Synthesis of inhibitors of polysialyltransferases PST and STX. Development of routes to synthesis, preparation and purification of carbohydrate and carbacycle-based potential inhibitors of the polysialyltransferase enzymes PST and STX

PolySialic acid (polySia) is a linear carbohydrate homopolymer of α- 2,8-linked sialic acids and a posttranslational modification of NCAM (neural cell adhesion molecule), biosynthesized by combined action of two polysialyltransferase enzymes, ST8SiaIV(PST) and ST8SiaII(STX). PolySia alters NCAM-dependent cell adhesion that is crucial for the CNS development. In adulthood, polySia expression is largely absent persisting only in areas of the brain associated with neuronal plasticity. Significantly, a number of malignant tumours re-express polySia and there is considerable evidence that its presence is related to higher malignancy, invasion and metastasis. The hypothesis underpinning this project is that inhibition of polySia biosynthesis will prevent (or reduce) tumour cell migration and invasion, thereby reducing the incidence of metastasis, which will lead to higher patient survival. The work reported in this thesis describes efforts towards the synthesis polysialyltransferase inhibitors that are structural analogues of CMP-Neu5Ac, the natural substrate. Specifically, development of methodology to synthesise building blocks suitable for conjugation as inhibitors is described. Quinic acid-based substrate analogues were explored, with a focus on development of chemistry to achieve substitution of C1-OH. Several protected quinic acid-based compounds were synthesized, and deoxygenation of the C1-OH through the use of a Barton-McCombie reaction was accomplished successfully, allowing an attempt to introduce different aliphatic groups at C1 position using the Mukayiama reaction. Synthesis of a cytidine building block, suitable for conjugation to either quinic acid or sialic acid is also reported. In parallel, studies towards the development of sialoside disulfide analogues are described, with novel conditions identified for their synthesis

Quantum spherical model with competing interactions

We analyze the phase diagram of a quantum mean spherical model in terms of the temperature $T$, a quantum parameter $g$, and the ratio $p=-J_{2}/J_{1}$, where $J_{1}>0$ refers to ferromagnetic interactions between first-neighbor sites along the $d$ directions of a hypercubic lattice, and $J_{2}<0$ is associated with competing antiferromagnetic interactions between second neighbors along $m\leq d$ directions. We regain a number of known results for the classical version of this model, including the topology of the critical line in the $g=0$ space, with a Lifshitz point at $p=1/4$, for $d>2$, and closed-form expressions for the decay of the pair correlations in one dimension. In the T=0 phase diagram, there is a critical border, $g_{c}=g_{c}(p)$ for $d\geq2$, with a singularity at the Lifshitz point if $d<(m+4)/2$. We also establish upper and lower critical dimensions, and analyze the quantum critical behavior in the neighborhood of $p=1/4$.Comment: 18 pages, 3 figures, refs added, minor modifications to match published versio

Productive indicator in a Holstein dairy herd: growth and height curves, reproductive and productive traits and genetic parameters

Data on weight, height, productive and reproductive performance of 1,272 Holstein heifers, born from 1990 to 1998, were used to evaluate the growth and height patterns of these females from birth to first calving, and the following traits: weight at first calving (PP), age at first calving (IP), milk production in the first lactation (PL) and first calving interval (IEP), and to estimate genetic parameters of these traits. The von Bertalanffy fitted models were: Yi=802.10 (1-0.630EXP (-0.0022t)) for weight, and Yi=1.40 (1-0.208EXP (-0.0038t)) for height. The average performance of heifers were: height 140cm, weight 602kg and 27 month of age at first calving. The total milk yield was 8,026kg and first IEP was 420 days. The (co)variance components estimates were obtained by a derivative-free algorithm with the DFREML. The estimates of heritabilities were 0.31, 0.35, 0.34, respectively for PP, IP and PL, and 0.10 for IEP. The genetic correlations estimates between PP and PL, PL and IP and IEP and PL were low. The correlation between IEP and PP was 0.49 and between IEP and IP was, -0.69, sugesting an antagonism between the two last traits.Foram analisados dados de peso, altura e desempenho produtivo e reprodutivo de 1.272 novilhas da raça Holandesa, nascidas no período de 1990 a 1998. Estudaram-se o desenvolvimento em peso e altura do nascimento até o primeiro parto, as características peso ao primeiro parto (PP), idade ao primeiro parto (IP), produção de leite na primeira lactação (PL), primeiro intervalo de partos (IEP), e os parâmetros genéticos pertinentes. As equações para as curvas de peso e altura, estimadas pelo modelo proposto por von Bertalanffy, foram: Yi= 802,10 (1 - 0,630EXP (-0,0022t)) e Yi= 1,40 (1 - 0,208EXP (-0,0038t)), respectivamente. As novilhas atingiram o primeiro parto com altura média de 140cm e peso de 602kg aos 27 meses de idade. A produção total de leite na primeira lactação foi de 8.026kg e o primeiro IEP 420 dias. Na obtenção dos componentes de (co)variância utilizou-se o método da máxima verossimilhança restrita livre de derivada. As estimativas de herdabilidade foram 0,31, 0,35 e 0,34, respectivamente, para PP, IP e PL, e 0,10 para IEP, evidenciando variância genética aditiva média para as três primeiras características. As correlações genéticas apresentaram pequena magnitude para PP e PL, PL e IP, e IEP e PL. A correlação entre IEP e PP foi 0,49; entre IEP e IP o valor foi negativo, -0,69, indicando provável antagonismo entre as duas últimas características.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Faculdade de Medicina de Ribeirão Preto Departamento de GenéticaUniversidade Estadual Paulista Faculdade de Medicina Veterinária e ZootecniaInstituto de ZootecniaUniversidade de São Paulo Escola Superior de Agricultura Luiz de QueirozUNIFESP, Faculdade de Medicina de Ribeirão Preto Depto. de GenéticaSciEL

