RESUMEN
Replication protein A (RPA) is a major regulator of eukaryotic DNA metabolism involved in multiple essential cellular processes. Maintaining appropriate RPA dynamics is crucial for cells to prevent RPA exhaustion, which can lead to replication fork breakage and replication catastrophe. However, how cells regulate RPA availability during unperturbed replication and in response to stress has not been well elucidated. Here, we show that HNRNPA2B1SUMO functions as an endogenous inhibitor of RPA during normal replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA to inhibit RPA accumulation at replication forks and impede local ATR activation. Declining HNRNPA2SUMO induced by DNA damage will release nuclear soluble RPA to localize to chromatin and enable ATR activation. Furthermore, we characterize that HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors. These findings establish HNRNPA2B1 as a critical player in RPA-dependent surveillance networks.
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Replicación del ADN , Proteína de Replicación A , Proteína de Replicación A/genética , Proteína de Replicación A/metabolismo , Replicación del ADN/genética , Sumoilación , Daño del ADN , Cromatina/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.
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Cromatina , Reparación del ADN , Animales , Cromatina/genética , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Mamíferos/metabolismo , Proteínas de Unión a Telómeros/genética , Proteína 1 de Unión al Supresor Tumoral P53/genética , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear. Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.
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Envejecimiento/genética , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Acetilación , Envejecimiento/metabolismo , Animales , Línea Celular , Daño del ADN , Proteínas de Unión al ADN/genética , Enzimas Desubicuitinizantes/metabolismo , Endopeptidasas/metabolismo , Femenino , Inestabilidad Genómica , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Dominios Proteicos , Procesamiento Proteico-Postraduccional , UbiquitinaciónRESUMEN
Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.
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Antígeno B7-H1/genética , Reparación del ADN , ADN de Neoplasias/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Regulación Neoplásica de la Expresión Génica , Receptor de Muerte Celular Programada 1/genética , Animales , Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Daño del ADN , ADN de Neoplasias/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Rayos gamma/uso terapéutico , Células HCT116 , Células HeLa , Humanos , Proteínas con Dominio MARVEL , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas de la Mielina , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Proteolisis/efectos de los fármacos , Proteolisis/efectos de la radiación , Estabilidad del ARN/efectos de los fármacos , Estabilidad del ARN/efectos de la radiación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In plant leaves, starch is composed of glucan polymers that accumulate in chloroplasts as the products of photosynthesis during the day; starch is mobilized at night to continuously provide sugars to sustain plant growth and development. Efficient starch degradation requires the involvement of several enzymes, including ß-amylase and glucan phosphatase. However, how these enzymes cooperate remains largely unclear. Here, we show that the glucan phosphatase LIKE SEX FOUR 1 (LSF1) interacts with plastid NAD-dependent malate dehydrogenase (MDH) to recruit ß-amylase (BAM1), thus reconstituting the BAM1-LSF1-MDH complex. The starch hydrolysis activity of BAM1 drastically increased in the presence of LSF1-MDH in vitro. We determined the structure of the BAM1-LSF1-MDH complex by a combination of cryo-electron microscopy, crosslinking mass spectrometry, and molecular docking. The starch-binding domain of the dual-specificity phosphatase and carbohydrate-binding module of LSF1 was docked in proximity to BAM1, thus facilitating BAM1 access to and hydrolysis of the polyglucans of starch, thus revealing the molecular mechanism by which the LSF1-MDH complex improves the starch degradation activity of BAM1. Moreover, LSF1 is phosphatase inactive, and the enzymatic activity of MDH was dispensable for starch degradation, suggesting nonenzymatic scaffold functions for LSF1-MDH in starch degradation. These findings provide important insights into the precise regulation of starch degradation.
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Proteínas de Arabidopsis , Arabidopsis , beta-Amilasa , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Malato Deshidrogenasa/metabolismo , beta-Amilasa/metabolismo , Simulación del Acoplamiento Molecular , Microscopía por Crioelectrón , Almidón/metabolismo , Glucanos/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.
