O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells

Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.

5.9-keV Mn K-shell X-ray luminosity from the decay of 55Fe in Type Ia supernova models

We show that the X-ray line flux of the Mn Kα line at 5.9 keV from the decay of 55Fe is a promising diagnostic to distinguish between Type Ia supernova (SN Ia) explosion models. Using radiation transport calculations, we compute the line flux for two three-dimensional explosion models: a near-Chandrasekhar mass delayed detonation and a violent merger of two (1.1 and 0.9 M⊙) white dwarfs. Both models are based on solar metallicity zero-age main-sequence progenitors. Due to explosive nuclear burning at higher density, the delayed-detonation model synthesizes ˜3.5 times more radioactive 55Fe than the merger model. As a result, we find that the peak Mn Kα line flux of the delayed-detonation model exceeds that of the merger model by a factor of ˜4.5. Since in both models the 5.9-keV X-ray flux peaks five to six years after the explosion, a single measurement of the X-ray line emission at this time can place a constraint on the explosion physics that is complementary to those derived from earlier phase optical spectra or light curves. We perform detector simulations of current and future X-ray telescopes to investigate the possibilities of detecting the X-ray line at 5.9 keV. Of the currently existing telescopes, XMM-Newton/pn is the best instrument for close (≲1-2 Mpc), non-background limited SNe Ia because of its large effective area. Due to its low instrumental background, Chandra/ACIS is currently the best choice for SNe Ia at distances above ˜2 Mpc. For the delayed-detonation scenario, a line detection is feasible with Chandra up to ˜3 Mpc for an exposure time of 106 s. We find that it should be possible with currently existing X-ray instruments (with exposure times ≲5 × 105 s) to detect both of our models at sufficiently high S/N to distinguish between them for hypothetical events within the Local Group. The prospects for detection will be better with future missions. For example, the proposed Athena/X-IFU instrument could detect our delayed-detonation model out to a distance of ˜5 Mpc. This would make it possible to study future events occurring during its operational life at distances comparable to those of the recent supernovae SN 2011fe (˜6.4 Mpc) and SN 2014J (˜3.5 Mpc).

Willingness to pay for personalised nutrition across Europe

BACKGROUND: Personalised nutrition (PN) may promote public health. PN involves dietary advice based on individual characteristics of end users and can for example be based on lifestyle, blood and/or DNA profiling. Currently, PN is not refunded by most health insurance or health care plans. Improved public health is contingent on individual consumers being willing to pay for the service.

METHODS: A survey with a representative sample from the general population was conducted in eight European countries (N= 8233). Participants reported their willingness to pay (WTP) for PN based on lifestyle information, lifestyle and blood information, and lifestyle and DNA information. WTP was elicited by contingent valuation with the price of a standard, non-PN advice used as reference.

RESULTS: About 30% of participants reported being willing to pay more for PN than for non-PN advice. They were on average prepared to pay about 150% of the reference price of a standard, non-personalised advice, with some differences related to socio-demographic factors.

CONCLUSION: There is a potential market for PN compared to non-PN advice, particularly among men on higher incomes. These findings raise questions to what extent personalized nutrition can be left to the market or should be incorporated into public health programs.

Electric field switching in a resonant tunneling diode electroabsorption modulator

The basic mechanism underlying electric field switching produced by a resonant tunneling diode (RTD) is analyzed and the theory compared with experimental results; agreement to within 12% is achieved. The electroabsorption modulator (EAM) device potential of this effect is explored in an optical waveguide configuration. It is shown that a RTD-EAM can provide significant absorption coefficient change, via the Franz– Keldysh effect, at appropriate optical communication wavelengths around 1550 nm and can achieve up to 28-dB optical modulation in a 200- m active length device. The advantage of the RTD-EAM over the conventional reverse-biased p–n junction EAM, is that the RTD-EAM has, in essence, an integrated electronic amplifier and, therefore, requires considerably less switching power.

