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1.
BMC Geriatr ; 23(1): 862, 2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38102562

RESUMO

BACKGROUND: Thiazide-associated hyponatremia (TAH) has been supposed to increase the risk of major adverse cardiovascular events (MACE) in the elderly. Therefore, this study aimed to evaluate the association of TAH with the risk of MACE in elderly Taiwanese patients. METHODS: Data from the longitudinal generation tracking database (LGTD 2010) of the Health and Welfare Data Science Center (HWDC) were retrospectively assessed. The TAH study group was defined as using > 30 cumulative daily defined doses (CDDDs) thiazide diuretics within one year before diagnosis of hyponatremia. The control group (1:3 propensity score matching) had no diagnosis of hyponatremia but had used > 30 CDDDs thiazide diuretics within one year. Data on MACE were extracted using International Classification of Diseases codes. Outcomes were assessed using a multivariable Cox proportional hazard model and Kaplan-Meier analysis. RESULTS: A total of 1155 and 3465 individuals were enrolled in the TAH and the control groups, respectively. The rates of MACE (11.1% vs. 7.3%) and death (22.8% vs.12.2%) were significantly higher in the TAH group than the control group. In the TAH group, the adjusted HRs were 1.29 (CI 1.01 ‒ 1.65) for MACE, 1.39 (CI 1.19 ‒ 1.63) for all-cause death, and 1.61 (CI 0.90 ‒ 2.92) for stroke. CONCLUSION: TAH in patients above 65-years-old is associated with a 29% higher risk of MACE, 39% higher risk of all-cause death, and 61% higher risk of stroke. This work suggests that thiazides prescription in elderly patients should be more careful. However, further research is required to confirm our findings.


Assuntos
Hiponatremia , Acidente Vascular Cerebral , Humanos , Idoso , Tiazidas , Hiponatremia/induzido quimicamente , Hiponatremia/diagnóstico , Hiponatremia/epidemiologia , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Estudos Retrospectivos , Fatores de Risco
2.
Plant J ; 108(5): 1241-1255, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34583419

RESUMO

Plants sense various pathogens and activate immunity responses through receptor-like kinases (RLKs). Cysteine-rich receptor-like kinases (CRKs) are involved in massive transduction pathways upon perception of a pathogen. However, the roles of CRKs in response to stripe rust are unclear. In the present study, we identified a CRK gene (designated TaCRK10) from wheat variety Xiaoyan 6 (XY6) that harbors high-temperature seedling-plant (HTSP) resistance to stripe rust caused by fungal pathogen Puccinia striiformis f. sp. tritici (Pst). The expression level of TaCRK10 was induced by Pst inoculation and high temperature treatment. Knockdown of TaCRK10 by virus-induced gene silencing resulted in attenuated wheat HTSP resistance to Pst, whereas there is no effect on Pst development and host responses under normal temperatures. Notably, overexpression of TaCRK10 in susceptible variety Fielder provided resistance only under normal temperatures at 14 days with reactive oxygen species accumulation and defense-related gene expression of the salicylic acid pathway. Moreover, TaCRK10 physically interacted with and phosphorylated a histone variant TaH2A.1, which belongs to the H2A.W group. Silencing of TaH2A.1 suppressed wheat resistance to Pst, indicating that TaH2A.1 plays a positive role in wheat resistance to Pst. Thus, TaCRK10 serves as an important sensor of Pst infection and high temperatures, and it activates wheat resistance to Pst through regulating nuclear processes. This knowledge helps elucidate the molecular mechanism of wheat HTSP resistance to Pst and promotes efforts in developing wheat varieties with resistance to stripe rust.


Assuntos
Resistência à Doença/genética , Interações Hospedeiro-Patógeno , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Puccinia/fisiologia , Triticum/genética , Histonas/metabolismo , Temperatura Alta , Fosforilação , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Espécies Reativas de Oxigênio/metabolismo , Ácido Salicílico/metabolismo , Plântula/genética , Plântula/imunologia , Plântula/microbiologia , Plântula/fisiologia , Triticum/imunologia , Triticum/microbiologia , Triticum/fisiologia
3.
J Artif Organs ; 25(1): 1-8, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33956261

