Spectroscopic characterization of the copper(I)-thiolate cluster in the DNA-binding domain of yeast ACE1 transcription factor

AbstractA polypeptide containing the amino-terminal region of ACEI (residues 1–122; 122*), the activator of yeast Cu-methallothionein gene transcription, shows charge-transfer and metal-centered UV absorption bands, and orange luminescence which are characteristic of Cu-cysteinyl thiolate cluster structures. These spectral features are abolished by the Cu(1) complexing agents CN* and diethyldithiocarbamate or exposure to acid, but not by the Cu(II)chelator. EDTA. Binding of the polypeptide to its specific DNA recognition site, but not to calf-thymus double-stranded DNA, induces quenching of its Tyr and Cu-S cluster luminescence emission. The CD spectrum is characteristic of a tightly folded structure that may be organized around the Cu cluster

Epigenomics and Metabolomics Reveal the Mechanism of the \u3cem\u3eAPOA2\u3c/em\u3e-Saturated Fat Intake Interaction Affecting Obesity

Background: The putative functional variant −265T \u3e C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. Objective: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. Design: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (\u3c 22 g/d) or high-SFA diet (≥ 22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites. Results: In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar results were observed in the GOLDN Study and the FHS. Additionally, in the FHS, cg04436964 methylation was negatively correlated with APOA2 expression in the blood of participants consuming a high-SFA diet. Furthermore, when consuming a high-SFA diet, CC carriers had lower APOA2 expression than those with the TT genotype. Lastly, metabolomic analysis identified 4 pathways as overrepresented by metabolite differences between CC and TT genotypes with high-SFA intake, including tryptophan and branched-chain amino acid (BCAA) pathways. Interestingly, these pathways were linked to rs5082-specific cg04436964 methylation differences in high-SFA consumers. Conclusions: The epigenetic status of the APOA2 regulatory region is associated with SFA intake and APOA2 -265T \u3e C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787

Nutritional management of the infant with chronic kidney disease stages 2-5 and on dialysis

The nutritional management of children with chronic kidney disease (CKD) is of prime importance in meeting the challenge of maintaining normal growth and development in this population. The objective of this review is to integrate the Pediatric Renal Nutrition Taskforce clinical practice recommendations for children with CKD stages 2-5 and on dialysis, as they relate to the infant from full term birth up to 1 year of age, for healthcare professionals, including dietitians, physicians, and nurses. It addresses nutritional assessment, energy and protein requirements, delivery of the nutritional prescription, and necessary dietary modifications in the case of abnormal serum levels of calcium, phosphate, and potassium. We focus on the particular nutritional needs of infants with CKD for whom dietary recommendations for energy and protein, based on body weight, are higher compared with children over 1 year of age in order to support both linear and brain growth, which are normally maximal in the first 6 months of life. Attention to nutrition during infancy is important given that growth is predominantly nutrition dependent in the infantile phase and the growth of infants is acutely impaired by disruption to their nutritional intake, particularly during the first 6 months. Inadequate nutritional intake can result in the failure to achieve full adult height potential and an increased risk for abnormal neurodevelopment. We strongly suggest that physicians work closely with pediatric renal dietitians to ensure that the infant with CKD receives the best possible nutritional management to optimize their growth and development.Peer reviewe

Epigenomics and metabolomics reveal the mechanism of the APOA2-saturated fat intake interaction affecting obesity

Background: The putative functional variant -265T\u3eC (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. Objective: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. Design: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (\u3c22 g/d) or high-SFA diet (≥22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites. Results: In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar results were observed in the GOLDN Study and the FHS. Additionally, in the FHS, cg04436964 methylation was negatively correlated with APOA2 expression in the blood of participants consuming a high-SFA diet. Furthermore, when consuming a high-SFA diet, CC carriers had lower APOA2 expression than those with the TT genotype. Lastly, metabolomic analysis identified 4 pathways as overrepresented by metabolite differences between CC and TT genotypes with high-SFA intake, including tryptophan and branched-chain amino acid (BCAA) pathways. Interestingly, these pathways were linked to rs5082-specific cg04436964 methylation differences in high-SFA consumers. Conclusions: The epigenetic status of the APOA2 regulatory region is associated with SFA intake and APOA2 -265T\u3eC genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787

Assessment and management of obesity and metabolic syndrome in children with CKD stages 2-5 on dialysis and after kidney transplantation-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce

Obesity and metabolic syndrome (O&MS) due to the worldwide obesity epidemic affects children at all stages of chronic kidney disease (CKD) including dialysis and after kidney transplantation. The presence of O&MS in the pediatric CKD population may augment the already increased cardiovascular risk and contribute to the loss of kidney function. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. We present CPRs for the assessment and management of O&MS in children with CKD stages 2-5, on dialysis and after kidney transplantation. We address the risk factors and diagnostic criteria for O&MS and discuss their management focusing on non-pharmacological treatment management, including diet, physical activity, and behavior modification in the context of age and CKD stage. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT.Peer reviewe

Low-Level Laser Application in the Early Myocardial Infarction Stage Has No Beneficial Role in Heart Failure

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination. LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akti NEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.Conselho Nacional de Desenvolvimento Cientifico e TecnologicoFAPESPNove de Julho Univ, Lab Biophoton, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Lab Cardiac Physiol, Sao Paulo, SP, BrazilNove de Julho Univ, Program Med, Sao Paulo, BrazilUniv Sao Judas Tadeu, Brazil Phys Educ & Aging Sci Program, Translat Physiol Lab, Sao Paulo, BrazilUniv Fed Sao Paulo, Lab Cardiac Physiol, Sao Paulo, SP, BrazilCNPq: 4400851/2014-8FAPESP: 09-54225/8FAPESP: 15/11028-9Web of Scienc

Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): A non-inferiority randomized controlled trial study protocol

Background: Retrospective observational studies suggest that transmission of Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for Preconceptional treatment to reduce parasitic load.The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300 mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300 mg course is not yet established. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed.Methods and design: We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150 mg/day (30d/150 mg) vs. BZN 60d/300 mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at 6 months postpartum, and follow them up with the following specific aims:Specific aim 1: to measure the effect of BZN 30d/150 mg compared to 60d/300 mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately and 10 months after treatment.Specific aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption.Fil: Cafferata, María L.. Instituto de Efectividad Clínica y Sanitaria; Argentina. Unicem; UruguayFil: Toscani, María A.. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Althabe, Fernando. Organizacion Mundial de la Salud; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Belizan, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Bergel, Eduardo. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Berrueta, Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Capparelli, Edmund V.. University of California; Estados UnidosFil: Ciganda, Álvaro. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Danesi, Emmaría. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Centro Nacional de Diagnóstico e Investigaciones Endemo-epidémicas; ArgentinaFil: Dumonteil, Eric. University of Tulane; Estados UnidosFil: Gibbons, Luz. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Gulayin, Pablo Elías. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Herrera, Claudia. University of Tulane; Estados UnidosFil: Momper, Jeremiah D.. University of California; Estados UnidosFil: Rossi, Steven. University of California; Estados UnidosFil: Shaffer, Jeffrey G.. University of Tulane; Estados UnidosFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Stella, Candela B.. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Klein, Karen. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Buekens, Pierre. University of Tulane; Estados Unido

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. VIII: The Eighth Year (2015-2016)

Continuing the project described by Kato et al. (2009, arXiv:0905.1757), we collected times of superhump maxima for 128 SU UMa-type dwarf novae observed mainly during the 2015-2016 season and characterized these objects. The data have improved the distribution of orbital periods, the relation between the orbital period and the variation of superhumps, the relation between period variations and the rebrightening type in WZ Sge-type objects. Coupled with new measurements of mass ratios using growing stages of superhumps, we now have a clearer and statistically greatly improved evolutionary path near the terminal stage of evolution of cataclysmic variables. Three objects (V452 Cas, KK Tel, ASASSN-15cl) appear to have slowly growing superhumps, which is proposed to reflect the slow growth of the 3:1 resonance near the stability border. ASASSN-15sl, ASASSN-15ux, SDSS J074859.55+312512.6 and CRTS J200331.3-284941 are newly identified eclipsing SU UMa-type (or WZ Sge-type) dwarf novae. ASASSN-15cy has a short (~0.050 d) superhump period and appears to belong to EI Psc-type objects with compact secondaries having an evolved core. ASASSN-15gn, ASASSN-15hn, ASASSN-15kh and ASASSN-16bu are candidate period bouncers with superhump periods longer than 0.06 d. We have newly obtained superhump periods for 79 objects and 13 orbital periods, including periods from early superhumps. In order that the future observations will be more astrophysically beneficial and rewarding to observers, we propose guidelines how to organize observations of various superoutbursts.Comment: 123 pages, 162 figures, 119 tables, accepted for publication in PASJ (including supplementary information