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BACKGROUND: No reliable clinical tools exist to predict acute kidney injury (AKI) progression. We aim to explore a scoring system for predicting the composite outcome of progression to severe AKI or death within seven days among early AKI patients after cardiac surgery. METHODS: In this study, we used two independent cohorts, and patients who experienced mild/moderate AKI within 48 h after cardiac surgery were enrolled. Eventually, 3188 patients from the MIMIC-IV database were used as the derivation cohort, while 499 patients from the Zhongshan cohort were used as external validation. The primary outcome was defined by the composite outcome of progression to severe AKI or death within seven days after enrollment. The variables identified by LASSO regression analysis were entered into logistic regression models and were used to construct the risk score. RESULTS: The composite outcome accounted for 3.7% (n = 119) and 7.6% (n = 38) of the derivation and validation cohorts, respectively. Six predictors were assembled into a risk score (AKI-Pro score), including female, baseline eGFR, aortic surgery, modified furosemide responsiveness index (mFRI), SOFA, and AKI stage. And we stratified the risk score into four groups: low, moderate, high, and very high risk. The risk score displayed satisfied predictive discrimination and calibration in the derivation and validation cohort. The AKI-Pro score discriminated the composite outcome better than CRATE score, Cleveland score, AKICS score, Simplified renal index, and SRI risk score (all P < 0.05). CONCLUSIONS: The AKI-Pro score is a new clinical tool that could assist clinicians to identify early AKI patients at high risk for AKI progression or death.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Progressão da Doença , Humanos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Feminino , Masculino , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Estudos de Coortes , Índice de Gravidade de Doença , Curva ROC , Medição de Risco , PrognósticoRESUMO
The etiopathogenesis of late-onset Alzheimer's disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.
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Doença de Alzheimer , Hipocampo , Transcriptoma , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Masculino , Feminino , Idoso , Predisposição Genética para Doença , Mitocôndrias/metabolismo , Mitocôndrias/genética , Estudo de Associação Genômica Ampla , Idoso de 80 Anos ou mais , Proteínas de Transporte da Membrana Mitocondrial/genética , Atrofia/genéticaRESUMO
Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis-the non-pathogenic hyper-production of red blood cells-that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34+ human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a ß-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.
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Objective: This study aimed to identify and characterize a novel endo-ß-glucanase, IDSGLUC9-4, from the rumen metatranscriptome of Hu sheep. Methods: A novel endo-ß-glucanase, IDSGLUC9-4, was heterologously expressed in Escherichia coli and biochemically characterized. The optimal temperature and pH of recombinant IDSGLUC9-4 were determined. Subsequently, substrate specificity of the enzyme was assessed using mixed-linked glucans including barley ß-glucan and Icelandic moss lichenan. Thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF) analyses were conducted to determine the products released from polysaccharides and cello-oligosaccharides substrates. Results: The recombinant IDSGLUC9-4 exhibited temperature and pH optima of 40 °C and pH 6.0, respectively. It exclusively hydrolyzed mixed-linked glucans, with significant activity observed for barley ß-glucan (109.59 ± 3.61 µmol·mg-1·min-1) and Icelandic moss lichenan (35.35 ± 1.55 µmol·mg-1·min-1). TLC and HPLC analyses revealed that IDSGLUC9-4 primarily released cellobiose, cellotriose, and cellotetraose from polysaccharide substrates. Furthermore, after 48 h of reaction, IDSGLUC9-4 removed most of the glucose, indicating transglycosylation activity alongside its endo-glucanase activity. Conclusion: The recombinant IDSGLUC9-4 was a relatively acid-resistant, mesophilic endo-glucanase (EC 3.2.1.4) that hydrolyzed glucan-like substrates, generating predominantly G3 and G4 oligosaccharides, and which appeared to have glycosylation activity. These findings provided insights into the substrate specificity and product profiles of rumen-derived GH9 glucanases and contributed to the expanding knowledge of cellulolytic enzymes and novel herbivore rumen enzymes in general.
