypocreales/patogenicidad , Hypocreales/genética , Hypocreales/metabolismo , Transducción de Señal , Interacciones Huésped-Patógeno , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Virulencia , Factores de Virulencia/metabolismo , Factores de Virulencia/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genéticaRESUMEN
The highly diverse Solanaceae family contains several widely studied models and crop species. Fully exploring, appreciating, and exploiting this diversity requires additional model systems. Particularly promising are orphan fruit crops in the genus Physalis, which occupy a key evolutionary position in the Solanaceae and capture understudied variation in traits such as inflorescence complexity, fruit ripening and metabolites, disease and insect resistance, self-compatibility, and most notable, the striking inflated calyx syndrome (ICS), an evolutionary novelty found across angiosperms where sepals grow exceptionally large to encapsulate fruits in a protective husk. We recently developed transformation and genome editing in Physalis grisea (groundcherry). However, to systematically explore and unlock the potential of this and related Physalis as genetic systems, high-quality genome assemblies are needed. Here, we present chromosome-scale references for P. grisea and its close relative Physalis pruinosa and use these resources to study natural and engineered variations in floral traits. We first rapidly identified a natural structural variant in a bHLH gene that causes petal color variation. Further, and against expectations, we found that CRISPR-Cas9-targeted mutagenesis of 11 MADS-box genes, including purported essential regulators of ICS, had no effect on inflation. In a forward genetics screen, we identified huskless, which lacks ICS due to mutation of an AP2-like gene that causes sepals and petals to merge into a single whorl of mixed identity. These resources and findings elevate Physalis to a new Solanaceae model system and establish a paradigm in the search for factors driving ICS.
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Physalis , Solanaceae , Solanaceae/genética , Physalis/genética , Physalis/metabolismo , Evolución Biológica , Mutación , Edición GénicaRESUMEN
Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P4) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P4 signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m6A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m6A modification. A luciferase assay revealed that the m6A modification in the 5' untranslated region (5'-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P4 signaling during embryo implantation via m6A-mediated translation control of Pgr mRNA.
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Progesterona , Receptores de Progesterona , Femenino , Ratones , Humanos , Animales , Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Implantación del Embrión/genética , Útero/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones Noqueados , ARN Mensajero/metabolismoRESUMEN
The juvenile-to-adult transition in plants is known as vegetative phase change and is marked by changes in the expression of leaf traits in response to a decrease in the level of miR156 and miR157. To determine whether this is the only mechanism of vegetative phase change, we measured the appearance of phase-specific leaf traits in 70 natural accessions of Arabidopsis thaliana. We found that leaf shape was poorly correlated with abaxial trichome production (two adult traits), that variation in these traits was not necessarily correlated with the level of miR156, and that there was little to no correlation between the appearance of adult-specific vegetative traits and flowering time. We identified eight quantitative trait loci controlling phase-specific vegetative traits from a cross between the Columbia (Col-0) and Shakdara (Sha) accessions. Only one of these quantitative trait loci includes genes known to regulate vegetative phase change (MIR156A and TOE1), which were expressed at levels consistent with the precocious phenotype of Sha. Our results suggest that vegetative phase change is regulated both by the miR156/SPL module and by genes specific to different vegetative traits, and that natural variation in vegetative phase change can arise from either source.
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Proteínas de Arabidopsis , Arabidopsis , MicroARNs , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , MicroARNs/genética , MicroARNs/metabolismo , Tricomas/metabolismoRESUMEN
Lymphangiogenesis is a dynamic process that involves the directed migration of lymphatic endothelial cells (LECs) to form lymphatic vessels. The molecular mechanisms that underpin lymphatic vessel patterning are not fully elucidated and, to date, no global regulator of lymphatic vessel guidance is known. In this study, we identify the transmembrane cell signalling receptor Plexin D1 (Plxnd1) as a negative regulator of both lymphatic vessel guidance and lymphangiogenesis in zebrafish. plxnd1 is expressed in developing lymphatics and is required for the guidance of both the trunk and facial lymphatic networks. Loss of plxnd1 is associated with misguided intersegmental lymphatic vessel growth and aberrant facial lymphatic branches. Lymphatic guidance in the trunk is mediated, at least in part, by the Plxnd1 ligands, Semaphorin 3AA and Semaphorin 3C. Finally, we show that Plxnd1 normally antagonises Vegfr/Erk signalling to ensure the correct number of facial LECs and that loss of plxnd1 results in facial lymphatic hyperplasia. As a global negative regulator of lymphatic vessel development, the Sema/Plxnd1 signalling pathway is a potential therapeutic target for treating diseases associated with dysregulated lymphatic growth.
