Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

Genomic analysis of the blood attributed to Louis XVI (1754-1793), king of France.

A pyrographically decorated gourd, dated to the French Revolution period, has been alleged to contain a handkerchief dipped into the blood of the French king Louis XVI (1754-1793) after his beheading but recent analyses of living males from two Bourbon branches cast doubts on its authenticity. We sequenced the complete genome of the DNA contained in the gourd at low coverage (similar to 2.5x) with coding sequences enriched at a higher similar to 7.3x coverage. We found that the ancestry of the gourd's genome does not seem compatible with Louis XVI's known ancestry. From a functional perspective, we did not find an excess of alleles contributing to height despite being described as the tallest person in Court. In addition, the eye colour prediction supported brown eyes, while Louis XVI had blue eyes. This is the first draft genome generated from a person who lived in a recent historical period; however, our results suggest that this sample may not correspond to the alleged king.

Mourning Becomes Electra by Eugene O’Neill: Aeschylus and Plato’s Cave to Create a Dark Drama

The fundamental debt of E. O’Neill’s Mourning Becomes Electra to Aeschylus, and to a lesser degree to Sophocles and Euripides, has been always recognised but, according to the author’s hypothesis, O’Neill might have taken advantage of the Platonic image of the cave in order to magnify his both Greek and American drama. It is certainly a risky hypothesis that stricto sensu cannot be proved, but it is also reader’s right to evaluate the plausibility and the possible dramatic benefit derived from such a reading. Besides indicating to what degree some of the essential themes of Platonic philosophy concerning darkness, light or the flight from the prison of the material world are not extraneous to O’Neill’s work, the author proves he was aware of the Platonic image of the cave thanks to its capital importance in the work of some of his intellectual mentors such as F. Nietzsche or Oscar Wilde. Nevertheless, the most significant aim of the author’s article is to emphasize both the dramatic benefits and the logical reflections derived, as said before, from reading little by little O’Neill’s drama bearing in mind the above mentioned Platonic parameter.

Vertical cultural transmission effects on demic front propagation: Theory and application to the Neolithic transition in Europe

It is shown that Lotka-Volterra interaction terms are not appropriate to describe vertical cultural transmission. Appropriate interaction terms are derived and used to compute the effect of vertical cultural transmission on demic front propagation. They are also applied to a specific example, the Neolithic transition in Europe. In this example, it is found that the effect of vertical cultural transmission can be important (about 30%). On the other hand, simple models based on differential equations can lead to large errors (above 50%). Further physical, biophysical, and cross-disciplinary applications are outlined

Traducción técnica del capítulo III del libro Advanced Data Warehouse design: from conventional to spatial and temporal applications

The proposal to work on this final project came after several discussions held with Dr. Elzbieta Malinowski Gadja, who in 2008 published the book entitled Advanced Data Warehouse Design: From Conventional to Spatial and Temporal Applications (Data-Centric Systems and Applications). The project was carried out under the technical supervision of Dr. Malinowski and the direct beneficiary was the University of Costa Rica (UCR) where Dr. Malinowski is a professor at the Department of Computer Science and Informatics. The purpose of this project was twofold: First, to translate chapter III of said book with the intention of generating educational material for the use of the UCR and, second, to venture in the field of technical translation related to data warehouse. For the first component, the goal was to generate a final product that would eventually serve as an educational tool for the post-graduate courses of the UCR. For the second component, this project allowed me to acquire new skills and put into practice techniques that have helped me not only to perfom better in my current job as an Assistant Translator of the Inter-American BAnk (IDB), but also to use them in similar projects. The process was lenggthy and required torough research and constant communication with the author. The investigation focused on the search of terms and definitions to prepare the glossary, which was the basis to start the translation project. The translation process itself was carried out by phases, so that comments and corrections by the author could be taken into account in subsequent stages. Later, based on the glossary and the translated text, illustrations had been created in the Visio software were translated. In addition to the technical revision by the author, professor Carme Mangiron was in charge of revising the non-technical text. The result was a high-quality document that is currently used as reference and study material by the Department of Computer Science and Informatics of Costa Rica.

