Outcomes of global coagulation assays in patients with Philadelphia-negative myeloproliferative neoplasms with respect to genetic determinants of clonal progression

Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that manifest with inflammation, promotion of atherosclerosis, hypercoagulability, fibrosis, and clonal evolution. The complex biological background lends itself to multi-omics studies. We have previously shown that reduced platelet fibrinogen receptor (PFR) expression may follow hyperactivation of plasma-dependent mechanisms, such as tissue factor (TF) release, unbalanced thrombin generation, involvement of protease-activated receptors (PARs). Acetylsalicylic acid (ASA) helped to restore the expression of PFRs. In this study, we enrolled 53 MPN patients, subjecting them to advanced genetic testing (panel of 30 genes in NGS), global coagulation testing (Rotational Thromboelastometry - ROTEM) and cytofluorometric determination of PFRs. ROTEM parameters appear to differ considerably depending on the type of pathology under investigation, cell count, and selected mutations. Essential thrombocythemia (ET) and CALR mutation appear to correlate with increased efficiency of both classical coagulation pathways, with significantly more contracted clot formation times (CFTs). In contrast, primary myelofibrosis (PMF) and polycythemia vera (PV) show greater imbalances in the hemostatic system. PV, probably due to its peculiar hematological features, shows a lengthening of the CFT and, at the same time, a selective contraction of parameters in INTEM with the increase of platelets and white blood cells. PMF - in contrast - seems to exploit the extrinsic pathway more to increase cell numbers. The presence of DNMT3A mutations is associated with reduced clotting time (CT) in EXTEM, while ASXL1 causes reduced maximal lysis (ML). EZH2 could be responsible for the elongation of CFT in INTEM assay. In addition, increased PFR expression is associated with history of hemorrhage and sustained CT time in FIBTEM under ASA prophylaxis. Our findings corroborate the existing models on the connection between fibrosis, genetic complexity, clonal progression, and hypercoagulability. Global coagulation assays and PFR expression are potentially useful tools for dynamic evaluation of treatments’ outcomes.

Intermittent Fasting Induces Hypothalamic Modifications Resulting In Low Feeding Efficiency, Low Body Mass And Overeating.

Intermittent fasting (IF) is an often-used intervention to decrease body mass. In male Sprague-Dawley rats, 24 hour cycles of IF result in light caloric restriction, reduced body mass gain, and significant decreases in the efficiency of energy conversion. Here, we study the metabolic effects of IF in order to uncover mechanisms involved in this lower energy conversion efficiency. After 3 weeks, IF animals displayed overeating during fed periods and lower body mass, accompanied by alterations in energy-related tissue mass. The lower efficiency of energy use was not due to uncoupling of muscle mitochondria. Enhanced lipid oxidation was observed during fasting days, whereas fed days were accompanied by higher metabolic rates. Furthermore, an increased expression of orexigenic neurotransmitters AGRP and NPY in the hypothalamus of IF animals was found, even on feeding days, which could explain the overeating pattern. Together, these effects provide a mechanistic explanation for the lower efficiency of energy conversion observed. Overall, we find that IF promotes changes in hypothalamic function that explain differences in body mass and caloric intake.

Obesogenic Environment By Excess Of Dietary Fats In Different Phases Of Development Reduces Spermatic Efficiency Of Wistar Rats At Adulthood: Correlations With Metabolic Status.

This study compares the impact of obesogenic environment (OE) in six different periods of development on sperm parameters and the testicular structure of adult rats and their correlations with sex steroid and metabolic scenario. Wistar rats were exposed to OE during gestation (O1), during gestation/lactation (O2), from weaning to adulthood (O3), from lactation to adulthood (O4), from gestation to sexual maturity (O5), and after sexual maturation (O6). OE was induced by a 20% fat diet, and control groups were fed a balanced diet (4% fat). Serum leptin levels and adiposity index indicate that all groups were obese, except for O1. Three progressive levels of impaired metabolic status were observed: O1 presented insulin resistance, O2 were insulin resistant and obese, and groups O3, O4, and O5 were insulin resistant, obese, and diabetic. These three levels of metabolic damage were proportional to the increase of leptin and decreased circulating testosterone. The impairment in the daily sperm production (DSP) paralleled these three levels of metabolic and hormonal damage being marginal in O1, increasing in O2, and being higher in groups O3, O4, O5, and O6. None of the OE periods affected the sperm transit time in the epididymis, and the lower sperm reserves were caused mainly by impaired DSP. In conclusion, OE during sexual maturation markedly reduces the DSP at adulthood in the rat. A severe reduction in the DSP also occurs in OE exposure during gestation/lactation but not in gestation, indicating that breast-feeding is a critical period for spermatogenic impairment under obesogenic conditions.

