Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease

Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erba) rescues Nr2e3- associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

Identification of Low-Risk Patients with Acute Symptomatic Pulmonary Embolism for Outpatient Therapy.

RATIONALE: Patients with acute symptomatic pulmonary embolism (PE) deemed to be at low risk for early complications might be candidates for partial or complete outpatient treatment. OBJECTIVES: To develop and validate a clinical prediction rule that accurately identifies patients with PE and low risk of short-term complications and to compare its prognostic ability with two previously validated models (i.e., the Pulmonary Embolism Severity Index [PESI] and the Simplified PESI [sPESI]) METHODS: Multivariable logistic regression of a large international cohort of patients with PE prospectively enrolled in the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry. MEASUREMENTS AND MAIN RESULTS: All-cause mortality, recurrent PE, and major bleeding up to 10 days after PE diagnosis were determined. Of 18,707 eligible patients with acute symptomatic PE, 46 (0.25%) developed recurrent PE, 203 (1.09%) bled, and 471 (2.51%) died. Predictors included in the final model were chronic heart failure, recent immobilization, recent major bleeding, cancer, hypotension, tachycardia, hypoxemia, renal insufficiency, and abnormal platelet count. The area under receiver-operating characteristic curve was 0.77 (95% confidence interval [CI], 0.75-0.78) for the RIETE score, 0.72 (95% CI, 0.70-0.73) for PESI (P < 0.05), and 0.71 (95% CI, 0.69-0.73) for sPESI (P < 0.05). Our RIETE score outperformed the prognostic value of PESI in terms of net reclassification improvement (P < 0.001), integrated discrimination improvement (P < 0.001), and sPESI (net reclassification improvement, P < 0.001; integrated discrimination improvement, P < 0.001). CONCLUSIONS: We built a new score, based on widely available variables, that can be used to identify patients with PE at low risk of short-term complications, assisting in triage and potentially shortening duration of hospital stay.

Nouveautés et perspectives dans la prise en charge des cancers colorectaux et gastriques avancés [News and perspectives in the treatment of advanced gastric and colorectal cancers].

Colorectal and gastric cancers are the fourth and third leading causes of cancer death world-wide. Unfortunately, gastric cancer is usually diagnosed at an advanced stage after becoming metastatic in distant sites, so that palliative therapy is the mainstay of treatment. Major progress in the understanding of the biology, the development of valid biomarkers and molecular targeted drugs have improved the treatment options and prognosis of both cancers significantly in the last years. Here, we review the current standards of care for patients with advanced and metastatic colorectal and gastric cancer and outline the perspectives for the future.

Functional and evolutionary analysis of DXL1, a non-essential gene encoding a 1-deoxy-D-xylulose 5-phosphate synthase like protein in Arabidopsis thaliana

The synthesis of 1-deoxy-D-xylulose 5-phosphate (DXP), catalyzed by the enzyme DXP synthase (DXS), represents a key regulatory step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis. In plants DXS is encoded by small multigene families that can be classified into, at least, three specialized subfamilies. Arabidopsis thaliana contains three genes encoding proteins with similarity to DXS, including the well-known DXS1/CLA1 gene, which clusters within subfamily I. The remaining proteins, initially named DXS2 and DXS3, have not yet been characterized. Here we report the expression and functional analysis of A. thaliana DXS2. Unexpectedly, the expression of DXS2 failed to rescue Escherichia coli and A. thaliana mutants defective in DXS activity. Coherently, we found that DXS activity was negligible in vitro, being renamed as DXL1 following recent nomenclature recommendation. DXL1 is targeted to plastids as DXS1, but shows a distinct expression pattern. The phenotypic analysis of a DXL1 defective mutant revealed that the function of the encoded protein is not essential for growth and development. Evolutionary analyses indicated that DXL1 emerged from DXS1 through a recent duplication apparently specific of the Brassicaceae lineage. Divergent selective constraints would have affected a significant fraction of sites after diversification of the paralogues. Furthermore, amino acids subjected to divergent selection and likely critical for functional divergence through the acquisition of a novel, although not yet known, biochemical function, were identified. Our results provide with the first evidences of functional specialization at both the regulatory and biochemical level within the plant DXS family.

An evaluation of the Swiss staging model for hypothermia using case reports from the literature.

