Unique among the intracellular lipid binding proteins, acyl CoA binding protein (ACBP) exclusively binds long chain fatty acyl CoAs (LCFA-CoAs). To test if ACBP is an essential protein in mammals, the ACBP gene was ablated by homologous recombination in mice. While ACBP heterozygotes appeared phenotypically normal, intercrossing of the heterozygotes did not result in any live homozygous deficient (null) ACBP^(-/-) pups. Heterozygous and wild type embryos were detected at all postimplantation stages, but no homozygous ACBP null embryos were obtained– suggesting that an embryonic lethality occurred at a preimplantation stage of development, or that embryos never formed. While ACBP null embryos were not detected at any blastocyst stage, ACBP null embryos were detected at the morula (8- cell), cleavage (2-cell), and zygote (1-cell) preimplantation stages. Two other LCFACoA binding proteins, sterol carrier protein-2 (SCP-2) and sterol carrier protein-x (SCPx) were significantly upregulated at these stages. These findings demonstrate for the first time that ACBP is an essential protein required for embryonic development and its loss of function may be initially compensated by concomitant upregulation of two other LCFA-CoA binding proteins only at the earliest preimplantation stages. The fact that ACBP is the first known intracellular lipid binding protein whose deletion results in embryonic lethality suggests its vital importance in mammals.

Decision makers often present military researchers with a most daunting challenge: to pursue, with some level of prophetic certainty, innovative concepts that will yield increased capabilities during future wars against forecasted threats in not-yet- determined locations. This conundrum is complicated further with the requirement that the proposed technology yield benefit throughout the various strata of military operations. In the maturation of an advanced capability enabled by a technological advancement, a groundbreaking design should simultaneously demonstrate performance overmatch against an envisioned foe while showing that the costs associated with development, procurement, and operation outweigh reverting to an incremental advancement in the conventional means of delivering combat power. This manuscript focuses on the construction and utilization of decision support tools for use by scientists and engineers charged with providing a quantitative evaluation of an advanced ground combat system. The concepts presented focus on the effects and synergy regarding the combat vehicle principal attributes of survivability, lethality, and mobility. Additionally, this study provides a framework for analysis of these attributes when screened at the tactical, operational, and strategic levels of war. These concepts are presented and demonstrated from both the candidate selection (or choice) perspective, and the concept development (or design) perspective. As an example of this approach, this study includes a comparison of conventional powder gun cannonry versus a specific type of electromagnetic launch device known as the railgun. The decision support tools formulated in this dissertation allow the user to distill, at a coarse level of fidelity, the parametric relationships between system survivability, lethality, and mobility for advanced weapon system concepts. The proposed methods are suited for evaluation at the nascent stages of development, when the information normally applied in standard methods is sparse. This general approach may also be valuable in contemporary acquisition strategies employed in urgent fielding efforts, where the immediacy of the problem can benefit from an expedient and efficient method of analyzing the coupled and synergistic effects of implementing a proposed technology. While advantage is typically measured in terms of performance overmatch at the platform level, the broadening of this consideration vertically to higher levels of military command can aid in identifying the competing issues and complementary relationships related to a technical approach. Finally, given the backdrop demonstration for the framework, this manuscript may serve as a brief summary of system fundamentals and design theory for direct fire powder gun cannonry and electromagnetic railguns. / text

No description available.

