Searching for therapeutic strategies in a mouse modelo of Machado-Joseph disease: targeting proteostases

Tese de Doutoramento em Ciências da Saúde

Prospecção de ocorrências filonianas do tipo LCT nas formações metassedimentares entre Boticas e Montalegre (N de Portugal)

Dissertação de mestrado em Geologia (área de especialização em Valorização de Recursos Geológicos)

Desenvolvimento de um motor BMW para servir de Range Extender

Dissertação de mestrado integrado em Engenharia Mecânica

An evaluation of septic tank effluent movement in soil and groundwater systems

Recent studies have shown that septic tank systems are a major source of groundwater pollution. Many public health workers feel that the most cri^cal aspect of the use of septic tanks as a means of sewage disposal is the contamination of private water wells with attendant human health hazards. In this study the movement and attenuation of septic tank effluents in a range of soil/overburden types and hydrogeological situations was investigated. The suitability of a number of chemical and biological tracer materials to monitor the movement of septic tank effluent constituents to groundwater sources was also examined. The investigation was divided into three separate but inteiTelated sections. In the first section of the study the movement of septic tank effluent from two soil treatment systems was investigated by direct measurements of soil nutrient concentrations and enteric bacterial numbers in the soil beneath and downgradient of the test systems. Two sites with different soil types and hydrogeological characteristics were used. The results indicated that the attenuation of the effluent in both of the treatment systems was incomplete. Migration of nitrate, ammonium, phosphate and fecal bacteria to a depth of 50 cm beneath the inverts of the distribution tiles was demonstrated on all sampling occasions. The lateral migration of the pollutants was less pronounced, although on occasions high nutrients levels and fecal bacterial numbers were detected at a lateral distance of 4.0 m downgradient of the test systems. There was evidence that the degree and extent of effluent migration was increased after periods of heavy or prolonged rainfall when the attenuating properties of the treatment systems were reduced as a result of saturation of the soil. The second part of the study examined the contamination of groundwaters downgradient of septic tank soil treatment systems. Three test sites were used in the investigation. The sites were chosen because of differences in the thicknesses and nature of the unsaturated zone available for effluent attenuation at each of the locations. A series of groundwater monitoring boreholes were installed downgradient of the test systems at each of the sites and these were sampled regularly to assess the efficiency of the overburden material in reducing the polluting potential of the wastewater. Effluent attenuation in the septic tank treatment systems was shown to be incomplete, resulting in chemical and microbiological contamination of the groundwaters downgradient of the systems. The nature and severity of groundwater contamination was dependent on the composition and thickness of the unsaturated zone and the extent of weathering in the underlying saturated bedrock. The movement of septic tank effluent through soil/overburdens to groundwater sources was investigated by adding a range of chemical and biological tracer materials to the three septic tank systems used in section two of the study. The results demonstrated that a single tracer type cannot be used to accurately monitor the movement of all effluent constituents through soils to groundwater. The combined use of lithium bromide and endospores of Bacillus globigii was found to give an accurate indication of the movement of both the chemical and biological effluent constituents.

Investigation into the feasibility of a West of Ireland Pumped Storage System

Ireland’s remote position on the tip of Europe ensures that the country is vulnerable to uncertainty of supply. The reliance on conventional sources of electricity has ensured that escalated prices and high carbon emissions have been witnessed whilst opportunities that inherent resources provide, such as the wind, have not been capitalised upon. The intermittent nature of the wind make it difficult to maximise its potential as in many cases the highest wind speeds are highest when demand is low. The West of Ireland’s combination of wind speeds and unique topography makes it suitable for and innovative wind powered pumped storage system, which can essentially regulate the wind generated electricity and integrate further penetration of renewable energy. In addition, its location along the Atlantic Ocean provides further scope for innovation as seawater can be integrated into the system design. The construction of such an unprecedented project in combination with increased interconnectors has the potential to make Ireland a rechargeable battery for Europe. However, such ambitious plans are at the very early stages and are in direct contrast to current events in the Irish energy market. This study focuses on the feasibility of West of Ireland pumped storage systems. Entailed within this is an extensive desk study, a detailed site selection process and a feasibility study of grid connection. To increase opportunities to identify the best possible site, the feasibility study was focused on the Galway and Mayo areas solely.

