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We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or â¼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.
Assuntos
Genoma , Primatas , Animais , Humanos , Sequência de Bases , Primatas/classificação , Primatas/genética , Evolução Biológica , Análise de Sequência de DNA , Variação Estrutural do GenomaRESUMO
The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.
Assuntos
Fatores de Restrição Antivirais , Encéfalo , Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Neurônios , Internalização do Vírus , Replicação Viral , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Restrição Antivirais/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Morte Celular , Sistemas CRISPR-Cas/genética , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Neurônios/virologia , Neurônios/metabolismo , Carga Viral , Nectinas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Interferon Tipo I , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/prevenção & controle , Doenças Neuroinflamatórias/virologiaRESUMO
Inner ear hair cells are characterized by the F-actin-based stereocilia that are arranged into a staircase-like pattern on the apical surface of each hair cell. The tips of shorter-row stereocilia are connected with the shafts of their neighboring taller-row stereocilia through extracellular links named tip links, which gate mechano-electrical transduction (MET) channels in hair cells. Cadherin 23 (CDH23) forms the upper part of tip links, and its cytoplasmic tail is inserted into the so-called upper tip-link density (UTLD) that contains other proteins such as harmonin. The Cdh23 gene is composed of 69 exons, and we show here that exon 68 is subjected to hair cell-specific alternative splicing. Tip-link formation is not affected in genetically modified mutant mice lacking Cdh23 exon 68. Instead, the stability of tip links is compromised in the mutants, which also suffer from progressive and noise-induced hearing loss. Moreover, we show that the cytoplasmic tail of CDH23(+68) but not CDH23(-68) cooperates with harmonin in phase separation-mediated condensate formation. In conclusion, our work provides evidence that inclusion of Cdh23 exon 68 is critical for the stability of tip links through regulating condensate formation of UTLD components.
Assuntos
Surdez , Perda Auditiva , Camundongos , Animais , Perda Auditiva/genética , Perda Auditiva/metabolismo , Células Ciliadas Auditivas/fisiologia , Surdez/genética , Células Ciliadas Auditivas Internas/metabolismo , Caderinas/metabolismo , Éxons/genéticaRESUMO
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
Assuntos
Doenças Cardiovasculares , Sulfeto de Hidrogênio , Sulfeto de Hidrogênio/metabolismo , Humanos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Gasotransmissores/metabolismoRESUMO
The interplay between microRNAs (miRNAs) and phytohormones allows plants to integrate multiple internal and external signals to optimize their survival of different environmental conditions. Here, we report that miR394 and its target gene LEAF CURLING RESPONSIVENESS (LCR), which are transcriptionally responsive to BR, participate in BR signaling to regulate hypocotyl elongation in Arabidopsis thaliana. Phenotypic analysis of various transgenic and mutant lines revealed that miR394 negatively regulates BR signaling during hypocotyl elongation, whereas LCR positively regulates this process. Genetically, miR394 functions upstream of BRASSINOSTEROID INSENSITIVE2 (BIN2), BRASSINAZOLEs RESISTANT1 (BZR1), and BRI1-EMS-SUPPRESSOR1 (BES1), but interacts with BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1 SUPRESSOR PROTEIN (BSU1). RNA-sequencing analysis suggested that miR394 inhibits BR signaling through BIN2, as miR394 regulates a significant number of genes in common with BIN2. Additionally, miR394 increases the accumulation of BIN2 but decreases the accumulation of BZR1 and BES1, which are phosphorylated by BIN2. MiR394 also represses the transcription of PACLOBUTRAZOL RESISTANCE1/5/6 and EXPANSIN8, key genes that regulate hypocotyl elongation and are targets of BZR1/BES1. These findings reveal a new role for a miRNA in BR signaling in Arabidopsis.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Brassinosteroides , Regulação da Expressão Gênica de Plantas , Hipocótilo , MicroRNAs , Transdução de Sinais , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Brassinosteroides/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Hipocótilo/crescimento & desenvolvimento , Hipocótilo/genética , Hipocótilo/metabolismo , Plantas Geneticamente Modificadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Reguladores de Crescimento de Plantas/metabolismo , Proteínas QuinasesRESUMO
