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Latinx populations are underrepresented in DNA-based research, and risk not benefiting from research if underrepresentation continues. Latinx populations are heterogenous; reflect complex social, migration, and colonial histories; and form strong global diasporas. We conducted a global study using a survey tool (Amazon’s Mechanical Turk portal) to ascertain willingness to participate in genetic research by Latin America birth-residency concordance. Participants in the global study identified as Latinx (n=250) were classified as the following: (1) born/live outside of Latin America and the Caribbean (LAC), (2) born within/live outside LAC, and (3) born/live within LAC. Latinx were similarly likely to indicated they would participate DNA-based research as their non-Latinx counterparts (52.8% vs. 56.2%, respectively). Latinx born and living in LAC were significantly more willing to participate in DNA-based research than Latinx born and living outside of LAC (OR: 2.5; 95% CI: 1.3, 4.9, p

Bacteriophage Librie was isolated from a soil sample from Clarksville, TN, using the bacterium Microbacterium foliorum . Librie has a 39,941 bp genome with 62 predicted protein-coding genes and 1 predicted gene for tRNA. Based on its gene content similarity to actinobacteriophages, Librie is grouped with phages in cluster EA5.

GIP receptor (GIPR) agonism enhances the reduction of food intake and weight loss induced by GLP-1 receptor (GLP-1R) agonism. Recently, GLP-1R agonists have been described that exhibit biased agonism as determined using cells engineered to facilitate measuring the two canonical signaling pathways engaged upon binding the GLP-1R. Such “biased agonists” retain the ability to activate the G alpha S/cyclic AMP (cAMP) pathway to a similar magnitude as native GLP-1 but exhibit markedly weaker ability to induce receptor recruitment of beta-arrestin. The prototype biased GLP-1R agonist Exendin-Phe1 (Ex-Phe1) is reported to exhibit greater weight and glucose control in diet-induced obese (DIO) mice than its unbiased parent Exendin-4 (Ex4). Herein, we investigated whether the enhanced weight loss of Ex-Phe1 erodes the ability of GIPR agonism to further enhance the efficacy of GLP-1R agonism. The peptides were first characterized in vitro to validate the biased nature of Ex-Ph1. In cells expressing either the human or murine GLP-1R, Ex-Phe1 activated cAMP signaling to a similar magnitude as GLP-1 and Ex4 but with approximately 5-fold lower potency than Ex4. The maximum effect of Ex-Phe1 upon human or mouse GLP-1R recruitment of beta-arrestin was 20% compared with full efficacy for Ex4 relative to GLP-1. In this assay Ex-Phe1 was marginally less potent than Ex4. In a 14-day osmotic minipump DIO mice study, Ex4 and Ex-Phe1 each dose dependently reduced food intake and lowered body weight. Ex-Phe1 was 10-fold more potent than Ex4, and at the maximum dose, delivered superior weight loss. Combination treatment with d-Ala-GIP resulted in similar additional body weight loss to that achieved by either Ex-Phe1 or Ex4 alone by enhancing food intake reduction and increasing energy expenditure. D-Ala-GIP alone had no effect on body weight. These findings indicate that GIPR agonism enhances GLP-1R agonism mediated weight loss irrespective of the pathway bias nature of the latter. Disclosure M. P. Coghlan: Employee; Self; Eli Lilly and Company. K. Sloop: Employee; Self; Eli Lilly and Company. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. L. O’farrell: None. A. D. Showalter: None. D. B. Wainscott: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company, Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. C. Stutsman: None. G. Cardona: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. O. Cabrera: None. J. Alsina-fernandez: None. F. S. Willard: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Background Postpartum Care is a strategy to improve survival of women and newborns, especially in low- and middle-income countries. Early post-partum care can promote healthy behaviors and the identification of risk factors associated with poorer pregnancy-related outcomes. The objective of this study was to assess the association of perceived social support with attendance to post-partum care in women from three Latin-American and Caribbean countries: Costa Rica, Dominican Republic and Honduras. Methods Women aged 18+ who completed a pregnancy in the past 5 years were interviewed in local healthcare and community settings in each country. Perceived social support (PSS) was the primary explanatory variable and the primary outcome was self-reported attendance to post-partum care. Odds Ratios (OR) with 95% confidence intervals derived from logistic regression documented the association between variables. Adjusted Odds Ratios (AOR) were calculated, controlling for social and pregnancy-related confounders. Hosmer– Lemeshow’s Goodness-of-Fit statistic was computed to assess model fit. Results Our cohort of 1199 women across the three Latin-American and Caribbean countries showed relatively high attendance to post-partum care (82.6%, n = 990). However, 51.7% (n = 581) of women reported lower levels of total PSS. Women were more likely to attend postpartum care if they had mean and higher levels of PSS Family subscale (OR: 1.9, 95%CI: 1.4, 2.7), Friends subscale (OR 1.3, 95%CI: 0.9,1.8), Significant Other subscale (OR 1.8, 95%CI: 1.3, 2.4) and the Total PSS (OR 1.8, 95%CI: 1.3, 2.5). All associations were statistically significant at p Conclusions Women with higher perceived social support levels were more likely to attend to post-partum care. From all countries, women from Dominican Republic had lower perceived social support levels and this may influence attendance at post-partum care for this subgroup. Societal and geographic factors can act as determinants when evaluating perceived social support during pregnancy.

Additional file 1.