A farinha de Rami como sucedâneo da farinha de fêno da alfafa, na alimentação de pintos

The ramie leaf meal was used in a feeding trial, in comparison with alfalfa hay meal in the range of 5% of the ration. Each lot consisted of two pens of 45 White American chicks was raised in batteries for 6 weeks. From results of the analisis of variance the AA. concluded for the superiority of the ramie leaf meal (586,4 g) over the alfalfa hay meal (540,1 g) in the conditions of the experiment.

Sabbatical stay at CREVER, University Rovira i Virgili

A three-year research proposal of international impact and quality was developed between the author and CREVER researchers, taking into account the infrastructure and research lines already being carried out at CREVER. The project is related to the study of new mixtures in thermal activated systems, by the addition of a third component to help the heat transfer processes. The project proposes the use of water and lithium nitrate as absorbents in ternary ammonia mixtures, varying the concentration with the objective of optimising the mixture for solar air conditioning purposes. Also, the research proposal will promote an intensive collaboration in the following years between CREVER and The Centro de Investigación en Energía-UNAM, Mexico.

Estudi energètic de les llars del barri de Haër (Senegal)

En el present estudi s’han analitzat quines són les fonts energètiques utilitzades a les llars de Haër, així com les repercussions que aquestes tenen sobre el medi natural i socioeconòmic de les famílies. Per tal de poder identificar quines són aquestes fonts i els seus efectes, s’ha realitzat un inventari i una diagnosi energètica. S’ha estudiat l’ús de l’energia en dos àmbits domèstics principals: la il·luminació i el cuinat, analitzant la freqüència d’ús i quantificant el consum energètic familiar. Les fonts energètiques detectades són: llenya, carbó, gas, querosè, piles i espelmes, de les quals, la llenya, el querosè i el carbó són les majoritàriament utilitzades. El consum energètic per càpita és de 2.100 kWh/any. Per altra banda, l’obtenció d’algunes d’aquestes fonts energètiques, suposen un cost econòmic molt elevat per les economies familiars, arribant a suposar un 60% dels ingressos. A partir de les dades obtingudes a la diagnosi, s’ha aplicat un indicador per tal de quantificar la magnitud de l’impacte sobre el medi produït pel model energètic seguit dins de les llars. L’indicador estudiat ha estat la petjada energètica, amb la qual s’ha traduït aquest consum en unitats de superfície biològicament productiva, requerida per absorbir el CO2 emès. El resultat ha estat que una persona produeix anualment 2,09·10-2 tCO2, que requereix de 7,53·10-3 gha/persona de superfície forestal per ser absorbides. S’ha comparat aquest resultat amb la petjada energètica domèstica calculada pel poble d’Araós, el qual, amb un model energètic totalment diferent, té una petjada energètica de 1,53 gha/persona. Un cop detectats els problemes o impactes causats pel model energètic actual, es proposa una alternativa energètica per tal de reemplaçar algunes fonts convencionals, principalment el querosè dels quinqués. Així doncs, mitjançant l’aprofitament de l’energia solar, es plantegen dos models fotovoltaics adaptats a dues tipologies de llars diferents, amb l’objectiu de minimitzar el cost i optimitzar els recursos energètics. Finalment es planteja una solució financera per abordar el cost inicial de la instal·lació solar.

Dinàmica de sistemes mesoscòpics amb correlacions quàntiques mitjançant la formulació de de Broglie-Bohm