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Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality in utero. However, in utero transfusions now enable survival to birth. Postnatally, patients face challenges similar to ß-thalassemia, including severe anemia and erythrotoxicity due to imbalance of ß-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for ß-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the ß-globin locus in αTM patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette dramatically increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently normal hemoglobin. By directing edited HSPCs toward increased production of clinically relevant RBCs instead of other divergent cell types, this approach has the potential to mitigate the limitations of traditional HSCT for the hemoglobinopathies, including low genome editing and low engraftment rates. These findings support development of a definitive ex vivo autologous genome editing strategy that may be curative for α-thalassemia.
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Electrospun polymeric nanofibrous membranes are emerging as the promising substrates for preparation of flexible SERS nanosensors due to their intrinsic nanoscale surface roughness, easy scalability as well as rich surface reactivity. Although the nanofiber membranes prepared from high performance thermoplastics exhibit good mechanical stability, the SERS nanosensors based on these substrates normally have lower signal-to-noise ratio because of the interference from background Raman signals of aromatic moieties. Herein, we synthesized an optically transparent polyurethane (PU) and rigid polyarylene ether amidoxime (PEA), which were electrospun into core-shell nanofibers membranes with a "beads-on-web" morphology. Furthermore, the PU-PEA membranes were coated with ultra-thin silver layer and thermally annealed to prepare the flexible SERS nanosensor without any background noises. In addition, the Raman enhancement of SERS nanosensor can be readily improved by tuning of PU-PEA composition, silver thickness as well as thermal annealing temperature. Finally, the optimized SERS nanosensor enables label-free detection of sulfamethoxazole as low as 0.1 nM with a good reproducibility and detection performance in real water sample. Meanwhile, the optimized SERS nanosensor shows long term anti-biofouling capacity. Thanks to its facile fabrication, competitive analytical performance and resistance to biofouling, the current work basically open new way for design of flexible SERS nanosensors for biomedical applications.
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Carotenoids are photosynthetic pigments and antioxidants that contribute to different plant colors. However, the involvement of TOPLESS (TPL/TPR)-mediated histone deacetylation in the modulation of carotenoid biosynthesis through ethylene-responsive element-binding factor-associated amphiphilic repression (EAR)-containing transcription factors (TFs) in apple (Malus domestica Borkh.) is poorly understood. MdMYB44 is a transcriptional repressor that contains an EAR repression motif. In the present study, we used functional analyses and molecular assays to elucidate the molecular mechanisms through which MdMYB44-MdTPR1-mediated histone deacetylation influences carotenoid biosynthesis in apples. We identified two carotenoid biosynthetic genes, MdCCD4 and MdCYP97A3, that were confirmed to be involved in MdMYB44-mediated carotenoid biosynthesis. MdMYB44 enhanced ß-branch carotenoid biosynthesis by repressing MdCCD4 expression, whereas MdMYB44 suppressed lutein level by repressing MdCYP97A3 expression. Moreover, MdMYB44 partially influences carotenoid biosynthesis by interacting with the co-repressor TPR1 through the EAR motif to inhibit MdCCD4 and MdCYP97A3 expression via histone deacetylation. Our findings indicate that the MdTPR1-MdMYB44 repressive cascade regulates carotenoid biosynthesis, providing profound insights into the molecular basis of histone deacetylation-mediated carotenoid biosynthesis in plants. These results also provide evidence that the EAR-harboring TF/TPL repressive complex plays a universal role in histone deacetylation-mediated inhibition of gene expression in various plants.
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Carotenoides , Regulação da Expressão Gênica de Plantas , Histonas , Malus , Proteínas de Plantas , Fatores de Transcrição , Carotenoides/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Malus/genética , Malus/metabolismo , Histonas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Acetilação , Plantas Geneticamente ModificadasRESUMO
Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 µM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.
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Rim , Parabenos , Transdução de Sinais , Peixe-Zebra , Animais , Humanos , Regulação para Baixo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Glucosídeos/farmacologia , Células HEK293 , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Nefropatias/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Parabenos/toxicidade , Fenóis/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Flexible and stretchable transparent heaters (THs) have been widely used in various applications, including deicing and defogging of flexible screens as well as thermotherapy pads. Ionic THs based on ionogels have emerged as a promising alternative to conventional electronic THs due to their unique advantages in terms of transparency-conductance conflict, uniform heating, and interfacial adhesion. However, the commonly used hydrophilic ionogels inevitably introduce a moisture-sensitive issue. In this work, we present a stretchable and transparent hydrophobic ionogel-based heater that utilizes ionic current-induced Joule heating under high-frequency alternating current. This ionogel-based TH exhibits exceptional multifunctional properties with low hysteresis, a fracture strain of 840%, transmittance of 93%, conductivity of 0.062 S m-1, temperature resistance up to 165 °C, voltage resistance up to 120 V, heating rate of 0.1 °C s-1, steady-state temperature at 115 °C, and uniform heating even when bent or stretched (up to 200%). Furthermore, it maintains its heating performance when it is directly exposed to water. This hydrophobic ionogel-based TH expands the range of materials available for ionic THs and paves the way for their practical applications.