Semi-determinate Growth Habit Adjusts The Vegetative-to-reproductive Balance And Increases Productivity And Water-use Efficiency In Tomato (solanum Lycopersicum).

Tomato (Solanum lycopersicum) shows three growth habits: determinate, indeterminate and semi-determinate. These are controlled mainly by allelic variation in the SELF-PRUNING (SP) gene family, which also includes the florigen gene SINGLE FLOWER TRUSS (SFT). Determinate cultivars have synchronized flower and fruit production, which allows mechanical harvesting in the tomato processing industry, whereas indeterminate ones have more vegetative growth with continuous flower and fruit formation, being thus preferred for fresh market tomato production. The semi-determinate growth habit is poorly understood, although there are indications that it combines advantages of determinate and indeterminate growth. Here, we used near-isogenic lines (NILs) in the cultivar Micro-Tom (MT) with different growth habit to characterize semi-determinate growth and to determine its impact on developmental and productivity traits. We show that semi-determinate genotypes are equivalent to determinate ones with extended vegetative growth, which in turn impacts shoot height, number of leaves and either stem diameter or internode length. Semi-determinate plants also tend to increase the highly relevant agronomic parameter Brix×ripe yield (BRY). Water-use efficiency (WUE), evaluated either directly as dry mass produced per amount of water transpired or indirectly through C isotope discrimination, was higher in semi-determinate genotypes. We also provide evidence that the increases in BRY in semi-determinate genotypes are a consequence of an improved balance between vegetative and reproductive growth, a mechanism analogous to the conversion of the overly vegetative tall cereal varieties into well-balanced semi-dwarf ones used in the Green Revolution.

G-quadruplex Formation Enhances Splicing Efficiency Of Pax9 Intron 1.

G-quadruplexes are secondary structures present in DNA and RNA molecules, which are formed by stacking of G-quartets (i.e., interaction of four guanines (G-tracts) bounded by Hoogsteen hydrogen bonding). Human PAX9 intron 1 has a putative G-quadruplex-forming region located near exon 1, which is present in all known sequenced placental mammals. Using circular dichroism (CD) analysis and CD melting, we showed that these sequences are able to form highly stable quadruplex structures. Due to the proximity of the quadruplex structure to exon-intron boundary, we used a validated double-reporter splicing assay and qPCR to analyze its role on splicing efficiency. The human quadruplex was shown to have a key role on splicing efficiency of PAX9 intron 1, as a mutation that abolished quadruplex formation decreased dramatically the splicing efficiency of human PAX9 intron 1. The less stable, rat quadruplex had a less efficient splicing when compared to human sequences. Additionally, the treatment with 360A, a strong ligand that stabilizes quadruplex structures, further increased splicing efficiency of human PAX9 intron 1. Altogether, these results provide evidences that G-quadruplex structures are involved in splicing efficiency of PAX9 intron 1.

Leaf Manganese Accumulation And Phosphorus-acquisition Efficiency.

Plants that deploy a phosphorus (P)-mobilising strategy based on the release of carboxylates tend to have high leaf manganese concentrations ([Mn]). This occurs because the carboxylates mobilise not only soil inorganic and organic P, but also a range of micronutrients, including Mn. Concentrations of most other micronutrients increase to a small extent, but Mn accumulates to significant levels, even when plants grow in soil with low concentrations of exchangeable Mn availability. Here, we propose that leaf [Mn] can be used to select for genotypes that are more efficient at acquiring P when soil P availability is low. Likewise, leaf [Mn] can be used to screen for belowground functional traits related to nutrient-acquisition strategies among species in low-P habitats.

Performance da resistencia muscular de membros inferiores em praticantes da modalidade esportiva voleibol, atraves do salto vertical

Universidade Estadual de Campinas. Faculdade de Educação Física

The effect of using mixed initiator systems on the efficiency of photopolymerization of dental resins

A study was performed in order to determine the efficiency of the simultaneous use of the photoinitiators phenylpropanedione (PPD) and camphorquinone (CQ) in the polymerization of acrylic polymers and evaluate possible mechanisms leading to synergism or antagonism. It was found that efficiencies of both initiators taken individually are higher than that of their mixture, indicating that when both dyes are used simultaneously there will be an energy transfer from the more efficient initiator (CQ) to the less efficient one (PPD). Also, there was no proof of any reaction between the amine present in the CQ formulation and the PPD excited state.

