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1.
Drug Discov Today ; 29(11): 104200, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39384032

RESUMO

This review discusses the growing importance of target validation within phase I (P1) trials as a new trend in drug development, especially in establishing proof of concept (POC) for first-in-class drugs. The paper describes two approaches: the P1-PIV approach, which directly evaluates the primary endpoint for a pivotal clinical study to confirm therapeutic effects during P1, and the newly introduced P1-FCTE, which assesses functional changes necessary for therapeutic effect as a novel target validation milestone in P1. By providing practical examples of first-in-class drugs, we compare the benefits, costs, hurdles and applicable therapeutic areas of these approaches. Finally, we discuss the potential of these novel approaches to facilitate POC success, shorten development timelines and ultimately increase drug discovery success rates.

2.
Yi Chuan ; 46(8): 649-660, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39140145

RESUMO

The localization of the meiotic specific regulatory molecule Moa1 to the centromere is regulated by the kinetochore protein CENP-C, and participates in the cohesion of sister chromatids in the centromere region mediated by the cohesin Rec8. To examine the interaction of these proteins, we analyzed the interactions between Moa1 and Rec8, CENP-C by yeast two-hybrid assays and identified several amino acid residues in Moa1 required for the interaction with CENP-C and Rec8. The results revealed that the interaction between Moa1 and CENP-C is crucial for the Moa1 to participate in the regulation of monopolar attachment of sister kinetochores. However, mutation at S143 and T150 of Moa1, which are required for interaction with Rec8 in the two-hybrid assay, did not show significant defects. Mutations in amino acid residues may not be sufficient to interfere with the interaction between Moa1 and Rec8 in vivo. Further research is needed to determine the interaction domain between Moa1 and Rec8. This study revealed specific amino acid sites at which Moa1 affects the meiotic homologous chromosome segregation, providing a deeper understanding of the mechanism of meiotic chromosome segregation.


Assuntos
Proteínas Cromossômicas não Histona , Meiose , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Ligação Proteica , Cinetocoros/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Técnicas do Sistema de Duplo-Híbrido , Segregação de Cromossomos , Coesinas , Fosfoproteínas
3.
Yi Chuan ; 46(7): 552-559, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39016088

RESUMO

During meiosis, defects in cohesin localization within the centromere region can result in various diseases. Accurate cohesin localization depends on the Mis4-Ssl3 loading complex. Although it is known that cohesin completes the loading process with the help of the loading complex, the mechanisms underlying its localization in the centromere region remain unclear. Previous studies suggest cohesin localization in the centromere is mediated by phosphorylation of centromeric proteins. In this study, we focused on the Fta2 protein, a component of the Sim4 centromere protein complex. Using bioinformatics methods, potential phosphorylation sites were identified, and fta2-9A and fta2-9D mutants were constructed in Schizosaccharomyces pombe. The phenotypes of these mutants were characterized through testing thiabendazole (TBZ) sensitivity and fluorescent microscopy localization. Results indicated that Fta2 phosphorylation did not impact mitosis but affected chromosome segregation during meiosis. This study suggests that Fta2 phosphorylation is vital for meiosis and may be related to the specific localization of cohesin during this process.


Assuntos
Meiose , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Centrômero/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/efeitos dos fármacos , Coesinas , Meiose/efeitos dos fármacos , Fosforilação , Schizosaccharomyces/citologia , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética
4.
Yi Chuan ; 46(6): 502-508, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38886153

RESUMO

Ssu72 is a component of the yeast cleavage/polyadenylation factor (CPF) complex, which catalyzes the dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II at S5-P and S7-P. It has been shown that Ssu72 phosphatase is involved in regulating chromosome cohesion during mitosis. To further clarify whether Ssu72 phosphatase affects chromosome separation during meiotic division in Schizosaccharomyces pombe, we utilized green fluorescent protein (GFP) to label centromeres and red fluorescent protein to label microtubule protein Atb2. The entire meiotic chromosome separation process of ssu72∆ cells was observed in real-time under fluorescence microscope. It was found that two spindles of ssu72∆ cells crossed during the metaphase and anaphase of the second meiotic division, and this spindle crossing led to a new type of spore defect distribution pattern. The results of this study can provide important reference significance for studying the roles of phosphatase Ssu72 in higher organisms.


Assuntos
Meiose , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Fuso Acromático , Schizosaccharomyces/genética , Schizosaccharomyces/enzimologia , Fuso Acromático/genética , Fuso Acromático/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Segregação de Cromossomos
5.
Life Sci Alliance ; 7(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38575358

RESUMO

For establishing sister chromatid cohesion and proper chromosome segregation in mitosis in fission yeast, the acetyltransferase Eso1 plays a key role. Eso1 acetylates cohesin complexes, at two conserved lysine residues K105 and K106 of the cohesin subunit Psm3. Although Eso1 also contributes to reductional chromosome segregation in meiosis, the underlying molecular mechanisms have remained elusive. Here, we purified meiosis-specific Rec8 cohesin complexes localized at centromeres and identified a new acetylation at Psm3-K1013, which largely depends on the meiotic kinetochore factor meikin (Moa1). Our molecular genetic analyses indicate that Psm3-K1013 acetylation cooperates with canonical acetylation at Psm3-K105 and K106, and plays a crucial role in establishing reductional chromosome segregation in meiosis.


