RESUMEN
Cellulose, the main component of the plant cell wall, is synthesized by the multimeric cellulose synthase (CESA) complex (CSC). In plant cells, CSCs are assembled in the endoplasmic reticulum or Golgi and transported through the endomembrane system to the plasma membrane (PM). However, how CESA catalytic activity or conserved motifs around the catalytic core influence vesicle trafficking or protein dynamics is not well understood. Here, we used yellow fluorescent protein (YFP)-tagged AtCESA6 and created 18 mutants in key motifs of the catalytic domain to analyze how they affected seedling growth, cellulose biosynthesis, complex formation, and CSC dynamics and trafficking in Arabidopsis thaliana. Seedling growth and cellulose content were reduced by nearly all mutations. Moreover, mutations in most conserved motifs slowed CSC movement in the PM as well as delivery of CSCs to the PM. Interestingly, mutations in the DDG and QXXRW motifs affected YFP-CESA6 abundance in the Golgi. These mutations also perturbed post-Golgi trafficking of CSCs. The 18 mutations were divided into 2 groups based on their phenotypes; we propose that Group I mutations cause CSC trafficking defects, whereas Group II mutations, especially in the QXXRW motif, affect protein folding and/or CSC rosette formation. Collectively, our results demonstrate that the CESA6 catalytic domain is essential for cellulose biosynthesis as well as CSC formation, protein folding and dynamics, and vesicle trafficking.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Dominio Catalítico , Mutación Puntual , Arabidopsis/genética , Arabidopsis/metabolismo , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Pared Celular/metabolismo , Plantones/metabolismo , Celulosa/metabolismoRESUMEN
Organ initiation from the shoot apical meristem first gives rise to leaves during vegetative development and then flowers during reproductive development. LEAFY (LFY) is activated after floral induction and together with other factors promotes the floral program. LFY functions redundantly with APETALA1 (AP1) to activate the class B genes APETALA3 (AP3) and PISTILLATA (PI), the class C gene AGAMOUS (AG), and the class E gene SEPALLATA3, which leads to the specification of stamens and carpels, the reproductive organs of flowers. Molecular and genetic networks that control the activation of AP3, PI, and AG in flowers have been well studied; however, much less is known about how these genes are repressed in leaves and how their repression is lifted in flowers. Here, we showed that two genes encoding Arabidopsis C2H2 ZINC FINGER PROTEIN (ZFP) transcription factors, ZP1 and ZFP8, act redundantly to directly repress AP3, PI, and AG in leaves. After LFY and AP1 are activated in floral meristems, they down-regulate ZP1 and ZFP8 directly to lift the repression on AP3, PI, and AG. Our results reveal a mechanism for how floral homeotic genes are repressed and derepressed before and after floral induction.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Dominio MADS , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Flores , Regulación de la Expresión Génica de las Plantas , Genes Homeobox , Proteínas de Homeodominio/metabolismo , Proteínas de Dominio MADS/genética , Proteínas de Dominio MADS/metabolismo , Hojas de la Planta/metabolismo , Dedos de ZincRESUMEN
BACKGROUND: Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear. METHODS: Here, we conducted single-cell transcriptome analyses of 212â 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls. RESULTS: KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4+ T, CD8+ T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B (tumor necrosis factor superfamily member 13b), CXCL16 (C-X-C motif chemokine ligand 16), TNFSF10 (tumor necrosis factor superfamily member 10), and IL1RN (interleukin 1 receptor antagonist), mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD. CONCLUSIONS: Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.
Asunto(s)
Enfermedad de la Arteria Coronaria , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Lactante , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/genética , Leucocitos Mononucleares , Vasos Coronarios/patología , Estudios Transversales , Transcriptoma , Factor de Necrosis Tumoral alfa , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/complicacionesRESUMEN
Two-dimensional (2D) heterostructures with ferromagnetism and ferroelectricity provide a promising avenue to miniaturize the device size, increase computational power, and reduce energy consumption. However, the direct synthesis of such eye-catching heterostructures has yet to be realized up to now. Here, we design a two-step chemical vapor deposition strategy to growth of Cr2S3/WS2 vertical heterostructures with atomically sharp and clean interfaces on sapphire. The interlayer charge transfer and periodic moiré superlattice result in the emergence of room-temperature ferroelectricity in atomically thin Cr2S3/WS2 vertical heterostructures. In parallel, long-range ferromagnetic order is discovered in 2D Cr2S3 via the magneto-optical Kerr effect technique with the Curie temperature approaching 170 K. The charge distribution variation induced by the moiré superlattice changes the ferromagnetic coupling strength and enhances the Curie temperature. The coexistence of ferroelectricity and ferromagnetism in 2D Cr2S3/WS2 vertical heterostructures provides a cornerstone for the further design of logic-in-memory devices to build new computing architectures.