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Vasos Linfáticos , Semaforinas , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Células Endoteliales/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Linfangiogénesis/genética , Vasos Linfáticos/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Proteínas Portadoras/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Dendritic cells (DCs), a driver of psoriasis pathogenesis, produce IL-23 and trigger IL-23/IL-17 cytokine axis activation. However, the mechanisms regulating IL-23 induction remain unclear. In the current study, we found that mice with E3 ligase FBXW7 deficiency in DCs show reduced skin inflammation correlated with the reduction of IL-23/IL-17 axis cytokines in the imiquimod-induced psoriasis model. Fbxw7 deficiency results in decreased production of IL-23 in DCs. FBXW7 interacts with the lysine N-methyltransferase suppressor of variegation 39 homolog 2 (SUV39H2), which catalyzes the trimethylation of histone H3 Lys9 (H3K9) during transcription regulation. FBXW7 mediates the ubiquitination and degradation of SUV39H2, thus decreasing H3K9m3 deposition on the Il23a promoter. The Suv39h2 knockout mice displayed exacerbated skin inflammation with the IL-23/IL-17 axis overactivating in the psoriasis model. Taken together, our results indicate that FBXW7 increases IL-23 expression in DCs by degrading SUV39H2, thereby aggravating psoriasis-like inflammation. Inhibition of FBXW7 or the FBXW7/SUV39H2/IL-23 axis may represent a novel therapeutic approach to psoriasis.
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Dermatitis , Psoriasis , Animales , Ratones , Células Dendríticas/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Epigénesis Genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Psoriasis/patología , Piel/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The prostate is a vital accessory gonad in the mammalian male reproductive system. With the ever-increasing proportion of the population over 60 years of age worldwide, the incidence of prostate diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), is on the rise and is gradually becoming a significant medical problem globally. The notch signaling pathway is essential in regulating prostate early development. However, the potential regulatory mechanism of Notch signaling in prostatic enlargement and hyperplasia remains unclear. In this study, we proved that overactivation of Notch1 signaling in mouse prostatic epithelial cells (OEx) led to prostatic enlargement via enhancing proliferation and inhibiting apoptosis of prostatic epithelial cells. Further study showed that N1ICD/RBPJ directly up-regulated the androgen receptor (AR) and enhanced prostatic sensitivity to androgens. Hyper-proliferation was not found in orchidectomized OEx mice without androgen supply but was observed after Dihydrotestosterone (DHT) supplementation. Our data showed that the number of mitochondrion in prostatic epithelial cells of OEx mice was increased, but the mitochondrial function was impaired, and the essential activity of the mitochondrial respiratory electron transport chain was significantly weakened. Disordered mitochondrial number and metabolic function further resulted in excessive accumulation of reactive oxygen species (ROS). Importantly, anti-oxidant N-Acetyl-L-Cysteine (NAC) therapy could alleviate prostatic hyperplasia caused by the over-activation of Notch1 signaling. Furthermore, we observed the incremental Notch signaling activity in progenitor-like club cells in the scRNA-seq data set of human BPH patients. Moreover, the increased number of TROP2+ progenitors and Club cells was also confirmed in our OEx mice. In conclusion, our study revealed that over-activated Notch1 signaling induces prostatic enlargement by increasing androgen receptor sensitivity, disrupting cellular mitochondrial metabolism, increasing ROS, and a higher number of progenitor cells, all of which can be effectively rescued by NAC treatment.