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Caries Dental , Estudio de Asociación del Genoma Completo , Humanos , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Modelos Genéticos , FenotipoRESUMEN
Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3- to 8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a senescent-like state, marked by cell cycle arrest, the down-regulation of ribosomes and histones and down-regulation of MYC and p53 activity. The arrested embryos can be divided into 3 types. Type I embryos fail to complete the maternal-zygotic transition, and Type II/III embryos have low levels of glycolysis and either high (Type II) or low (Type III) levels of oxidative phosphorylation. Treatment with the SIRT agonist resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype, which is accompanied by changes in metabolic activity. Overall, our data suggests metabolic and epigenetic dysfunctions underlie the arrest of human embryos.
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Embrión de Mamíferos , Fertilización In Vitro , Embrión de Mamíferos/metabolismo , Epigénesis Genética , Histonas/metabolismo , Humanos , Cigoto/metabolismoRESUMEN
Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis (n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells (n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.
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Dietilhexil Ftalato , Contaminantes Ambientales , Leiomioma , Ácidos Ftálicos , Humanos , Femenino , Dietilhexil Ftalato/toxicidad , Dietilhexil Ftalato/orina , Quinurenina , Triptófano , Supervivencia Celular , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transportador de Aminoácidos Neutros Grandes 1 , Exposición a Riesgos Ambientales/efectos adversos , Leiomioma/inducido químicamente , Leiomioma/orinaRESUMEN
Distal hereditary motor neuropathy (dHMN) is a progressive neurological disease characterized by distal limb muscle weakness and amyotrophy. Sigma 1 receptor (σ1R), a gene product of SIGMAR1, mutations have been reported to induce dHMN, but its mechanism remains unknown. This study aims to explore the effect of C238T and 31_50del mutations in σ1R on neuronal SH-SY5Y cell functions. The SH-SY5Y cells that overexpressed σ1R, C238T mutant σ1R (σ1RC238T) or 31_50del mutant σ1R (σ1R31_50del) were constructed by pEGFPN1 vectors. We used Western blot (WB) and immunofluorescence (IF) staining to detect the expression of σ1R and green fluorescent proteins (GFP). Then, we evaluated the impact of σ1R mutation on apoptosis, autophagy, endoplasmic reticulum stress, and the involvement of the unfolded protein response (UPR) pathway in SH-SY5Y cells. We found that σ1RC238T and σ1R31_50del downregulated σ1R and promoted the apoptosis of SH-SY5Y cells. σ1RC238T and σ1R31_50del increased p-PERK, p-eIF2α, p-JNK, BIP, ATF4, CHOP, ATF6, XBP1, Caspase3, Caspase12 expressions and Ca2+ concentration, whereas decreased ATP content in SH-SY5Y cells. Besides, the expressions of LC3B, Lamp1, ATG7, Beclin-1 and phosphorylation of AMPK and ULK1 were increased, while the p62 level decreased after C238T or 31_50del mutation of σ1R. Additionally, AMPK knockdown abolished the apoptosis mediated by σ1RC238T or σ1R31_50del in SH-SY5Y cells. Our results indicated that C238T or 31_50del mutation in σ1R promoted motor neuron apoptosis through the AMPK/ULK1 pathway in dHMN. This study shed light on a better understanding of the neurons pathological mechanisms mediated by σ1R C238T and σ1R 31-50del in dHMN.