RESUMEN
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Asunto(s)
Huesos/metabolismo , Proteína Coat de Complejo I/genética , Proteína Coatómero/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Osteoporosis/genética , Animales , Ácido Ascórbico/farmacología , Huesos/efectos de los fármacos , Huesos/patología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Proteína Coat de Complejo I/deficiencia , Proteína Coatómero/química , Proteína Coatómero/deficiencia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Embrión no Mamífero , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación del Desarrollo de la Expresión Génica , Aparato de Golgi , Haploinsuficiencia , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Osteoporosis/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Índice de Severidad de la Enfermedad , Pez CebraRESUMEN
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) typically present with a complex anatomical distribution, often accompanied by insidious symptoms. This combination contributes to its high incidence and poor prognosis. It is now understood that the immune features of cellular components within the tumor ecosystem and their complex interactions are critical factors influencing both tumor progression and the effective immune response. METHODS: We obtained single-cell RNA sequencing data of 26,496 cells from three tumor tissues and five normal tissues and performed subsequent analyses. Immunohistochemical staining on tumor sections was used to validate the presence of malignant cells. Additionally, we included bulk RNA sequencing data from 502 HNSCC patients. Kaplan-Meier analysis and the log-rank test were employed to assess predictors of patient outcomes. RESULTS: We identified three epithelial subclusters exhibiting immune-related features. These subclusters promoted the infiltration of T cells, dendritic cells, and monocytes into the tumor microenvironment. Additionally, cancer-associated fibroblasts displayed tumor-promoting and angiogenesis characteristics, contrasting with the predominant antigen-presenting and inflammatory roles observed in fibroblasts from normal tissues. Furthermore, tumor endothelial subsets exhibited a double-sided effect, promoting tumor progression and enhancing the effectiveness of immune response. Finally, follicular helper T cells and T helper 17 cells were found to be significantly correlated with improved outcomes in HNSCC patients. These CD4+ T cell subpopulations could promote the anti-tumor immune response by recruiting and activating B and T cells. CONCLUSION: Our findings provide deeper insights into the immune features of the tumor ecosystem and reveal the prognostic significance of follicular helper T cells and T helper 17 cells. These findings may pave the way for the development of therapeutic approaches.
Asunto(s)
Neoplasias de Cabeza y Cuello , Linfocitos Infiltrantes de Tumor , Análisis de Expresión Génica de una Sola Célula , Carcinoma de Células Escamosas de Cabeza y Cuello , Células Th17 , Microambiente Tumoral , Femenino , Humanos , Masculino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Linfocitos Infiltrantes de Tumor/inmunología , Pronóstico , RNA-Seq/métodos , Análisis de Expresión Génica de una Sola Célula/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células T Auxiliares Foliculares/inmunología , Células Th17/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Photocatalytic lignocellulose reforming for H2 production presents a compelling solution to solve environmental and energy issues. However, achieving scalable conversion under benign conditions faces consistent challenges including insufficient active sites for H2 evolution reaction (HER) and inefficient lignocellulose oxidation directly by photogenerated holes. Herein, it is found that Pt single atom-loaded CdS nanosheet (PtSA-CdS) would be an active photocatalyst for lignocellulose-to-H2 conversion. Theoretical and experimental analyses confirm that the valence band of CdS shifts downward after depositing isolated Pt atoms, and the slope of valence band potential on pH for PtSA-CdS is more positive than Nernstian equation. These characteristics allow PtSA-CdS to generate large amounts of â¢OH radicals even at pH 14, while the capacity is lacking with CdS alone. The employment of â¢OH/OH- redox shuttle succeeds in relaying photoexcited holes from the surface of photocatalyst, and the â¢OH radicals can diffuse away to decompose lignocellulose efficiently. Simultaneously, surface Pt atoms, featured with a thermoneutral Δ G H ∗ $\Delta G_{\mathrm{H}}^{\mathrm{*}}$ , would collect electrons to expedite HER. Consequently, PtSA-CdS performs a H2 evolution rate of 10.14 µmol h-1 in 1 m KOH aqueous solution, showcasing a remarkable 37.1-fold enhancement compared to CdS. This work provides a feasible approach to transform waste biomass into valuable sources.
