RESUMO
Singlet oxygen (1O2) has a very short half-life of 10-5 s; however, it is a strong oxidant that causes growth arrest and necrotic lesions on plants. Its signaling pathway remains largely unknown. The Arabidopsis flu (fluorescent) mutant accumulates a high level of 1O2 and shows drastic changes in nuclear gene expression. Only two plastid proteins, EX1 (executer 1) and EX2 (executer 2), have been identified in the singlet oxygen signaling. Here, we found that the transcription factor abscisic acid insensitive 4 (ABI4) binds the promoters of genes responsive to 1O2-signals. Inactivation of the ABI4 protein in the flu/abi4 double mutant was sufficient to compromise the changes of almost all 1O2-responsive-genes and rescued the lethal phenotype of flu grown under light/dark cycles, similar to the flu/ex1/ex2 triple mutant. In addition to cell death, we reported for the first time that 1O2 also induces cell wall thickening and stomatal development defect. Contrastingly, no apparent growth arrest was observed for the flu mutant under normal light/dim light cycles, but the cell wall thickening (doubled) and stomatal density reduction (by two-thirds) still occurred. These results offer a new idea for breeding stress tolerant plants.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Parede Celular/metabolismo , Regulação da Expressão Gênica de Plantas , Luz , Oxigênio Singlete/metabolismo , Transcriptoma , Estômatos de Plantas/metabolismoRESUMO
Abscisic acid (ABA) and gibberellins (GA) antagonistically mediate several biological processes, including seed germination, but the molecular mechanisms underlying ABA/GA antagonism need further investigation, particularly any role mediated by a transcription factors module. Here, we report that the DELLA protein RGL2, a repressor of GA signaling, specifically interacts with ABI4, an ABA signaling enhancer, to act as a transcription factor complex to mediate ABA/GA antagonism. The rgl2, abi3, abi4 and abi5 mutants rescue the non-germination phenotype of the ga1-t. Further, we demonstrate that RGL2 specifically interacts with ABI4 to form a heterodimer. RGL2 and ABI4 stabilize one another, and GA increases the ABI4-RGL2 module turnover, whereas ABA decreases it. At the transcriptional level, ABI4 enhances the RGL2 expression by directly binding to its promoter via the CCAC cis-element, and RGL2 significantly upregulates the transcriptional activation ability of ABI4 toward its target genes, including ABI5 and RGL2. Abscisic acid promotes whereas GA inhibits the ability of ABI4-RGL2 module to activate transcription, and ultimately ABA and GA antagonize each other. Genetic analysis demonstrated that both ABI4 and RGL2 are essential for the activity of this transcription factor module. These results suggest that the ABI4-RGL2 module mediates ABA/GA antagonism by functioning as a double agent.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Germinação , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Giberelinas/farmacologia , Giberelinas/metabolismo , Sementes/genéticaRESUMO
Cell cycle progression and the phytohormones auxin and abscisic acid (ABA) play key roles in primary root growth, but how ABA mediates the transcription of cell cycle-related genes and the mechanism of crosstalk between ABA and auxin requires further research. Here, we report that ABA inhibits primary root growth by regulating the ABA INSENSITIVE4 (ABI4)-CYCLIN-DEPENDENT KINASE B2;2 (CDKB2;2)/CYCLIN B1;1 (CYCB1;1) module-mediated cell cycle as well as auxin biosynthesis in Arabidopsis (Arabidopsis thaliana). ABA induced ABI4 transcription in the primary root tip, and the abi4 mutant showed an ABA-insensitive phenotype in primary root growth. Compared with the wild type (WT), the meristem size and cell number of the primary root in abi4 increased in response to ABA. Further, the transcription levels of several cell-cycle positive regulator genes, including CDKB2;2 and CYCB1;1, were upregulated in abi4 primary root tips. Subsequent chromatin immunoprecipitation (ChIP)-seq, ChIP-qPCR, and biochemical analysis revealed that ABI4 repressed the expression of CDKB2;2 and CYCB1;1 by physically interacting with their promoters. Genetic analysis demonstrated that overexpression of CDKB2;2 or CYCB1;1 fully rescued the shorter primary root phenotype of ABI4-overexpression lines, and consistently, abi4/cdkb2;2-cr or abi4/cycb1;1-cr double mutations largely rescued the ABA-insensitive phenotype of abi4 with regard to primary root growth. The expression levels of DR5promoter-GFP and PIN1promoter::PIN1-GFP in abi4 primary root tips were significantly higher than those in WT after ABA treatment, with these changes being consistent with changes in auxin concentration and expression patterns of auxin biosynthesis genes. Taken together, these findings indicated that ABA inhibits primary root growth through ABI4-mediated cell cycle and auxin-related regulatory pathways.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Divisão Celular , Ácidos Indolacéticos/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