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Apoptosis , Homólogo de la Proteína 1 Relacionada con la Autofagia , Autofagia , Estrés del Retículo Endoplásmico , Receptores sigma , Receptor Sigma-1 , Humanos , Receptores sigma/metabolismo , Receptores sigma/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Línea Celular Tumoral , Transducción de Señal , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Respuesta de Proteína Desplegada , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , MutaciónRESUMEN
Osteosarcoma (OS) is the most common primary malignant tumor of bone. The aim of this study was to investigate the regulatory mechanisms of M2 macrophage exosomes (M2-Exos) in ferroptosis in OS. A mouse model was established to investigate the in vivo role of M2-Exos. We investigated their effects on ferroptosis in OS using erastin, a ferroptosis activator, and deferoxamine mesylate, an iron chelator. In vitro, we investigated whether the Apoc1/Acyl-CoA Synthetase Family Member 2 (ACSF2) axis mediates these effects, using shApoc1 and shACSF2. The mechanisms whereby Apoc1 regulates ACSF2 were examined using cyclohexanone, a protein synthesis inhibitor, and MG132, a proteasomal inhibitor. M2-Exos reversed the inhibitory effects of erastin on OS cells, thus enhancing their viability, migration, invasion, proliferation, and reducing ferroptosis. Apoc1 was highly expressed in M2-Exos, and interfering with this expression reversed the effects of M2-Exos on OS cells. ACSF2 mediated the effects of M2-Exos-derived Apoc1. Apoc1 interacted with ACSF2, which, in turn, interacted with USP40. Apoc1 overexpression increased ACSF2 ubiquitination, promoting its degradation, whereas USP40 overexpression inhibited ACSF2 ubiquitination and promoted its expression. Apoc1 overexpression inhibited ACSF2 binding to USP40. M2-Exos-derived Apoc1 promoted ferroptosis resistance by inhibiting USP40 binding to ACSF2 and promoting ACSF2 ubiquitination and degradation, thus enhancing OS development.
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BACKGROUND: It is unknown whether D2 lymphadenectomy + complete mesogastric excision for gastric cancer improves survival compared with just D2 lymphadenectomy. METHODS: Between September 2014 and June 2018, patients with advanced gastric cancer were randomly assigned (1 : 1) to laparoscopic D2 lymphadenectomy or D2 lymphadenectomy + complete mesogastric excision gastrectomy. The modified intention-to-treat population was defined as patients who had pathologically confirmed gastric adenocarcinoma (pT1 N1-3 M0 and pT2-4 N0-3 M0). The primary endpoint was 3-year disease-free survival. Secondary endpoints were the recurrence pattern and overall survival. RESULTS: The median follow-up of patients in the D2 lymphadenectomy group (169 patients) and patients in the D2 lymphadenectomy +complete mesogastric excision group (169 patients) was 55 (interquartile range 37-60)â months and 51 (interquartile range 40-60)â months respectively. Recurrence occurred in 50 patients in the D2 lymphadenectomy group (29.6%) versus 33 patients in the D2 lymphadenectomy + complete mesogastric excision group (19.5%) (P = 0.032). The 3-year disease-free survival was 75.5% (95% c.i. 68.3% to 81.3%) in the D2 lymphadenectomy group versus 85.0% (95% c.i. 78.7% to 89.6%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.042). The HR for recurrence in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 0.99) by Cox regression (P = 0.045). The 3-year overall survival rate was 77.5% (95% c.i. 70.4% to 83.1%) in the D2 lymphadenectomy group versus 85.8% (95% c.i. 79.6% to 90.2%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.058). The HR for death in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 1.02) (P = 0.058). CONCLUSION: Compared with conventional D2 dissection, D2 lymphadenectomy + complete mesogastric excision is associated with better disease-free survival, but there is no statistically significant difference in overall survival. REGISTRATION NUMBER: NCT01978444 (http://www.clinicaltrials.gov).
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Adenocarcinoma , Gastrectomía , Escisión del Ganglio Linfático , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Gastrectomía/métodos , Escisión del Ganglio Linfático/métodos , Masculino , Femenino , Persona de Mediana Edad , Adenocarcinoma/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Laparoscopía/métodos , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia , Adulto , Tasa de Supervivencia , Estadificación de NeoplasiasRESUMEN
Meiosis is a fundamental process for sexual reproduction in most eukaryotes and the evolutionarily conserved recombinases RADiation sensitive51 (RAD51) and Disrupted Meiotic cDNA1 (DMC1) are essential for meiosis and thus fertility. The mitotic function of RAD51 is clear, but the meiotic function of RAD51 remains largely unknown. Here we show that RAD51 functions as an interacting protein to restrain the Structural Maintenance of Chromosomes5/6 (SMC5/6) complex from inhibiting DMC1. We unexpectedly found that loss of the SMC5/6 partially suppresses the rad51 knockout mutant in terms of sterility, pollen inviability, and meiotic chromosome fragmentation in a DMC1-dependent manner in Arabidopsis thaliana. Biochemical and cytological studies revealed that the DMC1 localization in meiotic chromosomes is inhibited by the SMC5/6 complex, which is attenuated by RAD51 through physical interactions. This study not only identified the long-sought-after function of RAD51 in meiosis but also discovered the inhibition of SMC5/6 on DMC1 as a control mechanism during meiotic recombination.
