Chemical interaction between ocean and atmosphere

The exchange of chemical constituents between ocean and atmosphere provides potentially important feedback mechanisms in the climate system. The aim of this study is to develop and evaluate a chemically coupled global atmosphere-ocean model. For this, an atmosphere-ocean general circulation model with atmospheric chemistry has been expanded to include oceanic biogeochemistry and the process of air-sea gas exchange. The calculation of seawater concentrations in the oceanic biogeochemistry submodel has been expanded from DMS, CO₂

Cytotoxicity and P-glycoprotein inhibition by cardiotonic steroids

Herzwirksame Glykoside sind in der Natur sowohl im Tier- als auch im Pflanzenreich zu finden und werden regelmäßig zur Therpaie von Herzinsuffizienz eingesetzt. In letzter Zeit belegten viele Studien, dass herzwirksame Glykoside vielversprechende Substanzen für die Behandlung von Krebs darstellen. Ihr Wirkmechanismus basiert auf der Hemmung der Na+/K+-ATPase. Die Na+/K+-ATPase spielt neuerdings eine wichtige Rolle in der Krebsbiologie, da sie viele relevante Signalwege beeinflusst. Multiresistenzen gegen Arzneimittel sind oftmals verantwortlich für das Scheitern einer Chemotherapie. Bei multi-drug-resistenten Tumoren erfolgt ein Transport der Chemotherapeutika aus der Krebszelle hinaus durch das Membranprotein P-Glykoprotein. In der vorliegenden Arbeit wurde die Zytotoxizität von 66 herzwirksamen Glykosiden und ihren Derivaten in sensitiven und resistenten Leukämie-Zellen getestet. Die Ergebnisse zeigen, dass diese Naturstoffe die Zell-Linien in verschiedenen molaren Bereichen abtöten. Allerdings waren die Resistenz-Indizes niedrig (d. h. die IC50 Werte waren in beiden Zell-Linien ähnlich). Die untersuchten 66 Substanzen besitzen eine große Vielfalt an chemischen Substituenten. Die Wirkung dieser Substituenten auf die Zytotoxizität wurde daher durch Struktur-Aktivitäts-Beziehung (SAR) erforscht. Des Weiteren wiesen quantitative Struktur-Aktivitäts-Beziehung (QSAR) und molekulares Docking darauf hin, dass die Na+/K+-ATPase in sensitiven und resistenten Zellen unterschiedlich stark exprimiert wird. Eine Herunterregulation der Na+/K+-ATPase in multi-drug-resistenten Zellen wurde durch Western Blot bestätigt und die Wirkung dieser auf relevante Signalwege durch Next-Generation-Sequenzierung weiter verfolgt. Dadurch konnte eine Verbindung zwischen der Überexpression von P-Glykoprotein und der Herunterregulation der Na+/K+-ATPase hergestellt werden. Der zweite Aspekt der Arbeit war die Hemmung von P-Glykoprotein durch herzwirksame Glykoside, welche durch Hochdurchsatz-Durchflusszytometrie getestet wurde. Sechs wirksame Glykoside konnten den P-Glykoprotein-vermittelten Transport von Doxorubicin inhibieren. Zudem konnte die Zytotoxität von Doxorubicin in multi-drug-resistenten Zellen teilweise wieder zurück erlangt werden. Unabhängig von herzwirksamen Glykosiden war die Bewertung der Anwendung von molekularem Docking in der P-Glykoprotein Forschung ein weiterer Aspekt der Arbeit. Es ließ sich schlussfolgern, dass molekulares Docking fähig ist, zwischen den verschiedenen Molekülen zu unterscheiden, die mit P-Glykoprotein interagieren. Die Anwendbarkeit von molekularem Docking in Bezug auf die Bestimmung der Bindestelle einer Substanz wurde ebenfalls untersucht.