RESUMEN
BACKGROUND: Olfactory dysfunction occurs frequently in Parkinson's disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines. RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis. CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
Asunto(s)
Trastornos del Olfato , Enfermedad de Parkinson , Humanos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Células HEK293 , Nicotina/farmacología , Enfermedad de Parkinson/complicaciones , Proteínas Proto-Oncogénicas c-akt , Trastornos del Olfato/complicaciones , Trastornos del Olfato/tratamiento farmacológicoRESUMEN
Phaeodactylum tricornutum a prominent source of industrial fucoxanthin production, faces challenges in its application due to its tolerance to high-temperature environments. This study investigates the physiological responses of P. tricornutum to high-temperature stress and its impact on fucoxanthin content, with a specific focus on the role of cis-zeatin. The results reveal that high-temperature stress inhibits P. tricornutum's growth and photosynthetic activity, leading to a decrease in fucoxanthin content. Transcriptome analysis shows that high temperature suppresses the expression of genes related to photosynthesis (e.g., psbO, psbQ, and OEC) and fucoxanthin biosynthesis (e.g., PYS, PDS1, and PSD2), underscoring the negative effects of high temperature on P. tricornutum. Interestingly, genes associated with cis-zeatin biosynthesis and cytokinesis signaling pathways exhibited increased expression under high-temperature conditions, indicating a potential role of cis-zeatin signaling in response to elevated temperatures. Content measurements confirm that high temperature enhances cis-zeatin content. Furthermore, the exogenous addition of cytokinesis mimetics or inhibitors significantly affected P. tricornutum's high-temperature resistance. Overexpression of the cis-zeatin biosynthetic enzyme gene tRNA DMATase enhanced P. tricornutum's resistance to high-temperature stress, while genetic knockout of tRNA DMATase reduced its resistance to high temperatures. Therefore, this research not only uncovers a novel mechanism for high-temperature resistance in P. tricornutum but also offers a possible alga species that can withstand high temperatures for the industrial production of fucoxanthin, offering valuable insights for practical utilization.IMPORTANCEThis study delves into Phaeodactylum tricornutum's response to high-temperature stress, specifically focusing on cis-zeatin. We uncover inhibited growth, reduced fucoxanthin, and significant cis-zeatin-related gene expression under high temperatures, highlighting potential signaling mechanisms. Crucially, genetic engineering and exogenous addition experiments confirm that the change in cis-zeatin levels could influence P. tricornutum's resistance to high-temperature stress. This breakthrough deepens our understanding of microalgae adaptation to high temperatures and offers an innovative angle for industrial fucoxanthin production. This research is a pivotal step toward developing heat-resistant microalgae for industrial use.