BACKGROUND: Postoperative central diabetes insipidus (CDI) is commonly observed in craniopharyngioma (CP) patients, and the inflammatory response plays an important role in CPs. We aimed to evaluate the predictive value of preoperative peripheral inflammatory markers and their combinations regarding CDI occurrence in CPs. METHODS: The clinical data including preoperative peripheral inflammatory markers of 208 CP patients who underwent surgical treatment were retrospectively collected and analyzed. The preoperative peripheral white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelet (PLT), neutrophil-to-lymphocyte ratio (NLR), derived-NLR (dNLR), monocyte-to-lymphocyte ratio (MLR) and PLT-to-lymphocyte ratio (PLR) were assessed in total 208 CP patients and different age and surgical approach CP patient subgroups. Their predictive values were evaluated by the receiver operator characteristic curve analysis. RESULTS: Preoperative peripheral WBC, neutrophils, NLR, dNLR, MLR, and PLR were positively correlated and lymphocyte was negatively associated with postoperative CDI occurrence in CP patients, especially when WBC ≥ 6.66 × 109/L or lymphocyte ≤ 1.86 × 109/L. Meanwhile, multiple logistic regression analysis showed that WBC > 6.39 × 109/L in the > 18 yrs age patients, WBC > 6.88 × 109/L or lymphocytes ≤ 1.85 × 109/L in the transcranial approach patients were closely associated with the elevated incidence of postoperative CDI. Furthermore, the area under the curve obtained from the receiver operator characteristic curve analysis showed that the best predictors of inflammatory markers were the NLR in total CP patients, the MLR in the ≤ 18 yrs age group and the transsphenoidal group, the NLR in the > 18 yrs age group and the dNLR in the transcranial group. Notably, the combination index NLR + dNLR demonstrated the most valuable predictor in all groups. CONCLUSIONS: Preoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, are promising predictors of postoperative CDI in CPs.
Assuntos
Craniofaringioma , Diabetes Insípido Neurogênico , Neoplasias Hipofisárias , Complicações Pós-Operatórias , Humanos , Craniofaringioma/cirurgia , Craniofaringioma/sangue , Craniofaringioma/complicações , Feminino , Masculino , Estudos Retrospectivos , Adulto , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/complicações , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/diagnóstico , Adolescente , Pessoa de Meia-Idade , Criança , Adulto Jovem , Diabetes Insípido Neurogênico/sangue , Diabetes Insípido Neurogênico/etiologia , Neutrófilos , Biomarcadores/sangue , Linfócitos , Inflamação/sangue , Contagem de Leucócitos , Período Pré-Operatório , Pré-Escolar , Prognóstico , Curva ROCRESUMO
INTRODUCTION: Acromegaly patients, in addition to the most prominent physical and endocrine changes, also exhibit a higher risk of cognitive dysfunction. However, the reasons and mechanisms underlying cognitive impairments in acromegaly patients remain unknown. METHODS: Acromegalic rats were induced by subcutaneous injection of tumor cells, with continuous monitoring of the body weight and hormones to confirm the occurrence of acromegaly. Behavioral assessments, including open field test, novel object recognition test, and Barnes maze test, were conducted to evaluate the animals' cognitive function. Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to examine changes in the hippocampal tau protein, Aß, and associated signaling pathways. RESULTS: The tumor cells secreting growth hormone increased the secretion of growth hormone, resulting in changes in body size and endocrine functions, thus causing acromegaly. The acromegaly model showed deficiencies in working memory and spatial memory. Hyperphosphorylation of tau protein was observed in the hippocampus of the acromegaly model, but no Aß deposition was observed. The acromegaly model exhibits hippocampal growth hormone (GH) resistance, decreased expression of GH receptors, and subsequently reduced expression activity of the PI3K-Akt-GSK3ß signaling pathway, which is responsible for the hyperphosphorylation of tau protein. CONCLUSION: The prolonged elevation of GH and insulin-like growth factor 1 caused by acromegaly may lead to abnormalities in the SD rat's PI3K-Akt-GSK3ß signaling pathway, subsequently resulting in hyperphosphorylation of the hippocampal tau protein and cognitive impairment.