RESUMO

An in-vitro study was conducted to investigate the general feasibility of using only one pumping chamber of the SynCardia total artificial heart (TAH) as a replacement of the single ventricle palliated by Fontan circulation. A mock circulation loop was used to mimic a Fontan circulation. The combination of both ventricle sizes (50 and 70 cc) and driver (Freedom Driver and Companion C2 Driver) was investigated. Two clinical relevant scenarios (early Fontan; late Fontan) as derived from literature data were set up in the mock loop. The impact of increased transpulmonary pressure gradient, low atrial pressure, and raised central venous pressure on cardiac output was studied. From a hemodynamic point, the single-chambered TAH performed sufficiently in the setting of the Fontan circulation. Increased transpulmonary pressure gradient, from ideal to pulmonary hypertension, decreased the blood flow in combinations by almost 2 L/min. In the early Fontan scenario, a cardiac output of 3-3.5 L/min was achieved using the 50 cc ventricle, driven by the Companion C2 Driver. Even under pulmonary hypertension, cardiac outputs greater than 4 L/min could be obtained with the 70 cc pump chamber in the late Fontan scenario. In the clinically relevant Fontan scenarios, implementation of the single chambered TAH performed successfully from a hemodynamic point of view. The replacement of the failing univentricular heart by a single chamber of the SynCardia TAH may provide an alternative to a complex biventricular repair procedure or ventricular support in Fontan patients.


Assuntos
Técnica de Fontan , Cardiopatias Congênitas , Coração Artificial , Débito Cardíaco , Técnica de Fontan/métodos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/cirurgia , Hemodinâmica/fisiologia , Humanos
4.
J Card Surg ; 37(12): 5257-5261, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36321714

RESUMO

BACKGROUND: Although all congenital heart defects (CHD) present unique challenges, univentricular CHD are especially challenging given the difficulty of passively perfusing pulmonary blood flow. Three surgical procedures are required within the first years of life, with the final completing a Fontan circulation in which the inferior vena cava is connected to the pulmonary artery and previously connected superior vena cava. This allows passive venous return to the pulmonary circulation then flow into the single ventricle for systemic circulation. METHODS: Although a Fontan provides successful palliation for two to three decades, many complications can arise as pulmonary resistance must remain low to allow adequate forward flow. Eventually, the failing Fontan circulation requires temporary support as the patient awaits a heart transplant. We reviewed PubMed, Google Scholar, and U. Kentucky library for different techniques evaluated to support a failing Fontan circulation. RESULTS: Multiple technologies have been developed as a bridge to transplant to decrease morbidity. Innovative types of extracorporeal membrane oxygenation, ventricular assist devices, and total artificial hearts have been attempted in laboratory settings as well as in Fontan patients with varying degrees of success. This article emphasizes the strengths and weaknesses of each technology in the context of Fontan physiology. CONCLUSION: The end game for these patients remains a heart transplant. Without easy access to donors, each of the options discussed is a potential bridge to limit morbidity and mortality until a suitable donor heart becomes available.


Assuntos
Técnica de Fontan , Cardiopatias Congênitas , Transplante de Coração , Coração Auxiliar , Humanos , Veia Cava Superior/cirurgia , Doadores de Tecidos , Técnica de Fontan/métodos , Artéria Pulmonar/cirurgia , Cardiopatias Congênitas/cirurgia , Hemodinâmica/fisiologia
5.
J Obstet Gynaecol ; 42(4): 687-691, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34396874

RESUMO

Post-operative nausea and vomiting (PONV) is a disturbing issue. Dexamethasone has been suggested for the prevention of PONV. The aim of the present study was to evaluate the efficacy of dexamethasone as an anti-emetic and analgesic following total abdominal hysterectomy. The study was performed as a double blind, placebo-controlled randomised clinical trial on 102 women undergoing an open total abdominal hysterectomy. The intervention group received 8 mg dexamethasone 1 h before surgery, and the control group received a placebo. The total number of emesis episodes during the 24 h after surgery did not show significant difference between the two groups, however, the number of emesis episodes in hours 2 and 4 after the surgery were less in the intervention group, but not in hours 0, 6, 12 and 24. The nausea severity in hours 0, 2, 4, 6 and 12 after the surgery, was less in the intervention group. The severity of pain was not different between the two groups.IMPACT STATEMENTWhat is already known on this subject? Post-operative nausea and vomiting (PONV) is an important and disturbing issue. It is one of the most common problems following gynaecological surgeries including open total abdominal hysterectomy (TAH). Dexamethasone has been suggested as a prophylaxis for the prevention of PONV.What do the results of this study add? Dexamethasone 8 mg is effective for the prevention of late onset PONV (after 2 h of surgery) in the cases of open total abdominal hysterectomy. However, it has no effect on PONV immediately following surgery (hour 0) and pain.What are the implications of these findings for clinical practice and/or further research? Dexamethasone can be considered as an effective prophylaxis for PONV for the first 24 h after an open total abdominal hysterectomy, but it has limited effects on the management of early onset of PONV; between 0 and 2 h after surgery. Since the highest rates of emesis episodes and nausea severity are at this time, it is suggested to combine another rapid onset medication with dexamethasone. Also, dexamethasone, 8 mg, cannot be considered for pain relief after an open total abdominal hysterectomy. Higher amounts of dexamethasone should be evaluated for this purpose, in order to find appropriate dosages.


