RESUMEN
Background: Previous study has indicated a potential link between gut microbiota and maternal pregnancy outcomes. However, the causal relationship between gut microbiota and premature rupture of membranes (PROM) remains a topic of ongoing debate. Methods: A two-sample Mendelian Randomization (MR) study was used to investigate the relationship between gut microbiota and PROM. Genetic data on gut microbiota was obtained from the MiBioGen consortium's largest genome-wide association study (GWAS) (n=14,306). Genetic data on PROM (3011 cases and 104247 controls) were sourced from publicly available GWAS data from the Finnish National Biobank FinnGen consortium. Various methods including Inverse variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were utilized to assess the causal relationship by calculating the odd ratio (OR) value and confidence interval (CI). Sensitivity analyses for quality control were performed using MR-Egger intercept tests, Cochran's Q tests, and leave-one-out analyses. Results: The IVW method revealed that class Mollicutes (IVW, OR=0.773, 95%CI: 0.61-0.981, pval = 0.034), genus Marvinbryantia (IVW, OR=00.736, 95%CI: 0.555-0.977, pval = 0.034), genus Ruminooccaceae UCG003 (IVW, OR=0.734, 95%CI: 0.568-0.947, pval = 0.017) and phylum Tenericutes (IVW, OR=0.773, 95%CI: 0.566-1.067, pval = 0.034) were associated with a reduced risk of PROM, while genus Collinsella (IVW, OR=1.444, 95%CI: 1.028-2.026, pval = 0.034), genus Intestinibacter (IVW, OR=1.304, 95%CI: 1.047-1.623, pval = 0.018) and genus Turicibacter (IVW, OR=1.282, 95%CI: 1.02-1.611, pval = 0.033) increased the risk of PROM. Based on the other four supplementary methods, six gut microbiota may have a potential effect on PROM. Due to the presence of pleiotropy (pval=0.045), genus Lachnoclostridium should be ruled out. No evidence of horizontal pleiotropy or heterogeneity was found in other microbiota (pval >0.05). Conclusions: In this study, we have discovered a causal relationship between the presence of specific probiotics and pathogens in the host and the risk of PROM. The identification of specific gut microbiota associated with PROM through MR studies offers a novel approach to diagnosing and treating this condition, thereby providing a new strategy for clinically preventing PROM.
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Rotura Prematura de Membranas Fetales , Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Embarazo , Rotura Prematura de Membranas Fetales/microbiología , Microbioma Gastrointestinal/genética , Femenino , Polimorfismo de Nucleótido Simple , Adulto , Factores de RiesgoRESUMEN
Latent membrane protein 1 (LMP1) is the primary oncoprotein of Epstein-Barr virus (EBV) and plays versatile roles in the EBV life cycle and pathogenesis. Despite decades of extensive research, the molecular basis for LMP1 folding, assembly, and activation remains unclear. Here, we report cryo-electron microscopy structures of LMP1 in two unexpected assemblies: a symmetric homodimer and a higher-order filamentous oligomer. LMP1 adopts a non-canonical and unpredicted fold that supports the formation of a stable homodimer through tight and antiparallel intermolecular packing. LMP1 dimers further assemble side-by-side into higher-order filamentous oligomers, thereby allowing the accumulation and specific organization of the flexible cytoplasmic tails for efficient recruitment of downstream factors. Super-resolution microscopy and cellular functional assays demonstrate that mutations at both dimeric and oligomeric interfaces disrupt LMP1 higher-order assembly and block multiple LMP1-mediated signaling pathways. Our research provides a framework for understanding the mechanism of LMP1 and for developing potential therapies targeting EBV-associated diseases.
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Herpesvirus Humano 4 , Proteínas de la Matriz Viral , Humanos , Microscopía por Crioelectrón , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Células HEK293 , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiología , Modelos Moleculares , Mutación , Multimerización de Proteína , Transducción de Señal , Proteínas de la Matriz Viral/metabolismo , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/genéticaRESUMEN
BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.