Background: Severe cutaneous adverse reactions to drugs (SCARs) are associated with high morbidity and mortality and with sequelae. Objective: To characterize patients with SCARs in 8 health care institutions in Latin America. Methods: We performed a cross-sectional, descriptive, multicenter study of patients diagnosed with SCARs in Latin America between January 2009 and December 2018. The analysis was carried out using a database in BD Clinic. Results: We collected 70 patients, of whom 42 (60%) were women. Mean age was 38.7 years. Forty-two patients (60%) had DRESS-DIHS, 12 (17.1%) TEN, 5 (7.1%) SJS, 6 (8.5%) AGEP, 4 (5.7%) other reactions not classified as SCARs, and 1 (1.4%) overlapping SJS-TEN. The main causative drugs were aromatic anticonvulsants in 31 cases (44.3%), ß-lactam antibiotics in 11 cases (15.7%), and non–ß-lactam antibiotics in 6 cases (8.6%). In all of the cases, the suspected drug was withdrawn at the first sign of a SCAR. Sixty-six patients (94.2%) received anti-inflammatory treatment, mostly systemic corticosteroids. Complications occurred in 53 cases (75.7%), and 3 patients died (4.3%). Thirteen patients (18.6%) had sequelae. Conclusions: This is the first multicenter report on SCARs in Latin America. DRESS-DIHS was the most frequently reported clinical entity, and anticonvulsants were the main triggers. Most of the patients received systemic corticosteroids. Complications were frequent, and 3 patients died.

Sr2HoRuO6 ceramic has been synthesized and its structural, morphological, magnetic, optical, and electronic properties studied. Rietveld refinement of x-ray diffraction patterns revealed that this oxide material crystallizes in monoclinic perovskite structure in space group P2 1 /n (no. 14). Scanning electron microscopy revealed polycrystalline surface morphology. x-Ray dispersive spectroscopy suggested that Sr2HoRuO6 was obtained with expected stoichiometry. Magnetic susceptibility curves as a function of temperature revealed ferrimagnetic feature of this material below the Neel temperature TN of 14 K. Evidence of magnetic disorder was provided by the irreversibility observed in the zero-field-cooled and field-cooled responses of the susceptibility below Tirr = 169 K. Analysis of the diffuse reflectance spectrum suggested that this material behaves as a semiconductor with energy gap Eg of 1.38 eV. Results of band structure and density-of-states calculations are in agreement with the interpretation of Sr2HoRuO6 as a semiconductor. The ferrimagnetic behavior is interpreted as due to exchange mechanisms of d–f (Ru–O–Ho) electrons. The effective magnetic moment calculated from density functional theory was 93.5% of the experimental value obtained from Curie–Weiss fitting of the susceptibility curve.

To date, Additive Manufacturing (AM), a driving technology for the Industry 4.0 paradigm, is a growing technology field but has not reached relevant impact in the construction sector. The reason exposed in this article is the fact that current capabilities in terms of control of the setting reaction of concrete in real time are limited. Experimentation with a state-of-the-art concrete AM print-head has evidenced that the full stabilization of concrete’s chemical reactions is complex and involves phenomena that are not yet fully understood. Addressing this problem and the development of a fully automatic closed loop control would allow a great step forward in the capabilities of concrete additive manufacturing. So, as a first step, valuable information from thermal and pressure sensors were collected along the printing process, and their variations associated with the control of actuators (mixers and pumps) have been noted. A path for full real-time automatic control can be foreseen, and will guide future research and developments.

In this paper the synthesis and study of the structural, morphological, electrical, magnetic and electronic properties of the LaBiFe2O6 novel material are reported. The material was produced using the standard ceramic method. The Rietveld analysis of experimental data of x-ray diffraction showed that it synthesizes in an orthorhombic perovskite structure (Pnma, #62 space group). Two types of grain, micro and submicrometric, with the LaBiFe2O6 stoichiometry were identified by scanning electron microscopy and X-ray dispersive spectroscopy. Results of electrical polarization and dielectric constant ferroelectric suggest the occurrence of response of the material at room temperature. A T=300 K the material is ferromagnetic and exhibits an anomaly at T=258 K, which is attributed to anisotropy effects, suggesting the occurrence of biferroic behaviour. Results of diffuse reflectance suggest a semiconductor behaviour with energy gap Eg=2,17 eV, which is in agreement with calculations of band structure and density of states for one spin orientation, while for the other spin configuration calculations suggest a conductor feature.