Novas perspectivas na gestão do sistema de saúde da Espanha

Ao longo dos últimos vinte e cinco anos, a organização do sistema de saúde na Espanha vem adotando diversas medidas que reorientaram seu gerenciamento, melhoraram sua eficiência e aprimoraram seu sistema de financiamento, resultado de profundas reformas e da introdução de novos instrumentos de gestão. Este artigo é resultado de uma análise documental que objetivou descrever a trajetória de conformação do sistema de saúde espanhol e sua organização na contemporaneidade. Apresenta alguns determinantes históricos que tornaram possíveis as reformas no setor sanitário, como a descentralização para o nível das Comunidades Autônomas, a incorporação de mecanismos de coordenação e a integração e o financiamento dos novos e distintos formatos organizativos coexistentes no país. Além disso, identifica desafios que emergem no cenário atual do Sistema Nacional de Saúde, como o fenômeno da imigração, o avançado processo de transição demográfica, a crescente demanda por melhorias na qualidade da atenção e de incorporação tecnológica. Todos esses fatores influem na sustentabilidade do sistema, o que motivou a criação de mais um espaço para estabelecimentos de consensos sobre o papel fundamental do sistema sanitário para o Estado de Bem-Estar espanhol.

Genetic parameters for productive life traits and reproductive efficiency traits at 6 years in Nellore cattle

The objective of the present study was to estimate (co)variance components for length of productive life (LPL) and some alternative reproductive traits of 6-year-old Nellore cattle. The data set contained 57,410 records for age at first calving from Nellore females and was edited to remove animal records with uncertain paternity and cows with just one piece of calving information. Only animals with age at first calving ranging from 23 to 48 months and calving intervals between 11 and 24 months were kept for analysis. LPL and life production ( LP) were used to describe productive life. LPL was defined as the number of months a cow was kept in the herd until she was 6 years old, given that she was alive at first calving and LP was defined as total number of calves in that time. Four traits were used to describe reproductive traits: two breeding efficiencies on original scale were estimated using Wilcox and Tomar functions (BEW and BET, respectively), and two breeding efficiencies transformed (ASBEW and ASBET, respectively), using the function [arcsine (square root (BEi/100))]. Estimates of heritability for measures of LPL and LP were low and ranged from 0.04 to 0.05. Estimates of heritability for breeding efficiencies on original and transformed scales oscillated from 0.18 to 0.32. Estimates of genetic correlations ranged from -0.57 to 0.79 for LPL and other traits and from 0.28 to 0.63 for LP and other traits.

Star formation efficiency in galaxy clusters

Context. The luminous material in clusters of galaxies exists in two forms: the visible galaxies and the X-ray emitting intra-cluster medium. The hot intra-cluster gas is the major observed baryonic component of clusters, about six times more massive than the stellar component. The mass contained within visible galaxies is approximately 3% of the dynamical mass. Aims. Our aim was to analyze both baryonic components, combining X-ray and optical data of a sample of five galaxy clusters (Abell 496, 1689, 2050, 2631 and 2667), within the redshift range 0.03 < z < 0.3. We determined the contribution of stars in galaxies and the intra-cluster medium to the total baryon budget. Methods. We used public XMM-Newton data to determine the gas mass and to obtain the X-ray substructures. Using the optical counterparts from SDSS or CFHT we determined the stellar contribution. Results. We examine the relative contribution of galaxies, intra-cluster light and intra-cluster medium to baryon budget in clusters through the stellar-to-gas mass ratio, estimated with recent data. We find that the stellar-to-gas mass ratio within r(500) (the radius within which the mean cluster density exceeds the critical density by a factor of 500), is anti-correlated with the ICM temperature, which range from 24% to 6% while the temperature ranges from 4.0 to 8.3 keV. This indicates that less massive cold clusters are more prolific star forming environments than massive hot clusters.

ZETA DETERMINANT AND OPERATOR DETERMINANTS

We apply techniques of zeta functions and regularized products theory to study the zeta determinant of a class of abstract operators with compact resolvent, and in particular the relation with other spectral functions.