Secure and Anonymous Multimedia Content Distribution in Peer-to-Peer Networks

Peer-reviewed

The Regulation of Skeletal and Cardiac Muscle Blood Flow in Humans. Studies by positron emission tomography with special reference to exercise, adenosine and nitric oxide

Virtually every cell and organ in the human body is dependent on a proper oxygen supply. This is taken care of by the cardiovascular system that supplies tissues with oxygen precisely according to their metabolic needs. Physical exercise is one of the most demanding challenges the human circulatory system can face. During exercise skeletal muscle blood flow can easily increase some 20-fold and its proper distribution to and within muscles is of importance for optimal oxygen delivery. The local regulation of skeletal muscle blood flow during exercise remains little understood, but adenosine and nitric oxide may take part in this process. In addition to acute exercise, long-term vigorous physical conditioning also induces changes in the cardiovasculature, which leads to improved maximal physical performance. The changes are largely central, such as structural and functional changes in the heart. The function and reserve of the heart’s own vasculature can be studied by adenosine infusion, which according to animal studies evokes vasodilation via it’s a_2A receptors. This has, however, never been addressed in humans in vivo and also studies in endurance athletes have shown inconsistent results regarding the effects of sport training on myocardial blood flow. This study was performed on healthy young adults and endurance athletes and local skeletal and cardiac muscle blod flow was measured by positron emission tomography. In the heart, myocardial blood flow reserve and adenosine A_2A receptor density, and in skeletal muscle, oxygen extraction and consumption was also measured. The role of adenosine in the control of skeletal muscle blood flow during exercise, and its vasodilator effects, were addressed by infusing competitive inhibitors and adenosine into the femoral artery. The formation of skeletal muscle nitric oxide was also inhibited by a drug, with and without prostanoid blockade. As a result and conclusion, it can be said that skeletal muscle blood flow heterogeneity decreases with increasing exercise intensity most likely due to increased vascular unit recruitment, but exercise hyperemia is a very complex phenomenon that cannot be mimicked by pharmacological infusions, and no single regulator factor (e.g. adenosine or nitric oxide) accounts for a significant part of exercise-induced muscle hyperemia. However, in the present study it was observed for the first time in humans that nitric oxide is not only important regulator of the basal level of muscle blood flow, but also oxygen consumption, and together with prostanoids affects muscle blood flow and oxygen consumption during exercise. Finally, even vigorous endurance training does not seem to lead to supranormal myocardial blood flow reserve, and also other receptors than A_2A mediate the vasodilator effects of adenosine. In respect to cardiac work, atheletes heart seems to be luxuriously perfused at rest, which may result from reduced oxygen extraction or impaired efficiency due to pronouncedly enhanced myocardial mass developed to excel in strenuous exercise.

Fibroblast Growth Factor 8 and its Receptors in The Growth and Angiogenesis of Experimental Breast Cancer . With Special Reference to Thrombospondin-1 as a Novel Target Gene for FGF-8