Single-cell ATAC-seq sequencing data (scATAC-seq) has been widely used to investigate chromatin accessibility on the single-cell level. One important application of scATAC-seq data analysis is differential chromatin accessibility (DA) analysis. However, the data characteristics of scATAC-seq such as excessive zeros and large variability of chromatin accessibility across cells impose a unique challenge for DA analysis. Existing statistical methods focus on detecting the mean difference of the chromatin accessible regions while overlooking the distribution difference. Motivated by real data exploration that distribution difference exists among cell types, we introduce a novel composite statistical test named "scaDA", which is based on zero-inflated negative binomial model (ZINB), for performing differential distribution analysis of chromatin accessibility by jointly testing the abundance, prevalence and dispersion simultaneously. Benefiting from both dispersion shrinkage and iterative refinement of mean and prevalence parameter estimates, scaDA demonstrates its superiority to both ZINB-based likelihood ratio tests and published methods by achieving the highest power and best FDR control in a comprehensive simulation study. In addition to demonstrating the highest power in three real sc-multiome data analyses, scaDA successfully identifies differentially accessible regions in microglia from sc-multiome data for an Alzheimer's disease (AD) study that are most enriched in GO terms related to neurogenesis and the clinical phenotype of AD, and AD-associated GWAS SNPs.
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Cromatina , Análise de Célula Única , Cromatina/genética , Cromatina/metabolismo , Cromatina/química , Análise de Célula Única/métodos , Análise de Célula Única/estatística & dados numéricos , Humanos , Biologia Computacional/métodos , Doença de Alzheimer/genética , Modelos Estatísticos , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Simulação por Computador , Animais , Análise de Sequência de DNA/métodos , AlgoritmosRESUMO
Rubus, the largest genus in Rosaceae, contains over 1400 species that distributed in multiple habitats across the world, with high species diversity in the temperate regions of Northern Hemisphere. Multiple Rubus species are cultivated for their valuable fruits. However, the intrageneric classification and phylogenetic relationships are still poorly understood. In this study, we sequenced, assembled, and characterized 17 plastomes of Rubus, and conducted comparative genomics integrating with 47 previously issued plastomes of this genus. The 64 plastomes of Rubus exhibited typical quadripartite structure with sizes ranging from 155,144 to 156,700 bp, and contained 132 genes including 87 protein-coding genes, 37 tRNA genes and eight rRNA genes. All plastomes are conservative in the gene order, the frequency of different types of long repeats and simple sequence repeats (SSRs), the codon usage, and the selection pressure of protein-coding genes. However, there are also some differences in the Rubus plastomes, including slight contraction and expansion of the IRs, a variation in the numbers of SSRs and long repeats, and some genes in certain clades undergoing intensified or relaxed purifying selection. Phylogenetic analysis based on whole plastomes showed that the monophyly of Rubus was strongly supported and resolved it into six clades corresponding to six subgenera. Moreover, we identified 12 highly variable regions that could be potential molecular markers for phylogenetic, population genetic, and barcoding studies. Overall, our study provided insight into plastomic structure and sequence diversification of Rubus, which could be beneficial for future studies on identification, evolution, and phylogeny in this genus.