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Carotenoids are major pigments contributing to fruit coloration. We previously reported that the apple (Malus domestica Borkh.) mutant fruits of "Beni Shogun" and "Yanfu 3" show a marked difference in fruit coloration. However, the regulatory mechanism underlying this phenomenon remains unclear. In this study, we determined that carotenoid is the main factor influencing fruit flesh color. We identified an R1-type MYB transcription factor (TF), MdMYBS1, which was found to be highly associated with carotenoids and abscisic acid (ABA) contents of apple fruits. Overexpression of MdMYBS1 promoted, and silencing of MdMYBS1 repressed, ß-branch carotenoids synthesis and ABA accumulation. MdMYBS1 regulates carotenoid biosynthesis by directly activating the major carotenoid biosynthetic genes encoding phytoene synthase (MdPSY2-1) and lycopene ß-cyclase (MdLCYb). 9-cis-epoxycarotenoid dioxygenase 1 (MdNCED1) contributes to ABA biosynthesis, and MdMYBS1 enhances endogenous ABA accumulation by activating the MdNCED1 promoter. In addition, the basic leucine zipper domain TF ABSCISIC ACID-INSENSITIVE5 (MdABI5) was identified as an upstream activator of MdMYBS1, which promotes carotenoid and ABA accumulation. Furthermore, ABA promotes carotenoid biosynthesis and enhances MdMYBS1 and MdABI5 promoter activities. Our findings demonstrate that the MdABI5-MdMYBS1 cascade activated by ABA regulates carotenoid-derived fruit coloration and ABA accumulation in apple, providing avenues in breeding and planting for improvement of fruit coloration and quality.
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Ácido Abscísico , Carotenoides , Frutas , Regulação da Expressão Gênica de Plantas , Malus , Proteínas de Plantas , Fatores de Transcrição , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Malus/genética , Malus/metabolismo , Malus/efeitos dos fármacos , Carotenoides/metabolismo , Frutas/genética , Frutas/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Pigmentação/genética , Pigmentação/efeitos dos fármacosRESUMO
Lumpy skin disease virus (LSDV) infection is a major socio-economic issue that seriously threatens the global cattle-farming industry. Here, a recombinant virus LSDV-ΔTK/EGFP, expressing enhanced green fluorescent protein (EGFP), was constructed with a homologous recombination system and applied to the high-throughput screening of antiviral drugs. LSDV-ΔTK/EGFP replicates in various kidney cell lines, consistent with wild-type LSDV. The cytopathic effect, viral particle morphology, and growth performance of LSDV-ΔTK/EGFP are consistent with those of wild-type LSDV. High-throughput screening allowed to identify several molecules that inhibit LSDV-ΔTK/EGFP replication. The strong inhibitory effect of theaflavin on LSDV was identified when 100 antiviral drugs were screened in vitro. An infection time analysis showed that theaflavin plays a role in the entry of LSDV into cells and in subsequent viral replication stages. The development of this recombinant virus will contribute to the development of LSDV-directed antiviral drugs and the study of viral replication and mechanisms of action.