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Hiperplasia Prostática , Animales , Humanos , Masculino , Ratones , Andrógenos/metabolismo , Mamíferos/metabolismo , Mitocondrias/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de SeñalRESUMEN
PubChem (https://pubchem.ncbi.nlm.nih.gov) is a popular chemical information resource that serves a wide range of use cases. In the past two years, a number of changes were made to PubChem. Data from more than 120 data sources was added to PubChem. Some major highlights include: the integration of Google Patents data into PubChem, which greatly expanded the coverage of the PubChem Patent data collection; the creation of the Cell Line and Taxonomy data collections, which provide quick and easy access to chemical information for a given cell line and taxon, respectively; and the update of the bioassay data model. In addition, new functionalities were added to the PubChem programmatic access protocols, PUG-REST and PUG-View, including support for target-centric data download for a given protein, gene, pathway, cell line, and taxon and the addition of the 'standardize' option to PUG-REST, which returns the standardized form of an input chemical structure. A significant update was also made to PubChemRDF. The present paper provides an overview of these changes.
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Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Bioensayo , Proteínas , QuimioinformáticaRESUMEN
CRISPR-Cas systems act as the adaptive immune systems of bacteria and archaea, targeting and destroying invading foreign mobile genetic elements (MGEs) such as phages. MGEs have also evolved anti-CRISPR (Acr) proteins to inactivate the CRISPR-Cas systems. Recently, AcrIIC4, identified from Haemophilus parainfluenzae phage, has been reported to inhibit the endonuclease activity of Cas9 from Neisseria meningitidis (NmeCas9), but the inhibition mechanism is not clear. Here, we biochemically and structurally investigated the anti-CRISPR activity of AcrIIC4. AcrIIC4 folds into a helix bundle composed of three helices, which associates with the REC lobe of NmeCas9 and sgRNA. The REC2 domain of NmeCas9 is locked by AcrIIC4, perturbing the conformational dynamics required for the target DNA binding and cleavage. Furthermore, mutation of the key residues in the AcrIIC4-NmeCas9 and AcrIIC4-sgRNA interfaces largely abolishes the inhibitory effects of AcrIIC4. Our study offers new insights into the mechanism of AcrIIC4-mediated suppression of NmeCas9 and provides guidelines for the design of regulatory tools for Cas9-based gene editing applications.
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Bacteriófagos , Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Proteína 9 Asociada a CRISPR/metabolismo , ARN Guía de Sistemas CRISPR-Cas , Edición Génica , Bacterias/genética , Bacteriófagos/genéticaRESUMEN
BACKGROUND AND AIMS: Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. METHODS: The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. RESULTS: Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as ß-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. CONCLUSIONS: These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Hipertensión , Receptores de LDL , Animales , Humanos , Ratones , Antihipertensivos , Cardiomiopatías Diabéticas/prevención & control , Hipertensión/prevención & control , Receptores de LDL/antagonistas & inhibidoresRESUMEN
Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.
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Keratin (KRT), a natural fibrous structural protein, can be classified into two categories: "soft" cytosolic KRT that is primarily found in the epithelia tissues (e.g., skin, the inner lining of digestive tract) and "hard" KRT that is mainly found in the protective tissues (e.g., hair, horn). The latter is the predominant form of KRT widely used in biomedical research. The oxidized form of extracted KRT is exclusively denoted as keratose (KOS) while the reduced form of KRT is termed as kerateine (KRTN). KOS can be processed into various forms (e.g., hydrogel, films, fibers, and coatings) for different biomedical applications. KRT/KOS offers numerous advantages over other types of biomaterials, such as bioactivity, biocompatibility, degradability, immune/inflammatory privileges, mechanical resilience, chemical manipulability, and easy accessibility. As a result, KRT/KOS has attracted considerable attention and led to a large number of publications associated with this biomaterial over the past few decades; however, most (if not all) of the published review articles focus on KRT regarding its molecular structure, biochemical/biophysical properties, bioactivity, biocompatibility, drug/cell delivery, and in vivo transplantation, as well as its applications in biotechnical products and medical devices. Current progress that is directly associated with KOS applications in tissue regeneration and drug delivery appears an important topic that merits a commentary. To this end, the present review aims to summarize the current progress of KOS-associated biomedical applications, especially focusing on the in vitro and in vivo effects of KOS hydrogel on cultured cells and tissue regeneration following skin injury, skeletal muscle loss, peripheral nerve injury, and cardiac infarction.