Asunto(s)
Diatomeas , Calor , Xantófilas , Xantófilas/metabolismo , Diatomeas/metabolismo , Diatomeas/genética , Diatomeas/crecimiento & desarrollo , FotosíntesisRESUMEN
Chryseobacterium arthrosphaerae strain FS91703 was isolated from Rana nigromaculata in our previous study. To investigate the genomic characteristics, pathogenicity-related genes, antimicrobial resistance, and phylogenetic relationship of this strain, PacBio RS II and Illumina HiSeq 2000 platforms were used for the whole genome sequencing. The genome size of strain FS91703 was 5,435,691 bp and GC content was 37.78%. A total of 4,951 coding genes were predicted; 99 potential virulence factors homologs were identified. Analysis of antibiotic resistance genes revealed that strain FS91703 harbored 10 antibiotic resistance genes in 6 categories and 2 multidrug-resistant efflux pump genes, including adeG and farA. Strain FS91703 was sensitive to ß-lactam combination drugs, cephem, monobactam and carbapenems, intermediately resistant to phenicol, and resistant to penicillin, aminoglycosides, tetracycline, fluoroquinolones, and folate pathway inhibitors. Phylogenetic analysis revealed that strain FS91703 and C. arthrosphaerae CC-VM-7T were on the same branch of the phylogenetic tree based on 16 S rRNA; the ANI value between them was 96.99%; and the DDH values were 80.2, 72.2 and 81.6% by three default calculation formulae. These results suggested that strain FS91703 was a species of C. arthrosphaerae. Pan-genome analysis showed FS91703 had 566 unique genes compared with 13 other C. arthrosphaerae strains, and had a distant phylogenetic relationship with the other C. arthrosphaerae strains of the same branch in phylogenetic tree based on orthologous genes. The results of this study suggest that strain FS91703 is a multidrug-resistant and highly virulent bacterium, that differs from other C. arthrosphaerae strains at the genomic level. The knowledge about the genomic characteristics and antimicrobial resistance of strain FS91703 provides valuable insights into this rare species, as well as guidance for the treatment of the disease caused by FS91703 in Rana nigromaculata.
Asunto(s)
Chryseobacterium , Animales , ADN Bacteriano/genética , Filogenia , Secuenciación Completa del Genoma , Chryseobacterium/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ranidae , Genoma BacterianoRESUMEN
Fucoxanthin, a natural carotenoid that has substantial pharmaceutical value due to its anticancer, antioxidant, antiobesity, and antidiabetic properties, is biosynthesized from glyceraldehyde-3-phosphate (G3P) via a series of enzymatic reactions. However, our understanding of the transcriptional mechanisms involved in fucoxanthin biosynthesis remains limited. Using reverse genetics, the med8 mutant was identified based on its phenotype of reduced fucoxanthin content, and the biological functions of MED8 in fucoxanthin synthesis were characterized using approaches such as gene expression, protein subcellular localization, protein-protein interaction and chromatin immunoprecipitation assay. Gene-editing mutants of MED8 exhibited decreased fucoxanthin content as well as reduced expression levels of six key genes involved in fucoxanthin synthesis, namely DXS, PSY1, ZDS-like, CRTISO5, ZEP1, and ZEP3, when compared to the wild-type (WT) strain. Furthermore, we showed that MED8 interacts with HSF3, and genetic analysis revealed their shared involvement in the genetic pathway governing fucoxanthin synthesis. Additionally, HSF3 was required for MED8 association with the promoters of the six fucoxanthin synthesis genes. In conclusion, MED8 and HSF3 are involved in fucoxanthin synthesis by modulating the expression of the fucoxanthin synthesis genes. Our results increase the understanding of the molecular regulation mechanisms underlying fucoxanthin synthesis in the diatom P. tricornutum.
