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1.
Mol Cell ; 84(15): 2838-2855.e10, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39019045

RESUMEN

Despite the unique ability of pioneer factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called chromatin immunoprecipitation with integrated synthetic oligonucleotides (ChIP-ISO) to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1, in human A549 cells. Combining ChIP-ISO with in vitro and neural network analyses, we find that (1) FOXA1 binding is strongly affected by co-binding transcription factors (TFs) AP-1 and CEBPB; (2) FOXA1 and AP-1 show binding cooperativity in vitro; (3) FOXA1's binding is determined more by local sequences than chromatin context, including eu-/heterochromatin; and (4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.


Asunto(s)
Factor Nuclear 3-alfa del Hepatocito , Unión Proteica , Factor de Transcripción AP-1 , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Humanos , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Sitios de Unión , Células A549 , Cromatina/metabolismo , Cromatina/genética , Inmunoprecipitación de Cromatina , Oligonucleótidos/metabolismo , Oligonucleótidos/genética
2.
Mol Cell ; 83(8): 1251-1263.e6, 2023 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-36996811

RESUMEN

Nucleosomes drastically limit transcription factor (TF) occupancy, while pioneer transcription factors (PFs) somehow circumvent this nucleosome barrier. In this study, we compare nucleosome binding of two conserved S. cerevisiae basic helix-loop-helix (bHLH) TFs, Cbf1 and Pho4. A cryo-EM structure of Cbf1 in complex with the nucleosome reveals that the Cbf1 HLH region can electrostatically interact with exposed histone residues within a partially unwrapped nucleosome. Single-molecule fluorescence studies show that the Cbf1 HLH region facilitates efficient nucleosome invasion by slowing its dissociation rate relative to DNA through interactions with histones, whereas the Pho4 HLH region does not. In vivo studies show that this enhanced binding provided by the Cbf1 HLH region enables nucleosome invasion and ensuing repositioning. These structural, single-molecule, and in vivo studies reveal the mechanistic basis of dissociation rate compensation by PFs and how this translates to facilitating chromatin opening inside cells.


Asunto(s)
Nucleosomas , Proteínas de Saccharomyces cerevisiae , Nucleosomas/genética , Nucleosomas/metabolismo , Histonas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Cromatina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética
3.
Mol Cell ; 78(5): 903-914.e4, 2020 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-32396821

RESUMEN

LSD1 (lysine specific demethylase; also known as KDM1A), the first histone demethylase discovered, regulates cell-fate determination and is overexpressed in multiple cancers. LSD1 demethylates histone H3 Lys4, an epigenetic mark for active genes, but requires the CoREST repressor to act on nucleosome substrates. To understand how an accessory subunit (CoREST) enables a chromatin enzyme (LSD1) to function on a nucleosome and not just histones, we have determined the crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome. We find that the LSD1 catalytic domain binds extranucleosomal DNA and is unexpectedly positioned 100 Å away from the nucleosome core. CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential function in demethylating nucleosome substrates. Our studies also show that the LSD1(K661A) frequently used as a catalytically inactive mutant in vivo (based on in vitro peptide studies) actually retains substantial H3K4 demethylase activity on nucleosome substrates.


Asunto(s)
Histona Demetilasas/metabolismo , Histona Demetilasas/ultraestructura , Secuencia de Aminoácidos , Dominio Catalítico , Cromatina/metabolismo , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Cristalografía por Rayos X/métodos , ADN/genética , ADN/metabolismo , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Metilación , Modelos Moleculares , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Nucleosomas/química , Nucleosomas/genética , Nucleosomas/metabolismo , Péptidos/metabolismo , Unión Proteica , Conformación Proteica
4.
N Engl J Med ; 390(20): 1862-1872, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38752650

RESUMEN

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).