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Doenças dos Bovinos , Doença Nodular Cutânea , Vírus da Doença Nodular Cutânea , Animais , Bovinos , Antivirais/farmacologia , Ensaios de Triagem em Larga Escala/veterinária , Replicação Viral , Linhagem CelularRESUMO
Temozolomide (TMZ) resistance presents a significant challenge in the treatment of gliomas. Although lysine demethylase 4A (KDM4A) has been implicated in various cancer-related processes, its role in TMZ resistance remains unclear. This study aims to elucidate the contribution of KDM4A to TMZ resistance in glioma cells and its potential implications for glioma prognosis. We assessed the expression of KDM4A in glioma cells (T98G and U251MG) using qRT-PCR and Western blot assays. To explore the role of KDM4A in TMZ resistance, we transfected siRNA targeting KDM4A into drug-resistant glioma cells. Cell viability was assessed using the CCK-8 assay and the TMZ IC50 value was determined. ChIP assays were conducted to investigate KDM4A, H3K9me3, and H3K36me3 enrichment on the promoters of ROCK2 and HUWE1. Co-immunoprecipitation confirmed the interaction between HUWE1 and ROCK2, and we examined the levels of ROCK2 ubiquitination following MG132 treatment. Notably, T98G cells exhibited greater resistance to TMZ than U251MG cells, and KDM4A displayed high expression in T98G cells. Inhibiting KDM4A resulted in decreased cell viability and a reduction in the TMZ IC50 value. Mechanistically, KDM4A promoted ROCK2 transcription by modulating H3K9me3 levels. Moreover, disruption of the interaction between HUWE1 and ROCK2 led to reduced ROCK2 ubiquitination. Inhibition of HUWE1 or overexpression of ROCK2 counteracted the sensitization effect of si-KDM4A on TMZ responsiveness in T98G cells. Our findings highlight KDM4A's role in enhancing TMZ resistance in glioma cells by modulating ROCK2 and HUWE1 transcription and expression through H3K9me3 and H3K36me3 removal.
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Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Histonas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Glioma/genética , Metilação , Resistencia a Medicamentos Antineoplásicos/genética , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
Lysine acetylation is a conserved regulatory posttranslational protein modification that is performed by lysine acetyltransferases (KATs). By catalyzing the transfer of acetyl groups to substrate proteins, KATs play critical regulatory roles in all domains of life; however, no KATs have yet been identified in cyanobacteria. Here, we tested all predicted KATs in the cyanobacterium Synechococcus sp. PCC 7002 (Syn7002) and demonstrated that A1596, which we named cyanobacterial Gcn5-related N-acetyltransferase (cGNAT2), can catalyze lysine acetylation in vivo and in vitro. Eight amino acid residues were identified as the key residues in the putative active site of cGNAT2, as indicated by structural simulation and site-directed mutagenesis. The loss of cGNAT2 altered both growth and photosynthetic electron transport in Syn7002. In addition, quantitative analysis of the lysine acetylome identified 548 endogenous substrates of cGNAT2 in Syn7002. We further demonstrated that cGNAT2 can acetylate NAD(P)H dehydrogenase J (NdhJ) in vivo and in vitro, with the inability to acetylate K89 residues, thus decreasing NdhJ activity and affecting both growth and electron transport in Syn7002. In summary, this study identified a KAT in cyanobacteria and revealed that cGNAT2 regulates growth and photosynthesis in Syn7002 through an acetylation-mediated mechanism.
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Lisina Acetiltransferases , Synechococcus , Lisina Acetiltransferases/genética , Lisina Acetiltransferases/metabolismo , Lisina/metabolismo , Acetiltransferases/genética , Acetiltransferases/metabolismo , Synechococcus/genética , Synechococcus/metabolismo , AcetilaçãoRESUMO
OBJECTIVE: Systematic evaluation of the efficacy and safety of conservative hemodynamic cure for venous insufficiency (CHIVA) compared with high ligation and stripping (HLS) in the treatment of varicose veins of lower extremities. METHODS: We conducted a systematic literature search and compared the randomized controlled trial and retrospective cohort study of CHIVA and HLS in the treatment of varicose veins of lower extremities in several databases, including China National Knowledge Infrastructure, Wanfang database, cqvip datebase, PubMed, Cochrane library and EMBASE, to identify articles that might meet the criteria. Meta-analysis was performed using Revman 5.3 and Stata 13.0 software. RESULTS: This Meta-analysis included a total of 14 research articles. This meta-analysis shows that CHIVA requires shorter operation time than HLS [mean difference (MD) = -13.57, 95% confidence interval (CI) (-21.05, -6.10), P = .0004]. There is less blood loss with CHIVA surgery [MD = -21.72, 95% CI (-30.35, -13.09), P < .00001]. The number of incisions made by the CHIVA technique is less [MD = -3.67, 95% CI (-4.03, -3.31), P < .00001]. Patients who underwent CHIVA had a shorter hospital stay [MD = -3.40, 95% CI (-4.72, -2.09), P < .00001]. The relapse rate was lower after CHIVA [OR = 0.36, 95% CI (0.18, 0.70), P = .003]. In terms of postoperative complications, CHIVA has a lower total complication rate [MD = 0.26, 95% CI (0.15, 0.46), P < .00001]. The incidence of deep vein thrombosis was lower after CHIVA [MD = 0.23, 95% CI (0.06, 0.92), P = .04]. CHIVA has a lower incidence of sensory disturbance than HLS [OR = 0.39, 95% CI (0.25, 0.60), P < .0001]. CHIVA technique has less nerve injury rate than HLS [OR = 0.11, 95% CI (0.02, 0.62), P = .01]. The incidence of hematoma was lower after CHIVA [OR = 0.48, 95% CI (0.27, 0.87), P = .02]. Among other metrics, the comparison results of the 2 techniques were similar. CONCLUSION: By comparison, it is found that CHIVA has shorter operation time, less blood loss, and fewer surgical incisions. Patients who underwent CHIVA surgery had shorter hospital stays and lower relapse rates. In terms of complications, the incidence of total complications after CHIVA is lower, and the incidence of postoperative deep vein thrombosis, postoperative sensory, nerve injury, and postoperative hematoma is also lower than that of HLS.