Substrate/semiconductor interface effects on the emission efficiency of luminescent polymers

The importance of interface effects for organic devices has long been recognized, but getting detailed knowledge of the extent of such effects remains a major challenge because of the difficulty in distinguishing from bulk effects. This paper addresses the interface effects on the emission efficiency of poly(p-phenylene vinylene) (PPV), by producing layer-by-layer (LBL) films of PPV alternated with dodecylbenzenesulfonate. Films with thickness varying from similar to 15 to 225 nm had the structural defects controlled empirically by converting the films at two temperatures, 110 and 230 degrees C, while the optical properties were characterized by using optical absorption, photoluminescence (PL), and photoluminescence excitation spectra. Blueshifts in the absorption and PL spectra for LBL films with less than 25 bilayers (<40-50 nm) pointed to a larger number of PPV segments with low conjugation degree, regardless of the conversion temperature. For these thin films, the mean free-path for diffusion of photoexcited carriers decreased, and energy transfer may have been hampered owing to the low mobility of the excited carriers. The emission efficiency was then found to depend on the concentration of structural defects, i.e., on the conversion temperature. For thick films with more than 25 bilayers, on the other hand, the PL signal did not depend on the PPV conversion temperature. We also checked that the interface effects were not caused by waveguiding properties of the excited light. Overall, the electronic states at the interface were more localized, and this applied to film thickness of up to 40-50 nm. Because this is a typical film thickness in devices, the implication from the findings here is that interface phenomena should be a primary concern for the design of any organic device. (C) 2011 American Institute of Physics. [doi:10.1063/1.3622143]

Molecular determinants of improved cathepsin B inhibition by new cystatins obtained by DNA shuffling

Background: Cystatins are inhibitors of cysteine proteases. The majority are only weak inhibitors of human cathepsin B, which has been associated with cancer, Alzheimer's disease and arthritis. Results: Starting from the sequences of oryzacystatin-1 and canecystatin-1, a shuffling library was designed and a hybrid clone obtained, which presented higher inhibitory activity towards cathepsin B. This clone presented two unanticipated point mutations as well as an N-terminal deletion. Reversing each point mutation independently or both simultaneously abolishes the inhibitory activity towards cathepsin B. Homology modeling together with experimental studies of the reverse mutants revealed the likely molecular determinants of the improved inhibitory activity to be related to decreased protein stability. Conclusion: A combination of experimental approaches including gene shuffling, enzyme assays and reverse mutation allied to molecular modeling has shed light upon the unexpected inhibitory properties of certain cystatin mutants against Cathepsin B. We conclude that mutations disrupting the hydrophobic core of phytocystatins increase the flexibility of the N-terminus, leading to an increase in inhibitory activity. Such mutations need not affect the inhibitory site directly but may be observed distant from it and manifest their effects via an uncoupling of its three components as a result of increased protein flexibility.

Biomass burning in Brazil`s Amazonian ""arc of deforestation"": Burning efficiency and charcoal formation in a fire after mechanized clearing at Feliz Natal, Mato Grosso

Estimates of greenhouse-gas emissions from deforestation are highly uncertain because of high variability in key parameters and because of the limited number of studies providing field measurements of these parameters. One such parameter is burning efficiency, which determines how much of the original forest`s aboveground carbon stock will be released in the burn, as well as how much will later be released by decay and how much will remain as charcoal. In this paper we examined the fate of biomass from a semideciduous tropical forest in the ""arc of deforestation,"" where clearing activity is concentrated along the southern edge of the Amazon forest. We estimated carbon content, charcoal formation and burning efficiency by direct measurements (cutting and weighing) and by line-intersect sampling (LIS) done along the axis of each plot before and after burning of felled vegetation. The total aboveground dry biomass found here (219.3 Mg ha(-1)) is lower than the values found in studies that have been done in other parts of the Amazon region. Values for burning efficiency (65%) and charcoal formation (6.0%, or 5.98 Mg C ha(-1)) were much higher than those found in past studies in tropical areas. The percentage of trunk biomass lost in burning (49%) was substantially higher than has been found in previous studies. This difference may be explained by the concentration of more stems in the smaller diameter classes and the low humidity of the fuel (the dry season was unusually long in 2007, the year of the burn). This study provides the first measurements of forest burning parameters for a group of forest types that is now undergoing rapid deforestation. The burning parameters estimated here indicate substantially higher burning efficiency than has been found in other Amazonian forest types. Quantification of burning efficiency is critical to estimates of trace-gas emissions from deforestation. (C) 2009 Elsevier B.V. All rights reserved.