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Corticoesteroides , COVID-19 , Enfermedad Crítica , Humanos , COVID-19/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Corticoesteroides/uso terapéutico , Corticoesteroides/biosíntesis , Anciano , SARS-CoV-2 , Zona Fascicular/metabolismo , Zona Fascicular/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Adulto , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/patología , Zona Glomerular/metabolismo , Zona Glomerular/efectos de los fármacos , Zona Glomerular/patología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacosRESUMEN
Defense-associated sirtuin 2 (DSR2) systems are widely distributed across prokaryotic genomes, providing robust protection against phage infection. DSR2 recognizes phage tail tube proteins and induces abortive infection by depleting intracellular NAD+, a process that is counteracted by another phage-encoded protein, DSR Anti Defense 1 (DSAD1). Here, we present cryo-EM structures of Bacillus subtilis DSR2 in its apo, Tube-bound, and DSAD1-bound states. DSR2 assembles into an elongated tetramer, with four NADase catalytic modules clustered in the center and the regulatory-sensing modules distributed at four distal corners. Interestingly, monomeric Tube protein, rather than its oligomeric states, docks at each corner of the DSR2 tetramer to form a 4:4 DSR2-Tube assembly, which is essential for DSR2 NADase activity. DSAD1 competes with Tube for binding to DSR2 by occupying an overlapping region, thereby inhibiting DSR2 immunity. Thus, our results provide important insights into the assembly, activation and inhibition of the DSR2 anti-phage defense system.
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Bacillus subtilis , Proteínas Bacterianas , Bacteriófagos , Bacillus subtilis/inmunología , Bacillus subtilis/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/inmunología , Bacteriófagos/genética , Bacteriófagos/inmunología , Microscopía por Crioelectrón , Evasión Inmune , Modelos Moleculares , NAD/metabolismo , Unión Proteica , Sirtuinas/metabolismo , Sirtuinas/genética , Proteínas Virales/metabolismo , Proteínas Virales/inmunología , Proteínas Virales/química , Proteínas Virales/genéticaRESUMEN
A systematic grasp of the evolution of the spatial and temporal patterns of ecosystem service value (ESV) in the Central Line Project for South-to-North Water Diversion (CLPSNWD) water source area is conducive to deepening the ecological protection and promoting high-quality development of the water source area. In this paper, the dynamically adjusted equivalent factor method is used to reveal the spatial and temporal evolution of ESV in the water source area under strong human activities from 1991 to 2020. The results show that (1) during the 30-year period, urban point expansion increased the construction land area by 63.66 km2, and the degree of fragmentation increased. The water area increased the most, reaching 209.43 km2. (2) The total increase in ESV over the 30-year period was $1434 million, with forests and water accounting for the largest increase, i.e., 98% of the total increase in value. Among the individual service functions, hydrologic regulation generated the most significant service value.
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Ecosistema , Monitoreo del Ambiente , Humanos , China , Actividades Humanas , AguaRESUMEN
Water resources are vital to the development of human society, and mastering the law of runoff changes is the basis for achieving sustainable use of water resources. To study the impact of reservoir construction on the changes of downstream river runoff, this paper decomposes the runoff before and after reservoir construction using the CEEMDAN method based on the runoff data from the Huayuankou hydrological station. The fluctuation characteristics of each decomposition series of runoff before and after reservoir construction and the intra-annual variation pattern of runoff are also analyzed by combining multi-time information entropy and coefficient of variation. The results show that after the operation of the Xiaolangdi Reservoir, the annual runoff variation cycle tends to be flat, and the monthly runoff cycle is significantly reduced. After reservoir construction, the entropy values of each IMF and Res of runoff become larger, the complexity and randomness of runoff changes increase, and predictability decreases. Before and after the operation of the Xiaolangdi Reservoir, the coefficient of variation of runoff were 0.28-1 and 0.38-0.83, the distribution of runoff was more uniform, and the percentage of runoff in the flood season was reduced from 51.51 to 39.89%.
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Inundaciones , Hidrología , Humanos , Entropía , Ríos , Estaciones del AñoRESUMEN
The actin-rich cortex plays a fundamental role in many cellular processes. Its architecture and molecular composition vary across cell types and physiological states. The full complement of actin assembly factors driving cortex formation and how their activities are spatiotemporally regulated remain to be fully elucidated. Using Dictyostelium as a model for polarized and rapidly migrating cells, we show that GxcM, a RhoGEF localized specifically in the rear of migrating cells, functions together with F-BAR protein Fbp17, a small GTPase RacC, and the actin nucleation-promoting factor WASP to coordinately promote Arp2/3 complex-mediated cortical actin assembly. Overactivation of this signaling cascade leads to excessive actin polymerization in the rear cortex, whereas its disruption causes defects in cortical integrity and function. Therefore, apart from its well-defined role in the formation of the protrusions at the cell front, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortical subcompartment in rapidly migrating cells.