Assuntos
Antieméticos , Dor Pós-Operatória , Náusea e Vômito Pós-Operatórios , Antieméticos/uso terapêutico , Dexametasona/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Histerectomia/efeitos adversos , Dor/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Náusea e Vômito Pós-Operatórios/etiologia , Náusea e Vômito Pós-Operatórios/prevenção & controle , Vômito/tratamento farmacológico
6.
Neuroradiology ; 63(12): 2111-2119, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34128086

RESUMO

PURPOSE: Acute hydrocephalus is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). It can be self-limiting or require cerebrospinal fluid diversion. We aimed to determine the transient acute hydrocephalus (TAH) rate in patients with aSAH treated endovascularly and evaluate its predictive factors. METHODS: A retrospective review of 357 patients with aSAH who underwent endovascular treatment from March 2013 to December 2019 was performed. Clinical and radiographic data were analyzed and risk factors with potential significance for acute hydrocephalus were identified. We constructed a new risk score, the Drainage Or Transiency of Acute Hydrocephalus after Aneurysmal SAH (DOTAHAS) score, that may differentiate patients who would experience TAH from those needing surgical interventions. RESULTS: Acute hydrocephalus occurred in 129 patients (36%), out of whom in 66 patients (51%) it was self-limiting while 63 patients (49%) required external ventricular drainage placement. As independent risk factors for acute hydrocephalus, we identified older age, poor initial clinical condition, aSAH from posterior circulation, and the extent of cisternal and intraventricular hemorrhage. The following three factors were shown to predict acute hydrocephalus transiency and therefore included in the DOTAHAS score, ranging from 0 to 7 points: Hunt and Hess grade ≥ 3 (1 point), modified Fisher grade 4 (2 points), and Ventricular Hijdra Sum Score (vHSS) ≥ 6 (4 points). Patients scoring ≥ 3 points had significantly higher risk for EVD (P < 0.0001) than other patients. CONCLUSION: The newly developed DOTAHAS score can be useful in identifying patients with transient acute hydrocephalus. Further score evaluation is needed.


Assuntos
Aneurisma , Embolização Terapêutica , Hidrocefalia , Aneurisma Intracraniano , Hemorragia Subaracnóidea , Idoso , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Aneurisma Intracraniano/terapia , Estudos Retrospectivos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/terapia
7.
J Environ Manage ; 278(Pt 1): 111404, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33129079

RESUMO

The presence of pharmaceuticals and personal care products (PPCPs) in biosolids applied to farmland is of concern due to their potential accumulation in the environment and the subsequent effects on humans. Thermo-alkaline hydrolysis (TAH) is a method used for greater stabilization of biosolids after anaerobic digestion. In this work, the effect of TAH on five selected PPCPs including fluoroquinolone antibiotics, ciprofloxacin (CIP), and ofloxacin (OFLX), and three commonly used antimicrobial agents, miconazole (MIC), triclosan (TCS) and triclocarban (TCC) was evaluated. At the onset, extraction and analytical methods were optimized for maximum simultaneous recovery and LC-MS quantification of the target PPCPs from both water and biosolids for improved accuracy. The compounds were detected in the range of 54 ± 3 to 6166 ± 532 ng/g in raw biosoilds collected from a local WWTP. Next, batch control adsorption experiments of the selected PPCPs were conducted in various sludges, which indicated about 89%-98% sorption of the PPCPs onto solid phase due to their high octanol-water coefficients. Subsequently, thermo-alkaline (pH 9.5, 75 °C, 45 min) hydrolysis (TAH) was conducted to determine the extent of degradation of these compounds in deionized (DI) water and biosolids due to treatment. The degradation of these compounds due to TAH ranged from 42% to 99% and 37%-41% in pure water and biosolids, respectively, potentially lowering their risk in the environment due to land application. A list of compounds for which the optimized analytical method potentially can be used for detection and quantification in environmental samples is provided in the supporting document.