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Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Recombinasa Rad51/genética , Rec A Recombinasas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Emparejamiento Cromosómico , Cromosomas de las Plantas , Regulación de la Expresión Génica de las Plantas , Mutación con Pérdida de Función , Meiosis , Complejos Multiproteicos/metabolismo , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Infertilidad Vegetal/genética , Polen/genética , Recombinasa Rad51/metabolismo , Rec A Recombinasas/genéticaRESUMEN
Chronic inflammation is an important pathogenetic factor that leads to the progression of Alzheimer's disease (AD), and specialized pro-resolving lipid mediators (SPMs) play critical role in regulating inflammatory responses during AD pathogenesis. Maresin1 (MaR1) is the latest discovered SPMs, and it is found that MaR1 improves AD cognitive impairment by regulating neurotrophic pathways to protect AD synapses and reduce Aß production, which made MaR1 as candidate agent for AD treatment. Unfortunately, the underlying mechanisms are still largely known. In this study, the AD mice and cellular models were subjected to MaR1 treatment, and we found that MaR1 reduced Aß production to ameliorate AD-related symptoms and increased the expression levels of ADAM10/17, sAPPα and sAPPß to exert its anti-inflammatory role. In addition, as it was determined by Western Blot analysis, we observed that MaR1 could affected the neuroprotective signal pathways. Specifically, MaR1 downregulated p57NTR and upregulated TrkA to activate the p75NTR/TrkA signal pathway, and it could increase the expression levels of p-PI3K and p-Akt, and downregulated p-mTOR to activate the PI3K/AKT/ERK/mTOR pathway. Finally, we verified the role of ADAM10/17 in regulating AD progression, and we found that silencing of ADAM10/17 inactivated the above neuroprotective signal pathways to aggravate AD pathogenesis. In conclusion, MaR1 is verified as potential therapeutic agent for AD by eliminating Aß production, upregulating ADAM10/17, sAPPα and sAPPß, and activating the neuroprotective p75NTR/TrkA pathway and the PI3K/AKT/ERK/mTOR pathway.
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Proteína ADAM10 , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Ácidos Docosahexaenoicos , Transducción de Señal , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Transducción de Señal/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/metabolismo , Péptidos beta-Amiloides/metabolismo , Ratones , Inflamación/metabolismo , Proyectos Piloto , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , MasculinoRESUMEN
We have demonstrated the molecular-weight effects of adding homopolystyrene (hPS) on the evolution of perforated layers and double gyroids in polystyrene-block-poly(methyl methacrylate)-based films during isothermal annealing. Two homopolystyrenes of 2.8 and 17 kg mol-1 were used. To prepare blend films, PS-b-PMMA and hPSx (x: 2.8 or 17) were mixed at a weight-fraction ratio of 75/25 in toluene and then spin-coated at SiOx/Si. Spin coating inevitably produced films with thick edges at the periphery of the substrate. The structural evolution of the spun films was in situ characterized by grazing incidence small-angle X-ray scattering (GISAXS). The annealed films were then characterized using a scanning electron microscope (SEM). We found that thin middle regions behaved differently from thick beads for the films. The middle of the blend films mainly formed perforated layers with different spatial orders and orientations, depending on the molecular weight of added hPS chains. Hexagonally perforated layers quickly formed at 205 °C for PS-b-PMMA/hPS2.8 films. However, when hPS17 was used instead of hPS2.8, perforated layers formed with defects in PS-b-PMMA/hPS17 films annealed at 205 °C. Annealing at 240 °C improved the spatial order and orientation of perforated layers for a PS-b-PMMA/hPS17 film. Nevertheless, annealing at 240 °C inversely depressed the in-plane spatial order of perforated layers for a PS-b-PMMA/hPS2.8 film. The depression in the in-plane spatial order is ascribed to a dilution effect of added short chains. Compared to the middle regions, the thick beads went through several metastable phases, such as perpendicularly oriented perforated layers and double gyroids.
