Regulation of B Cell Gene Expression and Function by Ikaros, Helios and Bcl6

B lymphocytes constitute a key branch of adaptive immunity by providing specificity to recognize a vast variety of antigens by B cell antigen receptors (BCR) and secreted antibodies. Antigen recognition activates the cells and can produce antibody secreting plasma cells via germinal center reaction that leads to the maturation of antigen recognition affinity and switching of antibody effector class. The specificity of antigen recognition is achieved through a multistep developmental pathway that is organized by interplay of transcription factors and signals through BCR. Lymphoid malignancies arise from different stages of development in abnormal function of transcriptional regulation. To understand the B cell development and the function of B cells, a thorough understanding of the regulation of gene expression is important. The transcription factors of the Ikaros family and Bcl6 are frequently associated with lymphoma generation. The aim of this study was to reveal the targets of Ikaros, Helios and Bcl6 mediated gene regulation and to find out the function of Ikaros and Helios in B cells. This study uses gene targeted DT40 B cell lines and establishes a role for Ikaros family factors Ikaros and Helios in the regulation of BCR signaling that is important at developmental checkpoints, for cell survival and in activation. Ikaros and Helios had opposing roles in the regulation of BCR signals. Ikaros was found to directly repress the SHIP gene that encodes a signaling lipid-metabolizing enzyme, whereas Helios had activating effect on SHIP expression. The findings demonstrate a balancing function for these two Ikaros family transcription factors in the regulation of BCR signaling as well as in the regulation of gene expression. Bcl6 was found to repress plasma cell gene expression program while maintaining gene expression profile of B cells. Analysis of direct Bcl6 target genes suggested novel mechanisms for Bcl6-mediated suppression of plasma cell differentiation and promoting germinal center phenotype.

Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.

Orthogonal function method in modelling paper web quality variation

This work is devoted to the analysis of signal variation of the Cross-Direction and Machine-Direction measurements from paper web. The data that we possess comes from the real paper machine. Goal of the work is to reconstruct the basis weight structure of the paper and to predict its behaviour to the future. The resulting synthetic data is needed for simulation of paper web. The main idea that we used for describing the basis weight variation in the Cross-Direction is Empirical Orthogonal Functions (EOF) algorithm, which is closely related to Principal Component Analysis (PCA) method. Signal forecasting in time is based on Time-Series analysis. Two principal mathematical procedures that we used in the work are Autoregressive-Moving Average (ARMA) modelling and Ornstein–Uhlenbeck (OU) process.

Seeder-fertilizer machine: energetic demand as a function of vegetal covering handling and manure deposition shank depth in no-tillage system

The purpose of this work was evaluating the energetic demand of a seeder-fertilizer machine as a function of the type and handling of vegetal covering culture and of the fertilizer deposition shank depth. A Valtra BM100 tractor was used implemented to pull a high precision seeder-fertilizer machine with four ranks of seeding, spaced 0.9 m for maize culture. Experiment was conducted with design in randomized blocks in factorial plots, in the Laboratory of Machines and Agricultural Mechanization experimental area (LAMMA) of UNESP-Jaboticabal, using two covering cultures (black-mucuna and crotalaria), three handlings of this covering, two mechanical (straw crusher and roller knife) and one chemical (pulverization of herbicide), performed 120 days after seeding of covering cultures and three depths of fertilizer deposition shank, completing 18 treatments, with four repetitions, totaling 72 observations. Parameters of displacement speed, gliding, force on traction bar, peak force, power on pulling bar and fuel consumption were evaluated. It was possible to conclude that force on traction bar was less for depths of 0.11 and 0.14 m of fertilizer plough shank, the same occurring for peak force, power on traction bar and volumetric consumption. The specific consumption was lower at a depth of 0.17 m of fertilizer plough shank. Covering cultures and their handlings did not interfere in the performance of machines under inquiry.