Asunto(s)
Antihipertensivos , Presión Sanguínea , Servicios Médicos de Urgencia , Hipertensión , Accidente Cerebrovascular , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ambulancias , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Tiempo de Tratamiento , Enfermedad Aguda , Estado Funcional , China
5.
J Biol Chem ; 299(2): 102874, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36623730

RESUMEN

Enzymes of the mixed lineage leukemia (MLL) family of histone H3 lysine 4 (H3K4) methyltransferases are critical for cellular differentiation and development and are regulated by interaction with a conserved subcomplex consisting of WDR5, RbBP5, Ash2L, and DPY30. While pairwise interactions between complex subunits have been determined, the mechanisms regulating holocomplex assembly are unknown. In this investigation, we systematically characterized the biophysical properties of a reconstituted human MLL1 core complex and found that the MLL1-WDR5 heterodimer interacts with the RbBP5-Ash2L-DPY30 subcomplex in a hierarchical assembly pathway that is highly dependent on concentration and temperature. Surprisingly, we found that the disassembled state is favored at physiological temperature, where the enzyme rapidly becomes irreversibly inactivated, likely because of complex components becoming trapped in nonproductive conformations. Increased protein concentration partially overcomes this thermodynamic barrier for complex assembly, suggesting a potential regulatory mechanism for spatiotemporal control of H3K4 methylation. Together, these results are consistent with the hypothesis that regulated assembly of the MLL1 core complex underlies an important mechanism for establishing different H3K4 methylation states in mammalian genomes.


Asunto(s)
Histonas , Leucemia , Multimerización de Proteína , Temperatura , Animales , Humanos , Proteínas de Unión al ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metilación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Multimerización de Proteína/fisiología , Estructura Cuaternaria de Proteína
6.
Clin Immunol ; 259: 109879, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38142901

RESUMEN

The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment.


Asunto(s)
Interleucina-6 , Miastenia Gravis , Humanos , Estudios Prospectivos , Estudios de Cohortes , Calidad de Vida , Miastenia Gravis/tratamiento farmacológico
7.
Anal Chem ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225442

RESUMEN

In this work, by ingeniously integrating catalytic hairpin assembly (CHA), double-end Mg2+-dependent DNAzyme, and hybridization chain reaction (HCR) as a triple cascade signal amplifier, an efficient concatenated CHA-DNAzyme-HCR (CDH) system was constructed to develop an ultrasensitive electrochemical biosensor with a low-background signal for the detection of microRNA-221 (miRNA-221). In the presence of the target miRNA-221, the CHA cycle was initiated by reacting with hairpins H1 and H2 to form DNAzyme structure H1-H2, which catalyzed the cleavage of the substrate hairpin H0 to release two output DNAs (output 1 and output 2). Subsequently, the double-loop hairpin H fixed on the electrode plate was opened by the output DNAs, to trigger the HCR with the assistance of hairpins Ha and Hb. Finally, methylene blue was intercalated into the long dsDNA polymer of the HCR product, resulting in a significant electrochemical signal. Surprisingly, the double-loop structure of the hairpin H could prominently reduce the background signal for enhancing the signal-to-noise ratio (S/N). As a proof of concept, an ultrasensitive electrochemical biosensor was developed using the CDH system with a detection limit as low as 9.25 aM, achieving favorable application for the detection of miRNA-221 in various cancer cell lysates. Benefiting from its enzyme-free, label-free, low-background, and highly sensitive characteristics, the CDH system showed widespread application potential for analyzing trace amounts of biomarkers in various clinical research studies.

8.
Proc Biol Sci ; 291(2027): 20241012, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39079664

RESUMEN

Persistent individual variation in behaviour, or 'personality', is a widespread phenomenon in animals, and understanding the evolution of animal personality is a key task of current biology. Natural selection has been proposed to promote the integration of personality with animal 'intrinsic states', such as metabolic or endocrine traits, and this integration varies with ecological conditions. However, these external ecological modulatory effects have rarely been examined. Here, we investigate the effects of thermal acclimation on between-individual covariations between physiology and behaviour in Asiatic toads (Bufo gargarizans) along an altitudinal gradient. Our results reveal that the thermal modulatory effects on the covariations depend on the altitudinal population. Specifically, at low altitudes, between-individual covariations are highly plastic, with risk-taking behaviour covarying with baseline glucocorticoids (GCs) under warm acclimation, but risk-taking and exploration behaviour covarying with resting metabolic rate (RMR) under cold acclimation. In contrast, between-individual covariations are relatively fixed at high altitudes, with risk-taking behaviour consistently covarying with baseline GCs. Furthermore, at low altitudes, changes in covariations between RMR and personality are associated with adjustment of energy management models. Evidently, animal physiological states that determine or covary with personality can adapt according to the seasonal thermal environment and the thermal evolutionary background of populations. Our findings highlight the importance of a multi-system physiological approach to understand the evolution of animal personality.