Assuntos
Genômica , Filogenia , Rubus , Rubus/genética , Genoma de Cloroplastos , Cloroplastos/genética , Repetições de Microssatélites , Evolução Molecular , RNA de Transferência/genética , Uso do CódonRESUMO
An interesting question is whether chalcogen atoms can emulate the role of carbon or boron elements stabilized between two transition metal layers, as observed in MXenes or MBenes. Here, we predict a new family of two-dimensional ternary compounds M4XY2 (where M = Pd, Y, Zr, etc.; X = S, Se, Te; and Y = Cl, Br, I), named M-chalcogene. Through first-principles calculations, we reveal diverse physical properties in these compounds, including superconducting, topological, and magnetic characteristics, where the bilayer transition metals play crucial roles. Moreover, the expected helical edge states and superconducting transition temperatures in Pd4SCl2 can be finely tuned by strains. Additionally, the Ti4SCl2 is predicted to be a topological insulator and shows promise as a gas sensor candidate for certain exotic gases. Our findings expand two-dimensional material families and provide promising platforms for diverse physical phenomena with efficient tunability by external stimuli for various applications.
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Cancer-cell-specific fluorescent photosensitizers (PSs) are highly desired molecular tools for cancer ablation with minimal damage to normal cells. However, such PSs that can achieve cancer specification and ablation and a self-reporting manner concurrently are rarely reported and still an extremely challenging task. Herein, we have proposed a feasible strategy and conceived a series of fluorescent PSs based on simple chemical structures for identifying and killing cancer cells as well as monitoring the photodynamic therapy (PDT) process by visualizing the change of subcellular localization. All of the constructed cationic molecules could stain mitochondria in cancer cells, identify cancer cells specifically, and monitor cancer cell viability. Among these, IVP-Br has the strongest ability to produce ROS, which serves as a potent PS for specific recognition and killing of cancer cells. IVP-Br could translocate from mitochondria to the nucleolus during PDT, self-reporting the entire therapeutic process. Mechanism study confirms that IVP-Br with light irradiation causes cancer cell ablation via inducing cell cycle arrest, cell apoptosis, and autophagy. The efficient ablation of tumor through PDT induced by IVP-Br has been confirmed in the 3D tumor spheroid chip. Particularly, IVP-Br could discriminate cancer cells from white blood cells (WBCs), exhibiting great potential to identify circulating tumor cells (CTCs).
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Apoptose , Mitocôndrias/metabolismo , Corantes/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although the regulatory mechanisms of dark and light-induced plant morphogenesis have been broadly investigated, the biological process in peanuts has not been systematically explored on single-cell resolution. Herein, 10 cell clusters were characterized using scRNA-seq-identified marker genes, based on 13 409 and 11 296 single cells from 1-week-old peanut seedling leaves grown under dark and light conditions. 6104 genes and 50 transcription factors (TFs) displayed significant expression patterns in distinct cell clusters, which provided gene resources for profiling dark/light-induced candidate genes. Further pseudo-time trajectory and cell cycle evidence supported that dark repressed the cell division and perturbed normal cell cycle, especially the PORA abundances correlated with 11 TFs highly enriched in mesophyll to restrict the chlorophyllide synthesis. Additionally, light repressed the epidermis cell developmental trajectory extending by inhibiting the growth hormone pathway, and 21 TFs probably contributed to the different genes transcriptional dynamic. Eventually, peanut AHL17 was identified from the profile of differentially expressed TFs, which encoded protein located in the nucleus promoted leaf epidermal cell enlargement when ectopically overexpressed in Arabidopsis through the regulatory phytohormone pathway. Overall, our study presents the different gene atlases in peanut etiolated and green seedlings, providing novel biological insights to elucidate light-induced leaf cell development at the single-cell level.