Study of predictive biomarkers of manganese toxicity : control and prevention of neurotoxicity associated with parenteral nutrition

Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2014

Identification of the cellular and molecular mechanism by which CD2AP, a regulator of neuronal intracellular transport contributes to the development of Alzheimer’s disease

Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências,2014

Descrição de uma população narcoléptica portuguesa

Tese de mestrado, Ciências do Sono, Faculdade de Medicina, Universidade de Lisboa, 2015

Índice de massa corporal e ganho ponderal gestacional como fator determinante do peso ao nascer do recém-nascido

RESUMO - Introdução: A literatura aponta que a gravidez é um período do ciclo reprodutivo associado com o excesso de peso, que se tem tornado um problema de saúde pública em ascensão. Na verdade, evidências sugerem que o excessivo peso pré-gestacional e o ganho ponderal excessivo estão associados a um peso elevado do RN. Objetivos: Relacionar o IMC antes da conceção e o ganho ponderal durante a gestação com o PN do RN. Métodos: Foi realizado um estudo epidemiológico, analítico, observacional e transversal, com uma amostra de cento e três mães e respetivos RNs, de termo, saudáveis e de gravidez única, da Unidade de Obstetrícia do Hospital Beatriz Ângelo. Estas foram recrutadas entre novembro de 2012 e março de 2013 inclusive. Para tal, foram recolhidos dados clínicos e outras informações relativas à gravidez e parto, nomeadamente o PN, através do sistema informático. Resultados: Após a análise dos resultados, constatou-se que mães com IMC superior a 25 antes da gravidez apresentam ganho ponderal durante a gravidez acima dos valores recomendados (47,2%). A prevalência de macrossomia e baixo peso ao nascer também foi maior em mães com excesso de peso (p=0,021), tal como de PIG e GIG (p=0,004). Observando a influência do ganho ponderal verificou-se que 9,5% (n=4) das mães com ganho ponderal excessivo tiveram RN com elevado peso ao nascer, enquanto 14,3% (n=4) das mães com ganho ponderal abaixo do recomendado tiveram RN com baixo peso ao nascer (p=0,018). Verificou-se também que o tempo de gestação é maior em mães com ganho ponderal acima do recomendado (p=0,024), e que este fator está positivamente associado com o PN (r=0,218; p=0,029), comprimento (r=0,221; p=0,027) e PC (r=0,249; p=0,012) do RN. No que se refere às correlações, encontrou-se uma correlação positiva moderada entre os fatores maternos (peso antes de engravidar; IMC pré-gestacional; e ganho ponderal) e o PN. Discussão/Conclusão: Desta forma, podemos concluir que tanto o excesso de peso pré-gestacional como o ganho de peso inadequado durante a gestação têm implicações diretas no peso do recém-nascido, nomeadamente aumentando o risco de macrossomia fetal.

Development and current use of parenteral nutrition in critical care - an opinion paper.

Critically ill patients depend on artificial nutrition for the maintenance of their metabolic functions and lean body mass, as well as for limiting underfeeding-related complications. Current guidelines recommend enteral nutrition (EN), possibly within the first 48 hours, as the best way to provide the nutrients and prevent infections. EN may be difficult to realize or may be contraindicated in some patients, such as those presenting anatomic intestinal continuity problems or splanchnic ischemia. A series of contradictory trials regarding the best route and timing for feeding have left the medical community with great uncertainty regarding the place of parenteral nutrition (PN) in critically ill patients. Many of the deleterious effects attributed to PN result from inadequate indications, or from overfeeding. The latter is due firstly to the easier delivery of nutrients by PN compared with EN increasing the risk of overfeeding, and secondly to the use of approximate energy targets, generally based on predictive equations: these equations are static and inaccurate in about 70% of patients. Such high uncertainty about requirements compromises attempts at conducting nutrition trials without indirect calorimetry support because the results cannot be trusted; indeed, both underfeeding and overfeeding are equally deleterious. An individualized therapy is required. A pragmatic approach to feeding is proposed: at first to attempt EN whenever and as early as possible, then to use indirect calorimetry if available, and to monitor delivery and response to feeding, and finally to consider the option of combining EN with PN in case of insufficient EN from day 4 onwards.