Assuntos
Acromegalia , Disfunção Cognitiva , Modelos Animais de Doenças , Hipocampo , Proteínas tau , Animais , Masculino , Ratos , Acromegalia/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Hormônio do Crescimento/metabolismo , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Aprendizagem em Labirinto/fisiologia , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Proteínas tau/metabolismoRESUMO
OBJECTIVE: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies. METHODS: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years. RESULTS: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy. CONCLUSION: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy.
RESUMO
Both seed germination and subsequent seedling establishment are key checkpoints during the life cycle of seed plants, yet flooding stress markedly inhibits both processes, leading to economic losses from agricultural production. Here, we report that melatonin (MT) seed priming treatment enhances the performance of seeds from several crops, including soybean, wheat, maize, and alfalfa, under flooding stress. Transcriptome analysis revealed that MT priming promotes seed germination and seedling establishment associated with changes in abscisic acid (ABA), gibberellin (GA), and reactive oxygen species (ROS) biosynthesis and signaling pathways. Real-time quantitative RT-PCR (qRT-PCR) analysis confirmed that MT priming increases the expression levels of GA biosynthesis genes, ABA catabolism genes, and ROS biosynthesis genes while decreasing the expression of positive ABA regulatory genes. Further, measurements of ABA and GA concentrations are consistent with these trends. Following MT priming, quantification of ROS metabolism-related enzyme activities and the concentrations of H2O2 and superoxide anions (O2 -) after MT priming were consistent with the results of transcriptome analysis and qRT-PCR. Finally, exogenous application of GA, fluridone (an ABA biosynthesis inhibitor), or H2O2 partially rescued the poor germination of non-primed seeds under flooding stress. Collectively, this study uncovers the application and molecular mechanisms underlying MT priming in modulating crop seed vigor under flooding stress.
Assuntos
Ácido Abscísico , Inundações , Germinação , Giberelinas , Melatonina , Espécies Reativas de Oxigênio , Plântula , Sementes , Melatonina/farmacologia , Melatonina/metabolismo , Germinação/efeitos dos fármacos , Ácido Abscísico/metabolismo , Giberelinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Plântula/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/genética , Sementes/efeitos dos fármacos , Sementes/metabolismo , Sementes/crescimento & desenvolvimento , Sementes/genética , Estresse Fisiológico , Produtos Agrícolas/metabolismo , Produtos Agrícolas/crescimento & desenvolvimento , Produtos Agrícolas/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacosRESUMO
Astrocyte-microglial interaction plays a crucial role in brain injury-associated neuroinflammation. Our previous data illustrated that astrocytes secrete microRNA, leading to anti-inflammatory effects on microglia. Long non-coding RNAs participate in neuroinflammation regulation after traumatic brain injury. However, the effect of astrocytes on microglial phenotype via long non-coding RNAs and the underlying molecular mechanisms remain elusive. We used long non-coding RNA sequencing on murine astrocytes and found that exosomal long non-coding RNA 4933431K23Rik attenuated traumatic brain injury-induced microglial activation in vitro and in vivo and ameliorated cognitive function deficiency. Furthermore, microRNA and messenger RNA sequencing together with binding prediction illustrated that exosomal long non-coding RNA 4933431K23Rik up-regulates E2F7 and TFAP2C expression by sponging miR-10a-5p. Additionally, E2F7 and TFAP2C, as transcription factors, regulated microglial Smad7 expression. Using Cx3cr1-Smad7 overexpression of adeno-associated virus, microglia specifically overexpressed Smad7 in the attenuation of neuroinflammation, resulting in less cognitive deficiency after traumatic brain injury. Mechanically, overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, preventing NF-κB signaling activation. The Smad7 activator asiaticoside alleviates neuroinflammation and protects neuronal function in traumatic brain injury mice. This study revealed that an exosomal long non-coding RNA from astrocytes attenuates microglial activation after traumatic brain injury by up-regulating Smad7, providing a potential therapeutic target.