Per a determinar la dinàmica espai-temporal completa d’un sistema quàntic tridimensional de N partícules cal integrar l’equació d’Schrödinger en 3N dimensions. La capacitat dels ordinadors actuals permet fer-ho com a molt en 3 dimensions. Amb l’objectiu de disminuir el temps de càlcul necessari per a integrar l’equació d’Schrödinger multidimensional, es realitzen usualment una sèrie d’aproximacions, com l’aproximació de Born–Oppenheimer o la de camp mig. En general, el preu que es paga en realitzar aquestes aproximacions és la pèrdua de les correlacions quàntiques (o entrellaçament). Per tant, és necessari desenvolupar mètodes numèrics que permetin integrar i estudiar la dinàmica de sistemes mesoscòpics (sistemes d’entre tres i unes deu partícules) i en els que es tinguin en compte, encara que sigui de forma aproximada, les correlacions quàntiques entre partícules. Recentment, en el context de la propagació d’electrons per efecte túnel en materials semiconductors, X. Oriols ha desenvolupat un nou mètode [Phys. Rev. Lett. 98, 066803 (2007)] per al tractament de les correlacions quàntiques en sistemes mesoscòpics. Aquesta nova proposta es fonamenta en la formulació de la mecànica quàntica de de Broglie– Bohm. Així, volem fer notar que l’enfoc del problema que realitza X. Oriols i que pretenem aquí seguir no es realitza a fi de comptar amb una eina interpretativa, sinó per a obtenir una eina de càlcul numèric amb la que integrar de manera més eficient l’equació d’Schrödinger corresponent a sistemes quàntics de poques partícules. En el marc del present projecte de tesi doctoral es pretén estendre els algorismes desenvolupats per X. Oriols a sistemes quàntics constituïts tant per fermions com per bosons, i aplicar aquests algorismes a diferents sistemes quàntics mesoscòpics on les correlacions quàntiques juguen un paper important. De forma específica, els problemes a estudiar són els següents: (i) Fotoionització de l’àtom d’heli i de l’àtom de liti mitjançant un làser intens. (ii) Estudi de la relació entre la formulació de X. Oriols amb la aproximació de Born–Oppenheimer. (iii) Estudi de les correlacions quàntiques en sistemes bi- i tripartits en l’espai de configuració de les partícules mitjançant la formulació de de Broglie–Bohm.

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers.

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.

Association of CYP3A5 genotypes with blood pressure and renal function in African families.

OBJECTIVE: Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associated with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. METHODS: Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles (*1, *3, *6 and *7) and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. RESULTS: CYP3A5*1 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5*1 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P = 0.003/0.045, respectively] and this effect was modified by age (CYP3A5*1 x age interactions, P = 0.017/0.018). For night-time ABP, the effect of CYP3A5*1 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5*1 carriers had a 7.6(3.8) ml/min lower GFR (P = 0.045) than non-carriers. Proximal sodium reabsorption decreased with age in non-carriers, but not in CYP3A5*1 carriers (P for interaction = 0.02). CONCLUSIONS: These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5*1 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.

Language and syntactic impairment following stroke in late bilingual aphasics.

PURPOSE: Bilingual aphasia generally affects both languages. However, the age of acquisition of the second language (L2) seems to play a role in the anatomo-functional correlation of the syntactical/grammatical processes, thus potentially influencing the L2 syntactic impairment following a stroke. The present study aims to analyze the influence of late age of acquisition of the L2 on syntactic impairment in bilingual aphasic patients. METHODS: Twelve late bilingual participants (speaking French as L2 and either English, German, Italian or Spanish as L1) with stroke-induced aphasia participated in the study. The MAST or BAT aphasia batteries were used to evaluate overall aphasia score. An auditory syntactic judgement task was developed and used to test participants syntactic performance. RESULTS: The overall aphasia scores did not differ between L1 and L2. In a multiple case analysis, only one patient had lower scores in L2. However, four patients presented significantly lower performances in syntactic processing in the late L2 than in their native language (L1). In these four patients the infarct was localized, either exclusively or at least partially, in the pre-rolandic region. CONCLUSION: This pilot study suggests that, in late bilingual aphasics, syntactic judgment abilities may be more severely impaired in L2, and that this syntactic deficit is most likely to occur following anterior lesions.

CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt.

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.

Eliminació autotròfica de nitrogen en una pila biològica (microbial fuel cells )