Assuntos
Cosméticos , Preparações Farmacêuticas , Triclosan , Biossólidos , Humanos , Esgotos
8.
Heart Fail Clin ; 17(4): 697-708, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34511216

RESUMO

Heart transplantation (HTx) is the treatment of choice in patients with late-stage advanced heart failure (Advanced HF). Survival rates 1, 5, and 10 years after transplantation are 87%, 77%, and 57%, respectively, and the average life expectancy is 9.16 years. However, because of the donor organ shortage, waiting times often exceed life expectancy, resulting in a waiting list mortality of around 20%. This review aims to provide an overview of current standard, recent advances, and future developments in the treatment of Advanced HF with a focus on long-term mechanical circulatory support and HTx.


Assuntos
Sistema Cardiovascular , Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Insuficiência Cardíaca/terapia , Humanos , Resultado do Tratamento , Listas de Espera
9.
J Comput Chem ; 41(1): 6-13, 2020 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-31568571

RESUMO

The elementometalation process is a fundamental chemical step in several catalytic cycles. In this work, density functional theory computations have elucidated the detailed elementometalation mechanism of activated alkyne RCCR(RCO2 Me) by Cp2 TaH3 and rationalized the selectivity in experimental findings. The calculated results show that in the formation process of (E)-olefin monohydride((E)-Pro), the Gibbs free energy barrier is low and the entire reaction is spontaneous and exothermic; thus, (E)-Pro can be formed easily. The formation of (Z)-η2 -olefin monohydride complex ((Z)-Pro) is difficult due to its high Gibbs free energy barrier. The formation process (E)-Pro consists of the following five steps: hydride H1-shift, conformational isomerism 1, hydride H2-shift, conformational isomerism 2, and olefin coordination process. Topological analysis shows that there is a five-membered ring plane structure in the reaction pathway and that the final product (E)-Pro belongs to a typical η2 -olefin monohydride complex. Our calculated results provide an explanation for experimental observations and useful insights for further development of olefin functionalization. © 2019 Wiley Periodicals, Inc.


Assuntos
Teoria da Densidade Funcional , Compostos Organometálicos/química , Termodinâmica , Alcinos/química , Dióxido de Carbono/química , Conformação Molecular , Nióbio/química , Eletricidade Estática , Estereoisomerismo , Tantálio/química
10.
Am J Kidney Dis ; 75(2): 256-264, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31606239

RESUMO

Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.


Assuntos
Hiponatremia/induzido quimicamente , Sódio/sangue , Tiazidas/efeitos adversos , Biomarcadores/sangue , Humanos , Hipertensão/tratamento farmacológico , Hiponatremia/sangue , Hiponatremia/diagnóstico
11.
Biol Res ; 52(1): 14, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30894225

RESUMO

BACKGROUND: Drought is a major abiotic stress affecting global wheat (Triticum aestivum L.) production. Exploration of drought-tolerant genes is essential for the genetic improvement of drought tolerance in wheat. Previous studies have shown that some histone encoding genes are involved in plant drought tolerance. However, whether the H2B family genes are involved in drought stress response remains unclear. METHODS: Here, we identified a wheat histone H2B family gene, TaH2B-7D, which was significantly up-regulated under drought stress conditions. Virus-induced gene silencing (VIGS) technology was used to further verify the function of TaH2B-7D in wheat drought tolerance. The phenotypic and physiological changes were examined in the TaH2B-7D knock-down plants. RESULTS: In the TaH2B-7D knock-down plants, relative electrolyte leakage rate and malonaldehyde (MDA) content significantly increased, while relative water content (RWC) and proline content significantly decreased compared with those in the non-knocked-down plants under drought stress conditions. TaH2B-7D knock-down plants exhibited severe sagging, wilting and dwarf phenotypes under drought stress conditions, but not in the non-knocked-down plants, suggesting that the former were more sensitive to drought stress. CONCLUSION: These results indicate that TaH2B-7D potentially plays a vital role in conferring drought tolerance in wheat.