Assuntos
Arachis , Regulação da Expressão Gênica de Plantas , Luz , Folhas de Planta , Plântula , Arachis/genética , Arachis/metabolismo , Arachis/crescimento & desenvolvimento , Arachis/efeitos da radiação , Folhas de Planta/genética , Folhas de Planta/efeitos da radiação , Folhas de Planta/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Plântula/genética , Plântula/efeitos da radiação , Plântula/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Escuridão , Perfilação da Expressão Gênica , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Análise da Expressão Gênica de Célula ÚnicaRESUMO
BACKGROUND: Primary lung mucinous adenocarcinomas (LMAs) could be subclassified as the pure-solid, part-solid, and pneumonic types according to the findings of high-resolution computed tomography. This study aimed to expound on the clinicopathologic, radiologic, and prognostic characteristics of LMAs based on radiologic classification within a large set of patients. METHODS: From November 2009 to December 2016, this study enrolled 294 resected LMAs, which were divided into the pure-solid (n = 169), part-solid (n = 87), and pneumonic (n = 38) types. The clinicopathologic and radiologic characteristics of the tumors were evaluated, and patient prognosis was determined through follow-up evaluation. Survival outcomes were calculated by Kaplan-Meier curves and compared using log-rank tests. The prognostic impact of clinicopathologic variables, including radiologic presentations, were evaluated by establishing a Cox proportional hazards model. RESULTS: The LMAs were infrequently associated with lymph node metastasis (5.4 %), lymphatic/vascular invasion (4.4 %), or visceral pleural invasion (5.1 %). During the median 71-month follow-up period, recurrence was observed in 62 patients and death in 44 patients. The patients with pneumonic-type LMAs had a poorer prognosis (5-year recurrence-free survival [RFS], 23.7 %; 5-year overall survival [OS], 44.7 %) than those with the pure-solid type (RFS, 83.2 %; OS, 100 %) or part-solid type (RFS, 93.7 %; OS, 100 %). Besides, lymph node metastasis, emphysema, and clinical T stage were independent predictors of RFS and OS. CONCLUSION: Solitary-type LMA patients had excellent prognoses, whereas the survival outcomes for pneumonic-type LMA patients were dismal. Furthermore, pneumonic-type LMA patients were prone to intrapulmonary metastasis by means of aerogenous dissemination rather than distant metastasis.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma Mucinoso , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Adenocarcinoma de Pulmão/patologia , Pulmão/patologia , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/cirurgia , Adenocarcinoma Mucinoso/patologia , Prognóstico , Estudos Retrospectivos , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.
Assuntos
Caveolina 1 , Dieta Hiperlipídica , Células Endoteliais , Endotélio Vascular , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III , Vasodilatação , Animais , Masculino , Camundongos , Aorta/enzimologia , Aorta/fisiopatologia , Aorta/metabolismo , Aorta/efeitos dos fármacos , Aorta/patologia , Caveolina 1/metabolismo , Caveolina 1/deficiência , Caveolina 1/genética , Células Cultivadas , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/enzimologia , Endotélio Vascular/efeitos dos fármacos , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/enzimologia , Obesidade/fisiopatologia , Obesidade/metabolismo , Transdução de Sinais , Esterol Esterase/metabolismo , Esterol Esterase/genética , Ubiquitinação , Vasodilatação/efeitos dos fármacosRESUMO
Myocardial ischemia-reperfusion injury (MIRI) poses a significant threat to patients with coronary heart disease. Adenosine A2A receptors have been known as a protective role in MIRI by regulating autophagy, so we assumed that activation of adenosine A2B receptor (A2BAR) might exert a similar effect during MIRI and underlying mechanism be related to proteostasis maintenance as well. In situ hearts were subjected to 30 min of ischemia and 120 min of reperfusion (IR), while invitro cardiomyocytes from neonatal rats experienced 6 h of oxygen-glucose deprivation followed by 12 h of reoxygenation (OGDR). Initially, we observed that post-ischemia-reperfusion induced autophagy flux blockade and ERS both in vivo and in vitro, evident through the increased expression of p62, LC3II, and BIP, which indicated the deteriorated proteostasis. We used a selective A2BAR agonist, Bay 60-6583, to explore the positive effects of A2BAR on cardiomyocytes and found that A2BAR activation rescued damaged cardiac function and morphological changes in the IR group and improved frail cell viability in the OGDR group. The A2BAR agonist also alleviated the blockage of autophagic flux, coupled with augmented ERS in the IR/OGDR group, which was reassured by using an autophagy inhibitor chloroquine (CQ) and ERS inhibitor (4-PBA) in vitro. Additionally, considering cAMP/PKA as a well-known downstream effector of A2BAR, we utilized H89, a selective PKA inhibitor. We observed that the positive efficacy of Bay 60-6583 was inhibited by H89. Collectively, our findings demonstrate that the A2BAR/cAMP/PKA signaling pathway exerts a protective role in MIRI by mitigating impaired autophagic flux and excessive ERS.