Asunto(s)
Diatomeas , Factores de Transcripción del Choque Térmico/metabolismo , Diatomeas/genética , Diatomeas/metabolismo , Xantófilas/metabolismo , Carotenoides/metabolismoRESUMEN
Pathological retinal angiogenesis is not only the hallmark of retinopathies, but also a major cause of blindness. Guanylate binding protein 2 (GBP2) has been reported to be associated with retinal diseases such as diabetic retinopathy and hypoxic retinopathy. However, GBP2-mediated pathological retinal angiogenesis remains largely unknown. The present study aimed to investigate the role of GBP2 in pathological retinal angiogenesis and its underlying molecular mechanism. In this study, we established oxygen-induced retinopathy (OIR) mice model for in vivo study and hypoxia-induced angiogenesis in ARPE-19 cells for in vitro study. We demonstrated that GBP2 expression was markedly downregulated in the retina of mice with OIR and ARPE-19 cells treated with hypoxia, which was associated with pathological retinal angiogenesis. The regulatory mechanism of GBP2 in ARPE-19 cells was studied by GBP2 silencing and overexpression. The regulatory mechanism of GBP2 in the retina was investigated by overexpressing GBP2 in the retina of OIR mice. Mechanistically, GBP2 downregulated the expression and secretion of vascular endothelial growth factor (VEGFA) in ARPE-19 cells and retina of OIR mice. Interestingly, overexpression of GBP2 significantly inhibited neovascularization in OIR mice, conditioned medium of GBP2 overexpressing ARPE-19 cells inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, we confirmed that GBP2 downregulated VEGFA expression and angiogenesis by inhibiting the AKT/mTOR signaling pathway. Taken together, we concluded that GBP2 inhibited pathological retinal angiogenesis via the AKT/mTOR/VEGFA axis, thereby suggesting that GBP2 may be a therapeutic target for pathological retinal angiogenesis.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Unión al GTP , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt , Neovascularización Retiniana , Vasos Retinianos , Transducción de Señal , Serina-Treonina Quinasas TOR , Factor A de Crecimiento Endotelial Vascular , Animales , Humanos , Ratones , Hipoxia de la Célula , Línea Celular , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/genética , Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Neovascularización Retiniana/genética , Neovascularización Retiniana/prevención & control , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Gastrointestinal cancer, one of the most common cancers, continues to be a major cause of mortality and morbidity globally. Accumulating evidence has shown that alterations in mitochondrial energy metabolism are involved in developing various clinical diseases. NADH dehydrogenase 1 alpha subcomplex 4 (NDUFA4), encoded by the NDUFA4 gene located on human chromosome 7p21.3, is a component of mitochondrial respiratory chain complex IV and integral to mitochondrial energy metabolism. Recent researchers have disclosed that NDUFA4 is implicated in the pathogenesis of various diseases, including gastrointestinal cancer. Aberrant expression of NDUFA4 leads to the alteration in mitochondrial energy metabolism, thereby regulating the growth and metastasis of cancer cells, indicating that it might be a new promising target for cancer intervention. This article comprehensively reviews the structure, regulatory mechanism, and biological function of NDUFA4. Of note, the expression and roles of NDUFA4 in gastrointestinal cancer including colorectal cancer, liver cancer, gastric cancer, and so on were discussed. Finally, the existing problems of NDUFA4-based intervention on gastrointestinal cancer are discussed to provide help to strengthen the understanding of the carcinogenesis of gastrointestinal cancer, as well as the development of new strategies for clinical intervention.
RESUMEN
Pulmonary hypertension (PH) is regarded as cardiovascular disease with an extremely poor prognosis, primarily due to irreversible vascular remodeling. Despite decades of research progress, the absence of definitive curative therapies remains a critical challenge, leading to high mortality rates. Recent studies have shown that serious metabolic disorders generally exist in PH animal models and patients of PH, which may be the cause or results of the disease. It is imperative for future research to identify critical biomarkers of metabolic dysfunction in PH pathophysiology and to uncover metabolic targets that could enhance diagnostic and therapeutic strategies. Metabolomics offers a powerful tool for the comprehensive qualitative and quantitative analysis of metabolites within specific organisms or cells. On the basis of the findings of the metabolomics research on PH, this review summarizes the latest research progress on metabolic pathways involved in processes such as amino acid metabolism, carbohydrate metabolism, lipid metabolism, and nucleotide metabolism in the context of PH.
Asunto(s)
Hipertensión Pulmonar , Metabolómica , Humanos , Metabolómica/métodos , Metabolómica/tendencias , Hipertensión Pulmonar/metabolismo , Animales , Metabolismo de los Lípidos/fisiologíaRESUMEN
Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Regulación Neoplásica de la Expresión Génica , Células Asesinas Naturales/inmunología , Neoplasias Pulmonares/genética , Melanoma Experimental/genética , Neoplasias Cutáneas/genética , Proteínas de Dominio T Box/inmunología , Animales , Diferenciación Celular , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Heterocigoto , Células Asesinas Naturales/patología , Selectina L/genética , Selectina L/inmunología , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Depleción Linfocítica , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Noqueados , Trasplante de Neoplasias , Transducción de Señal , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/secundario , Proteínas de Dominio T Box/genéticaRESUMEN
Single-molecule electronics can fabricate single-molecule devices via the construction of molecule-electrode interfaces and also provide a unique tool to investigate single-molecule scale physicochemical processes at these interfaces. To investigate single-molecule electronic devices with desired functionalities, an understanding of the interface evolution processes in single-molecule devices is essential. In this review, we focus on the evolution of molecule-electrode interface properties, including the background of interface evolution in single-molecule electronics, the construction of different types of single-molecule interfaces, and the regulation methods. Finally, we discuss the perspective of future characterization techniques and applications for single-molecule electronic interfaces.