BACKGROUND: Core body temperature is used to stage and guide the management of hypothermic patients, however obtaining accurate measurements of core temperature is challenging, especially in the pre-hospital context. The Swiss staging model for hypothermia uses clinical indicators to stage hypothermia. The proposed temperature range for clinical stage 1 is <35-32 °C (95-90 °F), for stage 2, <32-28 °C (<90-82 °F) for stage 3, <28-24 °C (<82-75 °F), and for stage 4 below 24 °C (75 °F). However, the evidence relating these temperature ranges to the clinical stages needs to be strengthened. METHODS: Medline was used to retrieve data on as many cases of accidental hypothermia (core body temperature <35 °C (95 °F)) as possible. Cases of therapeutic or neonatal hypothermia and those with confounders or insufficient data were excluded. To evaluate the Swiss staging model for hypothermia, we estimated the percentage of those patients who were correctly classified and compared the theoretical with the observed ranges of temperatures for each clinical stage. The number of rescue collapses was also recorded. RESULTS: We analysed 183 cases; the median temperature for the sample was 25.2 °C (IQR 22-28). 95 of the 183 patients (51.9 %; 95 % CI = 44.7 %-59.2 %) were correctly classified, while the temperature was overestimated in 36 patients (19.7 %; 95 % CI = 13.9 %-25.4 %). We observed important overlaps among the four stage groups with respect to core temperature, the lowest observed temperature being 28.1 °C for Stage 1, 22 °C for Stage 2, 19.3 °C for Stage 3, and 13.7 °C for stage 4. CONCLUSION: Predicting core body temperature using clinical indicators is a difficult task. Despite the inherent limitations of our study, it increases the strength of the evidence linking the clinical hypothermia stage to core temperature. Decreasing the thresholds of temperatures distinguishing the different stages would allow a reduction in the number of cases where body temperature is overestimated, avoiding some potentially negative consequences for the management of hypothermic patients.

Analysis of the process of inspection in recreational craft in Spain. Suggestions for safety improvement

Inspections of pleasure boats in Spain can be carried out by collaborating entities of inspection, entities that must be authorized by the Maritime Administration. This authorization allows to perform effective inspections and technical controls of recreational crafts. Recreational crafts are subjected to surveys that are based on the registration list and on the material used in the hull. In addition, required safety equipment of the recreational boat depends on the distance that the recreational boat is authorized to navigate. Following data obtained from inspections of recreational craft, this paper aims to analyze information about hulls within dry and afloat conditions, about the equipment for rescue and safety, and about other nautical equipment; as well as to perform and improve different verifications during the inspections. All this information points to several aspects relevant for the optimization of the inspection process, the ultimate target being increasing efficiency and effectiveness, and ensuring more safety in recreational craft.

As "Disquisitiones" do naturalista Arruda da Câmara (1752-1811) e as relações entre a Química e a Fisiologia no final do Século das Luzes

This work is intended to rescue the field of validity of the "Disquisitiones" by the naturalist Arruda da Câmara placing them in the scientific and historical context of the end of the "Century of Light". Thus, a tentative is made here to reconstruct the debate established among the several theories that served as background of the relationships between Chemistry and Physiology of that time. In the present work is presented by the first time an integral translation of the "Disquisitiones" and a biographical resume of the naturalist in the historical context of his epoch in Northeast Brazil, especially in Pernambuco.

Aplicaciones digitales con software libre para City Branding de Valledupar

El uso de las TIC se ha masificado dentro del ámbito del turismo convirtiéndose en herramienta fundamental y un aliado para llegar a conquistar turistas para los diferentes destinos que se promocionan a través de aplicaciones moviles o de website.Cada vez más las entidades turísticas o las empresas recurren a las tecnologías de la información, en particular Internet, como medio para promocionar sus productos y servicios turísticos. Estas nuevas tecnologías han cambiado el concepto de vida de personas en cuanto a la consulta de precio y rapidez de información de los diferentes servicios turísticos.En Valledupar se debe: aprovechar la tendencia mundial al rescate de los valores auténticos, el medio ambiente y las comunidades indígenas a través de diferentes modalidades de turismo: Ecoturismo, etnoturismo, agroturismo, cultural, religioso, compras, aventura, salud, deportivo, ciudad capital. Se debe ampliar el conocimiento del territorio municipal y de los valores autóctonos. Mediante uso de software libre y de código abierto se pueden crear soluciones para fortalecer la promoción del sector turístico de la ciudad de Valledupar.