Assuntos
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Coesinas , Segregação de Cromossomos/genética , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Acetilação , Meiose/genética , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo
6.
Life Sci Alliance ; 7(5)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38448160

RESUMO

In meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase I. The conserved meiosis-specific kinetochore protein meikin (Moa1 in fission yeast) associates with polo-like kinase: Plo1 and regulates both mono-orientation and cohesion protection. Although the phosphorylation of Rec8-S450 by Plo1 associated with Moa1 plays a key role in cohesion protection, how Moa1-Plo1 regulates mono-orientation remains elusive. Here, we identify Plo1 phosphorylation sites in the cohesin subunits, Rec8 and Psm3. The non-phosphorylatable mutations at these sites showed specific defects in mono-orientation. These results enabled the genetic dissection of meikin functions at the centromeres.


Assuntos
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Cinetocoros , Fosforilação , Coesinas , Meiose , Centrômero , Schizosaccharomyces/genética , Proteínas Serina-Treonina Quinases , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Ciclo Celular/genética
7.
Circ J ; 88(10): 1664-1671, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-38417888

RESUMO

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy. METHODS AND RESULTS: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.


Assuntos
Ruptura Aórtica , Bases de Dados Factuais , Procedimentos Endovasculares , Mortalidade Hospitalar , Humanos , Masculino , Idoso , Feminino , Ruptura Aórtica/mortalidade , Ruptura Aórtica/epidemiologia , Ruptura Aórtica/cirurgia , Ruptura Aórtica/terapia , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Tóquio/epidemiologia , Pessoa de Meia-Idade , Resultado do Tratamento , Tratamento Conservador , Fatores de Risco
9.
Front Psychiatry ; 14: 1334335, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38476817

RESUMO

Background: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. Patients and methods: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). Results: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. Conclusion: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

10.
Neuropsychopharmacol Rep ; 42(4): 468-477, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36151855

RESUMO

AIM: Clinical trials of antidepressants often fail to demonstrate their efficacy versus placebo, suggesting that patient selection based on physician ratings of depression may contribute to a high placebo response. METHODS: In the CCT-004 trial of vortioxetine, central monitoring was employed to compare physician and patient ratings of depression and anxiety at baseline and over time to identify factors contributing to a large placebo response, as well as to explore the potential of a unique patient-rated clinical measure combining QIDS-J and Himorogi Self-rating Anxiety Scale (HSAS), to contribute to optimal patient selection at baseline and patient monitoring over time. RESULTS: The CCT-004 trial showed similar trends between the QIDS-J and MADRS (Montgomery-Åsberg Depression Rating Scale) ratings. It was suggested that central monitoring of the QIDS-J and MADRS ratings of depression and anxiety symptoms helped reduce the baseline score inflation by calling the study sites' attention to discrepancies between these ratings at baseline; it also allowed these ratings to be assessed for their concordance over time. Of note, MDD patients with baseline QIDS-J scores ≥11/HSAS ≤19 were associated with the smallest placebo response, with the effect size being larger than that for those with QIDS-J scores ≤10/HSAS ≥20. CONCLUSION: The use of both physician and patient ratings of depression and anxiety symptoms at baseline and over time, as well as their central monitoring, helped minimize the baseline score inflation and optimize patient monitoring over time, and allowed the antidepressant to be evaluated for its full therapeutic potential.


Assuntos
Depressão , Transtorno Depressivo Maior , Humanos , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Piperazinas/uso terapêutico , Sulfetos/uso terapêutico , Vortioxetina/uso terapêutico
11.
J Med Chem ; 65(12): 8127-8143, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35652647

RESUMO

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats.


Assuntos
Insuficiência Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Animais , Anti-Hipertensivos , Eplerenona/farmacologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Oxazinas , Ratos , Receptores de Mineralocorticoides , Sulfonamidas
12.
Sci Immunol ; 7(70): eabn1889, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35452256

RESUMO

The circulating precursor cells that give rise to human resident memory T cells (TRM) are poorly characterized. We used an in vitro differentiation system and human skin-grafted mice to study TRM generation from circulating human memory T cell subsets. In vitro TRM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4+ T cells and granzyme B production in CD8+ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (TEM) had the highest conversion rate to TRM in vitro and in vivo, but central memory T cells (TCM) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of TRM. In summary, TCM are highly efficient precursors of human skin TRM, a feature that may underlie their known association with effective long-term immunity.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Animais , Humanos , Células T de Memória , Camundongos , Pele , Subpopulações de Linfócitos T
13.
Anticancer Res ; 42(4): 2023-2028, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35347024

RESUMO

BACKGROUND/AIM: Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events. PATIENTS AND METHODS: Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study. RESULTS: Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan-Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight <63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight. CONCLUSION: A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Peso Corporal , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Risco , Tioidantoínas/efeitos adversos
14.
Mol Biol Rep ; 49(3): 2015-2024, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34845648

RESUMO

BACKGROUND: GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. METHODS AND RESULTS: In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. CONCLUSIONS: Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.