Assuntos
Aminopiridinas , Isoquinolinas , Traumatismo por Reperfusão Miocárdica , Sulfonamidas , Humanos , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Receptor A2B de Adenosina/metabolismo , Miócitos Cardíacos/metabolismo , Autofagia , Isquemia/metabolismo , Estresse do Retículo Endoplasmático , ApoptoseRESUMO
BACKGROUND: Extensive research has explored altered structural and functional networks in major depressive disorder (MDD). However, studies examining the relationships between structure and function yielded heterogeneous and inconclusive results. Recent work has suggested that the structure-function relationship is not uniform throughout the brain but varies across different levels of functional hierarchy. This study aims to investigate changes in structure-function couplings (SFC) and their relevance to antidepressant response in MDD from a functional hierarchical perspective. METHODS: We compared regional SFC between individuals with MDD (n = 258) and healthy controls (HC, n = 99) using resting-state functional magnetic resonance imaging and diffusion tensor imaging. We also compared antidepressant non-responders (n = 55) and responders (n = 68, defined by a reduction in depressive severity of >50%). To evaluate variations in altered and response-associated SFC across the functional hierarchy, we ranked significantly different regions by their principal gradient values and assessed patterns of increase or decrease along the gradient axis. The principal gradient value, calculated from 219 healthy individuals in the Human Connectome Project, represents a region's position along the principal gradient axis. RESULTS: Compared to HC, MDD patients exhibited increased SFC in unimodal regions (lower principal gradient) and decreased SFC in transmodal regions (higher principal gradient) (p < 0.001). Responders primarily had higher SFC in unimodal regions and lower SFC in attentional networks (median principal gradient) (p < 0.001). CONCLUSIONS: Our findings reveal opposing SFC alterations in low-level unimodal and high-level transmodal networks, underscoring spatial variability in MDD pathology. Moreover, hierarchy-specific antidepressant effects provide valuable insights into predicting treatment outcomes.
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Vascular stiffness increases with aging, obesity and hypertension and predicts cardiovascular risk. The levels of histone H3-lysine-27 methylation (H3K27me) and the histone methyltransferase EZH2 both decrease in aging vessels, driving vascular stiffness. The impact of EZH2 inhibitors on vascular stiffness is unknown. We tested the hypothesis that the EZH2 inhibitor GSK126, currently in development for cancer treatment, increases vascular stiffness and explored underlying molecular mechanisms. Young (3 month) and middle-aged (12 month) male mice were treated with GSK126 for 1-2 months and primary human aortic smooth muscle cells (HASMCs) from young male and female donors were treated with GSK126 for 24-48 h. Stiffness was measured in vivo by pulse wave velocity and in vitro by atomic force microscopy (AFM) and vascular structure was quantified histologically. Extracellular matrix proteins were studied by qRT-PCR, immunoblotting, zymography and chromatin immunoprecipitation. GSK126 treatment decreased H3K27 methylation (H3K27me) and increased acetylation (H3K27ac) in mouse vessels and in HASMCs. In GSK126-treated mice, aortic stiffness increased without changes in vascular fibrosis. EZH2 inhibition enhanced elastin fiber degradation and matrix metalloprotease-2 (MMP2) expression. In HASMCs, GSK126 treatment increased synthetic phenotype markers and intrinsic HASMCs stiffness by AFM with altered cytoskeletal structure and increased nuclear actin staining. GSK126 also increased MMP2 protein expression, activity and enrichment of H3K27ac at the MMP2 promoter in HASMCs. GSK126 causes vascular stiffening, inducing MMP2 activity, elastin degradation, and modulation of SMC phenotype and cytoskeletal stiffness. These findings suggest that EZH2 inhibitors used to treat cancer could negatively impact the vasculature by enhancing stiffness and merits examination in human trials.