RESUMEN
BACKGROUNDS: This study aimed to identify risk factors for the progression of coronary artery lesions (CALs) in children with Kawasaki disease (KD) and to develop a nomogram prediction model. METHODS: This is a retrospective case-control study in which the participants were categorized into three groups based on the changes of the maximum Z score (Zmax) of coronary arteries at the 1-month follow-up compared with the baseline Zmax: CALs-progressed, CALs-improved, and CALs-unchanged. RESULTS: Of total 387 patients, 65 (27%), 319 (73%), and 3 (0.7%) patients were categorized into CALs-progressed group, CALs-improved group, and CALs-unchanged group, respectively. Six independent factors associated with CALs progression were identified, including initial IVIG resistance, baseline Zmax, the number of coronary arteries involved, C-reactive protein, albumin, and soluble interleukin-2 receptor (odds ratio: 7.19, 1.51, 2.32, 1.52, 0.86, and 1.46, respectively; all P-values < 0.01). The nomogram prediction model including these six independent risk factors yielded an area under the curve (AUC) of 0.80 (95% confidence interval, 0.74 to 0.86). The accuracy of this model reached 81.7% after the Monte-Carlo Bootstrapping 1000 repetitions. CONCLUSIONS: The nomogram prediction model can identify children at high risk for the progression of CALs at early stages. IMPACT: Six independent factors associated with CALs progression were identified, including initial IVIG resistance, baseline Zmax, the number of coronary arteries involved, CRP, ALB, and sIL-2R. The prediction model we constructed can identify children at high risk for the progression of CALs at early stages and help clinicians make individualized treatment plans. Prospective, multi-centered studies with larger sample sizes are warranted to validate the power of this prediction model in children with KD.
Asunto(s)
Enfermedad de la Arteria Coronaria , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Lactante , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Inmunoglobulinas Intravenosas , Vasos Coronarios/diagnóstico por imagen , Estudios Retrospectivos , Estudios de Casos y Controles , Estudios Prospectivos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/complicacionesRESUMEN
OBJECTIVES: To explore the value of the synthetic MRI (SyMRI), combined with amide proton transfer-weighted (APTw) MRI for quantitative and morphologic assessment of sinonasal lesions, which could provide relative scale for the quantitative assessment of tissue properties. METHODS: A total of 80 patients (31 malignant and 49 benign) with sinonasal lesions, who underwent the SyMRI and APTw examination, were retrospectively analyzed. Quantitative parameters (T1, T2, proton density (PD)) and APT % were obtained through outlining the region of interest (ROI) and comparing the two groups utilizing independent Student t test or a Wilcoxon test. Receiver operating characteristic curve (ROC), Delong test, and logistic regression analysis were performed to assess the diagnostic efficiency of one-parameter and multiparametric models. RESULTS: SyMRI-derived mean T1, T2, and PD were significantly higher and APT % was relatively lower in benign compared to malignant sinonasal lesions (p < 0.05). The ROC analysis showed that the AUCs of the SyMRI-derived quantitative (T1, T2, PD) values and APT % ranged from 0.677 to 0.781 for differential diagnosis between benign and malignant sinonasal lesions. The T2 values showed the best diagnostic performance among all single parameters for differentiating these two masses. The AUCs of combined SyMRI-derived multiple parameters with APT % (AUC = 0.866) were the highest than that of any single parameter, which was significantly improved (p < 0.05). CONCLUSION: The combination of SyMRI and APTw imaging has the potential to reflect intrinsic tissue characteristics useful for differentiating benign from malignant sinonasal lesions. CLINICAL RELEVANCE STATEMENT: Combining synthetic MRI with amide proton transfer-weighted imaging could function as a quantitative and contrast-free approach, significantly enhancing the differentiation of benign and malignant sinonasal lesions and overcoming the limitations associated with the superficial nature of endoscopic nasal sampling. KEY POINTS: ⢠Synthetic MRI and amide proton transfer-weighted MRI could differentiate benign from malignant sinonasal lesions based on quantitative parameters. ⢠The diagnostic efficiency could be significantly improved through synthetic MRI + amide proton transfer-weighted imaging. ⢠The combination of synthetic MRI and amide proton transfer-weighted MRI is a noninvasive method to evaluate sinonasal lesions.