Reporting of research quality characteristics of studies published in 6 major clinical dental specialty journals

The objective of this article was to record reporting characteristics related to study quality of research published in major specialty dental journals with the highest impact factor (Journal of Endodontics, Journal of Oral and Maxillofacial Surgery, American Journal of Orthodontics and Dentofacial Orthopedics; Pediatric Dentistry, Journal of Clinical Periodontology, and International Journal of Prosthetic Dentistry). The included articles were classified into the following 3 broad subject categories: (1) cross-sectional (snap-shot), (2) observational, and (3) interventional. Multinomial logistic regression was conducted for effect estimation using the journal as the response and randomization, sample calculation, confounding discussed, multivariate analysis, effect measurement, and confidence intervals as the explanatory variables. The results showed that cross-sectional studies were the dominant design (55%), whereas observational investigations accounted for 13%, and interventions/clinical trials for 32%. Reporting on quality characteristics was low for all variables: random allocation (15%), sample size calculation (7%), confounding issues/possible confounders (38%), effect measurements (16%), and multivariate analysis (21%). Eighty-four percent of the published articles reported a statistically significant main finding and only 13% presented confidence intervals. The Journal of Clinical Periodontology showed the highest probability of including quality characteristics in reporting results among all dental journals.

Applications of Stable Isotope Ratio Analysis for Social Science Research

Stable Isotope Ratio Analysis (SIRA) is the measurement of variation in different isotopes of same elements in a material. This technique is well-established in the natural sciences and has been long part of the methodological arsenal in fields such as geology and biology. More recently this technique has begun to be utilized in the social sciences, moving from initial applications in anthropology to potential uses in geography, public health, forensic science, and others. This presentation will discuss the techniques behind SIRA, examples of current applications in the natural and social sciences, and potential avenues of future research.

Multiple site phosphorylation of tyrosine hydroxylase: A potential role for protein kinase C in the regulation of catecholamine synthesis

Tyrosine hydroxylase (TH), the initial and rate limiting enzyme in the catecholaminergic biosynthetic pathway, is phosphorylated on multiple serine residues by multiple protein kinases. Although it has been demonstrated that many protein kinases are capable of phosphorylating and activating TH in vitro, it is less clear which protein kinases participate in the physiological regulation of catecholamine synthesis in situ. These studies were designed to determine if protein kinase C (PK-C) plays such a regulatory role.^ Stimulation of intact bovine adrenal chromaffin cells with phorbol esters results in stimulation of catecholamine synthesis, tyrosine hydroxylase phosphorylation and activation. These responses are both time and concentration dependent, and are specific for those phorbol ester analogues which activate PK-C. RP-HPLC analysis of TH tryptic phosphopeptides indicate that PK-C phosphorylates TH on three putative sites. One of these (pepetide 6) is the same as that phosphorylated by both cAMP-dependent protein kinase (PK-A) and calcium/calmodulin-dependent protein kinase (CaM-K). However, two of these sites (peptides 4 and 7) are unique, and, to date, have not been shown to be phosphorylated by any other protein kinase. These peptides correspond to those which are phosphorylated with a slow time course in response to stimulation of chromaffin cells with the natural agonist acetylcholine. The activation of TH produced by PK-C is most closely correlated with the phosphorylation of peptide 6. But, as evident from pH profiles of tyrosine hydroxylase activity, phosphorylation of peptides 4 and 7 affect the expression of the activation produced by phosphorylation of peptide 6.^ These data support a role for PK-C in the control of TH activity, and suggest a two stage model for the physiological regulation of catecholamine synthesis by phosphorylation in response to cholinergic stimulation. An initial fast response, which appears to be mediated by CaM-K, and a slower, sustained response which appears to be mediated by PK-C. In addition, the multiple site phosphorylation of TH provides a mechanism whereby the regulation of catecholamine synthesis appears to be under the control of multiple protein kinases, and allows for the convergence of multiple, diverse physiological and biochemical signals. ^

Adenosine induced pulmonary fibrosis and the contribution of the adenosine A2B receptor to the induction of osteopontin in a mouse model of pulmonary fibrosis