Rice (Oryza sativa L.) is an important cereal crop in Venezuela and is planted on approximately 200,000 ha. Fungal diseases caused by the Helminthosporium complex of fungi are considered a major constraint to rice production. In 2005, a blotter method was used to identify fungi associated with rice seed. Seeds (150) of cv. INIA-017 were placed on a plate with moistened filter paper and incubated at 26 ± 2°C with a 12-h light/12-h dark cycle for 5 days until fungal sporulation. Single spores were transferred to 2% water agar (WA). Germinated spores were then transferred to potato dextrose agar (PDA), and resultant colonies were preserved until used. To induce sporulation, 4-mm-diameter discs were cut from 72-h-old cultures, transferred to WA, and incubated at 26 ± 2°C for 48 h (modified technique of Alcorn [1]). Discolored seed yielded isolates of Bipolaris oryzae (Berda de Haan) Shoemaker and Exserohilum rostratum (Drechs.) Leonard and Suggs (2). Pathogenicity tests were performed on 60-day-old rice plants of cv. Blue Bonnet 50. Four plants per pot were used for each isolate. Before inoculation, plants were placed in humidity chambers for 48 h. Spores were harvested from discs into a beaker containing 50 mL of a dilute gelatin solution (Gelatin Difco; 5 g/100 mL of sterile distilled water [SDW]). Spore suspensions were filtered through cheesecloth and adjusted to 7 × 104 spores per ml. The inoculated plants were placed in humidity chambers for 72 h. Control plants were sprayed with SDW. Inoculated plants were removed from humidity chambers and placed on a greenhouse bench. Plants inoculated with B. oryzae were symptomatic 5 days after inoculation; resultant lesions were red-brown with chlorotic borders. Lesions subsequently turned gray with reddish borders and were rhombic in shape. Plants inoculated with E. rotratum were symptomatic 7 days after inoculation with elliptical lesions that were orange-brown along venation. These lesions turned gray with reddish borders. Both fungi were reisolated from symptomatic leaf tissue. To our knowledge, this is the first report of E. rostratum from rice in Venezuela. References: (1) J. L. Alcorn. Mycotaxon. 17:1, 1983. (2) A. Sivanesam. Mycol. Pap. 158, 1987.

1 recurso en línea (páginas 51-61)., We report structural analysis, surface morphology, magnetic ordering, dielectric response, optical feature and the electronic structure of the Dy2BiFeO6 novel complex perovskite. The samples were produced by the standard solid-state reaction recipe. Crystallographic analysis was performed by Rietveld refinement of experimental X-ray diffraction patterns. Results show that this material crystallizes in a perovskite with orthorhombic structure, which corresponds to the Pnma (#62) space group. From the Curie-Weiss fitting on the curve of susceptibility as a function of temperature we establish that the ordering corresponds to a paramagnetic-antiferromagnetic transition, with a Weiss temperature θ=-18,5 K, which is compatible with the behavior of the inverse of susceptibility as a function of temperature, and a Néel temperatura TN=50,8 K. The Curie constant allowed for us to obtain an effective magnetic moment of 15,7 μB. The result of magnetization as a function of the applied field, measured at T=50 K, shows a magnetic hysteresis behavior that corroborate the magnetic ordering present for this temperature value. Measurements of the dielectric constant as a function of applied frequencies at room temperature give as a result a high relative dielectric constant (ε=780). The reflectance curve as a function of the wavelength reveals the typical behavior of a double perovskite-like material and permits to obtain the energy gap 2,74 eV, which is characteristic of a semiconductor material., En este trabajo reportamos el análisis estructural, morfología superficial, ordenamiento magnético, respuesta dieléctrica y característica óptica de la nueva perovskita compleja Dy2BiFeO6. Las muestras fueron producidas mediante reacción de estado sólido. El análisis cristalográfico fue realizado a través de refinamiento Rietveld de los patrones experimentales de rayos X. Los resultados muestran que este material cristaliza en una perovskita ortorrómbica correspondiente al grupo espacial Pnma (#62). Por medio del ajuste de Curie-Weiss a la respuesta de la susceptibilidad magnética en función de la temperatura se estableció que el ordenamiento magnético se relaciona con una transición paramagnético-antiferromagnético con una temperatura de Weiss θ=-18,5 K, la cual es acorde con el comportamiento del inverso de la susceptibilidad en función de la temperatura, y una temperatura de Néel TN=50,8 K. La constante de Curie permitió determinar un momento magnético efectivo de 15,7 μB. Medidas de magnetización en función del campo aplicado a T=50 K, muestran un débil comportamiento histerético, que corrobora el ordenamiento magnético presente a esa temperatura. Mediciones de la constante dieléctrica en función de la frecuencia aplicada a temperatura ambiente dan como resultado una alta constante dieléctrica relativa a bajas frecuencias (ε=780). La curva de reflectancia en función de la longitud de onda revela el comportamiento típico de un material de tipo perovskita doble y permite la obtención de la brecha de energía de 2,74 eV característico de un material semiconductor., Bibliografía: páginas 60-61.

We report experimental and theoretical results of crystal structure, morphology, magnetic and electric features, and electronic structure for the Sr2DyNbO6 ceramic compound. Samples were produced by the solid-state reaction recipe. X-ray diffraction experiments show that the material crystallizes in a monoclinic structure, P21/n space group. SEM images exhibit a granular submicrometric surface. Temperature curves of magnetic susceptibility reveal a paramagnetic response. Curie law fitting permitted to obtain a magnetic moment 10.28 μB. Polarization as a function of electric fields shows a hysteretic feature with 264.28 relative dielectric constant at 300 K. DFT calculations of electronic structure suggest the semiconductor character of this material, energy gap 3.21 eV for the spin-up polarization and 0.26 eV for spin-down. The calculated effective magnetic moment was 10.0 μB, which is strongly in accordance with the measured value. The theoretical cell parameters obtained from the Murnaghan state-equation are 98.5% in agreement with the experimental result. Se reportan resultados experimentales y teóricos de estructura cristalina, morfología, carácter magnético y eléctrico, y estructura electrónica para el material cerámico Sr2DyNbO6. Las muestras fueron producidas mediante reacción sólida. Resultados de difracción de rayos X muestran que el material cristaliza en una estructura monoclínica, grupo espacial P21/n. Imágenes de MEB muestran superficies granulares submicrométricas. La susceptibilidad en función de la temperatura revela una respuesta paramagnética con momento magnético 10.28μB. La histéresis de polarización en función del campo eléctrico a 300K permitió obtener una constante dieléctrica de 264.28. Cálculos de estructura electrónica por DFT sugieren que el material es semiconductor con brecha de energía 3.21 eV para la orientación espín arriba y 0.26 eV para espín abajo. El momento magnético calculado es 10.0μB, muy próximo del valor medido. Los parámetros de red obtenidos mediante la ecuación de Murnaghan están de acuerdo con los resultados experimentales en un 98.5%.