L’aigua i l’energia formen un binomi indissociable. En relació al cicle de l’aigua, des de fa varies dècades s’han desenvolupat diferents formes per recuperar part de l’energia relacionada amb l’aigua, per exemple a partir de centrals hidroelèctriques. No obstant, l’ús d’aquesta aigua també porta associat un gran consum energètic, relacionat sobretot amb el transport, la distribució, la depuració, etc... La depuració d’aigües residuals porta associada una elevada demanda energètica (Obis et al.,2009). En termes energètics, tot i que la despesa elèctrica d’una EDAR varia en funció de diferents paràmetres com la configuració i la capacitat de la planta, la càrrega a tractar, etc... es podria considerar que el rati mig seria d’ aproximadament 0.5 KWh•m-3.Els principals costos d’explotació estan relacionats tant amb la gestió de fangs (28%) com amb el consum elèctric (25%) (50% tractament biològic). Tot i que moltes investigacions relacionades amb el tractament d’aigua residual estan encaminades en disminuir els costos d’operació, des de fa poques dècades s’està investigant la viabilitat de que l’aigua residual fins i tot sigui una font d’energia, canviant la perspectiva, i començant a veure l’aigua residual no com a una problemàtica sinó com a un recurs. Concretament s’estima que l’aigua domèstica conté 9.3 vegades més energia que la necessària per el seu tractament mitjançant processos aerobis (Shizas et al., 2004). Un dels processos més desenvolupats relacionats amb el tractament d’aigües residuals i la producció energètica és la digestió anaeròbia. No obstant, aquesta tecnologia permet el tractament d’altes càrregues de matèria orgànica generant un efluent ric en nitrogen que s’haurà de tractar amb altres tecnologies. Per altre banda, recentment s’està investigant una nova tecnologia relacionada amb el tractament d’aigües residuals i la producció energètica: les piles biològiques (microbial fuel cells, MFC). Aquesta tecnologia permet obtenir directament energia elèctrica a partir de la degradació de substrats biodegradables (Rabaey et al., 2005). Les piles biològiques, més conegudes com a Microbial Fuel Cells (acrònim en anglès, MFC), són una emergent tecnologia que està centrant moltes mirades en el camp de l’ investigació, i que es basa en la producció d’energia elèctrica a partir de substrats biodegradables presents en l’aigua residual (Logan., 2008). Els fonaments de les piles biològiques és molt semblant al funcionament d’una pila Daniell, en la qual es separa en dos compartiments la reacció d’oxidació (compartiment anòdic) i la de reducció (compartiment catòdic) amb l’objectiu de generar un determinat corrent elèctric. En aquest estudi, bàsicament es mostra la posada en marxa d'una pila biològica per a l'eliminació de matèria orgànica i nitrogen de les aigües residuals.

Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men

Rapport de synthèse:Le but de cette étude était d'investiguer pour la première fois chez l'homme l'effet du sodium alimentaire et de l'hypertension artérielle sur l'oxygénation tissulaire par une technique spéciale d'imagerie à résonance magnétique nommée 'BOLD-IRM' (Blood Oxygen Level Dependent-IRM). Le BOLD-IRM est une technique nouvelle qui permet de mesurer la bio disponibilité tissulaire d'oxygène de façon non-invasive chez l'homme, en utilisant le déoxyhémoglobine comme produit de contraste endogène.Le rational de cette étude était double. Premièrement, des changements dans l'apport sodique alimentaire devraient théoriquement influencer l'oxygénation tissulaire rénale, étant donné que la réabsorption tubulaire du sodium est un transport actif nécessitant de l'énergie et de l'oxygène. Deuxièmement, des études chez l'animal suggèrent une rôle possible de l'hypoxie tissulaire dans le développement de la néphropathie hypertensive.Nous avons déterminé l'oxygénation rénale avec le BOLD-IRM chez dix hommes normo tendus (âgés de 26.5±7.4 ans) et huit hommes hypertendus non-traités (âgés de 28.8±5.7 ans) une semaine après un régime riche en sel (>200 mmol/jour), et de nouveau une semaine après un régime pauvre en sel (<100 mmol/jour). En parallèle, nous avons mesuré la clearance de l'inuline, du p- aminohippurate (PAH) et du lithium endogène, afin de déterminer respectivement la filtration glomérulaire, le flux sanguin rénal et le 'renal sodium handling', tous des paramètres ayant la capacité d'influencer la consommation et/ou la disponibilité d'oxygène tissulaire. Nous nous attendions d'une côté à une oxygénation rénale diminuée chez les sujets hypertendus par rapport aux sujets normo tendus, et d'une autre côté à une augmentation de l'oxygénation tissulaire rénale après une semaine de régime pauvre en sel par rapport à la phase d'un régime riche en sel.Nous retenons comme résultat principal une augmentation de l'oxygénation rénale médullaire suite à une restriction sodique par rapport à un régime riche en sel chez tous les participants (normo-et hypertendus). Chez les participants normotendus ces changements correlaient avec des changements dans le transport actif du sodium, et ceci indépendamment du flux sanguin rénal. Contrairement à ce qu'on attendait, l'oxygénation rénale médullaire était plus élevé chez les sujets hypertendus par rapport aux sujets normotendus.En résumé, ces observations offrent possiblement une explication pour les bénéfices rénaux liés à un régime pauvre en sel. En plus, la combinaison d'études de clearance et le BOLD- IRM comme utilisé dans cette étude se sont révélés un outil performant et prometteur qui peut stimuler la recherche dans ce domaine.