Pulmonary fibrosis is a devastating and lethal lung disease with no current cure. Research into cellular signaling pathways able to modulate aspects of pulmonary inflammation and fibrosis will aid in the development of effective therapies for its treatment. Our laboratory has generated a transgenic/knockout mouse with systemic elevations in adenosine due to the partial lack of its metabolic enzyme, adenosine deaminase (ADA). These mice spontaneously develop progressive lung inflammation and severe pulmonary fibrosis suggesting that aberrant adenosine signaling is influencing the development and/or progression of the disease in these animals. These mice also show marked increases in the pro-fibrotic mediator, osteopontin (OPN), which are reversed through ADA therapy that serves to lower lung adenosine levels and ameliorate aspects of the disease. OPN is known to be regulated by intracellular signaling pathways that can be accessed through adenosine receptors, particularly the low affinity A2BR receptor, suggesting that adenosine receptor signaling may be responsible for the induction of OPN in our model. In-vitro, adenosine and the broad spectrum adenosine receptor agonist, NECA, were able to induce a 2.5-fold increase in OPN transcripts in primary alveolar macrophages. This induction was blocked through antagonism of the A2BR receptor pharmacologically, and through the deletion of the receptor subtype in these cells genetically, supporting the hypothesis that the A2BR receptor was responsible for the induction of OPN in our model. These findings demonstrate for the first time that adenosine signaling is an important modulator of pulmonary fibrosis in ADA-deficient mice and that this is in part due to signaling through the A2BR receptor which leads to the induction of the pro-fibrotic molecule, otseopontin. ^

Antibody chemical reactivity: Beneficial and pathogenic roles

Antibodies (Abs) to autoantigens and foreign antigens (Ags) mediate, respectively, various pathogenic and beneficial effects. Abs express enzyme-like nucleophiles that react covalently with electrophiles. A subpopulation of nucleophilic Abs expresses proteolytic activity, which can inactivate the Ag permanently. This thesis shows how the nucleophilicity can be exploited to inhibit harmful Abs or potentially protect against a virus. ^ Inactivation of pathogenic Abs from Hemophilia A (HA) patients by means of nucleophile-electrophile pairing was studied. Deficient factor VIII (FVIII) in HA subjects impairs blood coagulation. FVIII replacement therapy fails in 20-30% of HA patients due to production of anti-FVIII Abs. FVIII analogs containing electrophilic phosphonate group (E-FVIII and E-C2) were hypothesized to inactivate the Abs by reacting specifically and covalently with nucleophilic sites. Anti-FVIII IgGs from HA patients formed immune complexes with E-FVIII and E-C2 that remained irreversibly associated under conditions that disrupt noncovalent Ab-Ag complexes. The reaction induced irreversible loss of Ab anti-coagulant activity. E-FVIII alone displayed limited interference with coagulation. E-FVIII is a prototype reagent suitable for further development as a selective inactivator of pathogenic anti-FVIII Abs. ^ The beneficial function of Abs to human immunodeficiency virus type 1 (HIV-1) was analyzed. HIV-1 eludes the immune system by rapidly changing its coat protein structure. IgAs from noninfected subjects hydrolyzed gp120 and neutralized HIV-1 with modest potency by recognizing the gp120 421-433 epitope, a conserved B cell superantigenic region that is also essential for HIV-1 attachment to host cell CD4 receptors. An adaptive immune response to superantigens is generally prohibited due to their ability to downregulate B cells. IgAs from subjects with prolonged HIV-1 infection displayed improved catalytic hydrolysis of gp120 and exceptionally potent and broad neutralization of diverse CCR5-dependent primary HIV isolates attributable to recognition of the 421-433 epitope. This indicates that slow immunological bypass of the superantigenic character of gp120 is possible, opening the path to effective HIV vaccination. ^ My research reveals a novel route to inactivate pathogenic nucleophilic Abs using electrophilic antigens. Conversely, naturally occurring nucleophilic Abs may help impede HIV infection, and the Abs could be developed for passive immunotherapy of HIV infected subjects. ^

Investigation of I -compounds (newly discovered indigenous DNA modifications) by different approaches