Background: Allergic diseases are very common, with the estimated cumulative prevalence in Colombia for asthma and allergic rhinitis being 22.7% and 31.3% respectively, and with a clear upward trend. A major social as well as economic impact associated with allergic disease has been described. Because in Colombia there are no studies that assess the Health-Related Quality of Life (HRQOL) in allergic respiratory diseases, our aim is to describe the HRQOL in subjects with respiratory allergy and its association with clinical control variables. Methods: A prospective descriptive study was conducted among 76 Colombian subjects with rhinitis and asthma/allergic rhinitis. In order to evaluate the HRQOL, the instruments Kidscreen27 and SF-36 were applied. The scores obtained in the HRQOL fields were correlated with the following clinical variables: peak expiratory flow (PEF) and peak nasal inspiratory flow (PNIF). Results: In children, the better HRQL domain is present in the school environment (55.9) and the worst in psychological well-being (39.9). For adults the worst HRQL was found in the emotional function domain (55.6) while the physical function (81.7) had the best. There were no statistical differences between groups of asthma/allergic rhinitis and allergic rhinitis. Subjects with allergic asthma showed a strong correlation between the mental health domain and PEF values (r = −0717, p = 0.046). Conclusion: Mental health is more affected than physical health in Colombian subjects with respiratory allergy. There was a strong correlation between the mental health domain and the values of PEF in patients with asthma/allergic rhinitis COL0007121 COL0059567

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

OBJECTIVES/SPECIFIC AIMS: Island communities face greater environmental risks creating challenges in their populations. A community and participatory qualitative research method aiming to understand community perspectives regarding the ecology and environmental risks of the island of Culebra was performed to develop a community-centered Information and Communications Technology (ICT) intervention (an app). The island of Culebra, a municipality from the archipelago of Puerto Rico is located 17 miles from the eastern coast of Puerto Rico’s main island. This ICT—termed mZAP (Zonas, Acción & Protección)—is part of a Translational Biomedical doctoral degree dissertation housed at the University of Rochester’s Clinical Translational Science Institute (CTSI) Informatics Core funded by an NIH Clinical Translational Science Award (CTSA). In September 2017, the island of Culebra faced 2 major category hurricanes 2 weeks apart. Hurricane Irma and Hurricane Maria devastated homes, schools, health clinics, and local businesses, disrupting an already-fragile ecological balance on the island. METHODS/STUDY POPULATION: These 2 storms catastrophically affected the archipelago of Puerto Rico. Culebra’s geographically isolated location, along with the inefficient response from authorities, exacerbated the stressors caused by these natural disasters, increasing the gap of social determinants of health, including the lack of potable water. Leveraging a community engagement partnership established before the hurricanes by the mZAP participatory research, which naturally halted once the hurricanes hit a new humanitarian objective formed to deliver aid. Along with another NIH funded RCMI Translational Research Network, or RTRN institution (University of Puerto Rico, Medical Science Campus) students and faculty, The Puerto Rico Testsite for Exploring Contamination Threats Program (PROTECT) an NIEHS Funded Grant, and the National Guard, a “people to people” approach was established to ascertain needs and an opportunity to meet those needs. A people-to-people approach brings humanitarian needs, identified directly by the community to the people who need it most; without intermediaries and bureaucratic delays that typically occur during catastrophes. RESULTS/ANTICIPATED RESULTS: The consumption of potable water in plastic bottles and subsequent accumulation of plastic material has proven to be collateral damage of a vulnerable water distribution system creating another environmental hazard on the island of Culebra. Therefore, this humanitarian partnership, worked to delivered community and family sized water filters, providing a safe environmental alternative to drinkable water for the island. The success of this approach, People to People for Puerto Rico (#p2p4PUR), demonstrated the power of genuine community engagement—arising from a previous clinical research partnership—and true established commitment with members of the community. DISCUSSION/SIGNIFICANCE OF IMPACT: Research partnerships can (and should, when needed) lead to humanitarian partnerships that extend beyond research objectives. Research may subsequently be adapted based on new realities associated with natural disasters and the altered nature of existing partnerships, allowing for a rapid response to communities need. Further, #p2p4PUR was not only able to channel a partnership humanitarian response but also created an opportunity to reflect on how the commitment between members of society and academia (researchers) can create beneficial bilateral relationships, always putting the community needs first. The resulting shared experience elevates community interest and engagement with researchers, and helps researchers see communities as true partners, rather than—simply—research subjects.