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Actinas , Dictyostelium , Proteínas Protozoarias , Complejo 2-3 Proteico Relacionado con la Actina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/metabolismo , Dictyostelium/genética , Dictyostelium/metabolismo , Transducción de Señal , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismoRESUMEN
The Xiaolangdi Reservoir is the second largest water conservancy project in China and the last comprehensive water conservancy hub on the mainstream of the Yellow River, playing a vital role in the middle and lower reaches of the Yellow River. To study the effects of the construction of the Xiaolangdi Reservoir (1997-2001) on the runoff and sediment transport in the middle and lower reaches of the Yellow River, runoff and sediment transport data from 1963 to 2021 were based on the hydrological stations of Huayuankou, Gaocun, and Lijin. The unevenness coefficient, cumulative distance level method, Mann-Kendall test method, and wavelet transform method were used to analyze the runoff and sediment transport in the middle and lower reaches of the Yellow River at different time scales. The results of the study reveal that the completion of the Xiaolangdi Reservoir in the interannual range has little impact on the runoff in the middle and lower reaches of the Yellow River and a significant impact on sediment transport. The interannual runoff volumes of Huayuankou station, Gaocun station, and Lijin station were reduced by 20.1%, 20.39%, and 32.87%, respectively. In addition, the sediment transport volumes decreased by 90.03%, 85.34%, and 83.88%, respectively. It has a great influence on the monthly distribution of annual runoff. The annual runoff distribution is more uniform, increasing the runoff in the dry season, reducing the runoff in the wet season, and bringing forward the peak flow. The runoff and Sediment transport have obvious periodicity. After the operation of the Xiaolangdi Reservoir, the main cycle of runoff increases and the second main cycle disappears. The main cycle of Sediment transport did not change obviously, but the closer it was to the estuary, the less obvious the cycle was. The research results can provide a reference for ecological protection and high-quality development in the middle and lower reaches of the Yellow River.
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Monitoreo del Ambiente , Ríos , Abastecimiento de Agua , China , Estuarios , Sedimentos Geológicos/análisis , Sedimentos Geológicos/química , Ríos/química , Estaciones del Año , Agua/análisisRESUMEN
Hydrogenases are microbial metalloenzymes capable of catalyzing the reversible interconversion between molecular hydrogen and protons with high efficiency, and have great potential in the development of new electrocatalysts for renewable fuel production. Here, we engineered the intact proteinaceous shell of the carboxysome, a self-assembling protein organelle for CO2 fixation in cyanobacteria and proteobacteria, and sequestered heterologously produced [NiFe]-hydrogenases into the carboxysome shell. The protein-based hybrid catalyst produced in E. coli shows substantially improved hydrogen production under both aerobic and anaerobic conditions and enhanced material and functional robustness, compared to unencapsulated [NiFe]-hydrogenases. The catalytically functional nanoreactor as well as the self-assembling and encapsulation strategies provide a framework for engineering new bioinspired electrocatalysts to improve the sustainable production of fuels and chemicals in biotechnological and chemical applications.
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Cianobacterias , Hidrogenasas , Hidrogenasas/genética , Hidrogenasas/química , Hidrogenasas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Catálisis , Hidrógeno/químicaRESUMEN
Land use change and ecological sensitivity studies are relevant to the dynamic stability of the overall regional ecological environment. In this study, Nanyang City, a South-North Water Transfer water source area, was used as the study area to analyse land use changes and landscape pattern changes in Nanyang City from 1990 to 2020 based on land use data. Hierarchical analysis (AHP method) was used and combined with six sensitivity factors to conduct a multi-factor comprehensive ecological sensitivity evaluation of Nanyang City. The results show that: (1) between 1990 and 2020, the transfer of water and construction land in Nanyang City was larger, increasing by 30.25% and 99.56% respectively, with a small decrease in the area of cultivated land and a small increase in the area of forest land; the overall rate of land use change in Nanyang City during the 30-year period was first slow and then fast. (2) At the level of patch types, the fragmentation of cultivated land and construction land is the highest; during the study period, the overall fragmentation of the study area tends to decrease; at the level of landscape, each landscape type develops in the direction of equilibrium. (3) The ecological sensitivity increases gradually from the urban cluster in the central plain area to the periphery, with the highly sensitive areas distributed in the water area, the medium sensitive areas in the mountainous area, and the low sensitive areas and insensitive areas in the cultivated land and town planning area.