I-compounds are newly discovered covalent DNA modifications detected by the $\sp{32}$P-postlabeling assay. They are age-dependent, tissue-specific and sex-different. The origin(s), chemistry and function(s) of I-compounds are unknown. The total level of I-compounds in 8-10 month old rat liver is 1 adduct in 10$\sp7$ nucleotides, which is not neglectable. It is proposed that I-compounds may play a role in spontaneous tumorigenesis and aging.^ In the present project, I-compounds were investigated by several different approaches. (1) Dietary modulation of I-compounds. (2) Comparison of I-compounds with persistent carcinogen DNA adducts and 5-methylcytosine. (3) Strain differences of I-compounds in relation to organ site spontaneous tumorigenesis. (4) Effects of nongenotoxic hepatocarcinogenes on I-compounds.^ It was demonstrated that the formation of I-compounds is diet-related. Rats fed natural ingredient diet exhibited more complex I-spot patterns and much higher levels than rats fed purified diet. Variation of major nutrients (carbohydrate, protein and fat) in the diet, produced quantitative differences in I-compounds of rat liver and kidney DNAs. Physiological level of vitamin E in the diet reduced intensity of one I-spot compared with vitamin E deficient diet. However, extremely high level of vitamin E in the diet gave extra spot and enhanced the intensities of some I-spots.^ In regenerating rat liver, I-compounds levels were reduced, as carcinogen DNA adducts, but not 5-methylcytosine, i.e. a normal DNA modification.^ Animals with higher incidences of spontaneous tumor or degenerative diseases tended to have a lower level of I-compounds.^ Choline devoid diet induced a drastic reduction of I-compound level in rat liver compared with choline supplemented diet. I-compound levels were reduced after multi-doses of carbon tetrachloride (CCl$\sb4$) exposure in rats and single dose exposure in mice. An inverse relationship was observed between I-compound level and DNA replication rate. CCl$\sb4$-related DNA adduct was detected in mice liver and intensities of some I-spots were enhanced 24 h after a single dose exposure.^ The mechanisms and explanations of these observations will be discussed. I-compounds are potentially useful indicators in carcinogenesis studies. ^

Sobre el Constructivismo : Construcción social de lo real y práctica investigativa

Las ciencias sociales en su versión clásica -adoptando como modelo a las ciencias naturales- se centraron en el estudio de los hechos empíricos con la pretensión de arribar a un conocimiento objetivo de la realidad. Desde este enfoque la ciencia deviene una representación teórica de la naturaleza, mientras lo real se constituye con independencia de la mente humana. Pero, durante el pasado siglo, los fundamentos mismos del conocimiento - el estatuto ontológico y epistemológico, tanto del objeto como el sujeto- serán cuestionados. En este nuevo enfoque, el lenguaje -y la comunicación- devienen los recursos a través de los cuales los individuos y los grupos construyen su vida cotidiana en tanto el interés se orienta a develar los procesos de construcción de sentido. Esta perspectiva modifica radicalmente el paradigma prevaleciente en las ciencias sociales; sin embargo, la discusión acerca de su validez no ha sido resuelta, en particular porque en ella se encuentran involucradas algunas de las principales cuestiones de la modernidad y la posmodernidad. Así, el artículo se propone considerar los principales elementos que configuran este enfoque, identificando las distintas corrientes que conviven en su interior, las principales críticas y específicamente, las consecuencias que se derivan tanto desde la perspectiva de la producción del conocimiento como en relación al estudio de la sociedad

Sobre el Constructivismo : Construcción social de lo real y práctica investigativa

Las ciencias sociales en su versión clásica -adoptando como modelo a las ciencias naturales- se centraron en el estudio de los hechos empíricos con la pretensión de arribar a un conocimiento objetivo de la realidad. Desde este enfoque la ciencia deviene una representación teórica de la naturaleza, mientras lo real se constituye con independencia de la mente humana. Pero, durante el pasado siglo, los fundamentos mismos del conocimiento - el estatuto ontológico y epistemológico, tanto del objeto como el sujeto- serán cuestionados. En este nuevo enfoque, el lenguaje -y la comunicación- devienen los recursos a través de los cuales los individuos y los grupos construyen su vida cotidiana en tanto el interés se orienta a develar los procesos de construcción de sentido. Esta perspectiva modifica radicalmente el paradigma prevaleciente en las ciencias sociales; sin embargo, la discusión acerca de su validez no ha sido resuelta, en particular porque en ella se encuentran involucradas algunas de las principales cuestiones de la modernidad y la posmodernidad. Así, el artículo se propone considerar los principales elementos que configuran este enfoque, identificando las distintas corrientes que conviven en su interior, las principales críticas y específicamente, las consecuencias que se derivan tanto desde la perspectiva de la producción del conocimiento como en relación al estudio de la sociedad

Sobre el Constructivismo : Construcción social de lo real y práctica investigativa