Asunto(s)
Aclimatación , Altitud , Bufonidae , Personalidad , Animales , Bufonidae/fisiología , Metabolismo Basal , Conducta Animal
9.
J Inherit Metab Dis ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39227307

RESUMEN

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

10.
J Therm Biol ; 119: 103788, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38281315

RESUMEN

Foraging behavior is known to place demands on the metabolic characteristics of anurans. Active foragers feeding on sedentary prey typically have high aerobic capacity and low anaerobic capacity, whereas sit-and-wait foragers feeding on active and mobile prey have the opposite pattern. Thus, the energetic demands of foraging may influence their metabolic adaptations to harsh environments, such as high elevations. Anurans that engage in active foraging have been found to increase maximum metabolic rate (MMR) and aerobic scope (AS, the difference between MMR and resting metabolic rate, RMR) at high elevations. However, data are lacking in amphibian ambush foragers. In this study, we examined the RMR, MMR, AS, and feeding capacity of a sit-and-wait forager ─the Asiatic toad (Bufo gargarizans), from two populations that are in close geographic proximity but differ by 1350 m in elevation. Our results show that there is no elevational variation in RMR and feeding capacity in either males or females. However, there are sex-specific variations in MMR and AS along an elevational gradient; females from high elevations have lower MMR and smaller net AS than their counterparts from low elevations while males maintain similar MMR and net AS across elevations. Furthermore, aerobic performances do not appear to be associated with feeding capacity at either the individual or population level. Our results support the hypothesis that sit-and-wait foragers may not increase their aerobic capacity as a strategy in hypoxic and low food availability environments and the role of sex in these adaptive adjustments should not be overlooked.


Asunto(s)
Metabolismo Basal , Bufonidae , Humanos , Animales , Femenino , Masculino
11.
BMC Neurol ; 23(1): 112, 2023 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-36941592

RESUMEN

BACKGROUND: This study aimed to investigate the clinical risk factors of dysautonomic symptom burden in neuromyelitis optica spectrum disorder (NMOSD) and its impact on patients' quality of life. METHODS: A total of 63 NMOSD patients and healthy controls were enrolled. All participants completed the Composite Autonomic Symptom Score 31 (COMPASS-31) to screen for symptoms of autonomic dysfunction. A comprehensive clinical evaluation was performed on NMOSD patients, such as disease characteristics and composite evaluations of life status, including quality of life, anxiety/depression, sleep, and fatigue. Correlated factors of dysautonomic symptoms and quality of life were analyzed. RESULTS: The score of COMPASS-31 in the NMOSD group was 17.2 ± 10.3, significantly higher than that in healthy controls (P = 0.002). In NMOSD patients, the higher COMPASS-31 score was correlated with more attacks (r = 0.49, P < 0.001), longer disease duration (r = 0.52, P < 0.001), severer disability (r = 0.50, P < 0.001), more thoracic cord lesions (r = 0.29, P = 0.02), more total spinal cord lesions (r = 0.35, P = 0.005), severer anxiety (r = 0.55, P < 0.001), severer depression (r = 0.48, P < 0.001), severer sleep disturbances (r = 0.59, P < 0.001), and severer fatigue (r = 0.56, P < 0.001). The disability, total spinal cord lesions, and fatigue were revealed to be independently associated factors. Further analysis revealed that the COMPASS-31 score was independently correlated with scores of all the domains of patients' quality of life scale (P < 0.05). CONCLUSIONS: Dysautonomic symptom burden is correlated with decreased quality of life and certain clinical characteristics such as disability, the burden of spinal cord lesions, and fatigue in NMOSD patients. Investigation and proper management of autonomic dysfunction may help to improve the quality of life in patients with NMOSD.


Asunto(s)
Neuromielitis Óptica , Disautonomías Primarias , Humanos , Neuromielitis Óptica/patología , Calidad de Vida , Médula Espinal/patología , Fatiga/epidemiología , Fatiga/etiología
12.
Biol Pharm Bull ; 46(4): 574-585, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37005301

RESUMEN

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.