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Hidrogeles , Queratosis , Materiales Biocompatibles/análisis , Cabello/química , Humanos , Hidrogeles/análisis , Hidrogeles/química , Queratinas/análisis , Queratinas/química , Queratinas/farmacologíaRESUMEN
Spiral inorganic perovskite nanowires (NWs) possess unique morphologies and properties that allow them highly attractive for applications in optoelectronic and catalytic fields. In popular solution-based synthesis methodology, however, challenges persist in simultaneously achieving precise and facile control over morphological twisting and fantastic carrier lifetimes. Here, a cooperative strategy of concurrently employing selective etching and ligand engineering is applied to facilitate the formation of spiral CsPbBr3 perovskite NWs with an ultralong carrier lifetime of ≈2 µs. Specifically, a novel amine of 1-(p-tolyl)ethanamine is introduced to functionalize as both a selective etchant and the source of forming an effective ligand to passivate the exposed facets, favoring the structural twisting and the enhancement of carrier lifetimes. The twisting behaviors are dependent on the etch ratios, which are essentially associated with the densities of grain boundaries and dislocations in the NWs. The ultralong carrier lifetime and long-term stability of the spiral NWs open up new possibilities for all-inorganic perovskites in optoelectronic and photocatalytic fields, while the cooperative synthesis strategy paves the way for exploring complex spiral structures with tunable morphology and functionality.
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The tick-borne encephalitis virus (TBEV) serocomplex includes several medically important flavivirus members endemic to Europe, Asia, and North America, which can induce severe neuroinvasive or viscerotropic diseases with unclear mechanisms of pathogenesis. Langat virus (LGTV) shares a high sequence identity with TBEV but exhibits lower pathogenic potential in humans and serves as a model for virus-host interactions. In this study, we demonstrated that LGTV infection inhibits the activation of gp130/JAK/STAT (Janus kinases (JAK) and signal transducer and activator of transcription (STAT)) signaling, which plays a pivotal role in numerous biological processes. Our data show that the LGTV-infected cells had significantly lower phosphorylated STAT3 (pSTAT3) protein upon oncostatin M (OSM) stimulation than the mock-infected control. LGTV infection blocked the nuclear translocation of STAT3 without a significant effect on total STAT3 protein level. LGTV inhibited JAK1 activation and reduced gp130 protein expression in infected cells, with the viral NS5 protein mediating this effect. TBEV infection also reduces gp130 level. On the other hand, pretreatment of Vero cells with OSM significantly reduces LGTV replication, and STAT1/STAT2 knockdown had little effect on OSM-mediated antiviral effect, which suggests it is independent of STAT1/STAT2 and, instead, it is potentially mediated by STAT3 signlaing. These findings shed light on the LGTV and TBEV-cell interactions, offering insights for the future development of antiviral therapeutics and improved vaccines.