Effect of modified atmosphere on polyphenols during storage of pasteurised strawberry purees

The minimum loss of processed fruit nutritional quality must been guaranteed during storage and the atmosphere can be a limiting step. Strawberry pur ees flushed with gas mixtures: 10 kPa O2 þ 90 kPa N2, 100 kPa N2 and air (78 kPa N2 þ 21 kPa O2 þ 0.03 kPa CO2) were stored for 90 days at 4 and 23 C and revealed no effect in total antioxidant activity and in total phenolic content. The compounds (þ)-catechin, ( )-epicatechin and quercetin-3-rutinoside were not affected by the atmospheres for both temperatures and ellagic acid was the exception within strawberry phytochemicals, where its concentration was higher for samples stored in air. Total anthocyanin content was better preserved when strawberry pur ee was stored in 100 kPa N2 at 4 and 23 C, at which temperatures their levels decreased 24 and 77%, respectively. At 4 C cyanidin-3- glucoside presented no significant differences between atmospheres. Pelargonidin-3-glucoside and pelargonidin-3-rutinoside decreased both 27% for 100 kPa N2 and 45% for 10 kPa O2 and air. All the individual anthocyanins were not affected by the atmospheres when stored at 23 ºC.info:eu-repo/semantics/publishedVersio

Insulin therapy modulates mitochondrial dynamics and biogenesis, autophagy and tau protein phosphorylation in the brain of type 1 diabetic rats

AbstractThe main purpose of this study was to examine whether streptozotocin (STZ)-induced type 1 diabetes (T1D) and insulin (INS) treatment affect mitochondrial function, fission/fusion and biogenesis, autophagy and tau protein phosphorylation in cerebral cortex from diabetic rats treated or not with INS. No significant alterations were observed in mitochondrial function as well as pyruvate levels, despite the significant increase in glucose levels observed in INS-treated diabetic rats. A significant increase in DRP1 protein phosphorylated at Ser616 residue was observed in the brain cortex of STZ rats. Also an increase in NRF2 protein levels and in the number of copies of mtDNA were observed in STZ diabetic rats, these alterations being normalized by INS. A slight decrease in LC3-II levels was observed in INS-treated rats when compared to STZ diabetic animals. An increase in tau protein phosphorylation at Ser396 residue was observed in STZ diabetic rats while INS treatment partially reversed that effect. Accordingly, a modest reduction in the activation of GSK3β and a significant increase in the activity of phosphatase 2A were found in INS-treated rats when compared to STZ diabetic animals. No significant alterations were observed in caspases 9 and 3 activity and synaptophysin and PSD95 levels. Altogether our results show that mitochondrial alterations induced by T1D seem to involve compensation mechanisms since no significant changes in mitochondrial function and synaptic integrity were observed in diabetic animals. In addition, INS treatment is able to normalize the alterations induced by T1D supporting the importance of INS signaling in the brain

Identification of QTLs for grain yield and other traits in tropical maize under high and low soil-nitrogen environments.

Article purchased; Published online: 03 Nov 2017Low soil Nitrogen (low-N) is one of the most important abiotic stresses responsible for significant yield losses in maize (Zea mays. L.). The development and commercialization of low N tolerant genotypes can contribute to improved food security in developing countries. However, selection for low N tolerance is difficult because it is a complex trait with strong interaction between genotypes and environments. Marker assisted breeding holds great promise for improving such complex traits more efficiently in less time, but requires markers associated with the trait of interest. In this study, 150 BC2F1 families of CML 444 x CML 494 were evaluated at two location for two consecutive seasons to identify SNP markers associated with quantitative trait loci (QTLs) for yield and other agronomic traits under low- and high-N environments. A total of 13 QTLs were identified with 158 SNP markers, of which nine and four QTLs were detected under low- and high-N environments, respectively. Five QTLs one each for grain yield (qgy-1), days to silking (qdts-1) and anthesis- silking interval (qasi-6), and two for stay green characteristic (qsg-1 and qsg-4) were close to their adjacent markers, with an interval of 0.7 to 5.2 cM between them and explained phenotypic variance of 9 to 21%. These QTLs would be invaluable for rapid introgression of genomic regions into maize populations using marker assisted selection (MAS) approaches. However, further validation of these QTLs is needed before use in MAS

The Action of Polyphenols in Diabetes Mellitus and Alzheimer's Disease: A Common Agent for Overlapping Pathologies