Assuntos
Lesões Encefálicas Traumáticas , MicroRNAs , RNA Longo não Codificante , Camundongos , Animais , Microglia/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Astrócitos/metabolismo , Doenças Neuroinflamatórias , MicroRNAs/metabolismo , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Fenótipo , Camundongos Endogâmicos C57BLRESUMO
A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.
Assuntos
Apoptose , Compostos Benzidrílicos , Cálcio , Glucose , Glucosídeos , Sistema de Sinalização das MAP Quinases , Mitocôndrias , Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glucose/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Cálcio/metabolismo , Animais , Ratos , Linhagem Celular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Caspase 3/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismoRESUMO
Transcriptional regulation plays a key role in the control of seed dormancy, and many transcription factors (TFs) have been documented. However, the mechanisms underlying the interactions between different TFs within a transcriptional complex regulating seed dormancy remain largely unknown. Here, we showed that TF PHYTOCHROME-INTERACTING FACTOR4 (PIF4) physically interacted with the abscisic acid (ABA) signaling responsive TF ABSCISIC ACID INSENSITIVE4 (ABI4) to act as a transcriptional complex to promote ABA biosynthesis and signaling, finally deepening primary seed dormancy. Both pif4 and abi4 single mutants exhibited a decreased primary seed dormancy phenotype, with a synergistic effect in the pif4/abi4 double mutant. PIF4 binds to ABI4 to form a heterodimer, and ABI4 stabilizes PIF4 at the protein level, whereas PIF4 does not affect the protein stabilization of ABI4. Subsequently, both TFs independently and synergistically promoted the expression of ABI4 and NCED6, a key gene for ABA anabolism. The genetic evidence is also consistent with the phenotypic, physiological and biochemical analysis results. Altogether, this study revealed a transcriptional regulatory cascade in which the PIF4-ABI4 transcriptional activator complex synergistically enhanced seed dormancy by facilitating ABA biosynthesis and signaling.
Assuntos
Ácido Abscísico , Proteínas de Arabidopsis , Arabidopsis , Regulação da Expressão Gênica de Plantas , Dormência de Plantas , Transdução de Sinais , Fatores de Transcrição , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/genética , Dormência de Plantas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ligação Proteica , Sementes/metabolismo , Sementes/genética , Mutação/genéticaRESUMO
The Taiwan Society of Cardiology (TSOC) and Taiwan Society of Plastic Surgery (TSPS) have collaborated to develop a joint consensus for the management of patients with advanced vascular wounds. The taskforce comprises experts including preventive cardiologists, interventionists, and cardiovascular and plastic surgeons. The consensus focuses on addressing the challenges in diagnosing, treating, and managing complex wounds; incorporates the perfusion evaluation and the advanced vascular wound care team; and highlights the importance of cross-disciplinary teamwork. The aim of this joint consensus is to manage patients with advanced vascular wounds and encourage the adoption of these guidelines by healthcare professionals to improve patient care and outcomes. The guidelines encompass a range of topics, including the definition of advanced vascular wounds, increased awareness, team structure, epidemiology, clinical presentation, medical treatment, endovascular intervention, vascular surgery, infection control, advanced wound management, and evaluation of treatment results. It also outlines a detailed protocol for assessing patients with lower leg wounds, provides guidance on consultation and referral processes, and offers recommendations for various wound care devices, dressings, and products. The 2024 TSOC/TSPS consensus for the management of patients with advanced vascular wounds serves as a catalyst for international collaboration, promoting knowledge exchange and facilitating advancements in the field of advanced vascular wound management. By providing a comprehensive and evidence-based approach, this consensus aims to contribute to improved patient care and outcomes globally.
