Effects of direct ATP delivery to ischemic skeletal muscle.

The purpose of this dissertation was to demonstrate that a new method of direct intracellular energy delivery was effective in maintaining viability of in vitro Human Umbilical Vein Endothelial Cells (HUVECs) when exposed to chemical ischemia for prolonged periods of time and in preventing in vivo ischemia reperfusion injury in a composite tissue transplantation model. Ischemia and reperfusion injury is a well recognized phenomenon that occurs in situations like organ transplantation, shock, cardiac surgery, etc, where tissues are temporarily deprived of nutrients and oxygen for energy production. When exposed to short periods of ischemia, cells utilize their stored energy to survive. If ischemia is extended beyond certain limits, cellular energy stores become depleted leading to metabolic and structural changes. One of the effects of this lack of energy is the malfunctioning of the membrane adenosine triphosphate (ATP)-dependent ionic pumps which are ultimately responsible for maintaining cellular volume, intracellular pH and ionic homeostasis. Thus it is hypotesized that the negative effects of energy depletion on cellular homeostasis could be overcome by delivering energy directly into the cell. This method of direct energy delivery into cells is based on fusogenic lipid vesicles (FLVs) composed of lipids very similar to those that form the cellular membrane. These vesicles are very small and when put in contact with cell membranes, rapidly fuse to the cell membrane delivering their content into the cell interior. Making use of this phenomenon, the vesicles are loaded with ATP magnesium chloride (Mg-ATP) that is delivered directly into the cell, providing it with a readily usable form of energy. We hypothesized that, under chemical hypoxia, endothelial cell viability could be preserved and the Na + K +- ATPase pump activity could be maintained by delivering Mg-ATP directly into the cells. Further, we hypothesized that ischemia reperfusion injury due to tissue transplantation could be reduced by perfusing tissues ex vivo before reimplantation with a solution containing Mg-ATP-loaded FLVs. The first two hypotheses were tested in the following manner. First, we determined the optimal concentration of Mg-ATP that the FLVs needed to be loaded with to maintain the viability of HUVECs exposed to 4 hours of chemical hypoxia. Second, we tested if the Na + K + ATPase pump activity could be maintained by delivering Mg-ATP to HUVECs exposed to chemical hypoxia. The results of these experiments demonstrated that direct delivery of Mg-ATP using FLVs was effective in maintaining cell viability and Na + K + ATPase pump activity in cells exposed to chemical hypoxia. The third hypothesis was tested using a rat hind limb transplantation model. Hind limbs were harvested and perfused ex vivo with a preservation solution containing Mg-ATP-loaded FLVs. After 13 or 21 hours of ischemia limbs, were transplanted to the recipient. Limbs perfused with the Mg-ATP FLV solution had a greater survival rate than limbs perfused with control solutions. The application of this method of direct cellular energy delivery could have great implications in clinical situations where tissues are exposed to long periods of ischemia such as transplants or limb amputations. Further investigation is needed to optimize this preservation solution to allow its use as routine therapy in these situations

A calcareous nannofossil and organic geochemical study of marine palaeoenvironmental changes across the Sinemurian/Pliensbachian (early Jurassic, ~191Ma) in Portugal

The Sinemurian/Pliensbachian boundary (~ 191 Ma) is acknowledged as one of the most important steps in the radiation of planktonic organisms, especially primary producers such as dinoflagellates and coccolithophores. To date, there is no detailed study documenting changes in planktonic assemblages related to palaeoceanographic changes across this boundary. The aim of this study is to characterize the palaeoenvironmental changes occurring across the Sinemurian/Pliensbachian boundary at the São Pedro de Moel section (Lusitanian Basin, Portugal) using micropalaeontology and organic geochemistry approaches. Combined calcareous nannofossil assemblage and lipid biomarker data document for a decrease in primary productivity in relation to a major sea-level rise occurring above the boundary. The Lusitanian Basin was particularly restricted during the late Sinemurian with a relatively low sea level, a configuration that led to the recurrent development of black shales. After a sharp sea-level fall, the basin became progressively deeper and more open during the earliest Pliensbachian, subsequently to a major transgression. This sea-level increase seems to have been a global feature and could have been related to the opening of the Hispanic Corridor that connected the Tethys and palaeo-Pacific oceans. The palaeoceanographic and palaeoclimatic changes induced by this opening may have played a role in the diversification of coccolithophores with the first occurrence or colonization of Tethyan waters by placolith-type coccoliths