The regulation and function of collagenase-3 (MMP-13) in cutaneous wound healing and squamous cell carcinoma

Matrix metalloproteinase-13 (MMP-13) is a potent proteolytic enzyme, whose expression has been previously associated with fetal bone development and postnatal bone remodeling and with adult gingival wound healing. MMP-13 is also known to be involved in the growth and invasion of various cancers including squamous cell carcinoma (SCC) of the skin. The aim of this study was to further elucidate the function and regulation of MMP-13 in wound repair and cancer. In this study, it was shown that fetal skin fibroblasts express MMP-13 in response to transforming growth factor-β in a p38 MAP kinase dependent manner. In addition, MMP-13 was found to be expressed in vivo by wound fibroblasts in human fetal skin grafted on SCID mice. Adenovirally delivered expression of MMP-13 enhanced collagen matrix contraction by fibroblasts in vitro in association with altered cytoskeletal structure, enhanced proliferation and survival. These results indicate that MMP-13 is involved in cell-mediated collagen matrix remodeling and suggest a role for MMP-13 in superior matrix remodeling and scarless healing of fetal skin wounds. Using an MMP-13 deficient mouse strain, it was shown that MMP-13 is essential for the normal development of experimental granulation tissue in mice. MMP-13 was implicated in the regulation of myofibroblast function and angiogenesis and the expression of genes involved in cellular proliferation and movement, immune response, angiogenesis and proteolysis. Finally, epidermal mitogen, keratinocyte growth factor (KGF) was shown to suppress the malignant properties of skin SCC cells by downregulating the expression of several target genes with potential cancer promoting properties, including MMP-13, and by reducing SCC cell invasion. These results provide evidence that MMP-13 potently regulates cell viability, myofibroblast function and angiogenesis associated with wound healing and cancer. In addition, fibroblasts expressing MMP-13 show high collagen reorganization capacity. Moreover, the results suggest that KGF mediates the anti-cancer effects on skin SCC

Fuel consumption of a tractor in function of wear, of ballasting and tire inflation pressure

When using appropriate inflation pressures and load capacity (ballast), it may obtain a higher yield and prolongation of the life of the tire, besides it may minimize the problems of loss of traction, increased slippage and fuel consumption. This study aimed to evaluate the fuel consumption of a tractor operating with new and worn tires in three conditions of ballasting and three inflation pressures, when driving on compacted soil with vegetation cover. The experiment was conducted at the experimental unit from the Department of Animal Science, Federal University of Lavras, state of Minas Gerais, Brazil, in an agricultural soil compacted by cattle trampling and with vegetation cover. It was used a tractor 4x2 with front wheel assist, of a 65.62 kW engine power. The tires were of R1 type, diagonal (front: 12.4 to 24; and rear: 18.4 to 30), the average height of the clutches of the new tires were 0.3 and 0.35 m for front and rear tires, respectively, and for the worn tires were 0.018 and 0.0045 m, for the front and the rear tires, respectively. The results showed advantages for the tractor equipped with new tires.

Estimating the most important criteria for hatching eggs as function of broiler breeders age

This research aimed to compare two female broiler breeder ages during the incubation period regarding management using the Analytic Hierarchy Process method (AHP). This method is characterized by the possibility of analyzing a multicriteria problem and assists a decision making. This study was carried out on a commercial hatchery located in São Paulo, Brazil. Two ages of broiler breeder (42 and 56 weeks) were compared relative to production rate. Production index data were the same in both ages and were submitted to multicriteria decision analysis using the AHP method. The results indicate that broiler breeders of 42 weeks presented better performance than those of 56 week-old. The setter phase (incubation) is more critical than the hatcher. The AHP method was efficient for this analysis and can serve as a methodological basis for future studies to improve the hatchability of broilers eggs.