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BACKGROUND: Weeds are not only economically important but also fascinating models for studying the adaptation of species in human-mediated environments. Aegilops tauschii is the D-genome donor species of common wheat but is also a weed that influences wheat production. How shading stress caused by adjacent wheat plants affects Ae. tauschii growth is a fundamental scientific question but is also important in agriculture, such as for weed control and wheat breeding. RESULT: The present study indicated that shade avoidance is a strategy of Ae. tauschii in response to shading stress. Ae. tauschii plants exhibited growth increases in specific organs, such as stem and leaf elongation, to avoid shading. However, these changes were accompanied by sacrificing the growth of other parts of the plants, such as a reduction in tiller number. The two reverse phenotype responses seem to be formed by systemically regulating the expression of different genes. Fifty-six genes involved in the regulation of cell division and cell expansion were found to be downregulated, and one key upstream negative regulator (RPK2) of cell division was upregulated under shading stress. On the other hand, the upregulated genes under shading stress were mainly enriched in protein serine/threonine kinase activity and carbon metabolism, which are associated with cell enlargement, signal transduction and energy supply. The transcription factor WRKY72 may be important in regulating genes in response to shading stress, which can be used as a prior candidate gene for further study on the genetic regulation of shade avoidance. CONCLUSIONS: This study sheds new light on the gene expression changes and molecular processes involved in the response and avoidance of Ae. tauschii to shading stress, which may aid more effective development of shading stress avoidance or cultivars in wheat and other crops in the future.
Assuntos
Aegilops , Humanos , Aegilops/genética , Triticum , Transcriptoma , Melhoramento Vegetal , FenótipoRESUMO
Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases associated with the degradation of memory and cognitive ability. Current pharmacotherapies show little therapeutic effect in AD treatment and still cannot prevent the pathological progression of AD. Deep brain stimulation (DBS) has shown to enhance memory in morbid obese, epilepsy and traumatic brain injury patients, and cognition in Parkinson's disease (PD) patients deteriorates during DBS off. Some relevant animal studies and clinical trials have been carried out to discuss the DBS treatment for AD. Reviewing the fornix trials, no unified conclusion has been reached about the clinical benefits of DBS in AD, and the dementia ratings scale has not been effectively improved in the long term. However, some patients have presented promising results, such as improved glucose metabolism, increased connectivity in cognition-related brain regions and even elevated cognitive function rating scale scores. The fornix plays an important regulatory role in memory, attention, and emotion through its complex fibre projection to cognition-related structures, making it a promising target for DBS for AD treatment. Moreover, the current stereotaxic technique and various evaluation methods have provided references for the operator to select accurate stimulation points. Related adverse events and relatively higher costs in DBS have been emphasized. In this article, we summarize and update the research progression on fornix DBS in AD and seek to provide a reliable reference for subsequent experimental studies on DBS treatment of AD.
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Doença de Alzheimer , Estimulação Encefálica Profunda , Animais , Humanos , Doença de Alzheimer/terapia , Estimulação Encefálica Profunda/métodos , Fórnice/metabolismo , Fórnice/patologia , Encéfalo/patologia , CogniçãoRESUMO
INTRODUCTION: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. METHODS: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0-43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. RESULTS: Compared with mean monthly ESA dose of 15,000-25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001-43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000-25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. CONCLUSIONS: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.
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Eritropoetina , Hematínicos , Humanos , Hematínicos/efeitos adversos , Estudos Retrospectivos , Eritropoese , Diálise Renal/métodos , Epoetina alfa , Hemoglobinas , Eritropoetina/efeitos adversosRESUMO
A novel method for the preparation of tetrahydropentaleno[1,2-c]pyrroles (8) is described via the reaction of anilines with 1-en-4-yn-3-ols in the presence of Lewis acid. Oxidation of 8 with Br2 gave pentaleno[1,2-c]pyrroles (10), which is the first reported tricyclic 5/5/5 ring with a fully conjugated system. Structures of these obtained compounds were characterized by spectroscopic methods, and compounds 8a,b and 10c were further confirmed by X-ray crystallographic determination.