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Conservación de los Recursos Naturales , Ecosistema , Agua , Monitoreo del Ambiente/métodos , Bosques , Ciudades , ChinaRESUMEN
The carboxysome is a protein-based nanoscale organelle in cyanobacteria and many proteobacteria, which encapsulates the key CO2-fixing enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrase (CA) within a polyhedral protein shell. The intrinsic self-assembly and architectural features of carboxysomes and the semipermeability of the protein shell provide the foundation for the accumulation of CO2 within carboxysomes and enhanced carboxylation. Here, we develop an approach to determine the interior pH conditions and inorganic carbon accumulation within an α-carboxysome shell derived from a chemoautotrophic proteobacterium Halothiobacillus neapolitanus and evaluate the shell permeability. By incorporating a pH reporter, pHluorin2, within empty α-carboxysome shells produced in Escherichia coli, we probe the interior pH of the protein shells with and without CA. Our in vivo and in vitro results demonstrate a lower interior pH of α-carboxysome shells than the cytoplasmic pH and buffer pH, as well as the modulation of the interior pH in response to changes in external environments, indicating the shell permeability to bicarbonate ions and protons. We further determine the saturated HCO3- concentration of 15 mM within α-carboxysome shells and show the CA-mediated increase in the interior CO2 level. Uncovering the interior physiochemical microenvironment of carboxysomes is crucial for understanding the mechanisms underlying carboxysomal shell permeability and enhancement of Rubisco carboxylation within carboxysomes. Such fundamental knowledge may inform reprogramming carboxysomes to improve metabolism and recruit foreign enzymes for enhanced catalytical performance.
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Anhidrasas Carbónicas , Ribulosa-Bifosfato Carboxilasa , Proteínas Bacterianas/metabolismo , Bicarbonatos , Carbono/metabolismo , Dióxido de Carbono/metabolismo , Anhidrasas Carbónicas/metabolismo , Concentración de Iones de Hidrógeno , Orgánulos/metabolismo , Oxigenasas/metabolismo , Permeabilidad , Protones , Ribulosa-Bifosfato Carboxilasa/química , Ribulosa-Bifosfato Carboxilasa/metabolismoRESUMEN
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy mainly due to its extensive metastasis. Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a newly discovered splice variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3), has been reported to be overexpressed in several types of cancer. However, the biological function of Ct-OATP1B3 remains largely unknown. Here, we reveal that Ct-OATP1B3 is overexpressed in HGSOC and promotes the metastasis of HGSOC in vivo and in vitro. Mechanically, Ct-OATP1B3 directly interacts with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an RNA-binding protein, which results in enhancement of the mRNA stability and expression of carnitine palmitoyltransferase 1A (CPT1A) and NADH:Ubiquinone Oxidoreductase Subunit A2 (NDUFA2), leading to increased mitochondrial fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) activities. The increased FAO and OXPHOS activities further facilitate adenosine triphosphate (ATP) production and cellular lamellipodia formation, which is the initial step in the processes of tumor cell migration and invasion. Taken together, our study provides an insight into the function and underlying mechanism of Ct-OATP1B3 in HGSOC metastasis, and highlights Ct-OATP1B3 as a novel prognostic marker as well as therapeutic target in HGSOC.
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Transportadores de Anión Orgánico , Neoplasias Ováricas , Ácidos Grasos , Femenino , Humanos , Neoplasias Ováricas/genética , Fosforilación Oxidativa , Proteínas de Unión al ARNRESUMEN
Acetolactate synthase (AHAS) catalyses the first common step in the biosynthesis pathways of three branched-chain amino acids (BCAAs) of valine, isoleucine and leucine. Here, we characterized one regulatory subunit (VdILV6) and three catalytic subunits (VdILV2A, VdILV2B and VdILV2C) of AHAS from the important cotton Verticillium wilt fungus Verticillium dahliae. Phenotypic analysis showed that VdILV6 knockout mutants were auxotrophic for valine and isoleucine and were defective in conidial morphogenesis, hypha penetration and virulence to cotton, and lost ability of microscletotial formation. The growth of single catalytic subunit gene knockout mutants were significantly inhibited by leucine at higher concentration and single catalytic subunit gene knockout mutants showed significantly reduced virulence to cotton. VdILV2B knockout also led to obviously reduced microscletotial formation and conidial production, VdILV2C knockout led to reduced conidial production. Further studies suggested that both feedback inhibition by leucine and the inhibition by AHAS inhibiting herbicides of tribenuron and bispyribac resulted in significantly down-regulated expression of the four subunit VdILVs genes (VdILV2A, VdILV2B, VdILV2C and VdILV6). Any single catalytic subunit gene knockout led to reduced expression of the other three subunit genes, whereas VdILV6 knckout induced increased expression of the three catalytic subunit genes. VdILV2B, VdILV2C and VdILV6 knockout resulted in increased expression of VdCPC1 regulator gene of the cross-pathway control of amino acid biosynthesis. Taken together, these results indicate multiple roles of four VdILVs genes in the biosynthesis of BCAAs, virulence, fungal growth and development in the filamentous fungi V. dahliae.