Shadows of Relic Neutrino Masses and Spectra on Highest Energy GZK Cosmic Rays

The Ultra High Energy (UHE) neutrino scattering onto relic cosmic neutrinos in galactic and local halos offers an unique way to overcome GZK cut-off. The UHE nu secondary of UHE photo-pion decays may escape the GZK cut-off and travel on cosmic distances hitting local light relic neutrinos clustered in dark halos. The Z resonant production and the competitive W^+W^-, ZZ pair production define a characteristic imprint on hadronic consequent UHECR spectra. This imprint keeps memory both of the primary UHE nu spectra as well as of the possible relic neutrino masses values, energy spectra and relic densities. Such an hadronic showering imprint should reflect into spectra morphology of cosmic rays near and above GZK 10^{19}-10^{21}eV cut-off energies. A possible neutrino degenerate masses at eVs or a more complex and significant neutrino mass split below or near Super-Kamiokande \triangle m_{\nu_{SK}}= 0.1 eV masses might be reflected after each corresponding Z peak showering, into new twin unexpected UHECR flux modulation behind GZK energies: E_{p} sim 3(frac{triangle m_{\nu_{SK}}}/m_{\nu}10^{21}),eV. Other shadowsof lightest, nearly massless, neutrinos m_{nu_{2K} simeq 0.001eV simeq kT_{\nu}, their lowest relic temperatures, energies and densities might be also reflected at even higher energies edges near Grand Unification: E_{p} \sim 2.2(m_{\nu_{2K}/E_{\nu}})10^{23}, eV .Comment: 14 pages, 6 Figures,Invited Talk Heidelberg DARK 200

Vibraciones libres de placas rectangulares con una perforación circular central

Este trabajo presenta el desarrollo y aplicación de un algoritmo general para la determinación de coeficientes de frecuencia de una placa rectangular con un agujero central libre. El algoritmo está basado en la aplicación del método de Rayleigh-Schmidt. Los resultados numéricos obtenidos que han podido ser comparados con trabajos de investigación previos, en general, están caracterizados por una buena precisión. Es posible aplicar el algoritmo en un amplio rango de condiciones de restricciones elásticas rotacionales, incluyendo las condiciones de apoyo clásicas, así como para distintas relaciones de lados de la placa y dimensiones de la perforación central.The present work deals with the development and application of a general algorithm for the determination of values of frequency coefficients for a rectangular plate with a central free hole. The algorithm is based on the application of Rayleigh-Schmidt method. The numerical results obtained and compared with previous works are characterized by a good accuracy. It is possible to applied it in a wide range of conditions of elastically rotational restrictions, including the classical boundary conditions and also for different aspect plate coefficients and dimensions of the central hole.Peer Reviewe

Vibraciones libres de placas rectangulares con una perforación circular central

Este trabajo presenta el desarrollo y aplicación de un algoritmo general para la determinación de coeficientes de frecuencia de una placa rectangular con un agujero central libre. El algoritmo está basado en la aplicación del método de Rayleigh-Schmidt. Los resultados numéricos obtenidos que han podido ser comparados con trabajos de investigación previos, en general, están caracterizados por una buena precisión. Es posible aplicar el algoritmo en un amplio rango de condiciones de restricciones elásticas rotacionales, incluyendo las condiciones de apoyo clásicas, así como para distintas relaciones de lados de la placa y dimensiones de la perforación central.The present work deals with the development and application of a general algorithm for the determination of values of frequency coefficients for a rectangular plate with a central free hole. The algorithm is based on the application of Rayleigh-Schmidt method. The numerical results obtained and compared with previous works are characterized by a good accuracy. It is possible to applied it in a wide range of conditions of elastically rotational restrictions, including the classical boundary conditions and also for different aspect plate coefficients and dimensions of the central hole.Peer Reviewe

FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases

From Theory to Practice: Plug and Play with Succinct Data Structures

Engineering efficient implementations of compact and succinct structures is a time-consuming and challenging task, since there is no standard library of easy-to- use, highly optimized, and composable components. One consequence is that measuring the practical impact of new theoretical proposals is a difficult task, since older base- line implementations may not rely on the same basic components, and reimplementing from scratch can be very time-consuming. In this paper we present a framework for experimentation with succinct data structures, providing a large set of configurable components, together with tests, benchmarks, and tools to analyze resource requirements. We demonstrate the functionality of the framework by recomposing succinct solutions for document retrieval.Comment: 10 pages, 4 figures, 3 table

OperA/ALIVE/OperettA

Comprehensive models for organizations must, on the one hand, be able to specify global goals and requirements but, on the other hand, cannot assume that particular actors will always act according to the needs and expectations of the system design. Concepts as organizational rules (Zambonelli 2002), norms and institutions (Dignum and Dignum 2001; Esteva et al. 2002), and social structures (Parunak and Odell 2002) arise from the idea that the effective engineering of organizations needs high-level, actor-independent concepts and abstractions that explicitly define the organization in which agents live (Zambonelli 2002).Peer ReviewedPostprint (author's final draft