Suizid gehört in den meisten Ländern weltweit zu den zehn führenden Todesursachen und wird laut Studien der WHO im Jahr 2020 2,4% des weltweiten „Burden of Disease“ ausmachen (1998:1,8%). Auch Suizidversuche, deren Zahl auf das 10-20fache der Suizide geschätzt wird, stellen eine starke Belastung und einen hohen Kostenfaktor für die Gesundheitssysteme dar. Bezüglich der vollendeten Suizide sind Männer ungefähr 2 bis 3mal so häufig betroffen wie Frauen, bei Suizidversuchen verhält es sich umgekehrt. Mit dem Ziel, dieses Phänomen zu verstehen und effektivere Suizidpräventionsmethoden zu finden, wurden diverse Gründe für die Geschlechtsunterschiede diskutiert und beforscht. Die geschlechtsspezifische Methodenwahl, verschiedene Rollenmodelle, Suchterkrankungen und soziale Unterstützung werden unter anderem als Gründe benannt. Das Ziel dieser Dissertation ist zu untersuchen, ob die Geschlechtsunterschiede in Suizidraten alleine durch die Wahl letalerer Suizidmethoden durch Männer erklärt werden können. Es wird in vielen Studien angenommen, dass Männer zu harten Suizidmethoden wie Erschießen oder Erhängen und Frauen zu weichen Suizidmethoden wie Vergiften neigen. Anhand eines Datensatzes zu Suiziden und Suizidversuchen soll die methodenspezifische „Case Fatality“ (Suizide/Suizide+Suizidversuche) ermittelt werden. Die Hypothese lautet, dass unterschiedliche „Case Fatality rates“ darauf hinweisen, dass über die Methodenwahl hinaus weitere zentrale Gründe die höheren männlichen Suizidraten erklären bzw. dass gleiche „Case Fatality rates“ annehmen lassen, dass die Methodenwahl der Hauptgrund für die Geschlechtsunterschiede ist. In dem Artikel, welcher den Kern der Dissertation ausmacht, wird gezeigt, dass die Methodenwahl bei Männern nicht der ausschlaggebende Faktor für höhere Suizidraten ist. Vielmehr scheinen Männer einzelne Suizidmethoden mit einer höheren Letalität durchzuführen. Auch nach der Kontrolle von Alterseinflüssen zeigt sich dieses Ergebnis signifikant, speziell bei den Methoden Erhängen und Vergiften, Beispiele für eine harte und eine weiche Methode. Dies weist darauf hin, dass dahinterstehende Gründe, z.B. die Intention zu sterben, eine größere Rolle spielen und in zukünftigen Studien weiter beforscht werden sollten. / Background: In most countries worldwide suicide rates are higher for males whereas attempted suicide rates are higher for females. The aim is to investigate if the choice of more lethal methods by males explains gender differences in suicide rates. Methods: Data on completed and attempted suicides were collected (n=3235, Nuremberg and Wuerzburg, years 2000–2004). The research question was analyzed by comparing the methodspecific case fatality (= completed suicides /completed+attempted suicides) for males and females. Results: Among the events captured, men chose high-risk methods like hanging significantly more often than women ( =−0.27; pb0.001). However, except for drowning, case fatalities were higher for males than for females within each method. This was most apparent in “hanging” (men 83.5%, women 55.3%; =−0.28; pb0.001) and “poisoning by drugs” (men 7.2%, women 3.4%; =−0.09; pb0.001). Limitations: The sample size (n=3235) was not enough for comparing method and gender specific case fatalities with a fine-meshed stratification regarding age. Conclusions: Higher suicide rates in males not only result from the choice of more lethal methods. Other factors have to be considered.

Less than half of patients with epithelial ovarian cancer (EOC) survive five years following diagnosis, underscoring the imperative need for improved treatment. Many patients, including those with advanced disease, initially respond to platinum agents, which constitute the backbone of therapy. However, tumors ultimately become resistant, rendering further treatment ineffective. Additionally, the poor tolerability of these agents warrants the exploration of more targeted treatments – one such strategy is exploiting synthetic lethal genetic relationships. Recent genomic sequencing efforts have revealed that as many of half of EOCs have homologous recombination (HR) alterations. HR is a critical pathway for the repair of platinum-induced ICLs, thus compromised HR is hypothesized to explain the initial response to chemotherapy in many patients. Accordingly, women whose tumors harbor mutations in the critical HR genes, BRCA1 or BRCA2 (BRCA1/2), demonstrate improved prognosis. BRCA1/2 mutations also confer exquisite sensitivity to inhibitors of the enzyme, poly(ADP-ribose) polymerase 1 (PARPis), hence loss of BRCA1/2 and PARP1 is synthetic lethal. A number of models have been proposed to explain this synthetic lethality, yet a consensus model that accounts for the diverse cellular roles of BRCA1/2 and PARP1 has yet to be established. Delineating the precise molecular underpinnings of PARPi action in BRCA1/2-deficient cells will aid clinicians in identifying the appropriate population of women with EOC likely to benefit from PARPi treatment and provide insight into resistance mechanisms that arise in these patients. Combining this approach with retrospective analysis of PARPi clinical trials will best define the proper indication for PARPi in EOC and other human cancers.

