RESUMO
Ghobadi and Jafari have mentioned some points about our article titled "Diet quality in relation to the risk of hypertension among Iranian adults: cross-sectional analysis of Fasa PERSIAN cohort study" which was published in the Nutrition Journal. Thanks for their consideration, the following is provided as a response to their comments.
Assuntos
Dieta , Hipertensão , Humanos , Hipertensão/epidemiologia , Irã (Geográfico)/epidemiologia , Estudos Transversais , Dieta/métodos , Dieta/estatística & dados numéricos , Adulto , Fatores de Risco , Estudos de Coortes , MasculinoRESUMO
Background and Aims: Epidemiologic studies show a strong association between chronic inflammation and type 2 diabetes (T2D). Diet may also affect the risk of T2D by modulating inflammation. This meta-analysis aimed to assess the relation of dietary inflammatory index (DII) and risk of T2D. Methods: PubMed and Scopus were systematically searched from their inception to September 2020 to identify relevant studies. Relative risks, hazard ratios, or odds ratios (OR), with their corresponding 95% confidence intervals (95% CI), were calculated and pooled using a random-effects model. Results: A total of 48 different studies, with a total sample size of 1,687,424 participants, were eligible to be included in this meta-analysis. In the overall analysis, no significant association was observed between DII and risk of T2D (OR = 1.03, 95% CI: 0.91 to 1.15), with significant evidence for heterogeneity (I 2 = 96.5%, P < 0.001); however, higher DII was identified as being significantly related to increased risk of T2D in high quality studies (OR = 1.58, 95% CI: 1.15 to 2.17). In the stratified analysis by the dietary assessment tool, background disease, and sex of participants, DII showed no significant association with T2D. Conclusions: Higher DII might be associated with an increased risk of T2D. Additional well-designed studies are required to confirm this finding.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Humanos , Inflamação , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Hypertension is a common chronic disease with various complications and is a main contributing factor to cardiovascular disease (CVD). This study aimed to assess the association of diet quality, assessed by dietary diversity score (DDS), Mediterranean dietary score (MDS), diet quality index-international (DQI-I), and healthy eating index-2015 (HEI-2015) with the risk of hypertension. METHODS: This study recruited a total of 10,111 individuals (45.14% male) with mean age of 48.63 ± 9.57 years from the Fasa Cohort Study, Iran. Indices of diet quality, including MDS, HEI-2015, DQI-I, and DDS were computed by a 125-item Food Frequency Questionnaire. Participants were diagnosed as hypertensive if they had a diastolic blood pressure (DBP) ≥90 mmHg, systolic blood pressure (SBP) ≥140 mmHg,, or used antihypertensive drugs. RESULTS: Hypertension was prevalent in 28.3% of the population (21.59% in males and 33.74% in females). In the whole population, after adjustment for potential covariates, including daily energy intake, age, gender, physical activity, smoking, family history of hypertension, body mass index, and the level of education, higher adherence to the MDS (OR: 0.86, 95%CI = 0.75-0.99) and HEI-2015 (OR: 0.79, 95%CI = 0.68-0.90) was significantly associated with decreased risk of hypertension. The protective effect of HEI-2015 against hypertension remained significant for both males (OR: 0.80, 95%CI = 0.64-0.99) and females (OR: 0.78, 95%CI = 0.66-0.94), while, for MDS, this relationship disappeared in the subgroup analysis by gender. DQI-I and DDS were not related to the odds of hypertension. CONCLUSIONS: Adhering to MDS and HEI-2015 diets could contribute to the prevention of hypertension.
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Dieta , Hipertensão , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Irã (Geográfico)/epidemiologia , MasculinoRESUMO
The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild-type function.