Asunto(s)
Neoplasias de la Próstata , Saponinas , Humanos , Masculino , Animales , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Línea Celular Tumoral , Transducción de Señal , Saponinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Proliferación Celular , Apoptosis , Movimiento Celular , Sistema de Señalización de MAP Quinasas , Proteína Forkhead Box O1/metabolismo
13.
Food Microbiol ; 115: 104311, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37567617

RESUMEN

Biosurfactants from Pseudomonas spp. have been reported to exhibit antibacterial and anti-adhesive properties, but their role during meat spoilage remains unclear. In this study, the biosurfactant was isolated from an isolate of Pseudomonas fragi with strong spoilage potential, and its surface tension and emulsification ability were determined. The chemical and microbial characteristics of the biosurfactant-treated meat samples were periodically analyzed. The results demonstrated that the biosurfactant produced by P. fragi could reduce surface tension and showed good emulsification properties. For the in situ spoilage trials, biosurfactant from P. fragi changed the microbial diversity on meat, helping Pseudomonas establish a dominant position in the population. However, biosurfactant treatment caused chicken meat to exhibit a weaker spoilage state, as indicated by the growth of psychrophilic microorganisms, total volatile basic nitrogen (TVBN) and meat color. These results provide practical information for understanding the role of P. fragi biosurfactant during chilled meat storage.


Asunto(s)
Microbiota , Pseudomonas fragi , Pseudomonas , Carne/microbiología , Nitrógeno
14.
World J Surg Oncol ; 21(1): 289, 2023 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-37700312

RESUMEN

BACKGROUND: Uncut Roux-en-Y (URY) effectively alleviates the prevalent complexities connected with RY, such as Roux-en-Y stasis syndrome (RSS). Nevertheless, for gastric cancer (GC) patients, it is still controversial whether URY has an impact on long-term prognosis and whether it has fewer afferent loop recanalization. Therefore, compare whether URY and RY have differences in prognosis and long-term complications of GC patients undergoing totally laparoscopic gastrectomy (TLG). METHODS: We analyzed the data of patients who underwent TLG combined with digestive tract reconstruction from dual-center between 2016 and 2022. Only patients undergoing URY and RY were selected for analysis. Relapse-free survival (RFS) and overall survival (OS) were estimated. Bias between the groups was reduced by propensity score matching (PSM). The Cox proportional hazard regression model was used to further analyze the influence of URY on prognosis. RESULTS: Two hundred forty two GC patients were enrolled. The URY had significantly shorter operation time, liquid food intake time, and in-hospital stays than the RY (P < 0.001). The URY had fewer long-term and short-term postoperative complications than the RY, especially with regard to RSS, reflux esophagitis, and reflux gastritis. The 3-year and 5-year OS of the URY group and the RY group before PSM: 87.5% vs. 65.6% (P < 0.001) and 81.4% vs. 61.7% (P = 0.001). PSM and Cox multivariate analysis confirmed that compared to RY, URY can improve the short-term and long-term prognosis of GC patients. CONCLUSION: TLG combined with URY for GC, especially for advanced, older, and poorly differentiated patients, may promote postoperative recovery and improve long-term prognosis.


Asunto(s)
Laparoscopía , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Estudios Retrospectivos , Anastomosis en-Y de Roux , Gastrectomía/efectos adversos , Laparoscopía/efectos adversos
15.
Phytochem Anal ; 34(3): 317-328, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36691258

RESUMEN

INTRODUCTION: Atractylodes chinensis is a Chinese herb that is used in traditional medicine; it contains volatile components that have enormous potential for pharmaceutical, food, and cosmetic applications. The destruction of wild resources demands significant improvement in the quality of artificial cultivation of Atractylodes chinensis. However, little is known about the compositional differences in the volatile substances derived from the wild and cultivated varieties of Atractylodes chinensis. OBJECTIVES: We aimed to evaluate the specific components of Atractylodes chinensis and analyse the similarities and differences between the volatile components and metabolic pathways in the wild and cultivated varieties. MATERIAL AND METHODS: Metabolomic analysis using gas chromatography-mass spectrometry (GC-MS) was employed following the extraction of volatile components from Atractylodes chinensis using headspace solid-phase microextraction (HS-SPME). RESULTS: A total of 167 volatile metabolites were extracted, and 137 substances were matched with NIST and Wiley databases. Among them, 76 compounds exhibited significant differences between the two sources; these mainly included terpenes, aromatics, and esters. KEGG enrichment analysis indicated that the differential metabolites were primarily involved in the biosynthesis of secondary metabolites, terpene biosynthesis, and limonene and pinene degradation; all these pathways have geranyl diphosphate (GDP) as the common link. CONCLUSION: The total content of volatile substances extracted from wild Atractylodes chinensis was 2.5 times higher than that from the cultured variety; however, each source had different dominant metabolites. This study underscores the necessity for protecting wild Atractylodes chinensis resources, while enhancing the quality of cultivated Atractylodes chinensis.