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Two new energetic coordination compounds with 1D helical chain structures have been synthesized. First, the polyamine precursor 4,5-diamino-2-((4-amino-1,2,5-oxadiazole-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-imino chloride salt (TATAF-Cl) is obtained by incorporating 4-(chloromethyl)-1,2,5-oxadiazol-3-amine with 4H-1,2,4-triazole-3,4,5-triamine. Using a simple hydrothermal method, two energetic complexes, Ag(TATAF)(ClO4)2 (ECP-1) and Ag(TATAF)(NO3)2·H2O (ECP-2), with a helical 1D MOF structure of furazan and triazole were synthesized. Compounds ECP-1 and ECP-2 have relatively high nitrogen and oxygen content (N + O%: 52.04%, 61.04%), excellent crystal density (2.229 g cm-3, 2.116 g cm-3 at 298 K) and high heat of detonation (1.18 kcal g-1, 1.06 kcal g-1), good detonation performance (P: 35.34 GPa, 29.52 GPa; Dv: 8412 m s-1, 7794 m s-1), and moderate sensitivity (IS: 8 J, 13 J; FS: 72 N, 64 N). Structurally, the Ag+ of the two ECPs is coordinated with two energetic cations, two perchlorates, or one nitrate via tetragonal coordination to form a single helical structure that is interspersed up and down in two directions.
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A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available ß-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.
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BACKGROUND: Empathy is a critical component of nursing care, impacting both nurses' and patients' outcomes. However, perceived empathy from spouses during pregnancy and its impact on health-related quality of life (HRQoL) are unclear. This study aimed to examine pregnant women's perceived empathy from their spouses and assess the relation of perceived empathy on HRQoL. METHODS: This cross-sectional study, performed in the obstetric clinics or wards of four well-known hospitals in Anhui Province, China, included 349 pregnant women in the second or third trimester; participants were recruited by convenience sampling and enrolled from October to December 2021. A general information questionnaire, the Interpersonal Reactivity Index (IRI), a purpose-designed empathy questionnaire and the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12) were used to evaluate the pregnant women's general information, perceptions of empathy and HRQoL. Data were analysed using SPSS 22 at a threshold of P < 0.05. Descriptive analysis, Pearson correlation analysis, Student's t test, ANOVA, and multiple regression analysis were used for analysis. RESULTS: The pregnant women's total empathy, physical component summary (PCS) and mental component summary (MCS) scores were 41.6 ± 9.0, 41.6 ± 7.6, and 47.7 ± 9.1, respectively. Correlation analysis revealed that the purpose-designed empathy questionnaire items were significantly positively correlated with perspective taking and empathic concern but were not correlated with the personal distress dimension and were only partially correlated with the fantasy dimension. Maternal physical condition during pregnancy, planned pregnancy, and occupational stress were predictors of the PCS score (ß = 0.281, P < 0.01; ß = 0.132, P = 0.02; ß = -0.128, P = 0.02). The behavioural empathy item of our purpose-designed empathy questionnaire and empathic concern were important predictors of the MCS score (ß = 0.127, P = 0.02; ß = 0.158, P < 0.01), as well as other demographic and obstetric information, explaining 22.0% of the variance in MCS scores totally (F = 12.228, P < 0.01). CONCLUSIONS: Pregnant women perceived lower empathy from their spouses and reported lower HRQoL. Perceived empathy, particularly behavioural empathy, may significantly impact pregnant women's MCS scores but has no effect on their PCS scores. Strategies that foster perceived empathy from spouses among pregnant women are essential for facilitating healthy pregnancies and potentially improving maternal and child health.