Assuntos
Rigidez Vascular , Animais , Feminino , Masculino , Camundongos , Elastina , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Inibidores Enzimáticos/farmacologia , Histona Metiltransferases , Metaloproteinase 2 da Matriz , Análise de Onda de PulsoRESUMO
BACKGROUND: The pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) remained unclear. We aimed to profile the metabolic alterations in urine of SFTS patients and provide new evidence for its pathogenesis. METHODS: A case-control study was conducted in the 154th hospital in China. Totally 88 cases and 22 controls aged ≥ 18 years were enrolled. The cases were selected from laboratory-confirmed SFTS patients. The controls were selected among SFTSV-negative population. Those with diabetes, cancer, hepatitis and other sexually transmitted diseases were excluded in both groups. Fatal cases and survival cases were 1:1 matched. Inter-group differential metabolites and pathways were obtained, and the inter-group discrimination ability was evaluated. RESULTS: Tryptophan metabolism and phenylalanine metabolism were the top one important metabolism pathway in differentiating the control and case groups, and the survival and fatal groups, respectively. The significant increase of differential metabolites in tryptophan metabolism, including 5-hydroxyindoleacetate (5-HIAA), L-kynurenine (KYN), 5-hydroxy-L-tryptophan (5-HTP), 3-hydroxyanthranilic acid (3-HAA), and the increase of phenylpyruvic acid and decrease of hippuric acid in phenylalanine metabolism indicated the potential metabolic alterations in SFTSV infection. The increase of 5-HIAA, KYN, 5-HTP, phenylpyruvic acid and hippuric acid were involved in the fatal progress of SFTS patients. CONCLUSIONS: Tryptophan metabolism and phenylalanine metabolism might be involved in the pathogenesis of SFTSV infection. These findings provided new evidence for the pathogenesis and treatment of SFTS.
Assuntos
Febre Grave com Síndrome de Trombocitopenia , Humanos , 5-Hidroxitriptofano , Estudos de Casos e Controles , Ácido Hidroxi-Indolacético , Triptofano , FenilalaninaRESUMO
In this investigation, polystyrene (PS) nanofibers were prepared by electrospinning for the adsorption of naphthalene (Nap), phenanthrene (Phe), and pyrene (Pyr) from an aqueous solution. Surface morphology and physicochemical characteristics of PS nanofibers were analyzed using Fourier transform infrared spectroscopy (FT-IR) and point-of-zero-charge calorimetry (pHpzc). The effects of pH, ion concentration, and temperature on the adsorption were also investigated. The adsorption mechanism of target pollutants on PS nanofibers was investigated by a batch adsorption method. The adsorption kinetic studies showed that the adsorption of the three polycyclic aromatic hydrocarbons (PAHs) on PS nanofibers conformed to the pseudo-second-order kinetic model in both single and ternary systems. Meanwhile, in a single system, the three PAHs adsorbed on nanofibers were controlled by both intraparticle diffusion and liquid film diffusion, whereas the adsorption of Nap in a ternary system was controlled mainly by intraparticle diffusion, and the adsorption of Phe and Pyr was controlled mainly by liquid film diffusion. The isotherm data indicated that the Freundlich model performed better than the Langmuir model for the adsorptions of Nap, Phe, and Pyr on PS nanofibers in both the single system and the ternary system. Due to competitive adsorption, the adsorption capacities of Nap and Pyr on PS nanofibers decreased from 105.816 and 19.098 mg g-1 in the single system to 23.626 and 12.126 mg g-1 in the ternary system, but the adsorption of Phe was not affected. π-π interactions and pore filling may be jointly involved in the adsorption of PAHs on PS nanofibers.