RESUMEN
PURPOSE: To assess the safety and clinical effectiveness of empiric embolization (EE) compared with targeted embolization (TE) in the treatment of delayed postpancreatectomy hemorrhage (PPH). MATERIALS AND METHODS: The data of patients with delayed PPH between January 2012 and August 2022 were analyzed retrospectively. In total, 312 consecutive patients (59.6 years ± 10.8; 239 men) were included. The group was stratified into 3 cohorts according to angiographic results and treatment strategies: TE group, EE group, and no embolization (NE) group. The χ2 or Fisher exact test was implemented for comparing the clinical success and 30-day mortality. The variables related to clinical failure and 30-day mortality were identified by univariable and multivariable analyses. RESULTS: Clinical success of transcatheter arterial embolization was achieved in 70.0% (170/243) of patients who underwent embolization. There was no statistical difference in clinical success and 30-day mortality between the EE and TE groups. Multivariate analyses demonstrated that malignant disease (odds ratio [OR] = 5.76), Grade C pancreatic fistula (OR = 7.59), intra-abdominal infection (OR = 2.54), and concurrent extraluminal and intraluminal hemorrhage (OR = 2.52) were risk factors for clinical failure. Moreover, 33 patients (13.6%) died within 30 days after embolization. Advanced age (OR = 2.59) and intra-abdominal infection (OR = 5.55) were identified as risk factors for 30-day mortality. CONCLUSIONS: EE is safe and as effective as TE in preventing rebleeding and mortality in patients with angiographically negative delayed PPH.
Asunto(s)
Embolización Terapéutica , Infecciones Intraabdominales , Masculino , Humanos , Estudios Retrospectivos , Hemorragia/diagnóstico por imagen , Hemorragia/etiología , Hemorragia/terapia , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Resultado del Tratamiento , Infecciones Intraabdominales/complicaciones , Infecciones Intraabdominales/terapia , Hemorragia Posoperatoria/diagnóstico por imagen , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/terapia , Hemorragia Gastrointestinal/terapiaRESUMEN
OBJECTIVE: This study aimed to explore the characteristics of carbapenem-resistant Enterobacterales (CRE) patients in the intensive care unit (ICU) in different regions of Henan Province to provide evidence for the targeted prevention and treatment of CRE. METHODS: This was a cross-sectional study. CRE screening was conducted in the ICUs of 78 hospitals in Henan Province, China, on March 10, 2021. The patients were divided into provincial capital hospitals and nonprovincial capital hospitals for comparative analysis. RESULTS: This study involved 1009 patients in total, of whom 241 were CRE-positive patients, 92 were in the provincial capital hospital and 149 were in the nonprovincial capital hospital. Provincial capital hospitals had a higher rate of CRE positivity, and there was a significant difference in the rate of CRE positivity between the two groups. The body temperature; immunosuppressed state; transfer from the ICU to other hospitals; and use of enemas, arterial catheters, carbapenems, or tigecycline at the provincial capital hospital were greater than those at the nonprovincial capital hospital (P < 0.05). However, there was no significant difference in the distribution of carbapenemase strains or enzymes between the two groups. CONCLUSIONS: The detection rate of CRE was significantly greater in provincial capital hospitals than in nonprovincial capital hospitals. The source of the patients, invasive procedures, and use of advanced antibiotics may account for the differences. Carbapenem-resistant Klebsiella pneumoniae (CR-KPN) was the most prevalent strain. Klebsiella pneumoniae carbapenemase (KPC) was the predominant carbapenemase enzyme. The distributions of carbapenemase strains and enzymes were similar in different regions.