Fabrication and characterization of silicon position sensitive particle detectors

Position sensitive particle detectors are needed in high energy physics research. This thesis describes the development of fabrication processes and characterization techniques of silicon microstrip detectors used in the work for searching elementary particles in the European center for nuclear research, CERN. The detectors give an electrical signal along the particles trajectory after a collision in the particle accelerator. The trajectories give information about the nature of the particle in the struggle to reveal the structure of the matter and the universe. Detectors made of semiconductors have a better position resolution than conventional wire chamber detectors. Silicon semiconductor is overwhelmingly used as a detector material because of its cheapness and standard usage in integrated circuit industry. After a short spread sheet analysis of the basic building block of radiation detectors, the pn junction, the operation of a silicon radiation detector is discussed in general. The microstrip detector is then introduced and the detailed structure of a double-sided ac-coupled strip detector revealed. The fabrication aspects of strip detectors are discussedstarting from the process development and general principles ending up to the description of the double-sided ac-coupled strip detector process. Recombination and generation lifetime measurements in radiation detectors are discussed shortly. The results of electrical tests, ie. measuring the leakage currents and bias resistors, are displayed. The beam test setups and the results, the signal to noise ratio and the position accuracy, are then described. It was found out in earlier research that a heavy irradiation changes the properties of radiation detectors dramatically. A scanning electron microscope method was developed to measure the electric potential and field inside irradiated detectorsto see how a high radiation fluence changes them. The method and the most important results are discussed shortly.

NMR studies of mixed tetrahaloborates and some related boron trihalide complexes /|nGary John Schrobilgen. -- 260 St. Catharines, Ont. : [s. n.],

Nuclear magnetic resonance spectroscopy has been used to study donor-acceptor complexes of boron trifluoride with several ureas, tetramethylthiourea, tetramethylselenourea, and tetramethylquanidine as well as adducts of tetramethyl- -urea with BF2Cl, BFC1 2 , and BC1 3 - A large number of mixed tetrahaloborate ions, including some of the ternary ones such as BF2CIBr-,have been obtained by ligand exchange reactions and studied by NMR techniques. The bonding in these ions is of the same inherent interest as the bonding in the isoelectronic tetrahalomethanes which have been the subject of many detailed studies and have been involved in a controversy concerning the existence of and the nature of "fluorine hyperconjugation" or C-F P1T- Pn bonding_ Ligand exchange reactions also gave rise to the difluoroboron cation, (TMU)20BF2+o The difluoroboron cation has been observed in solutions of TMU-BF3 , and has been proposed as a possible intermediate for fluorine exchange reactions in BF3 adducts.

Palladium and platinum complexes of vitamin Bâ

Palladium and platinum complexes of pyridoxamine, pyridoxine and pyridoxal have been prepared. The structures of the complexes PtCI2PM.H20, trans-PdC12 (PN)2 and [PLH+ ]2[PtC16] 2- ,H20 have been determined by use of single crystal x-ray studies. The compounds PdC12PH, trans-PdC12 (PN) 2 , cis-PdCI2 (PN)2 and cis PdC12 (PL)2 were also studied by use of carbon-13 nmr spectroscopy. All the complexes have also been characterised by use of infrared spectral studies. In the complexes, PtCI2PM.H20 and PdC12PM, the ligand pyridoxamine is chela ted to the metal through the aminomethyl nitrogen and the phenolate oxygen atoms whereas in the complexes, trans-PdCI2 (PN)2' cis-PdCI2 (PN)2 and cis-PdC12 (PL)2 the vitamin B6 ligands are coordinated to the metal through the pyridine ring nitrogen. The compounds [PLH+ ]2[PtCI6] 2- .H20 and [PMH2] 2+ [PdCI4] 2- .H20have no direct metal-ligand bonding, In all the complexes, the metal maintains a square planar coordination except in [PLH +] 2[PtCI6] 2- ,H20 where the metal is octahedrally coordinated. PH pyridoxamine [PMH ] 2+ = diprotonated pyridoxamine 2 PN = pyridoxine PL pyridoxal PLH+ protonated pyridoxal