Las ciencias sociales en su versión clásica -adoptando como modelo a las ciencias naturales- se centraron en el estudio de los hechos empíricos con la pretensión de arribar a un conocimiento objetivo de la realidad. Desde este enfoque la ciencia deviene una representación teórica de la naturaleza, mientras lo real se constituye con independencia de la mente humana. Pero, durante el pasado siglo, los fundamentos mismos del conocimiento - el estatuto ontológico y epistemológico, tanto del objeto como el sujeto- serán cuestionados. En este nuevo enfoque, el lenguaje -y la comunicación- devienen los recursos a través de los cuales los individuos y los grupos construyen su vida cotidiana en tanto el interés se orienta a develar los procesos de construcción de sentido. Esta perspectiva modifica radicalmente el paradigma prevaleciente en las ciencias sociales; sin embargo, la discusión acerca de su validez no ha sido resuelta, en particular porque en ella se encuentran involucradas algunas de las principales cuestiones de la modernidad y la posmodernidad. Así, el artículo se propone considerar los principales elementos que configuran este enfoque, identificando las distintas corrientes que conviven en su interior, las principales críticas y específicamente, las consecuencias que se derivan tanto desde la perspectiva de la producción del conocimiento como en relación al estudio de la sociedad

Occurrence (presence-only) of living Lophelia pertusa reefs in the Irish continental margin

The present data set was used as a training set for a Habitat Suitability Model. It contains occurrence (presence-only) of living Lophelia pertusa reefs in the Irish continental margin, which were assembled from databases, cruise reports and publications. A total of 4423 records were inspected and quality assessed to ensure that they (1) represented confirmed living L. pertusa reefs (so excluding 2900 records of dead and isolated coral colony records); (2) were derived from sampling equipment that allows for accurate (<200 m) geo-referencing (so excluding 620 records derived mainly from trawling and dredging activities); and (3) were not duplicated. A total of 245 occurrences were retained for the analysis. Coral observations are highly clustered in regions targeted by research expeditions, which might lead to falsely inflated model evaluation measures (Veloz, 2009). Therefore, we coarsened the distribution data by deleting all but one record within grid cells of 0.02° resolution (Davies & Guinotte 2011). The remaining 53 points were subject to a spatial cross-validation process: a random presence point was chosen, grouped with its 12 closest neighbour presence points based on Euclidean distance and withheld from model training. This process was repeated for all records, resulting in 53 replicates of spatially non-overlapping sets of test (n=13) and training (n=40) data. The final 53 occurrence records were used for model training.

Los contenidos de expresión corporal en el titulo de grado en ciencias del deporte