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Citocinas/farmacologia , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Citometria de Fluxo , Humanos , Janus Quinase 2/genética , Mutação/genética , Fosforilação/efeitos dos fármacos , Domínios Proteicos/genética , Domínios Proteicos/fisiologiaRESUMO
BACKGROUND AND OBJECTIVE: Almond consumption has an inverse relationship with obesity and factors related to metabolic syndrome. However, the results of available clinical trials are inconsistent. Therefore, we analyzed the results of 37 randomized controlled trials (RCTs) and evaluated the association of almond consumption with subjective appetite scores and body compositions. METHODS: Net changes in bodyweight, body mass index (BMI), waist circumference (WC), fat mass (FM), body fat percent, fat-free mass (FFM), waist-to-hip ratio (WHR), visceral adipose tissue (VAT), and subjective appetite scores were used to calculate the effect size, which was reported as a weighted mean differences (WMD) and 95% confidence interval (CI). RESULTS: This meta-analysis was performed on 37 RCTs with 43 treatment arms. The certainty in the evidence was very low for appetite indices, body fat percent, FFM, VAT, and WHR, and moderate for other parameters as assessed by the GRADE evidence profiles. Pooled effect sizes indicated a significant reducing effect of almond consumption on body weight (WMD: -0.45 kg, 95% CI: -0.85, -0.05, p = 0.026), WC (WMD: -0.66 cm, 95% CI: -1.27, -0.04, p = 0.037), FM (WMD: -0.66 kg, 95% CI: -1.16, -0.17, p = 0.009), and hunger score (WMD: -1.15 mm, 95% CI: -1.98, -0.32, p = 0.006) compared with the control group. However, almond did not have a significant effect on BMI (WMD: -0.20 kg m-2, 95% CI: -0.46, 0.05, p = 0.122), body fat percent (WMD: -0.39%, 95% CI: -0.93, 0.14, p = 0.154), FFM (WMD: -0.06, 95% CI: -0.47, 0.34, p = 0.748), WHR (WMD: -0.04, 95% CI: -0.12, 0.02, p = 0.203), VAT (WMD: -0.33 cm, 95% CI: -0.99, 0.32), fullness (WMD: 0.46 mm, 95% CI: -0.95, 1.88), desire to eat (WMD: 0.98 mm, 95% CI: -4.13, 2.23), and prospective food consumption (WMD: 1.08 mm, 95% CI: -2.11, 4.28). Subgroup analyses indicated that consumption of ≥50 g almonds per day resulted in a significant and more favorable improvement in bodyweight, WC, FM, and hunger score. Body weight, WC, FM, body fat percent, and hunger scores were decreased significantly in the trials that lasted for ≥12 weeks and in the subjects with a BMI < 30 kg/m2. Furthermore, a significant reduction in body weight and WC was observed in those trials that used a nut-free diet as a control group, but not in those using snacks and other nuts. The results of our analysis suggest that almond consumption may significantly improve body composition indices and hunger scores when consumed at a dose of ≥50 g/day for ≥12 weeks by individuals with a BMI < 30 kg/m2. CONCLUSION: However, further well-constructed randomized clinical trials are needed in order ascertain the outcome of our analysis.
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Apetite , Composição Corporal , Peso Corporal , Obesidade , Prunus dulcis , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Composição Corporal/fisiologia , Apetite/fisiologia , Obesidade/dietoterapia , Índice de Massa Corporal , Suplementos Nutricionais , Circunferência da CinturaRESUMO
Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.
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Sequenciamento de Cromatina por Imunoprecipitação/métodos , Análise de Célula Única/métodos , Animais , Cromatina , Biologia Computacional , Epigenômica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Motor , Análise de Sequência de DNA/métodosRESUMO
OBJECTIVE: To evaluate, in a well-controlled study, the effect of surgically induced partial bladder outlet obstruction (PBOO) on male erectile function in a rat model. MATERIALS AND METHODS: PBOO was created in 17 adult male Sprague-Dawley rats by partial ligation of the proximal urethra. Sham-operated and PBOO rats were evaluated for urodynamic and erectile function at 4-8 weeks after surgery. Erectile responses to electrical field stimulation (EFS) to the major pelvic ganglion, and to erectogenic agents (1,1-diethyl-2-hydroxy-2-nitroso-hydrazine, DEA-NO, and Y-27632) were evaluated and the area under the curve (AUC, a product of the intracavernous pressure and duration) was used to denote the erectile response. RESULTS: Experimental PBOO in rats significantly increased the mean (sem) bladder weight, to 256 (25) mg in PBOO rats vs 123 (24) mg in sham controls, and the voiding frequency to 1.01 (0.1) voids/min vs 0.72 (0.14) voids/min in sham controls (P < 0.05). There was no significant difference between the erectile response to EFS, with a mean AUC in sham control rats at 1.5, 3.0 and 4.5 V of 2603 (372), 3200 (332) and 3357 (166), respectively, vs 2273 (183), 3794 (211) and 4177 (306) in PBOO rats (P > 0.05); or to the erectogenic agents, the AUC for DEA-NO being 9000 (975) in PBOO rats vs 13 201 (2756) in sham controls, and the AUC for Y-27 632 being 44 915 (2462) and 45 907 (7408), respectively (P > 0.05). There was greater immunoreactivity to RhoA in bladder and penile tissues of PBOO than control rats. CONCLUSION: PBOO does not affect erectile function in rats. Additional mechanisms or pathways might be involved in lower urinary tract symptom-related erectile dysfunction in humans.