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Fenómenos Biológicos , Virus de la Encefalitis Transmitidos por Garrapatas , Animales , Chlorocebus aethiops , Humanos , Quinasas Janus/metabolismo , Células Vero , Receptor gp130 de Citocinas/metabolismo , Antivirales/metabolismoRESUMEN
BACKGROUND: The relationship between the triglyceride-glucose (TyG) index and its derived index, the triglyceride glucose-waist height ratio (TyG-WHtR), with mortality and cardiovascular diseases (CVDs) in patients with non-alcoholic fatty liver disease (NAFLD) remains unclear. METHODS: This study enrolled 6627 adults aged 18 and above diagnosed NAFLD from the National Health and Nutrition Examination Survey (NHANES, 1999-2018). Binary weighted logistic regression analyses, cox proportional hazards model and restricted cubic spline (RCS) were used to analyze the relationship between TyG and TyG-WHtR with all-cause mortality, CVD mortality and CVDs. Mediation analysis explored the mediating role of glycohemoglobin, insulin and hypertension in the above relationships. Meanwhile, the incremental predictive value of the TyG index and TyG-WHtR was further assessed. RESULTS: Except for no significant association between the TyG index and both all-cause mortality and chronic heart failure (CHF), both TyG and TyG-WHtR exhibited significant positive correlations or trends of positive correlation with all-cause mortality, CVD mortality, total-CVD, CHF, coronary heart disease (CHD) and angina pectoris. For all-cause mortality, CVD mortality and CHF, TyG-WHtR was a better predictor than TyG (TyG-WHtR: HR 1.31, 95%CI 1.03-1.66; HR 2.22, 95%CI 1.42-3.47; OR 3.99, 95%CI 1.79-8.93). In contrast, TyG index demonstrated a stronger association with total-CVD, CHD and angina pectoris (TyG index: OR 2.00, 95%CI 1.26-3.18; OR 1.85, 95%CI 1.19-2.91; OR 2.93, 95%CI 1.23-7.00). RCS analysis showed that after adjusting for covariates, most of the aforementioned relationships were linear(P overall < 0.0001, P-nonlinear > 0.05), while the associations of the TyG index and TyG-WHtR with all-cause mortality and CHF were non-linear(P overall < 0.0001, P nonlinear < 0.05). The addition of the TyG index and TyG-WHtR to the basic model for outcomes improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value. CONCLUSIONS: The predictive value of TyG or TyG-WHtR for all-cause mortality and cardiovascular risk in NAFLD patients was significant. The TyG index and TyG-WHtR might be valid predictors of cardiovascular outcomes of patients with NAFLD.
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Biomarcadores , Glucemia , Enfermedades Cardiovasculares , Causas de Muerte , Enfermedad del Hígado Graso no Alcohólico , Encuestas Nutricionales , Triglicéridos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/mortalidad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Adulto , Medición de Riesgo , Triglicéridos/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Estados Unidos/epidemiología , Pronóstico , Factores de Tiempo , Anciano , Factores de Riesgo , Estudios Transversales , Adulto JovenRESUMEN
BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common pathological type in oral tumors. This study intends to construct a novel prognostic nomogram model based on China populations for these resectable OCSCC patients, and then validate these nomograms. METHODS: A total of 607 postoperative patients with OCSCC diagnosed between June 2012 and June 2018 were obtained from two tertiary medical institutions in Xinxiang and Zhengzhou. Then, 70% of all the cases were randomly assigned to the training group and the rest to the validation group. The endpoint time was defined as overall survival (OS) and disease-free survival (DFS). The nomograms for predicting the 3-, and 5-year OS and DFS in postoperative OCSCC patients were established based on the independent prognostic factors, which were identified by the univariate analysis and multivariate analysis. A series of indexes were utilized to assess the performance and net benefit of these two newly constructed nomograms. Finally, the discrimination capability of OS and DFS was compared between the new risk stratification and the American Joint Committee on Cancer (AJCC) stage by Kaplan-Meier curves. RESULTS: 607 postoperative patients with OCSCC were selected and randomly assigned to the training cohort (n = 425) and validation cohort (n = 182). The nomograms for predicting OS and DFS in postoperative OCSCC patients had been established based on the independent prognostic factors. Moreover, dynamic nomograms were also established for more convenient clinical application. The C-index for predicting OS and DFS were 0.691, 0.674 in the training group, and 0.722, 0.680 in the validation group, respectively. Besides, the calibration curve displayed good consistency between the predicted survival probability and actual observations. Finally, the excellent performance of these two nomograms was verified by the NRI, IDI, and DCA curves in comparison to the AJCC stage system. CONCLUSION: The newly established and validated nomograms for predicting OS and DFS in postoperative patients with OCSCC perform well, which can be helpful for clinicians and contribute to clinical decision-making.