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Acetolactato Sintasa , Verticillium , Acetolactato Sintasa/genética , Acetolactato Sintasa/metabolismo , Acremonium , Aminoácidos de Cadena Ramificada , Dominio Catalítico/genética , Proteínas Fúngicas/metabolismo , Isoleucina , Lactatos , Leucina , Enfermedades de las Plantas/microbiología , Esporas Fúngicas , Valina , Virulencia/genéticaRESUMEN
The sequence and structure of antioxidant peptides play fundamental roles in their antioxidant functions. However, the structural mechanism of antioxidant peptides is still unclear. In this study, we used quantum calculations to reveal the antioxidant mechanism of the peptide PMRGGGGYHY. PMRGGGGYHY has multiple antioxidant active sites, and two tyrosine residues were determined to be the major active sites. Based on the structure-activity relationships of PMRGGGGYHY, the antioxidant activity of the modified peptide significantly improved by 4.8-fold to 9.73 ± 0.61 µmol TE/µmol. In addition, the removal of glycine residues from PMRGGGGYHY would increase the energy of the HOMOs and simplify the hydrogen bonding network, causing a significant increase in antioxidant activity. The intracellular ROS scavenging ability gradually decreased with decreasing glycine content. This same peptide has very different effects in vitro versus as a cellular antioxidant. This paper provides new insights into the structural mechanism and rational design/modification of novel antioxidant peptides.
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Antioxidantes/química , Antioxidantes/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Secuencia de Aminoácidos , Relación Estructura-ActividadRESUMEN
Compartmentalization is a ubiquitous building principle in cells, which permits segregation of biological elements and reactions. The carboxysome is a specialized bacterial organelle that encapsulates enzymes into a virus-like protein shell and plays essential roles in photosynthetic carbon fixation. The naturally designed architecture, semi-permeability, and catalytic improvement of carboxysomes have inspired rational design and engineering of new nanomaterials to incorporate desired enzymes into the protein shell for enhanced catalytic performance. Here, we build large, intact carboxysome shells (over 90 nm in diameter) in the industrial microorganism Escherichia coli by expressing a set of carboxysome protein-encoding genes. We develop strategies for enzyme activation, shell self-assembly, and cargo encapsulation to construct a robust nanoreactor that incorporates catalytically active [FeFe]-hydrogenases and functional partners within the empty shell for the production of hydrogen. We show that shell encapsulation and the internal microenvironment of the new catalyst facilitate hydrogen production of the encapsulated oxygen-sensitive hydrogenases. The study provides insights into the assembly and formation of carboxysomes and paves the way for engineering carboxysome shell-based nanoreactors to recruit specific enzymes for diverse catalytic reactions.