Asunto(s)
Atractylodes , Compuestos Orgánicos Volátiles , Cromatografía de Gases y Espectrometría de Masas/métodos , Microextracción en Fase Sólida/métodos , Terpenos , Limoneno/análisis , Compuestos Orgánicos Volátiles/análisis
16.
J Mol Evol ; 90(5): 389-399, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36029325

RESUMEN

High-elevation adaptation provides an excellent system for examining adaptive evolution, and adaptive variations may manifest at gene expression or any other phenotypic levels. We examined gene expression profiles of Asiatic toads (Bufo gargarizans) along an elevational gradient from both wild and common-garden acclimated populations. Asiatic toads originated from high altitudes have distinctive gene expression patterns. We identified 18 fixed differentially expressed genes (DEGs), which are different in both wild and acclimated samples, and 1217 plastic DEGs, which are different among wild samples. The expression levels of most genes were linearly correlated with altitude gradient and down-regulated in high-altitude populations. Expression variations of several genes associated with metabolic process are fixed, and we also identified a co-expression module that is significantly different between acclimated populations and has functions related to DNA repair. The differential expression of the vast majority genes, however, are due to phenotypic plasticity, revealing the highly plastic nature of gene expression variations. Expression modification of some specific genes related to metabolism and response to UV radiation play crucial role in adaptation to high altitude for Asiatic toads. Common-garden experiments are essential for evaluating adaptive evolution of natural populations.


Asunto(s)
Bufonidae , Rayos Ultravioleta , Altitud , Animales , Bufonidae/genética , Expresión Génica/genética , Plásticos
17.
Neurosurg Rev ; 45(3): 2231-2237, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35067805

RESUMEN

Optimal treatment strategies for traumatic intracranial internal carotid artery (ICA) pseudoaneurysms are controversial. The low-profile visualized intraluminal support (LVIS) device is a braided stent with a metal coverage rate between traditional laser cut stents and flow diversion devices. We report here our therapy strategy using the LVIS stent-assisted coiling for treatment of traumatic intracranial ICA pseudoaneurysms. Patients with traumatic intracranial ICA pseudoaneurysms treated by the LVIS stent-assisted coiling in our center between January 2015 and June 2021 were reviewed. The complications, radiographic, and clinical outcomes of these patients were analyzed. A total of 12 patients with 12 pseudoaneurysms were included. The mean maximum aneurysm diameter was 6.2 ± 3.1 mm. Nine patients had a subarachnoid hemorrhage; five patients with Hunt-Hess grade III and four patients with grade IV. All procedures were successfully performed without intraoperative complications. Immediate postoperative angiogram showed that six (50%) aneurysms were Raymond grade 1, four (33.3%) were grade 2, and two (16.7%) were grade 3. Postoperative multiple cerebral infarction occurred in two patients because of vasospasm. Of the ten patients with angiographic follow-up (mean, 29.9 months), two received additional coiling because of recanalization of the pseudoaneurysm, and all aneurysms were completely obliterated at the last examination of the patients. During the clinical follow-up period (mean, 26.8 months), the overall mortality and morbidity were 25% (3/12) and 8.3% (1/12), respectively. LVIS stent-assisted coiling was a feasible approach for the treatment of traumatic ICA pseudoaneurysms.