La Expresión Corporal como materia educativa tiene su origen en España, de forma ligada a la Educación Física y su desarrollo en el ámbito universitario, durante la segunda mitad del siglo XX. Pero su corpus teórico no se encuentra definitivamente asentado, dando lugar a diferentes interpretaciones y consideraciones sobre cuáles deben ser considerados contenidos propios de la materia y sobre cómo deben ser estructurados. La presente tesis tiene por objeto de estudio precisamente los contenidos de la Expresión Corporal como materia perteneciente a las Ciencias de la Actividad Física y del Deporte, tratando de dar una respuesta fundamentada al planteamiento anterior. Para lo cual se seleccionaron y analizaron las principales obras de referencia para la materia en base a las cuales establecer una estructura de bloques de contenido y categorías asociadas. Se analizó la oferta formativa que, desde las universidades públicas españolas, se realizaba sobre el título de licenciado en Ciencias de la Actividad Física y del Deporte, comprobando por una parte la heterogeneidad en el tratamiento dado y por otra su adecuación a la estructura generada. Y en tercer lugar se examinó la normativa que articula y desarrolla el tratamiento de la Expresión Corporal en la Ley Orgánica de Educación, concretando el análisis en la etapa de Secundaria, en un proceso de triangulación sobre las fuentes documentales de mayor influencia, constatando una aparente falta de estructura en la selección y planteamiento de los contenidos a desarrollar dentro de la asignatura de Educación Física. En base a estas investigaciones, a la propia experiencia docente del doctorando y a la contribución de diferentes expertos en la materia se desarrolla una propuesta estructurada de contenidos de Expresión Corporal, la cual es implementada en el título de grado en Ciencias de la Actividad Física y del Deporte ofertado por la Universidad Politécnica de Madrid, analizando finalmente el nivel de relevancia que perciben los alumnos respecto de los contenidos de la materia planteados, infiriendo de los resultados obtenidos que se produce un aprendizaje significativo por parte de los futuros titulados. Se organizó la investigación en torno a cinco fases, utilizando en las tres primeras como metodología principal en análisis de contenido de las principales fuentes documentales (obras de referencia, programas docentes universitarios y normativa educativa), la cual es apoyada por otras herramientas como el grupo de discusión. La cuarta fase consistente en la elaboración de una propuesta estructurada de contenidos, contó con la valoración de un grupo de expertos en la materia. Mientras que en la fase de implementación y evaluación se recurrió al formato de entrevista colectiva mediante el empleo de cuestionario auto cumplimentado. La principal contribución de este trabajo es por tanto la presentación de una propuesta de estructuración de contenidos en Expresión Corporal, como parte de las manifestaciones básicas de la motricidad humana y enmarcada en el ámbito de las Ciencias de la Actividad Física y del Deporte; que tiene respaldo en las obras de referencia de la materia, en la formación inicial de los licenciados en Ciencias de la Actividad Física y del Deporte y en el desarrollo normativo de la Ley Orgánica de Educación; y que ha sido implementada en el actual título de Grado en Ciencias de la Actividad Física y del Deporte de la Universidad Politécnica de Madrid con resultados satisfactorios. ABSTRACT Corporal Expression as an educational subject has it origin s in Spain, linked to physical education and its development at University context, during the second half of the twentieth century. But his academic corpus has not been definitively settled, leading to different interpretations and considerations about what should be considered as proper contents of subject and how they should be structured. This thesis aims to study precisely the contents of the Corporal Expression as a subject belonging to Sciences of Physical Activity and Sport, trying to give a reasoned response to the previous approach. Taking this objective into consideration, main reference works were selected and analyzed to set a content structure and associated categories. The training offer of Spanish public universities in the Science of Physical Activity and Sport degree was analyzed, checking on the one hand the heterogeneity in the treatment and on the other their suitability to the structure generated. Thirdly, normative related to the treatment of Corporal Expression in the Ley Orgánica de Educación was examined paying special attention to the Secondary School stage. The process of triangulation which was performed using the most influential documentary sources suggested an apparent lack of structure and approach in the selection of contents to be developed in the subject of Physical Education. Based on these investigations, on the own teaching experience of the candidate and on the contribution of various experts in the field, a structured proposal of Corporal Expression contents is offered. This proposal has been implemented in the bachelor's degree in Sports Science offered by the Technical University of Madrid. Level of importance of the implemented contents perceived by students was analyzed and results suggested the presence of meaningful learning among graduates. Research was split into five phases. In the first three phases content analysis of the main documentary sources (reference books, university programs and educational standards), which was supported by other tools like the discussion group was the principal methodology. The fourth phase consisted in the development of a proposal structured content, involving the assessment of a group of experts in the field. In the implementation and evaluation phase collective interview using self-completed questionnaire was conducted The main contribution of this work is therefore presenting a proposal for structuring content in Corporal Expression, as a part of the basic manifestations of human motorskill and framed in the field of Sciences of Physical Activity and Sport; which draws on the support of reference works, initial training of graduates in Science of Physical Activity and Sport and the development of the normative of the Ley Orgánica de Educación; and has been implemented in the current Degree in Sports Science of the Technical University of Madrid with satisfactory results.

Proof for a nonproteinaceous calcium-selective channel in Escherichia coli by total synthesis from (R)-3-hydroxybutanoic acid and inorganic polyphosphate

Traditionally, the structure and properties of natural products have been determined by total synthesis and comparison with authentic samples. We have now applied this procedure to the first nonproteinaceous ion channel, isolated from bacterial plasma membranes, and consisting of a complex of poly(3-hydroxybutyrate) and calcium polyphosphate. To this end, we have now synthesized the 128-mer of hydroxybutanoic acid and prepared a complex with inorganic calcium polyphosphate (average 65-mer), which was incorporated into a planar lipid bilayer of synthetic phospholipids. We herewith present data that demonstrate unambiguously that the completely synthetic complex forms channels that are indistinguishable in their voltage-dependent conductance, in their selectivity for divalent cations, and in their blocking behavior (by La3+) from channels isolated from Escherichia coli. The implications of our finding for prebiotic chemistry, biochemistry, and biology are discussed.