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Neoplasias de la Boca , Nomogramas , Humanos , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Pronóstico , Anciano , Periodo Posoperatorio , Adulto , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Estadificación de NeoplasiasRESUMEN
Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus and causes primarily acute self-limiting infections. The ORF1 of the HEV genome encodes a polyprotein around 190 kDa, which contains several putative domains, including helicase and RNA-dependent RNA polymerase. The HEV-encoded helicase is a member of the superfamily 1 helicase family and possesses multiple enzymatic functions, such as RNA 5'-triphosphatase, RNA unwinding, and NTPase, which are thought to contribute to viral RNA synthesis. However, the helicase interaction with cellular proteins remains less known. Oxysterol binding protein (OSBP) is a lipid regulator that shuffles between the Golgi apparatus and the endoplasmic reticulum for cholesterol and phosphatidylinositol-4-phosphate exchange and controls the efflux of cholesterol from cells. In this study, the RNAi-mediated silencing of OSBP significantly reduced HEV replication. Further studies indicate that the HEV helicase interacted with OSBP, shown by co-immunoprecipitation and co-localization in co-transfected cells. The presence of helicase blocked OSBP preferential translocation to the Golgi apparatus. These results demonstrate that OSBP contributes to HEV replication and enrich our understanding of the HEV-cell interactions.
Asunto(s)
Aparato de Golgi , Virus de la Hepatitis E , Receptores de Esteroides , Replicación Viral , Virus de la Hepatitis E/fisiología , Virus de la Hepatitis E/genética , Receptores de Esteroides/metabolismo , Receptores de Esteroides/genética , Humanos , Aparato de Golgi/metabolismo , Aparato de Golgi/virología , Interacciones Huésped-Patógeno , Línea Celular , Unión Proteica , Hepatitis E/virología , Hepatitis E/metabolismoRESUMEN
The intestines of mice are colonized by diverse, as-yet-uncultivated bacteria. In this report, we describe the isolation, culture, genotypic and phenotypic characterization, as well as taxonomic classification of three novel anaerobic bacterial strains derived from the caecal contents of C57BL/6J male mice. According to the phenotypic and genotype-based polyphasic taxonomy, we propose three novel species within the family Oscillospiraceae. They are Acutalibacter caecimuris sp. nov. (type strain M00118T=CGMCC 1.18042T=KCTC 25739T), Acutalibacter intestini sp. nov. (type strain M00204T=CGMCC 1.18044T=KCTC 25741T) and Neglectibacter caecimuris sp. nov. (type strain M00184T=CGMCC 1.18043T=KCTC 25740T).
Asunto(s)
Técnicas de Tipificación Bacteriana , Ciego , ADN Bacteriano , Ratones Endogámicos C57BL , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Animales , Masculino , Ciego/microbiología , Ratones , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Ácidos Grasos/química , Composición de BaseRESUMEN
BACKGROUND: Missing data is frequently an inevitable issue in cohort studies and it can adversely affect the study's findings. We assess the effectiveness of eight frequently utilized statistical and machine learning (ML) imputation methods for dealing with missing data in predictive modelling of cohort study datasets. This evaluation is based on real data and predictive models for cardiovascular disease (CVD) risk. METHODS: The data is from a real-world cohort study in Xinjiang, China. It includes personal information, physical examination data, questionnaires, and laboratory biochemical results from 10,164 subjects with a total of 37 variables. Simple imputation (Simple), regression imputation (Regression), expectation-maximization(EM), multiple imputation (MICE) , K nearest neighbor classification (KNN), clustering imputation (Cluster), random forest (RF), and decision tree (Cart) were the chosen imputation methods. Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) are utilised to assess the performance of different methods for missing data imputation at a missing rate of 20%. The datasets processed with different missing data imputation methods were employed to construct a CVD risk prediction model utilizing the support vector machine (SVM). The predictive performance was then compared using the area under the curve (AUC). RESULTS: The most effective imputation results were attained by KNN (MAE: 0.2032, RMSE: 0.7438, AUC: 0.730, CI: 0.719-0.741) and RF (MAE: 0.3944, RMSE: 1.4866, AUC: 0.777, CI: 0.769-0.785). The subsequent best performances were achieved by EM, Cart, and MICE, while Simple, Regression, and Cluster attained the worst performances. The CVD risk prediction model was constructed using the complete data (AUC:0.804, CI:0.796-0.812) in comparison with all other models with p<0.05. CONCLUSION: KNN and RF exhibit superior performance and are more adept at imputing missing data in predictive modelling of cohort study datasets.