Assuntos
Esquizofrenia , Feminino , Estudos de Associação Genética , Glutamato Descarboxilase/genética , Humanos , Receptores de GABA-B/genética , Esquizofrenia/genética , Esquizofrenia Resistente ao Tratamento
15.
Contemp Clin Trials ; 111: 106596, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34653648

RESUMO

INTRODUCTION: The COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date. METHODS: The targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a "telepsychiatry group" (at least 50% of treatments to be conducted using telemedicine, with at least one face-to-face treatment [FTF] within six months) or an "FTF group" (all treatments to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group. DISCUSSION: This study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry. TRIAL REGISTRATION: jRCT1030210037, Japan Registry of Clinical Trials (jRCT).


Assuntos
COVID-19 , Psiquiatria , Telemedicina , Humanos , Japão , Pandemias , SARS-CoV-2
17.
Nat Commun ; 12(1): 3750, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145229

RESUMO

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.


Assuntos
Adenosina Trifosfatases/genética , Transtorno Bipolar/genética , Exoma/genética , Predisposição Genética para Doença/genética , Adulto , Éxons/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do Exoma
18.
Int J Psychiatry Clin Pract ; 25(4): 385-392, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33840340

RESUMO

OBJECTIVE: Anxious distress (ANXD), which is common in major depressive disorder (MDD), is associated with poor outcomes. We investigated clinical characteristics of MDD patients with the DSM-5 ANXD specifier and only mild residual symptoms without comorbid anxiety disorders in the continuation/maintenance phase. METHODS: We recruited 110 outpatients with MDD without comorbid anxiety disorders. They were interviewed; the presence of the DSM-5 ANXD specifier was assessed. They completed the Quick Inventory of Depressive Symptomatology (QIDS), the Eysenck Personality Questionnaire (S-EPQ), the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A). RESULTS: The mean QIDS total score was 9.7 ± 5.5. The DSM-5 ANXD specifier was identified in 73 patients (66.4%). A univariate analysis indicated ANXD was significantly associated with younger age; unmarried status; living alone; higher QIDS total score; higher S-EPQ neuroticism score; and higher TEMPS-A cyclothymic, depressive and irritable scores. After covariate adjustment, a multivariable linear regression analysis revealed a significant association between the QIDS total score and ANXD (three different models). CONCLUSION: The DSM-5 ANXD was also common among MDD patients without comorbid anxiety disorders in the continuation/maintenance phase; it was significantly associated with greater depression severity and might be related to temperament associated with bipolar disorder.Key pointsDSM-5 anxious distress is common among MDD patients without comorbid anxiety disorders in the continuation/maintenance phase and correlated with some of their socio-demographic and clinical characteristics. • The presence of DSM-5 anxious distress was significantly associated with greater severity of depression and might be related to temperament associated with bipolar disorder.• The evaluation of the DSM-5 anxiety distress was revealed to have some significance not only in the acute phase but also in the continuation/maintenance phase of MDD.


Assuntos
Ansiedade , Transtorno Depressivo Maior , Angústia Psicológica , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/terapia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos
19.
Genes Dev ; 35(9-10): 692-697, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33888556

RESUMO

The conserved meiosis-specific kinetochore regulator, meikin (Moa1 in fission yeast) plays a central role in establishing meiosis-specific kinetochore function. However, the underlying molecular mechanisms remain elusive. Here, we show how Moa1 regulates centromeric cohesion protection, a function that has been previously attributed to shugoshin (Sgo1). Moa1 is known to associate with Plo1 kinase. We explore Plo1-dependent Rec8 phosphorylation and identify a key phosphorylation site required for cohesion protection. The phosphorylation of Rec8 by Moa1-Plo1 potentiates the activity of PP2A associated with Sgo1. This leads to dephosphorylation of Rec8 at another site, which thereby prevents cleavage of Rec8 by separase.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Meiose/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/genética , Proteínas Serina-Treonina Quinases/metabolismo , Schizosaccharomyces/enzimologia , Proteínas de Schizosaccharomyces pombe/genética , Separase/metabolismo
20.
Heart Vessels ; 36(7): 1088-1097, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33763729

RESUMO

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.


Assuntos
Anestesia por Inalação/métodos , Fibrilação Atrial/tratamento farmacológico , Halotano/farmacologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ranolazina/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Feminino , Átrios do Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Infusões Intravenosas , Bloqueadores dos Canais de Sódio/administração & dosagem
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