The growth of breast cancer is regulated by hormones and growth factors. Recently, aberrant fibroblast growth factor (FGF) signalling has been strongly implicated in promoting the progression of breast cancer and is thought to have a role in the development of endocrine resistant disease. FGFs mediate their auto- and paracrine signals through binding to FGF receptors 1-4 (FGFR1-4) and their isoforms. Specific targets of FGFs in breast cancer cells and the differential role of FGFRs, however, are poorly described. FGF-8 is expressed at elevated levels in breast cancer, and it has been shown to act as an angiogenic, growth promoting factor in experimental models of breast cancer. Furthermore, it plays an important role in mediating androgen effects in prostate cancer and in some breast cancer cell lines. We aimed to study testosterone (Te) and FGF-8 regulated genes in Shionogi 115 (S115) breast cancer cells, characterise FGF-8 activated intracellular signalling pathways and clarify the role of FGFR1, -2 and -3 in these cells. Thrombospondin-1 (TSP-1), an endogenous inhibitor of angiogenesis, was recognised as a Te and FGF-8 regulated gene. Te repression of TSP-1 was androgen receptor (AR)-dependent. It required de novo protein synthesis, but it was independent of FGF-8 expression. FGF-8, in turn, downregulated TSP-1 transcription by activating the ERK and PI3K pathways, and the effect could be reversed by specific kinase inhibitors. Differential FGFR1-3 action was studied by silencing each receptor by shRNA expression in S115 cells. FGFR1 expression was a prerequisite for the growth of S115 tumours, whereas FGFR2 expression alone was not able to promote tumour growth. High FGFR1 expression led to a growth advantage that was associated with strong ERK activation, increased angiogenesis and reduced apoptosis, and all of these effects could be reversed by an FGFR inhibitor. Taken together, the results of this thesis show that FGF-8 and FGFRs contribute strongly to the regulation of the growth and angiogenesis of experimental breast cancer and support the evidence for FGF-FGFR signalling as one of the major players in breast cancers.

Pierre Bourdieu and medical education

The contemporary discussion about the transformation of the training of health professionals has focused primarily on the change in method. This article discusses this issue in the light of Pierre Bourdieu's theoretical contributions - habitus, field, symbolic capital, symbolic violence and reproduction. The conclusion is drawn that pedagogical change alone is not enough to change the profile of medical graduates.

Kaksoislaatuisesta rakenneputkesta hitsatun X-liitoksen kestävyys ja muodonmuutoskyky

Rautaruukki Oyj:n uusi Ruukki double grade S420MH/S355J2H -rakenneputki yhdistää putkilajien S420MH ja S355J2H ominaisuudet. Eurocode 3:n suunnitteluohjeiden mukaan Ruukki double graden käyttöön on sovellettava lujuusluokan S420 mukaista hitsien mitoitusta ja rakenneputkiliitosten staattista mitoituskestävyyttä alentavaa varmuuskerrointa, kun halutaan hyödyntää lujuusluokan S420 ominaisuudet Ruukki double gradea käytettäessä. Tässä työssä tutkittiin S420-lujuusluokkaa vastaavien suunnittelumääräysten soveltamistarvetta Ruukki double grade -rakenneputken käyttöön. Työn tavoitteena oli arvioida Ruukki double grade -rakenneputkesta hitsaamalla valmistetun X-liitoksen kestävyyden ja muodonmuutoskyvyn riittävyys, kun hitsit mitoitettiin S355-lujuusluokkaa vastaavien Eurocode 3:n suunnitteluohjeiden mukaisesti. X-liitosten kestävyyttä ja muodonmuutoskykyä tutkittiin kokeellisesti -40 C lämpötilassa suoritettujen laboratoriokokeiden avulla sekä analyyttisen laskennan ja elementtimenetelmän keinoin. Kestävyyden riittävyyttä arvioitiin vertaamalla laboratoriokokeista saatuja liitosten kestävyyksiä Eurocode 3:n ja myötöviivateorian mukaisiin kestävyyksiin. Elementtimenetelmän ja laboratoriokokeen pohjalta piirrettyjä liitoksen voima-siirtymäkuvaajia vertailtiin keskenään, kun elementtimalli analysoitiin eri materiaalimalleilla. Lisäksi verrattiin elementtimallin voima-venymäkuvaajia liitoksen venymäliuskan arvoihin. Kaikki koesarjan S355-lujuusluokan mukaisilla hitsin a-mitoilla valmistetut liitokset täyttivät kestävyydelle ja muodonmuutoskyvylle asetetut vaatimukset. Täten tämän koesarjan perusteella ei ollut tarpeellista soveltaa S420-lujuusluokan mukaista hitsien mitoitusta ja staattista mitoituskestävyyttä alentavaa varmuuslukua Ruukki double grade -rakenneputkeen. Elementtimenetelmästä ja laboratoriokokeesta saadut liitoksen voima-siirtymäkuvaajat vastasivat hyvin toisiaan. Sen sijaan elementtimallin voima-venymä-kuvaajat eivät vastanneet venymäliuskojen mittausdataa kovin hyvin.

Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Using data mining to identify factors that influence the degree of leg injuries in broilers

Locomotor problems prevent the bird to move freely, jeopardizing the welfare and productivity, besides generating injuries on the legs of chickens. The objective of this study was to evaluate the influence of age, use of vitamin D, the asymmetry of limbs and gait score, the degree of leg injuries in broilers, using data mining. The analysis was performed on a data set obtained from a field experiment in which it was used two groups of birds with 30 birds each, a control group and one treated with vitamin D. It was evaluated the gait score, the asymmetry between the right and left toes, and the degree of leg injuries. The Weka ® software was used in data mining. In particular, C4.5 algorithm (also known as J48 in Weka environment) was used for the generation of a decision tree. The results showed that age is the factor that most influences the degree of leg injuries and that the data from assessments of gait score were not reliable to estimate leg weakness in broilers.

Evaluation of protein extraction methods to obtain protein concentrate from cassava leaf

The cassava leaf, waste generated in the harvest of the roots, is characterized by high content of protein, vitamins and minerals; however, its use is limited due to the high fiber content and antinutritional substances, which can be removed by obtaining protein concentrates. In this context, the objective of this study was to evaluate protein extraction processes, aiming the use of cassava leaves (Manihot esculenta Crantz) as an alternative protein. Four methods were tested: 1) Coagulation of Proteins by Lowering the Temperature, 2) Extraction by Isoelectric Precipitation, 3) Solubilization of Proteins and 4) Fermentation of Filter Leaf Juice. To obtain the concentrates, the use of fresh or dried leaves and extraction in one or two steps were also evaluated. The solubilization of proteins (method 3) showed a higher extraction yield; however, with concentrate of low quality. The fermentation of the juice (method 4) produced concentrates with higher quality and lower costs and the isoelectric precipitation (method 2) promoted the obtention of concentrates in less time, both with good prospects for use. The use of two extraction steps was not advantageous to the process and there was no difference between the use of fresh or dried leaf, and the use of fresh leaves is presented as a good option for the simplicity of the method.

Shewhart's control charts and process capability ratio applied to a sewage treatment station

The current study used statistical methods of quality control to evaluate the performance of a sewage treatment station. The concerned station is located in Cascavel city, Paraná State. The evaluated parameters were hydrogenionic potential, settleable solids, total suspended solids, chemical oxygen demand and biochemical oxygen demand in five days. Statistical analysis was performed through Shewhart control charts and process capability ratio. According to Shewhart charts, only the BOD(5.20) variable was under statistical control. Through capability ratios, we observed that except for pH the sewage treatment station is not capable to produce effluents under characteristics that fulfill specifications or standard launching required by environmental legislation.

Improving alumni administration by self-built information system : building IMMIT connected' to enhance alumni connection

Alumni are considered as precious resource of the institutions, thus improving alumni adminis-tration is critical. In information era, alumni administration is assisted by widespread information technology, such as social network sites. This paper aims to discover if a self-built information sys-tem would enhance alumni connection in the IMMIT context, and what kind of attributes would be helpful applying to the special context. The current online alumni services at other universities and at the IMMIT host university are analyzed, and then social media is introduced. After illustrating the social capital existing in IM-MIT, the type of the self-built information system is suggested, following an interpretation of the prototype. Two research models are utilized in this article: TAM and intentional social action model. The second model is adjusted with proposed parameters. Afterwards, a survey and an interview protocol are designed under the guidance of the models. The results are analyzed in several groups, and the proposed parameters are tested. A conclusion is drawn to indicate how to improve alumni‟s intention to use and how to achieve a better-accepted design.