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Varizes , Trombose Venosa , Humanos , Estudos Retrospectivos , Procedimentos Cirúrgicos Vasculares/métodos , Varizes/cirurgia , Extremidade Inferior , Complicações Pós-Operatórias , Ultrassonografia de Intervenção , Hematoma , Recidiva , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer's disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. OBJECTIVE: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAß KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. METHODS: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAß KI mice as well as primary neuron cultures. RESULTS: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. CONCLUSIONS: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.
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Doença de Alzheimer , Grelina , Humanos , Camundongos , Animais , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Peptídeos beta-Amiloides , Hipocampo/metabolismo , Envelhecimento/genética , Doença de Alzheimer/genéticaRESUMO
Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid ß 42 (Aß42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Aß (humanized Aß-knockin [hAß-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aß42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Aß, intramitochondrial Aß was relatively preserved from activated microglial phagocytosis in aged hAß-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aß sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Aß, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.
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Doença de Alzheimer , Humanos , Animais , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Mitocôndrias/metabolismo , Encéfalo/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Esophageal gastric anastomosis is a common surgical technique used to treat patients with gastric cancer who undergo total gastrectomy. However, using simple anastomosis techniques alone may not meet the needs of patients in some cases and can lead to complications such as anastomotic stenosis and ulceration. In order to overcome these issues and improve patient prognosis, muscle flap reconstruction technique has emerged. Muscle flap reconstruction is a method of improving gastric-esophageal anastomosis by transplanting muscle tissue. By covering the anastomotic site with muscle tissue, it not only enhances the stability of the anastomosis site but also increases blood supply, promoting healing and recovery of the anastomosis. Therefore, the use of muscle flap reconstruction technique in esophageal gastric anastomosis during total gastrectomy for gastric cancer is increasingly widely applied. AIM: To determine the effectiveness of esophagogastric anastomosis using the muscle flap reconstruction technology in total abdominal gastrectomy for gastric cancer and perform follow-up experiments to understand the factors affecting patients' prognosis. METHODS: The study subjects were 60 patients with gastric cancer who were admitted to our hospital between October 2018 and January 2022. All patients underwent esophagogastric anastomosis using the double muscle flap reconstruction technology in total abdominal gastrectomy. Perioperative indicators were determined, and patients were followed up for 1 year. Furthermore, patient outcomes were observed within 1 year, followed by patient classification based on different outcomes. Moreover, clinicopathological parameters were observed and relevant factors affecting patient prognosis were analyzed. RESULTS: The operation time was 318 ± 43 min, the formation time of esophageal double muscle flap anastomosis was 110 ± 13 min, the number of lymph node dissections was 26 ± 6, the incision length was 3 ± 0.6 cm, intraoperative bleeding volume was 48 ± 15 mL, first anal exhaust time was 5.3 ± 1.8 d, first meal time was 6.0 ± 1.6 d, length of hospital stay was 11.8 ± 2.5, and treatment cost was 5.8 ± 0.7 thousand yuan. The patient experienced three postoperative complications: 2 cases of pulmonary infection and 1 case of respiratory discomfort. During 1-year follow-up, 50 patients survived and 10 died. Univariate analysis revealed that histological types, tumor size, tumor-node-metastasis staging, vascular invasion, and postoperative adjuvant radiotherapy and chemotherapy were the main factors affecting the prognosis of surviving patients. Furthermore, Cox regression analysis revealed that postoperative adjuvant radiotherapy and chemotherapy were the main factors affecting patient prognosis. The survival time of the survival group was significantly higher than that of the death group (P < 0.05). CONCLUSION: Esophagogastric anastomotic using muscle flap reconstruction exhibits good effects on patients who undergo total abdominal gastrectomy for cancer. Postoperative adjuvant radiotherapy and chemotherapy are the main factors affecting patient prognosis.