Assuntos
Pirróis , Pirróis/química , Cristalografia por Raios X , Oxirredução , Estrutura MolecularRESUMO
Clinical trials are essential to the process of new drug development. As clinical trials involve significant investments of time and money, it is crucial for trial designers to carefully investigate trial settings prior to designing a trial. Utilizing trial documents from ClinicalTrials.gov, we aim to understand the common characteristics of successful and unsuccessful cancer drug trials to provide insights about what to learn and what to avoid. In this research, we first computationally classified cancer drug trials into successful and unsuccessful cases and then utilized natural language processing to extract eligibility criteria information from the trial documents. To provide explainable and potentially modifiable recommendations for new trial design, contrast mining was applied to discoverhighly contrasted patterns with a significant difference in prevalence between successful (completion with advancement to the next phase) and unsuccessful (suspended, withdrawn, or terminated) groups. Our method identified contrast patterns consisting of combinations of drug categories, eligibility criteria, study organization, and study design for nine major cancers. In addition to a literature review for the qualitative validation of mined contrast patterns, we found that contrast-pattern-based classifiers using the top 200 contrast patterns as feature representations can achieve approximately 80% F1 score for eight out of ten cancer types in our experiments. In summary, aligning with the modernization efforts of ClinicalTrials.gov, our study demonstrates that understanding the contrast characteristics of successful and unsuccessful cancer trials may provide insights into the decision-making process for trial investigators and therefore facilitate improved cancer drug trial design.
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Antineoplásicos , Neoplasias , Humanos , Projetos de Pesquisa , Processamento de Linguagem Natural , Definição da ElegibilidadeRESUMO
BACKGROUND: This study aimed to identify adverse events following the first three doses of COVID-19 vaccines in hemodialysis (HD) patients. Risk factors associated with postvaccination adverse events were explored. METHODS: Postvaccination adverse events in 438 HD patients who received 3 doses of COVID-19 vaccines were prospectively assessed. The adverse events among three doses were compared using generalized linear mixed models. Factors associated with adverse events were assessed with multivariate analyses. RESULTS: The vast majority of participants received Oxford/AstraZeneca ChAdOx1 as their first two doses and Moderna mRNA-1273 as their third dose. Overall, 79%, 50% and 84% of the participants experienced at least one adverse event after their first, second, and third doses, respectively. These adverse events were mostly minor, short-lived and less than 5% reported daily activities being affected. Compared with the first dose, the second dose caused a lower rate of adverse events. Compared with the first dose, the third dose elicited a higher rate of injection site reactions and a lower rate of systemic reactions. Multivariate analyses showed that every 10-year increase of age (odds ratio 0.67, 95% confidence intervals 0.57-0.79) was associated with decreased risk of adverse events, while female sex (2.82, 1.90-4.18) and arteriovenous fistula (1.73, 1.05-2.84) were associated with increased risk of adverse events. Compared with Oxford/AstraZeneca ChAdOx1, Moderna mRNA-1273 was associated with an increased risk of injection site reactions. CONCLUSIONS: COVID-19 vaccination was well tolerated in HD patients. Age, sex, dialysis vascular access and vaccine types were associated with postvaccination adverse events.
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Vacinas contra COVID-19 , COVID-19 , Humanos , Feminino , Vacinas contra COVID-19/efeitos adversos , Vacina de mRNA-1273 contra 2019-nCoV , Reação no Local da Injeção , COVID-19/prevenção & controle , Diálise Renal , Vacinação/efeitos adversosRESUMO
OBJECTIVE: Mandibular distraction osteogenesis (MDO) is a powerful tool for the correction of hemifacial microsomia (HFM). The temporomandibular joint (TMJ) is the focus of attention in the diagnosis and treatment of HFM. This observational retrospective cross-sectional study aimed to investigate morphologic changes in TMJ post-MDO in type IIa HFM. METHODS: We recruited 48 patients with unilateral type IIa HFM who had completed MDO and mandibular distractor extraction (MDE). Data relating to the length, distance, angle, and volume of the TMJ were measured on 3-dimension models created by the analysis of computed tomography data. Normality analysis was performed by using the Shapiro-Wilk test. Data were compared with the paired t test and Wilcoxon signed-ranks test. RESULTS: The spaces between the affected condyle and the affected glenoid fossa before MDO were all significantly larger than before MDE (P<0.05). The breadth of the affected glenoid fossa before MDO was significantly longer than before MDE (P<0.001). The height of the affected condyle before MDO was significantly longer than before MDE (P<0.001). The volume of the affected condyle before MDO was significantly larger than before MDE (P<0.001). The ratio between the volume of the affected condyle and unaffected condyle before MDO was 0.20±0.13. The ratio between the volume of the affected condyle before MDE and MDO was 0.65±0.32. The resorption rate of the affected condyle post-MDO was 0.35±0.32. CONCLUSION: Herein, we characterized anatomic changes of the TMJ in type- IIa HFM post-MDO. Condylar resorption and the compression of space between the condyle and the glenoid fossa on the affected side were 2 typical manifestations. Our findings enhanced the understanding of the application of MDO on HFM.