Assuntos
Secas , Regulação da Expressão Gênica de Plantas/genética , Inativação Gênica , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Triticum/genética , Fenótipo , Fenômenos Fisiológicos Vegetais/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Reação em Cadeia da Polimerase em Tempo Real , Estresse Fisiológico/fisiologia , Triticum/metabolismo
12.
Bratisl Lek Listy ; 120(5): 325-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113193

RESUMO

INTRODUCTION: Implantation of a total artificial heart is an alternative to durable biventricular assist device support in selected patients. We present our initial experience with the implantation of the SynCardia total artificial heart (TAH) in three patients. The first patient, was the first SynCardia (TAH) implantation in the Visegrad Four (V4) countries METHOD: Three patients with severe refractory end stage biventricular heart failure listed for heart transplant were indicated for SynCardia TAH implantationRESULTS: We present in details the perioperative and postoperative outcomes of these patients. The first and the third patient, after 195 and 126 days of TAH support respectively, had a successful heart transplants, the second patient died on 11th postoperative day. The cause of death was brain bleeding due to ruptured undiagnosed brain aneurysm. CONCLUSION:   SynCardia TAH is an alternative therapy in patients with end-stage biventricular heart failure waiting for heart transplantation. The SynCardia TAH with pulsatility resembles the physiologic circulation, improves the condition of the patients and increases survival compared to the biventricular assist devices. It is an intermediate step until the development of genetically modified animal hearts, engineered bioartificial hearts or hearts from induced pluripotent stem cells that would replace the failing heart in the patients with end-stage heart disease (Tab. 2, Fig. 1, Ref. 27).


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Coração Artificial , Coração Auxiliar , Animais , Humanos , Período Pós-Operatório
13.
Adv Exp Med Biol ; 1106: 73-83, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484153

RESUMO

Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin-like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3-kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co-cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works.


Assuntos
Chaperonas Moleculares/química , Animais , Microscopia Crioeletrônica , Proteínas de Choque Térmico HSP90/química , Humanos , Neoplasias , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae
14.
Perfusion ; 32(1): 81-83, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27422864

RESUMO

We report our first clinical use of the new Protek DuoTM cannula for peripheral veno-venous extra-corporeal life support (ECLS). A 53-year-old male patient underwent implantation of a total artificial heart (TAH) for biventricular failure. However, due to the development of post-operative respiratory dysfunction, the patient required ECLS for six days.


Assuntos
Cateterismo/métodos , Oxigenação por Membrana Extracorpórea/métodos , Coração Artificial , Implantação de Prótese/métodos , Cânula , Coração Artificial/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Implantação de Prótese/efeitos adversos , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia
15.
Nitric Oxide ; 57: 85-91, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27178802

RESUMO

Nitric oxide (NO) is a ubiquitous signaling molecule involved in the regulation of a large number of cellular functions. The regulatory mechanism of NO generation in unicellular eukaryotic yeast cells is poorly understood due to the lack of mammalian and bacterial NO synthase (NOS) orthologues, even though yeast produces NO under oxidative stress conditions. Recently, we reported that the flavoprotein Tah18, which was previously shown to transfer electrons to the iron-sulfur cluster protein Dre2, is involved in NOS-like activity in the yeast Saccharomyces cerevisiae. On the other hand, Tah18 was reported to promote apoptotic cell death after exposure to hydrogen peroxide (H2O2). Here, we showed that NOS-like activity requiring Tah18 induced cell death upon treatment with H2O2. Our experimental results also indicate that Tah18-dependent NO production and cell death are suppressed by enhancement of the interaction between Tah18 and its molecular partner Dre2. Our findings indicate that the Tah18-Dre2 complex regulates cell death as a molecular switch via Tah18-dependent NOS-like activity in response to environmental changes.


Assuntos
Óxido Nítrico/biossíntese , Oxirredutases/fisiologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/metabolismo , Morte Celular , Peróxido de Hidrogênio/farmacologia , Proteínas Ferro-Enxofre/fisiologia , Complexos Multiproteicos/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/efeitos dos fármacos
16.
Biochim Biophys Acta ; 1839(2): 71-87, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24389346

RESUMO

The term molecular chaperone was first used to describe the ability of nucleoplasmin to prevent the aggregation of histones with DNA during the assembly of nucleosomes. Subsequently, the name was extended to proteins that mediate the post-translational assembly of oligomeric complexes protecting them from denaturation and/or aggregation. Hsp90 is a 90-kDa molecular chaperone that represents the major soluble protein of the cell. In contrast to most conventional chaperones, Hsp90 functions as a refined sensor of protein function and its principal role in the cell is to facilitate biological activity to properly folded client proteins that already have a preserved tertiary structure. Consequently, Hsp90 is related to basic cell functions such as cytoplasmic transport of soluble proteins, translocation of client proteins to organelles, and regulation of the biological activity of key signaling factors such as protein kinases, ubiquitin ligases, steroid receptors, cell cycle regulators, and transcription factors. A growing amount of evidence links the protective action of this molecular chaperone to mechanisms related to posttranslational modifications of soluble nuclear factors as well as histones. In this article, we discuss some aspects of the regulatory action of Hsp90 on transcriptional regulation and how this effect could have impacted genetic assimilation mechanism in some organisms.