The goal of this project is to reconstruct the operational sequence of manufacture of Iberian Iron Age pottery, from clay procurement to firing in a reconstructed kiln. Although pottery is the most characteristic artefact recovered on Iberian Iron Age excavations, most of its complex processes and production techniques remain poorly known. The first phase of this experiment began in 2007 with the construction of a scaled replica of the Iron Age Iberian kiln brought to light at the excavation of Alcalá de Júcar (Province of Albacete). This reconstruction employed materials and techniques identified on the archaeological dig, as well as ethnographic parallels. Some parallels were drawn from the Catalonian town of Verdú, the location of the experiment. This town has an uninterrupted 500 year tradition of ceramic production. The kiln comprised two chambers separated by a grate. Four sensors installed in the kiln recorded a maximum temperature of 600° C. This temperature is probably due to the fact that the kiln was empty during its initial firing. Replicas of Iberian Culture vessels thrown by potters from Verdú were fired in a second experiment. This revealed information regarding the general firing process of vertical updraught kilns in all its complexity, as well as the techniques of temperature control and oxidation and reduction processes, subjects to be examined in future research.

OBJECTIVE: The acute decrease in iodide organification in the thyroid in response to excess iodide is termed the acute Wolff-Chaikoff effect and normal organification resumes in spite of continued high plasma iodide concentrations (escape from the acute Wolff-Chaikoff effect). We have recently reported that large doses of iodide given to rats chronically decrease the sodium/iodide symporter (NIS) mRNA and protein, suggesting that escape is due to a decrease in NIS and subsequent iodide transport. We have now studied the effect of excess iodide on NIS in FRTL-5 cells to further explore the mechanisms whereby excess iodide decreases NIS. DESIGN: FRTL-5 cells were employed and were incubated in the presence or absence of various concentrations of iodide. NIS mRNA and protein and the turnover of NIS were assessed. METHODS: NIS mRNA was measured by Northern analysis, NIS protein by Western analysis and NIS turnover by pulse-chase labeling experiments. RESULTS: Iodide (10(-) mol/l) had no effect on NIS mRNA in FRTL-5 cells at 24 and 48 h compared with cells cultured in the absence of iodide. However, excess iodide decreased NIS protein by 50% of control values at 24 h and by 70% at 48 h. This effect of iodide was dose dependent. Pulse-chase experiments demonstrated that there was no effect of iodide on new NIS protein synthesis and that the turnover of NIS protein in the presence of iodide was 27% faster than in the absence of added iodide. CONCLUSIONS: Excess iodide does not decrease NIS mRNA in FRTL-5 cells but does decrease NIS protein, suggesting that in this in vitro thyroid cell model iodide modulates NIS, at least in part, at a post-transcriptional level. This iodide-induced decrease in NIS protein appears to be due, at least partially, to an increase in NIS protein turnover.

Nuclear hormone receptors activate gene transcription through ligand-dependent association with coactivators. Specific LXXLL sequence motifs present in these cofactors are sufficient to mediate these ligand-induced interactions. A thyroid hormone receptor (TR)-binding protein (TRBP) was cloned by a Sos-Ras yeast two-hybrid system using TRβ1-ligand binding domain as bait. TRBP contains 2063 amino acid residues, associates with TR through a LXXLL motif, and is ubiquitously expressed in a variety of tissues and cells. TRBP strongly transactivates through TRβ1 and estrogen receptor in a dose-related and ligand-dependent manner, and also exhibits coactivation through AP-1, CRE, and NFκB-response elements, similar to the general coactivator CBP/p300. The C terminus of TRBP binds to CBP/p300 and DRIP130, a component of the DRIP/TRAP/ARC complex, which suggests that TRBP may activate transcription by means of such interactions. Further, the association of TRBP with the DNA-dependent protein kinase (DNA-PK) complex and DNA-independent phosphorylation of TRBP C terminus by DNA-PK point to a potential connection between transcriptional control and chromatin architecture regulation.

In 1948, Wolff and Chaikoff reported that organic binding of iodide in the thyroid was decreased when plasma iodide levels were elevated (acute Wolff-Chaikoff effect), and that adaptation or escape from the acute effect occurred in approximately 2 days, in the presence of continued high plasma iodide concentrations. We later demonstrated that the escape is attributable to a decrease in iodide transport into the thyroid, lowering the intrathyroidal iodine content below a critical inhibitory threshold and allowing organification of iodide to resume. We have now measured the rat thyroid sodium/iodide symporter (NIS) messenger RNA (mRNA) and protein levels, in response to both chronic and acute iodide excess, in an attempt to determine the mechanism responsible for the decreased iodide transport. Rats were given 0.05% NaI in their drinking water for 1 and 6 days in the chronic experiments, and a single 2000-μg dose of NaI ip in the acute experiments. Serum was collected for iodine and hormone measurements, an...

Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that regulate target gene transcription. We report the molecular cloning and characterization of a novel human cDNA encoding TRAM-1, a thyroid hormone receptor activator molecule, a approximately 160-kDa protein homologous with SRC-1/TIF2, by far-Western-based expression screening. TRAM-1 binds to thyroid hormone receptor (TR) and other NRs in a ligand-dependent manner and enhances ligand-induced transcriptional activity of TR. The AF-2 region in NRs has been thought to play a critical role in mediating ligand-dependent transactivation by the interaction with coactivators. Surprisingly, TRAM-1 retains strong ligand-dependent interaction with an AF-2 mutant of TR (E457A), while SRC-1 fails to interact with this mutant. Furthermore, we identified a critical TRAM-1 binding site in rat TRbeta1 outside of AF-2, as TRAM-1 shows weak ligand-dependent interaction with a helix 3 ligand binding domain TR mutant (K288A), compared with SRC-1. These results suggest that TRAM-1 is a coactivator that may exhibit its activity by interacting with subdomains of NRs other than the AF-2 region, in contrast to SRC-1/TIF2.