Assuntos
Síndrome de Goldenhar , Osteogênese por Distração , Humanos , Estudos Transversais , Estudos Retrospectivos , Articulação TemporomandibularRESUMO
OBJECTIVE: This observational retrospective cross-sectional study aimed to investigate the morphological characteristics of the temporomandibular joint (TMJ) in type IIa hemifacial microsomia (HFM). METHODS: We recruited 88 patients with unilateral type IIa HFM. Data relating to the length, distance, and angle of the TMJ, were measured on 3-dimensional models created by the analysis of computed tomography data. Normality analysis was performed by using the Shapiro-Wilk test. Data were compared with the paired t test and Wilcoxon signed-rank test. RESULTS: The height, long axis, and short axis of the affected condyle were significantly shorter than the unaffected side ( P <0.001); the ratios were 0.41±0.15, 0.75±0.20, and 0.95±0.24, respectively. The spaces between the condyle and the glenoid fossa were significantly larger in affected TMJs ( P <0.001). The ratio between the ipsilateral and contralateral anterior space in the sagittal plane was 4.62±2.59; this was significantly different than the ratio of inner space (1.50±1.70), superior space (1.70±0.97), and lateral space (1.28±0.62) in the coronal plane ( P <0.001) and the ratio of superior space (1.43±1.05) and posterior space (1.47±0.98) in the sagittal plane ( P <0.001); there were no statistical differences between the 5 spaces ( P >0.05). The breadth and depth of the glenoid fossa were significantly shorter in affected TMJs ( P <0.001), the ratio of the breadth in the affected and unaffected glenoid fossa was between 0.5 and 1 and the depth of the affected glenoid fossa was almost half of that on the unaffected side. The ratio between the ipsilateral and contralateral height of the condyle was significantly different when compared with the length of the mandibular ramus ( P <0.001). The ratio between the ipsilateral height of the condyle and the length of the mandibular ramus was significantly different when compared with that of the contralateral side ( P <0.001). The height of the affected condyle were significantly different ( P =0.005) among different ages. CONCLUSIONS: We found that hypoplasia was more severe in terms of the height of the condyle than the long axis and short axis of the condyle. The degree of condyle deformity was more severe than the mandible. And the affected condyle still had growth potential in the vertical direction with age.
Assuntos
Síndrome de Goldenhar , Humanos , Estudos Retrospectivos , Estudos Transversais , Articulação Temporomandibular , Mandíbula , Côndilo MandibularRESUMO
Seed dormancy is an important agronomic trait in cereals and leguminous crops as low levels of seed dormancy during harvest season, coupled with high humidity, can cause preharvest sprouting. Seed longevity is another critical trait for commercial crop propagation and production, directly influencing seed germination and early seedling establishment. Both traits are precisely regulated by the integration of genetic and environmental cues. Despite the significance of these two traits in crop production, the relationship between them at the molecular level is still elusive, even with contradictory conclusions being reported. Some studies have proposed a positive correlation between seed dormancy and longevity in association with differences in seed coat permeability or seed reserve accumulation, whereas an increasing number of studies have highlighted a negative relationship, largely with respect to phytohormone-dependent pathways. In this review paper, we try to provide some insights into the interactions between regulatory mechanisms of genetic and environmental cues, which result in positive or negative relationships between seed dormancy and longevity. Finally, we conclude that further dissection of the molecular mechanism responsible for this apparently contradictory relationship between them is needed.