Ultralujasta teräksestä valmistetun henkilönostimen teleskooppipuomin kehittäminen

Tässä työssä kehitettiin palo- ja pelastuskäyttöön tarkoitettuun henkilönostimeen teleskooppipuomin profiilit. Profiilien valmistusmateriaalina oli kuumavalssattu, ultraluja säänkestävä rakenneteräs. Työssä kehitettiin standardien ja ohjeiden pohjalta laskentapohja, jolla voidaan tutkia teleskooppipuomin jaksojen tukireaktioita, taivutus- ja vääntömomentteja ja leikkaus ja normaalivoimia. Laskentapohjassa voidaan varioida eri kuormitusten suuntia, teleskooppipuomin sivusuuntaista ulottumaa ja nostokulmaa. Profiilien alustavassa mitoituksessa hyödynnettiin paikallisen lommahduksen huomioon ottavia standardeja ja suunnitteluohjeita. Eri poikkileikkausten ominaisuuksia verrattiin keskenään ja profiili valittiin yhdessä kohdeyrityksen kanssa. Alustavan mitoituksen yhteydessä muodostettiin apuohjelma valitulle poikkileikkaukselle, jolla voitiin tutkia profiilin eri muuttujien vaikutusta mm. paikalliseen lommahdukseen ja jäykkyyteen. Laskentapohjaan sisällytettiin myös optimointirutiini, jolla voitiin minimoida poikkileikkauksen pinta-ala ja tätä kautta profiilin massa. Lopullinen mitoitus suoritettiin elementtimenetelmällä. Mitoituksessa tutkittiin alustavasti mitoitettujen profiilien paikallista lommahdusta lineaarisen stabiilius- ja epälineaarisen analyysin pohjalta. Profiilien jännityksiä tutkittiin tarkemmin mm. varioimalla kuormituksia ja osittelemalla elementtien normaalijännityksiä. Diplomityössä kehitetyllä ja analysoidulla teleskooppipuomilla voitiin keventää jaksojen painoja 15-30 %. Sivusuuntainen ulottuma parani samalla lähes 20 % ja nimelliskuorma kasvoi 25 %.

Camillo Berneri: la pluma y la pistola: contribuciones al debate sobre la función social de los intelectuales

Este trabajo pretende rescatar la figura, no exenta de polèmica, de Camillo Berneri. Para algunos Berneri fue una de las mentes más claras del periodo de entreguerres. También se tratará el periodo histórico concreto de la revolución social que sucedió en la España de 1936

GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish

Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing.

Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domain shave been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a GuA transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N- terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.

Om tennets och dess malmers beskaffenhet

Invocatio: I.J.N.

O Instituto de Química da Universidade Federal do Rio de Janeiro, da pós-graduação à incorporação dos cursos de graduação: uma perspectiva histórica

This work intends to present the history of top-level Chemistry education in Rio de Janeiro. It's important to rescue the history of Chemistry Institute of Federal University of Rio de Janeiro since 1959. It's also important to understand the incorporation of two undergraduate courses: Chemistry and Chemistry bachelor's degree. It covers historical background of Chemistry education in old National Faculty of Philosophy, considering power disputes between Industrial Chemistry Course and Chemical Engineering; when and in which circumstances the Institute was created; political context and its relation with postgraduate. Finally, discuss the incorporation of undergraduate courses and curriculum modifications since 1968.

Henkilöstöresurssien organisointi suuren alusöljyvahingon torjunnassa

Tässä pro gradu -tutkielmassa tarkastellaan henkilöstöresurssien organisointia suuren alusöljyvahingon torjuntatilanteessa. Tavoitteena on suunnitella Suomenlahden rannikon öljyntorjunnasta vastaavien viranomaisten käyttöön optimaalinen rekrytointistrategia pahimman todennäköisen alusöljyvahingon varalle. Tutkimuksessa selvitetään myös millainen työsopimus öljyntorjuntatyöntekijöiden kanssa voidaan sopia. Näiden lisäksi etsitään vastausta siihen,kuinka työvoima saadaan pidettyä. Tämän laadullisen tutkimuksen teoreettinen osuus toteutettiin kirjallisuuskatsauksena. Tutkimuksen empiirinen aineisto kerättiin haastattelemalla yhdeksää asiantuntijaa syksyn 2009 aikana. Haastattelut olivat muodoltaan puolistrukturoituja teemahaastatteluja. Tutkimustulosten mukaan merkittävin lisätyövoiman tarve ilmenee käsin tehtävässä rantapuhdistustyössä. Etenkin puhdistustyön pitkittyessä pelastusviranomaiset tarvitsevat avukseen ulkopuolista työvoimaa. Rekrytointi suoritetaan muutamien viikkojen kuluessa öljyvahingon aiheutumisen jälkeen. Alueellinen pelastuslaitos suorittaa rekrytoinnin käyttäen tehokkaita, laajan kohderyhmän tavoittavia rekrytointiviestinnän välineitä (esim. sanomalehdet, TV ja Internet). Työntekijöiden kanssa sovitaan määräaikainen, Kunnallista virkaja työehtosopimusta noudattava työsopimus. Tärkeimpinä puhdistustyöntekijöitä motivoivina tekijöinä nähdään työn merkitys yhteiskunnalle, selkeästi määritelty, saavutettavissa oleva tavoite sekä palaute tehdystä työstä.