Resumen: La lipodistrofia generalizada congénita o síndrome de Berardinelli-Seip es una entidad rara con herencia autosómica recesiva que se caracteriza por una ausencia congénita de tejido adiposo y secundariamente un defecto en la síntesis de leptina. Los sujetos afectos presentan un fenotipo clásico con rasgos acromegaloides, atrofia generalizada del tejido graso subcutáneo, apariencia musculada, acantosis nigricans, hepatomegalia y abdomen prominente. Desde el punto de vista metabólico, y como consecuencia del déficit de la leptina son características la hipertrigliceridemia marcada, que suele conllevar esteatosis hepática y la resistencia a la insulina. Presentamos el caso de dos sujetos de distintas familias afectos de lipodistrofia generalizada congénita que durante su evolución desarrollaron diabetes mellitus con mal control que fueron tratados con dosis elevadas de insulina y que presentaron precozmente complicaciones microvasculares. Se constató la existencia de mutación para el gen LMNA en uno de los sujetos. Abstract: Generalized congenital lipodystrophy or Berardinelli-Seip Syndrome is a rare autosomal recessive condition characterized by the absence of adipose tissue and eventually a defect in leptin synthesis. Affected subjects tend to show a classical phenotype with acromegaloid appearance, generalized atrophy of subcutaneous adipose tissue with muscular hypertrophy, acanthosis nigricans, hepatomegaly and prominent abdomen. From metabolic point of view and as a consequence of leptin absence, hypertriglyceridemia leading to hepatic steatosis and insulin resistance may appear. Two cases of unrelated subjects affected of generalized congenital lipodystrophy are presented. Both developed difficult-to-manage diabetes mellitus and were treated with high doses of insulin. In both cases early microvascular complications were present. A mutation for LMNA gene was found in one of the subjects.

Generalized congenital lipodystrophy or Berardinelli-Seip Syndrome is a rare autosomal recessive condition characterized by the absence of adipose tissue and eventually a defect in leptin synthesis. Affected subjects tend to show a classical phenotype with acromegaloid appearance, generalized atrophy of subcutaneous adipose tissue with muscular hypertrophy, acanthosis nigricans, hepatomegaly and prominent abdomen. From metabolic point of view and as a consequence of leptin absence, hypertriglyceridemia leading to hepatic steatosis and insulin resistance may appear. Two cases of unrelated subjects affected of generalized congenital lipodystrophy are presented. Both developed difficult-to-manage diabetes mellitus and were treated with high doses of insulin. In both cases early microvascular complications were present. A mutation for LMNA gene was found in one of the subjects.

The evolution of nutritional habits has experienced many changes through the time, but it has always been supported with the basic criterion to maintain the health. Every day the exigencies of the consumers go more to the search of new products with functional properties that can provide in addition to the nutritious value, other components with physiological activity that allow a better physical and mental state, reducing therefore the risk of diseases and extending the life at the same time that maintaining its quality This review describes an overview about the most important aspects of the foods and ingredients with functional characteristics through the past, present and future.

A survey of parity-changing E1 transitions has been pursued in N>~Z nuclei near 56Ni using data from an EUROBALL experiment. Linear polarization measurements have been combined with angular correlations of coincident gamma rays to determine the electromagnetic character of numerous transitions. The impact of the results on shell-model parametrizations is briefly discussed.

Ligand-dependent interaction of nuclear receptors and coactivators is a critical step in nuclear receptor-mediated transcriptional regulation. TR-binding protein (TRBP) interacts with nuclear receptors through a single LXXLL motif. Evidence suggested that the sequences flanking the LXXLL motif in a number of coactivators determine receptor selectivity. We performed mutagenesis studies at residues adjacent to the TRBP LXXLL motif and identified S884 of TRBP at the -3 position of the LXXLL motif as a key residue for receptor selectivity. Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERbeta, TR, and RXR vs. ERalpha. Transient transfection studies further confirmed that the LXXLL-binding affinity correlates with TRBP transcriptional activity. Consistent with the structural modeling, an E380G substitution within ERalpha altered the binding to TRBP mutants, demonstrating the direct contact between TRBP S884 and ERalpha E380, which is a residue that distinguishes receptor subclasses. Furthermore, S884 can be phosphorylated by MAPK in vitro, an event that significantly altered the binding of TRBP to ER and suggests a potential mechanism for regulatory interaction. As the differential recruitment of TRBP to ERalpha and ERbeta may rely on S884, our finding provides insight into estrogen signaling and may lead to the development of therapeutic receptor-selective peptide antagonists.