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Empatía , Esposos , Embarazo , Niño , Humanos , Femenino , Estudios Transversales , Mujeres Embarazadas , Calidad de Vida , ChinaRESUMEN
BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).
Asunto(s)
Enterocolitis Necrotizante , Enfermedades del Prematuro , Síndrome de Dificultad Respiratoria del Recién Nacido , Femenino , Recién Nacido , Humanos , Recien Nacido Prematuro , Estado Nutricional , Enterocolitis Necrotizante/epidemiología , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/prevención & control , Emulsiones , Estudios Retrospectivos , Enfermedades del Prematuro/epidemiología , Enfermedades del Prematuro/etiología , Enfermedades del Prematuro/prevención & control , Factores de RiesgoRESUMEN
Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is one of the most devastating diseases in citrus industry worldwide. Most citrus cultivars such as sweet orange are susceptible to canker disease. Here, we utilized wild citrus to identify canker-resistant germplasms, and found that Atalantia buxifolia, a primitive (distant-wild) citrus, exhibited remarkable resistance to canker disease. Although the susceptibility gene LATERAL ORGAN BOUNDARIES 1 (LOB1) could also be induced in Atalantia after canker infection, the induction extent was far lower than that in sweet orange. In addition, three of amino acids encoded by transcription factor TFIIAγ in Atalantia (AbTFIIAγ) exhibited difference from those in sweet orange (CsTFIIAγ) which could stabilize the interaction between effector PthA4 and effector binding element (EBE) of LOB1 promoter. The mutation of AbTFIIAγ did not change its interaction with transcription factor binding motifs (TFBs). However, the AbTFIIAγ could hardly support the LOB1 expression induced by the PthA4. In addition, the activity of AbLOB1 promoter was significantly lower than that of CsLOB1 under the induction by PthA4. Our results demonstrate that natural variations of AbTFIIAγ and effector binding element (EBE) in the AbLOB1 promoter are crucial for the canker disease resistance of Atalantia. The natural mutations of AbTFIIAγ gene and AbLOB1 promoter in Atalantia provide candidate targets for improving the resistance to citrus canker disease.
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Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/genética , Rutaceae/genética , Factor de Transcripción TFIIA/genética , Citrus/genética , Citrus/crecimiento & desarrollo , Citrus/microbiología , Regulación de la Expresión Génica de las Plantas , Mutación/genética , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/genética , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Rutaceae/crecimiento & desarrollo , Rutaceae/microbiología , Xanthomonas/genética , Xanthomonas/patogenicidadRESUMEN
AIMS: The aims of the study were to explore the experiences of women with gestational diabetes mellitus (GDM) and their partners and examine the factors influencing partner involvement in GDM management, seeking to inform a targeted couple-based intervention. DESIGN: A descriptive qualitative study. METHODS: We conducted semi-structured interviews with 14 women with GDM and their partners. Participants were recruited through convenience sampling from a tertiary hospital in Xi'an, China. Data were analysed using thematic analysis. RESULTS: Three themes and 12 subthemes were identified. Theme I: Women's expectations of their partner's involvement in GDM management-practical support and emotional support. Theme II: Partner involvement in GDM management-constructive involvement, unhelpful involvement with good intentions and insufficient involvement. Theme III: Factors that influence partner involvement in GDM-knowledge of GDM, GDM risk perception, health consciousness, attitudes towards the treatment plan, couple communication regarding GDM management, family roles and appraisal of GDM management responsibility. CONCLUSION: Women desired practical and emotional support from partners. The types of partner involvement in GDM management varied. Some partners provided constructive support, while some partners' involvement was limited, non-existent or actively unhelpful. By combining these results with the factors influencing partner involvement, our findings may help healthcare professionals develop strategies to involve partners in GDM care and enhance women's ability to manage GDM. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Partner involvement in GDM care may help them understand and better attend to women's needs, thus improving their experience and potential outcomes. This study highlights novel factors that need to be considered in developing couple-based interventions for this population. REPORTING METHOD: The reporting follows the COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: Some patients were involved in data interpretation. There is no public contribution.