Diabetes Mellitus (DM) and Alzheimer's disease (AD) are two prevalent diseases in modern societies, which are caused mainly by current lifestyle, aging and genetic alterations. It has already been demonstrated that these two diseases are associated, since individuals suffering from DM are prone to develop AD. Conversely, it is also known that individuals with AD are more susceptible to DM, namely type 2 diabetes (T2DM). Therefore, these two pathologies, although completely different in terms of symptomatology, end up sharing several mechanisms at the molecular level, with the most obvious being the increase of oxidative stress and inflammation. Polyphenols are natural compounds widely spread in fruits and vegetables whose dietary intake has been considered inversely proportional to the incidence of DM and AD. So, it is believed that this group of phytochemicals may have preventive and therapeutic potential, not only by reducing the risk and delaying the development of these pathologies, but also by improving brain's metabolic profile and cognitive function. The aim of this review is to understand the extent to which DM and AD are related pathologies, the degree of similarity and the relationship between them, to detail the molecular mechanisms by which polyphenols may exert a protective effect, such as antioxidant and anti-inflammatory effects, and highlight possible advantages of their use as common preventive and therapeutic alternatives.info:eu-repo/semantics/publishedVersio

Expanded equine cumulus-oocyte complexes exhibit higher meiotic competence and lower glucose consumption than compact cumulus-oocyte complexes

Publicado en: Reproduction, Fertility and Development 30(2) 297-306 https://doi.org/10.1071/RD16441 Submitted: 4 November 2016 Accepted: 6 June 2017 Published: 6 July 2017Equine cumulus-oocyte complexes (COCs) are classified as compact (cCOC) or expanded (eCOC) and vary in their meiotic competence. This divergence could be related to different glucose metabolism. To test this hypothesis eCOCs, cCOCs, and expanded or compact mural granulosa cells (EC and CC respectively) were matured in vitro for 30 hours and the maturation rate, glucose metabolism, and expression of genes involved in glucose transport, glycolysis, apoptosis and meiotic competence were determined. Significant differences were found between eCOCs and cCOCs maturation rates (50% vs. 21.7 %; n = 192 and 46 respectively, p < 0.001), glucose consumption (1.8 ± 0.5 vs. 27.9 ± 5.9 nmol/COC; mean ± SEM), pyruvate production (0.1 ± 0.0 vs. 2.4 ± 0.8 nmol/COC; mean ± SEM) and lactate production (4.7 ± 1.3 vs. 64.1 ± 20.6 nmol/COC; mean ± SEM) respectively (p < 0.05). Moreover, similar glucose consumption was observed for EC and CC. Hyaluronan binding protein (TNFAIP6) expression was increased in eCOCs and EC, solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) was increased in eCOCs, while glycolysis-related enzymes and solute carrier family 2 (facilitated glucose transporter) member 3 (SLC2A3) expression did not vary between COCs or mural granulosa cell type. Our data demonstrate that metabolic and genomic differences exist between eCOCs and cCOCs and mural granulosa cells in the horse.This work was financed by AGL2015-66145-R funding from the Spanish Ministry of Economy, Industry and 364 Competitiveness and by AGL2015-73249-JIN(AEI/FEDER/UE) from the "Agencia Estatal de Investigación" 365 (AEI) (Spanish Ministry of Economy, Industry and Competitiveness) and "Fondo Europeo de Desarrollo 366 Regional" (FEDER). Beatriz Macías-García holds a postdoctoral grant "Juan de la Cierva Incorporación"(IJCI-367 2014-19428) from the Spanish Ministry of Economy, Industry and Competitiveness. L.G.-F. (Grant reference: 368 SFRH/BPD/85532/2012) and B. M.-G. (Grant reference: SFRH/BPD/84354/2012) were also partially funded by 369 Fundação para a Ciência e a Tecnologia (Portuguese Ministry for Science, Technology and Higher Education) co370 funded by Programa Operacional Potencial Humano (POPH) financed by European Social Fund (ESF) and 371 Portuguese national funds from Ministry for Science, Technology and Higher Education. The authors thank 372 CECA/ICETA (University of Porto) for funding the abattoir dislocations. The collaboration of Linda Rosa 373 Abattoir is highly appreciated. The authors wish to thank the Laboratory of Applied Physiology (Department of 374 Aquatic Production) of the ICBAS (University of Porto) and especially Mariana Hinzmann for allowing us to use 375 their fluorescence microscope. RNAlater was kindly provided by Dr. Michael Jowers

L-Theanine promotes cultured human Sertoli cells proliferation and modulates glucose metabolism

L-Theanine is the major free amino acid present in tea (Camellia sinensis L.). The effects of several tea constituents on male reproduction have been investigated, but L-theanine has been overlooked. Sertoli cells (SCs) are essential for the physical and nutritional support of germ cells. In this study, we aimed to investigate the ability of L-theanine to modulate important mechanisms of human SCs (hSCs) metabolism, mitochondrial function and oxidative profile, which are essential to prevent or counteract spermatogenesis disruption in several health conditions.info:eu-repo/semantics/publishedVersio