A Leishmaniose Visceral (LV) é uma doença infecciosa de carater sistêmico. Estima-se que 350 milhões de pessoas no mundo estão expostas ao risco de infecção, com uma prevalência de 12 milhões de infectados e letalidade mundial de 59.000 casos por ano (OMS), sendo que 90%dos casos de LV ocorrem em países onde existe grande parte da população em situação de pobreza.Na América Latina a maioria dos casos ocorre no Brasil (96%) com média de 3.500 casos/ano. As áreas de maior endemia encontram-se nas regiões mais carentes do Norte e Nordeste.A donça afeta animais e o homem, podendo levar ao óbito em 100% dos casos, tendo como seu principal vetor a Lutzomyia longipalpis e como agente etiológico, a Leishmania Infantum. O Estado do Tocantins apresenta elevado número de casos autóctones, e é considerada área endêmica pelo Minisério da Saúde devido a doença estar presente na maioria dos seus municípios. A cidade de Araguaína, com 55,8% dos casos do Tocantins, é classificada pelo Ministério da Saúde como área de transmissão intensa.O objetivo geral deste trabalho foi analisar casos confirmados de Leishmaniose visceral grave CID-B55 internados no Hospital de Doenças Tropicais do Tocantins (HDT), na cidade de Araguaína - TO que evoluíram para óbito no periodo de janeiro de 2002 a dezembro de 2015. Pretendeu-se identificar e descrever dados epidemiológicos, clínicos e laboratoriais, e variáveis relacionadas ao tratamento. Foi feito um estudo epidemiológico, observacional, retrospectivo, descritivo, utilizando dados secundários de prontuários médicos de pacientes internados, no Hospital de Doenças Tropicais do Estado do Tocantins, na cidade de Araguaína - TO. Resultados: sexo masculino, 60,8 e 39,2% sexo feminino. 49,2% idade entre 0 e 10 anos; 20% maiores de 51 anos. Local de procedência em relação ao município 40,9% são de Araguaína; e ao Estado a 89% são do Tocantins. Presença de febre em 70,8%; esplenomegalia e hepatomegalia 76,7%. Hemoglobina < 7g/dl 50%, plaquetopenia 76,7%;leucopenia 50% e hipoalbuminemia 84,9%.Tempo de febre até a internação > que 30 dias 30,8%; Tempo de diagnóstico 5,1 dias; tempo de diagnóstico ao óbito 11,6 dias; RIFI 1/80 em 53,3%; Teste Rápido positivo 88,2% droga de escolha para tratmento foi Glucantime 43% seguida por anfotericina 32% e anfotericina lipossomal 25%. A principal causa do óbito na DO(Declaração de aÓbito) foi kalazar 33,3% e também Infecções respiratorias 31,7%.Conclui-se que a maior incidencia ocorre em individuo do sexo masculino menores de 10 anos, residentes no Estado do Tocantins, apresentando quadro febril prolongado, anemia severa e hipoalbuminemia grave, podendo este quadro ter influenciado na evolução ao óbito. / American Visceral Leishmaniasis (AVL) is an infectious disease of a systemic nature. It is estimated that 350 million people worldwide are at risk of infection, with a prevalence of 12 million infected and worldwide lethality of 59,000 cases per year (WHO), with 90% of cases of VL occurring in countries where there is of the population living in poverty. In Latin America, most cases occur in Brazil (96%) with an average of 3,500 cases / year. The most endemic areas are in the poorest regions of the North and Northeast, affecting animals and man, and can lead to death in 100% of cases, having as its main vector Lutzomyia longipalpis and as an etiological agent, Leishmania Infantum. The State of Tocantins presents a high number of autochthonous cases, considered an area endemic by the Ministry of Health because the disease is present in most of its municipalities. The city of Araguaína, with 55.8% of the Tocantins cases, is classified by the Ministry of Health as an intense transmission area. The general objective was to analyze confirmed cases of severe visceral leishmaniasis ICD-B55 hospitalized at the Tropical Diseases Hospital of Tocantins (HDT), in the city of Araguaína - TO, which evolved to death in the period from January 2002 to December 2015. The aim was to identify and describe epidemiological, clinical and laboratory data, and treatment-related variables. Study was an epidemiological, observational, retrospective, descriptive study, using secondary data from medical records of hospitalized patients, at the Tropical Diseases Hospital of the State of Tocantins, in the city of Araguaína - TO. Results: male, 60.8% and 39.2% female. 49.2% age between 0 and 10 years; 20% greater than 51 years. Place of origin in relation to the municipality 40.9% are from Araguaína; And to the State, 89% are from Tocantins. Presence of fever in 70.8%; Splenomegaly and hepatomegaly 76.7%. Hemoglobin <7g/dl 50%, thrombocytopenia 76.7%, leukopenia 50% and hypoalbuminemia 84.9%. Fever time until hospitalization > 30 days 30.8%; Diagnostic time 5.1 days; Diagnostic time at death 11.6 days; RIFI 1/80 53.3% Positive Fast test 88,2%; drug of choice for Glucantime treatment 43% followed By amphotericin 32% and liposomal amphotericin 25%. The main cause of the OD was kalazar 33,3% followed by respiratory infections 31.7%. It is concluded that the highest incidence occurs in a male under 10 years of age, living in the state of Tocantins, presenting a prolonged febrile condition, severe anemia and severe hypoalbuminemia, which may have influenced the evolution to death.

Master of Science

No description available.

No description available.

The toxic interaction of caffeine and phenytoin during pregnancy was investigated in mice of the ICR strain on E10 of gestation. Caffeine, over a range of dosages, showed limited embryotoxic activity. Phenytoin was also weakly teratogenic and dosages needed to elicit embryotoxicity were accompanied by a significant increase in maternal lethality. Pretreatment with caffeine enhanced phenytoin-induced toxicity and teratogenicity and these observations confirm that caffeine has the ability to function as a coteratogen. Pretreatment with phenytoin produced a significant increase in maternal lethality following caffeine administration but no co-teratogenic effect. It is suggested that these results are the consequence of a yet undefined interaction at critical receptor sites in the maternal-embryo unit.