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OBJECTIVE: To evaluate the chronic health risk of heavy metals and metalloid in drinking water through oral ingestion in a typical area. METHODS: Monitoring data of seven heavy metals and metalloid elements(Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd) in drinking water in a typical area of Huaihe River Basin were collected from 2015 to 2019. The health risks of heavy metals and metalloid in drinking water in the area were assessed using the classic four-step health risk assessment model. RESULTS: The average concentrations of Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd in drinking water in the typical area of Huaihe River Basin were(0.13±0.45), (0.49±0.49), (0.34±0.99), (1.10±2.49), (32.29±126.64), (2.13±0.50) and(0.03±0.04) µg/L, respectively. In which, Hg, Mn and Ni exceeded the limit of the Standard for Drinking Water(GB 5749-2006), the exceedance rates were 2.14%, 6.79% and 0.3%, respectively, and the maximum exceedance times were 2.61, 8.90 and 0.34, respectively. The chronic non-carcinogenic risks of Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd were 1.32×10~(-2), 4.99×10~(-2), 2.97×10~(-3), 1.68×10~(-3), 7.04×10~(-3), 2.17×10~(-2) and 1.83×10~(-3), respectively. The carcinogenic risks of As, Pb, Cr~(6+) and Cd were 2.24×10~(-5), 8.82×10~(-8), 3.25×10~(-5) and 5.86×10~(-7), respectively. CONCLUSION: Hg, Mn and Ni in drinking water exceeded the standard in a typical area of Huaihe River Basin from 2015 to 2019. The chronic non-carcinogenic risks of Hg, As and other 7 heavy metals and metalloid are at an acceptable level(HQ≤1), while As and Cr~(6+) have certain carcinogenic risks(10~(-6)≤CR≤10~(-4)).
Assuntos
Água Potável , Metaloides , Metais Pesados , Poluentes Químicos da Água , Cádmio , China , Água Potável/análise , Água Potável/química , Monitoramento Ambiental , Chumbo , Mercúrio , Metaloides/análise , Metais Pesados/análise , Medição de Risco , Rios , Poluentes Químicos da Água/análise , HumanosRESUMO
Six phosphorescence-emitting metal-organic mononuclear Cu(I) complexes, namely four quinoline-containing three-coordinate Cu(I) complexes and two N-heterocyclic carbene-containing four-coordinate Cu(I) complexes, have been successfully developed and fully characterized. All these Cu(I) complexes include the same bis(2-diphenylphosphinophenyl)ether bidentate auxiliary ligand. Significantly, four-coordinate Cu(I) complexes 1 and 2 display typical aggregation-induced emission phenomena. Their solid samples of luminogenic complexes 1-6 emit a variety of different phosphorescence. Furthermore, solid-state phosphorescence of these Cu(I) complexes can be effectively manipulated by external mechanical force. Remarkably, luminophores 1, 2 and 5 exhibit blue-shifted mechanoluminochromism responses, while luminophores 3, 4 and 6 present red-shifted mechanoluminochromism characteristics. All of the observed mechano-responsive phosphorescence changes of solids 1-6 are reversible by the method of solvent fuming. Powder X-ray diffraction results confirm that the reversible mechanically induced phosphorescence changes of complexes 1-6 are due to the mutual transformation of ordered crystalline and metastable amorphous states.