Asunto(s)
Aneurisma Falso , Embolización Terapéutica , Procedimientos Endovasculares , Aneurisma Intracraneal , Aneurisma Falso/etiología , Aneurisma Falso/cirugía , Arteria Carótida Interna/cirugía , Angiografía Cerebral/métodos , Embolización Terapéutica/métodos , Procedimientos Endovasculares/métodos , Humanos , Aneurisma Intracraneal/terapia , Estudios Retrospectivos , Stents/efectos adversos , Resultado del Tratamiento
18.
J Stroke Cerebrovasc Dis ; 31(2): 106256, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34923434

RESUMEN

OBJECTIVES: To prospectively evaluate the clinical usefulness of Silent magnetic resonance angiography (Silent MRA) in the follow-up of endovascular-treated intracranial aneurysms by comparing it with time-of-flight magnetic resonance angiography (TOF MRA) and digital subtraction angiography (DSA). METHODS: Patients with endovascular-treated saccular aneurysms and followed with Silent MRA, TOF MRA, and DSA in our center were included. The visualization of the treated sites in the two MRA sequences was assessed using a 5-point scale. The aneurysm occlusion status according to each of the three imaging modalities was assessed using a 3-point scale. RESULTS: Forty-one patients with 46 saccular aneurysms were recruited. The image quality score of Silent MRA was significantly higher than that of TOF MRA (4.32 ± 0.87 vs. 3.08 ± 1.48, P < 0.001). In the aneurysms treated by simple coiling, the maximal aneurysm diameter showed a strong negative correlation with image quality score in TOF MRA (Spearman's r = -0.519, P = 0.033), while it showed no significant correlation in Silent MRA (r = -0.037, P = 0.887). For the aneurysm occlusion status, inter-modality agreement was excellent (κ = 0.845) between DSA and Silent MRA, but poor (κ = 0.185) between DSA and TOF MRA. CONCLUSIONS: Silent MRA was superior to TOF MRA in the follow-up of endovascular-treated intracranial aneurysms and showed excellent consistency with DSA in the evaluation of aneurysm occlusion. Therefore, Silent MRA is useful for the follow-up of endovascular-treated aneurysms.


Asunto(s)
Cuidados Posteriores , Aneurisma Intracraneal , Angiografía por Resonancia Magnética , Procedimientos Endovasculares , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/cirugía , Angiografía por Resonancia Magnética/métodos , Estudios Prospectivos , Reproducibilidad de los Resultados
19.
Mol Cell ; 49(6): 1108-20, 2013 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-23453805

RESUMEN

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.


Asunto(s)
Proteínas de Unión al ADN/química , N-Metiltransferasa de Histona-Lisina/química , Histonas/química , Proteína de la Leucemia Mieloide-Linfoide/química , Proteínas Nucleares/química , Factores de Transcripción/química , Ubiquitinación , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Animales , Proteínas de Unión al ADN/genética , Estabilidad de Enzimas , Expresión Génica , Células HeLa , Histona Metiltransferasas , Histonas/fisiología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Metilación , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Nucleosomas , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Factores de Transcripción/genética , Ubiquitina C/química , Enzimas Ubiquitina-Conjugadoras/química , Xenopus , Proteínas de Xenopus/química
20.
Proc Natl Acad Sci U S A ; 115(40): 10010-10015, 2018 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-30224453

RESUMEN

The Gcn5 histone acetyltransferase (HAT) subunit of the SAGA transcriptional coactivator complex catalyzes acetylation of histone H3 and H2B N-terminal tails, posttranslational modifications associated with gene activation. Binding of the SAGA subunit partner Ada2 to Gcn5 activates Gcn5's intrinsically weak HAT activity on histone proteins, but the mechanism for this activation by the Ada2 SANT domain has remained elusive. We have employed Fab antibody fragments as crystallization chaperones to determine crystal structures of a yeast Ada2/Gcn5 complex. Our structural and biochemical results indicate that the Ada2 SANT domain does not activate Gcn5's activity by directly affecting histone peptide binding as previously proposed. Instead, the Ada2 SANT domain enhances Gcn5 binding of the enzymatic cosubstrate acetyl-CoA. This finding suggests a mechanism for regulating chromatin modification enzyme activity: controlling binding of the modification cosubstrate instead of the histone substrate.


Asunto(s)
Acetilcoenzima A/química , Histona Acetiltransferasas/química , Histonas/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/química , Factores de Transcripción/química , Acetilcoenzima A/metabolismo , Cristalografía por Rayos X , Activación Enzimática , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Unión Proteica , Dominios Proteicos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo
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