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Impotência Vasculogênica/etiologia , Ereção Peniana/fisiologia , Obstrução do Colo da Bexiga Urinária/complicações , Animais , Impotência Vasculogênica/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Centrioles are ancient organelles that build centrosomes, the major microtubule-organizing centers of animal cells. Extra centrosomes are a common feature of cancer cells. To investigate the importance of centrosomes in the proliferation of normal and cancer cells, we developed centrinone, a reversible inhibitor of Polo-like kinase 4 (Plk4), a serine-threonine protein kinase that initiates centriole assembly. Centrinone treatment caused centrosome depletion in human and other vertebrate cells. Centrosome loss irreversibly arrested normal cells in a senescence-like G1 state by a p53-dependent mechanism that was independent of DNA damage, stress, Hippo signaling, extended mitotic duration, or segregation errors. In contrast, cancer cell lines with normal or amplified centrosome numbers could proliferate indefinitely after centrosome loss. Upon centrinone washout, each cancer cell line returned to an intrinsic centrosome number "set point." Thus, cells with cancer-associated mutations fundamentally differ from normal cells in their response to centrosome loss.
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Centríolos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Sulfonas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Sulfonas/químicaRESUMO
Aurora kinases are essential for cell division and are frequently misregulated in human cancers. Based on their potential as cancer therapeutics, a plethora of small molecule Aurora kinase inhibitors have been developed, with a subset having been adopted as tools in cell biology. Here, we fill a gap in the characterization of Aurora kinase inhibitors by using biochemical and cell-based assays to systematically profile a panel of 10 commercially available compounds with reported selectivity for Aurora A (MLN8054, MLN8237, MK-5108, MK-8745, Genentech Aurora Inhibitor 1), Aurora B (Hesperadin, ZM447439, AZD1152-HQPA, GSK1070916), or Aurora A/B (VX-680). We quantify the in vitro effect of each inhibitor on the activity of Aurora A alone, as well as Aurora A and Aurora B bound to fragments of their activators, TPX2 and INCENP, respectively. We also report kinome profiling results for a subset of these compounds to highlight potential off-target effects. In a cellular context, we demonstrate that immunofluorescence-based detection of LATS2 and histone H3 phospho-epitopes provides a facile and reliable means to assess potency and specificity of Aurora A versus Aurora B inhibition, and that G2 duration measured in a live imaging assay is a specific readout of Aurora A activity. Our analysis also highlights variation between HeLa, U2OS, and hTERT-RPE1 cells that impacts selective Aurora A inhibition. For Aurora B, all four tested compounds exhibit excellent selectivity and do not significantly inhibit Aurora A at effective doses. For Aurora A, MK-5108 and MK-8745 are significantly more selective than the commonly used inhibitors MLN8054 and MLN8237. A crystal structure of an Aurora A/MK-5108 complex that we determined suggests the chemical basis for this higher specificity. Taken together, our quantitative biochemical and cell-based analyses indicate that AZD1152-HQPA and MK-8745 are the best current tools for selectively inhibiting Aurora B and Aurora A, respectively. However, MK-8745 is not nearly as ideal as AZD1152-HQPA in that it requires high concentrations to achieve full inhibition in a cellular context, indicating a need for more potent Aurora A-selective inhibitors. We conclude with a set of "good practice" guidelines for the use of Aurora inhibitors in cell biology experiments.