RESUMO
PURPOSE: This study aimed to develop and validate an ultrasound (US)-based nomogram for the preoperative differentiation of renal urothelial carcinoma (rUC) from central renal cell carcinoma (c-RCC). METHODS: Clinical data and US images of 655 patients with 655 histologically confirmed malignant renal tumors (521 c-RCCs and 134 rUCs) were collected and divided into training (n = 455) and validation (n = 200) cohorts according to examination dates. Conventional US and contrast-enhanced US (CEUS) tumor features were analyzed to determine those that could discriminate rUC from c-RCC. Least absolute shrinkage and selection operator regression was applied to screen clinical and US features for the differentiation of rUC from c-RCC. Using multivariate logistic regression analysis, a diagnostic model of rUC was constructed and visualized as a nomogram. The diagnostic model's performance was assessed in the training and validation cohorts by calculating the area under the receiver operating characteristic curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness of the US-based nomogram. RESULTS: Seven features of both clinical features and ultrasound imaging were selected to build the diagnostic model. The nomogram achieved favorable discrimination in the training (AUC = 0.996, 95% CI: 0.993-0.999) and validation (AUC = 0.995, 95% CI: 0.974, 1.000) cohorts, and good calibration (Brier scores: 0.019 and 0.016, respectively). DCA demonstrated the clinical usefulness of the US-based nomogram. CONCLUSION: A noninvasive clinical and US-based nomogram combining conventional US and CEUS features possesses good predictive value for differentiating rUC from c-RCC.
Assuntos
Carcinoma de Células Renais , Carcinoma de Células de Transição , Neoplasias Renais , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Carcinoma de Células de Transição/diagnóstico por imagem , Nomogramas , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , UltrassonografiaRESUMO
Various 2,2-difunctionalized 2H-azirines were synthesized via I2-mediated annulation reactions of readily accessible enamines in the presence of nitrogen or non-nitrogen nucleophiles. The features of the present synthesis process also include no use of transition metals, simple operation, mild reaction conditions, a broad substrate scope, and gram-scale synthesis.
RESUMO
BACKGROUND: Pancreaticoduodenectomy (PD) is a complex procedure and easily accompanied by healthcare-associated infections (HAIs). This study aimed to assess the impact of PBD on postoperative infections and clinical outcomes in PD patients. METHODS: The retrospective cohort study were conducted in a tertiary hospital from January 2013 to December 2022. Clinical and epidemiological data were collected from HAIs surveillance system and analyzed. RESULTS: Among 2842 patients who underwent PD, 247 (8.7%) were diagnosed with HAIs, with surgical site infection being the most frequent type (n = 177, 71.7%). A total of 369 pathogenic strains were detected, with Klebsiella pneumoniae having the highest proportion, followed by Enterococcu and Escherichia coli. Although no significant association were observed generally between PBD and postoperative HAIs, subgroup analysis revealed that PBD was associated with postoperative HAIs in patients undergoing robotic PD (aRR = 2.174; 95% CI:1.011-4.674; P = 0.047). Prolonging the interval between PBD and PD could reduce postoperative HAIs in patients with cholangiocarcinoma (≥4 week: aRR = 0.292, 95% CI 0.100-0.853; P = 0.024) and robotic PD (≤2 week: aRR = 3.058, 95% CI 1.178-7.940; P = 0.022). PBD was also found to increase transfer of patients to ICU (aRR = 1.351; 95% CI 1.119-1.632; P = 0.002), extended length of stay (P < 0.001) and postoperative length of stay (P = 0.004). CONCLUSION: PBD does not exhibit a significant association with postoperative HAIs or other outcomes. However, the implementation of robotic PD, along with a suitable extension of the interval between PBD and PD, appear to confer advantages concerning patients' physiological recuperation. These observations suggest potential strategies that may contribute to enhanced patient outcomes.