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Proteínas Bacterianas/metabolismo , Reactores Biológicos , Hidrógeno/metabolismo , Orgánulos/metabolismo , Proteínas Bacterianas/genética , Biocatálisis , Bioingeniería , Reactores Biológicos/microbiología , Escherichia coli/genética , Escherichia coli/metabolismo , Genes Bacterianos , Halothiobacillus/genética , Halothiobacillus/metabolismo , Hidrogenasas/metabolismo , Proteínas Hierro-Azufre/metabolismo , Nanocápsulas/química , Nanocápsulas/ultraestructura , Orgánulos/genética , Orgánulos/ultraestructura , Fotosíntesis , Ribulosa-Bifosfato Carboxilasa/genética , Ribulosa-Bifosfato Carboxilasa/metabolismoRESUMEN
Lung cancer is one of most common malignant cancer worldwide. It is emerging that PCYT1A, a rate-limiting enzyme required for the biosynthesis of phosphatidylcholine, is associated with cancer progression. However, the biological functions and underlying molecular mechanisms of PCYT1A in lung adenocarcinoma is still unknown. Here we found that PCYT1A suppressed lung adenocarcinoma cancer cell proliferation and migration. Mechanically, PCYT1A served as a novel negative regulator of mTORC1 signaling. PCYT1A knockdown enhanced the malignant proliferation and migration of lung adenocarcinoma cells by activating mTORC1. The promoting effects of PCYT1A silencing on cell proliferation and migration could be abolished when mTORC1 signaling was inhibited by rapamycin or RAPTOR depletion. Importantly, PCYT1A high expression predicted longer survival of lung cancer patients. The expression of PCYT1A was also negatively correlated with mTORC1 activation in the clinical lung cancer samples. We therefore reveal that PCYT1A suppresses proliferation and migration by inhibiting the mTORC1 signaling pathway in lung adenocarcinoma. PCYT1A shows as a potential promising biomarker in lung adenocarcinoma.
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Adenocarcinoma del Pulmón/metabolismo , Citidililtransferasa de Colina-Fosfato/metabolismo , Neoplasias Pulmonares/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Transducción de Señal , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Humanos , Neoplasias Pulmonares/patologíaRESUMEN
Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.
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Neoplasias Encefálicas , Glioblastoma , Invasividad Neoplásica/patología , Zixina , Animales , Biomarcadores de Tumor , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Técnicas de Silenciamiento del Gen , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Ratones , Ratones Endogámicos NOD , Pronóstico , Estatmina/análisis , Estatmina/genética , Estatmina/metabolismo , Zixina/análisis , Zixina/genética , Zixina/metabolismoRESUMEN
PURPOSE: This study sought to identify a disease-related gene in a consanguineous Chinese family in which there were two premature ovarian insufficiency (POI) sisters. METHOD: We used whole-exome sequencing and Sanger sequencing to identify the disease-causing gene. Results were verified using an assay of mutant protein and in silico analyses. RESULT: We identified a novel missense mutation (NM_000303: c.556G>A, p.Gly186Arg) in the PMM2 gene. The two sisters suffer from premature ovarian insufficiency (POI) only and have no other symptoms of congenital disorder of glycosylation type-1a (CDG-Ia). We found that the enzymic activity of the mutant PMM2 protein was reduced by 55.21% (p < 0.05) when compared with wild type, and many in silico tools suggested the mutation is disease-related. CONCLUSION: This particular gene modification results in changes in activity of phosphomannomutase modification, which could lead to PMM2-CDG-Ia with an uncommon phenotype.
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Predisposición Genética a la Enfermedad , Fosfotransferasas (Fosfomutasas)/genética , Insuficiencia Ovárica Primaria/genética , Adulto , China , Consanguinidad , Femenino , Humanos , Mutación Missense/genética , Linaje , Fenotipo , Insuficiencia Ovárica Primaria/fisiopatología , HermanosRESUMEN
The special ecological environment of the Arctic has brought about a large number of salt-tolerant and psychrotolerant microorganisms. We isolated two culturable bacterial strains of the genus Mesonia; one from the Arctic ocean, Mesonia algae K4-1, and one from the tropical sea, Mesonia sp. HuA40. Our genome analysis and phenotypic experiments indicated that Mesonia algae K4-1 is a moderately halophilic and psychrophilic bacterium. Mesonia algae K4-1 can tolerate 3-14% NaCl and grow at a wide range of temperatures from 4 to 50°C. Mesonia sp. HuA40 is a mesophilic bacterium that can only grow with 3-9% NaCl. In addition, the salt adaptation strategy of Mesonia algae K4-1 accumulates organic osmolytes in the cell. RNA helicases, glutathione and organic compatible solutes may play important roles in maintaining the metabolism and physiological function of Mesonia algae K4-1 under cold stress. Moreover, the ability of Mesonia algae K4-1 to adapt to an oligotrophic marine environment is likely due to the synthesis of a large number of extracellular polysaccharides and the secretion of various families of extracellular proteases. This study systematically analyzed the relationship between genomic differentiation and environmental factors of the Mesonia genus and revealed the possible adaptation mechanism of Mesonia algae K4-1 in the extreme Arctic marine environment at the genomic level.