Nuclear receptors are members of a superfamily of DNA-binding transcriptional factors. Hormone-induced gene activation by nuclear receptors involves a variety of biological phenomena such as cell proliferation, differentiation, and development (31, 33). A central question in the field is how a single nuclear receptor molecule elicits complex responses of gene activation or repression in response to a hormonal stimulus in a cell-specific manner. There is evidence that tissue selectivity of gene expression induced by liganded receptors involves the coordination and assembly of an array of coregulatory proteins (9, 15, 26, 33, 53). Together with nuclear receptors, these cofactors are regulated at multiple levels, including tissue-specific distribution (22, 41, 54), variation of the assembly on each subset of hormone response elements (57), and cell-specific interactions between the nuclear receptors and their cofactors (33, 36, 54). Members of the nuclear receptor family share several structurally related domains (31). The N-terminal transactivation regions of the receptors have variable primary sequences and are largely responsible for the functional differences among the receptor isoforms. The DNA-binding domain (DBD), which targets the receptors to their cognate hormone response elements, is composed of two conserved zinc fingers (31). The C-terminal ligand-binding domain (LBD) is responsible for binding to ligand and enables ligand-dependent disassociation of corepressor and association with coactivators (9). A common LXXLL motif present in most coactivators provides the interface for interaction between conserved LBD and coactivator molecules, including CBP/p300 (24), the SRC-1 family (26, 37), PGC-1 (22, 35, 41), CIA (48), and TRBP/ASC-2/AIB3/RAP250/PRIP/NRC (11, 23, 25, 30, 58). However, whether selective interaction between various nuclear receptors and coactivators occurs to mediate cell-specific action remains to be elucidated (54). Protein cofactors specialized for interaction with the DBD of nuclear receptors are less characterized or defined. The DBD is the most highly conserved domain among members of the nuclear receptor superfamily (31). It plays an important role in determining the selectivity of DNA binding as well as directing the dimerization of nuclear receptors (6). Extensive studies of the structure and function of the DBD have revealed that receptor dimerization and binding of the DBD to each hormone response element rely on the variation of primary sequences around its zinc fingers and, in turn, contribute to its selectivity (6, 57). However, much less is known about regulation by nuclear cofactors that bind to the DBD. Several cofactors that interact with the DBDs of nuclear receptors have been reported, including SNURF. SNURF is characterized as a small nuclear RING finger protein that activates androgen receptor (AR)-mediated transcription by interaction with the DBD of AR (34, 39). Interestingly, SNURF facilitates nuclear trafficking of AR in a ligand-dependent manner (40). Several other protein factors, including ANPK, ARIP3, and ARIP4, have also been suggested to bind to the AR DBD and to modulate AR-mediated transactivation (21). In addition, DNA-dependent protein kinase was shown to interact with the DBD of progesterone receptor (PR) (45). The DBD of thyroid hormone receptor (TR) was suggested to interact with cofactors with repressive function (28). A recent report also indicates that the DBD of TR and retinoid X receptor (RXR) associates with PSF, a corepressor that recruits Sin3A to the receptor DBD (32). Another group of proteins that influence DNA binding of nuclear receptors is the high-mobility-group (HMG) proteins (7, 8, 38, 43). In addition to facilitating the binding of nuclear receptors to DNA, HMG proteins have diverse regulatory functions in DNA binding and chromatin architecture (16). The DBDs of nuclear receptors have also been shown to interact with other transcriptional factors such as NF-κB and AP-1, with resultant regulation of transcriptional repression (51). Since the DBDs of nuclear receptors are evolutionarily conserved, DBD-binding coactivators might also retain other conserved functions in the action of various DBDs of nuclear receptors. Nuclear receptor-mediated target gene expression is largely tissue and cell specific, and it is subject to coordinate regulation by cytoplasmic signaling (31). Compared to the extensive studies of the nuclear function of nuclear receptors and cofactors, the regulation of these cofactors by signaling pathways, including phosphorylation, is less clear. However, the cytoplasmic hormonal effects of nuclear receptor ligands, now also referred to as rapid or nongenomic effects, have long been observed in cells. For example, thyroid hormone stimulates the epidermal growth factor pathway (27), estrogen induces mitogen-activated protein kinase (MAPK) and phosphatidylinositol (PI) 3-kinase signaling (29), and tamoxifen affects insulin-like growth factor I receptor action in breast cancer cells (17). In addition to binding of the receptor LBD in the nucleus, ligands may thus stimulate various signaling molecules and ultimately modify protein factors, including the coactivators that are important for nuclear receptor action. In this regard, the regulation of cofactors by hormones via kinase signaling might also contribute to a large extent of the cell-specific effects. Several lines of evidence have supported the notion that nuclear cofactors are kinase regulated. These include phosphorylation of p300 by protein kinase C (PKC) at Ser89 with inhibition of its transactivation (56), phosphorylation and regulation of SRC-1 by MAPK via protein kinase A (PKA) signaling (10), and phosphorylation of TRBP by DNA-dependent protein kinase (23). Thus, posttranslational modification of cofactors may be a common mechanism to mediate, at least in part, the specificity and selectivity of nuclear receptors in transcriptional regulation. We report here the isolation and characterization of a tissue-specific nuclear receptor coactivator, GT198. GT198 contains a leucine dimerization domain and interacts with nuclear receptors via the DBD. GT198 enhances nuclear receptor-mediated transcription, and coactivation by GT198 may be subject to kinase regulation. The mechanism of its activation is distinguishable from LBD-interacting coactivators such as SRC-1, TRBP, and CBP. GT198 represents a new class of DBD-interacting nuclear receptor coactivators.

Compounds The perovskites are materials with physical and chemical characteristics that make them optimal for application in the technological and scientist. When the ideal formula of perovskite ABO3 is modified by introducing a special structural arrangement can get to get triple perovskites, which correspond to the formula A3B2B'O9. In this work we report the synthesis process and the study of electronic structure and crystal Sr3Sb2CoO9 new triple perovskite. From the experiments of X-ray Diffraction and the application of the Rietveld refinement method was revealed that the system crystallizes in a perovskite structure with a characteristic triple given by the space group Immm (#71) and lattice parameters a=9.791(9) A, b=5.656(7) A and c=16.957(8) A. Ab initio calculations of density of states (DOS) and electronic structure were carried out for this perovskite-like system by using the Quantum EXPRESSO code. The exchange-correlation potential was treated using the Generalized Gradient Approximation (GGA). All calculations were carried-out using spin polarization. ©2013 Elsevier Science. All rights reserved.