Assuntos
Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Choque Térmico HSP90/genética , Humanos , Modelos Genéticos , Chaperonas Moleculares/genética , Ligação Proteica , Fatores de Transcrição/genética
17.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 5): 1197-206, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25945584

RESUMO

Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6-(Hsp90)2-Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes.


Assuntos
Ciclofilinas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Peptidil-Prolil Isomerase F , Ciclofilinas/química , Proteínas de Choque Térmico HSP90/química , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Chaperonas Moleculares/química , Dados de Sequência Molecular , Complexos Multiproteicos/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estrutura Secundária de Proteína , Proteínas de Saccharomyces cerevisiae/química , Homologia de Sequência de Aminoácidos
18.
J Cell Sci ; 126(Pt 17): 3982-9, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23813958

RESUMO

The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.


Assuntos
Reparo do DNA/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Homeostase do Telômero/genética , Telômero/metabolismo , Linhagem Celular , Proliferação de Células , DNA/metabolismo , Dano ao DNA/genética , Células HEK293 , Proteínas de Homeodomínio/genética , Humanos , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias , Interferência de RNA , RNA Interferente Pequeno , Telomerase/biossíntese , Telomerase/genética , Telomerase/metabolismo
19.
Trop Med Int Health ; 20(6): 707-18, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25694261

RESUMO

OBJECTIVES: To review current and emerging tools for Gambiense HAT control and elimination, and propose strategies that integrate these tools with epidemiological evidence. METHODS: We reviewed the scientific literature to identify contemporary and emerging tools and strategies for controlling and eliminating Gambiense HAT. Through an iterative process involving key stakeholders, we then developed comprehensive scenarios leading to elimination, considering both established and new tools for diagnosis, case treatment and vector control. RESULTS: Core components of all scenarios include detecting and treating cases with established or emerging techniques. Relatively more intensive scenarios incorporate vector control. New tools considered include tiny targets for tsetse fly control, use of rapid diagnostic tests and oral treatment with fexinidazole or oxaboroles. Scenarios consider the time when critical new tools are expected to become ready for deployment by national control programmes. Based on a review of the latest epidemiological data, we estimate the various interventions to cover 1,380,600 km(2) and 56,986,000 people. CONCLUSIONS: A number of new tools will fill critical gaps in the current armamentarium for diagnosing and treating Gambiense HAT. Deploying these tools in endemic areas will facilitate the comprehensive and sustainable control of the disease considerably and contribute to the ultimate goal of elimination.


Assuntos
Erradicação de Doenças , Doenças Negligenciadas/prevenção & controle , Trypanosoma brucei gambiense/fisiologia , Tripanossomíase Africana/prevenção & controle , África/epidemiologia , Animais , Humanos , Insetos Vetores/parasitologia , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/parasitologia , Saúde Pública , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/parasitologia
20.
Int J Surg Case Rep ; 114: 109102, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38061090

RESUMO

INTRODUCTION: Immune Thrombocytopenic Purpura poses unique challenges in surgical settings due to an increased risk of bleeding. This report details the perioperative management of a patient with Immune Thrombocytopenic Purpura undergoing Total Abdominal Hysterectomy, emphasizing the importance of tailored approaches for such cases. CASE PRESENTATION: A 41-year-old female with Immune Thrombocytopenic Purpura and symptomatic uterine fibroids, despite medical management, opted for Total Abdominal Hysterectomy. Prednisolone therapy and platelet transfusion were used preoperatively to optimize platelet counts. DISCUSSION: Effective management was achieved through meticulous surgery, continued prednisolone therapy, and vigilant postoperative monitoring. This case highlights the value of a multidisciplinary approach in ensuring positive surgical outcomes for Immune Thrombocytopenic Purpura patients. CONCLUSION AND RECOMMENDATION: This case underscores the significance of individualized perioperative care for Immune Thrombocytopenic Purpura patients undergoing major surgery. By optimizing medical therapy and maintaining close monitoring, favorable results can be achieved, enhancing the quality of life for such patients. It is recommended that such comprehensive approaches are considered in similar cases.

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