In 1948, Wolff and Chaikoff reported that organic binding of iodide in the thyroid was decreased when plasma iodide levels were elevated (acute Wolff-Chaikoff effect), and that adaptation or escape from the acute effect occurred in approximately 2 days, in the presence of continued high plasma iodide concentrations. We later demonstrated that the escape is attributable to a decrease in iodide transport into the thyroid, lowering the intrathyroidal iodine content below a critical inhibitory threshold and allowing organification of iodide to resume. We have now measured the rat thyroid sodium/iodide symporter (NIS) messenger RNA (mRNA) and protein levels, in response to both chronic and acute iodide excess, in an attempt to determine the mechanism responsible for the decreased iodide transport. Rats were given 0.05% NaI in their drinking water for 1 and 6 days in the chronic experiments, and a single 2000-microg dose of NaI i.p. in the acute experiments. Serum was collected for iodine and hormone measurements, and thyroids were frozen for subsequent measurement of NIS, TSH receptor, thyroid peroxidase (TPO), thyroglobulin, and cyclophilin mRNAs (by Northern blotting) as well as NIS protein (by Western blotting). Serum T4 and T3 concentrations were significantly decreased at 1 day in the chronic experiments and returned to normal at 6 days, and were unchanged in the acute experiments. Serum TSH levels were unchanged in both paradigms. Both NIS mRNA and protein were decreased at 1 and 6 days after chronic iodide ingestion. NIS mRNA was decreased at 6 and 24 h after acute iodide administration, whereas NIS protein was decreased only at 24 h. TPO mRNA was decreased at 6 days of chronic iodide ingestion and 24 h after acute iodide administration. There were no iodide-induced changes in TSH receptor and thyroglobulin mRNAs. These data suggest that iodide administration decreases both NIS mRNA and protein expression, by a mechanism that is likely to be, at least in part, transcriptional. Our findings support the hypothesis that the escape from the acute Wolff-Chaikoff effect is caused by a decrease in NIS, with a resultant decreased iodide transport into the thyroid. The observed decrease in TPO mRNA may contribute to the iodine-induced hypothyroidism that is common in patients with Hashimoto's thyroiditis.

The response of the pituitary gonadotrope to gonadotropin-releasing hormone (GnRH) correlates directly with the concentration of GnRH receptors (GnRHR) on the cell surface, which is mediated in part at the level of GnRHR gene expression. Several hormones have been implicated in this regulation, most notably GnRH itself. Despite these observations and the central role that GnRH is known to play in reproductive development and function, the molecular mechanism(s) by which GnRH regulates transcription of the GnRHR gene has not been well elucidated. Previous studies in this laboratory have identified and partially characterized the promoter region of the mouse GnRHR gene and demonstrated that the regulatory elements for tissue-specific expression as well as for GnRH regulation are present within the 1.2-kilobase 5′-flanking sequence. By using deletion and mutational analysis as well as functional transfection studies in the murine gonadotrope-derived αT3-1 cell line, we have localized GnRH responsiveness of the mouse GnRHR gene to two DNA sequences at −276/−269 (designated Sequence UnderlyingResponsiveness to GnRH-2 (SURG-2), which contains the consensus sequence for the activating protein-1-binding site) and −292/−285 (a novel element designated SURG-1), and demonstrated that this response is mediated via protein kinase C. By using the electrophoretic mobility shift assay, we further demonstrate that a member(s) of the Fos/Jun heterodimer superfamily is responsible in part for the DNA-protein complexes formed on SURG-2, using αT3-1 nuclear extracts. These data define a bipartite GnRH response element in the mouse GnRHR 5′-flanking sequence and suggest that the activating protein-1 complex plays a central role in conferring GnRH responsiveness to the murine GnRHR gene.

Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). SRC-1 contains three such motifs in the central (nuclear receptor binding domain-1, NBD-1) and a single one in the C-terminal (NBD-2) regions. To define the nature and role of the two NBDs in SRC-1, interaction studies between the two NBDs and thyroid hormone receptor (TR) were performed. Although NBD-1 and NBD-2 showed similar ligand- and AF-2-dependent interactions with TR in solution, these two NBDs possessed distinct interaction properties with TR when TR is bound to a thyroid hormone-response element (TRE). Both in vitro and in vivo interaction studies demonstrate that NBD-1, but not NBD-2, exhibits ligand-dependent interaction with TR in the presence of TREs. In addition, a natural isoform of SRC-1, SRC-1E, which lacks NBD-2, preserved TR as well as progesterone receptor-mediated coactivator function on reporter gene expression. Finally, we found that NBD-1 failed to interact with a TR and retinoid X receptor heterodimer complex on a transcriptionally inactive direct repeat +4 TRE in electrophoretic mobility shift assays. These observations indicate that DNA-induced, as well as ligand-induced, conformational change(s) of TR may influence the nature of its binding to SRC-1, and that the two NBDs of SRC-1 may play different roles to regulate ligand-dependent transactivation of TRs.