Energetic efficiency of an agricultural tractor in function of tire inflation pressure

The tire inflation pressure, among other factors, determines the efficiency in which a tractor can exert traction. It was studied the effect of using two tire inflation pressures, 110.4 kPa in the front and rear wheels, 124.2 kPa in the front wheel and 138 kPa in the rear wheels, the energetic efficiency of an agricultural tractor of 147 kW of engine power, in the displacement speed of 6.0 km.h-1, on track with firm surface, with the tractor engine speed of 2000 rpm. For each condition of the tire pressure, the tested tractor was subjected to constant forces in the drawbar of 45 kN and 50 kN, covering 30 meters. It was used a randomized complete block with a 2x2 factorial arrangement (tire pressure and drawbar power) with four replications, totaling 16 experimental units. Data were subjected to analysis of variance, using the Tukey test at 5% probability for comparison averages. The lowest hourly and specific fuel consumption, the lowest slippage of the wheelsets and the highest efficiency in the drawbar was obtained with the tire inflation pressure of 110.4 kPa in the front and rear tires of the tractor, highlighting that lower pressures improve energetic and operational performance of the tractor.

Corn productivity in function of surface application of lime in differents management systems and cultural preparation

The evaluation of technologies employed at the agricultural production system such as crop rotation and soil preparation, both associated with crop-livestock integration, is crucial. Therefore, the aim of the present study was to evaluate the incorporation of lime for three no-tillage systems and cultural managements in system of crop-livestock integration, with emphasis on corn grain yield. The experiment was conducted from January 2003 to April 2005 at Selvíria city, MS, in Dystroferric Red Latosol, clay texture. The experimental design was randomized blocks with split plots consisted of three main treatments, aimed the soil physics conditioning and the incorporation of lime: PD - No-no-tillage; CM - minimum no-tillage, and PC - conventional no-tillage; and of two secondary treatments related to the management: rotation and crop succession, with four replications. Data on agronomic traits of maize were analyzed: plant height, stem diameter, height of the first spike insertion, 100 grains weight and grain yield. The results showed that the maize produced under the system of crop-livestock integration is quite feasible, showing that grain yields are comparable to averages in the region and the different soil physical conditioning and incorporation of lime did not influence the corn yield as well as the cultural managements, rotation and succession, did not affect the maize crop behavior after two years of cultivation.

Quality of peanut mechanical sowing in function of seeding density and size of the seeds

ABSTRACTPeanut crop (Arachis hypogaeaL.) mechanization has been improved over the years; however there are drawbacks that affect the quality of operations. Thus, this article’s objectives were to evaluate the operational performance of the mechanized sowing of peanut crop according to seeding densities (10, 14, and 18 seeds m-1) and seed sizes (21 and 23 mm). It was observed that the seeds of 23 mm had shorter average number of days to emergence and a higher percentage of emergences, occurring the opposite to the seeding density of 18 seeds m-1. The higher the seeding density, the largest was the plant stand, whereas the 23 mm seed obtained the best results and the same with the seeding density of 14 seeds m-1 that had a higher percentage of normal spacing. The densities of 14 and 18 seeds m-1 reflected in higher yields, being always superior to the 23 mm seeds.

Ankle-brachial index, high-sensitivity C-reactive protein and endothelial function in a cardiovascular risk population

Atherosclerotic vascular disease is the leading cause of death in the Western world. Its main three manifestations are coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Asymptomatic peripheral arterial disease is usually diagnosed using the ankle brachial index, and values ≤ 0.90 are used to determine the diagnosis. The classical risk factors of peripheral arterial disease, such as smoking and diabetes, are well known and early interventions are mandatory to improve the prognosis. What is not well known is the role of inflammation as a risk factor. Yet, a novel approach to cardiovascular diseases is the measurement of endothelial function. In this thesis, we studied the ankle-brachial index, C-reactive protein and endothelial function in a cardiovascular risk population. A total of 2856 subjects were invited to the study and 2085 (73%) responded. From these subjects, a cohort of 1756 risk persons was screened. We excluded the subjects with previously known cardiovascular disease or diabetes, because they were already under systematic follow-up. Out of the study subjects, 983 (56%) were women and 773 (44%) men. The ankle brachial index and high-sensitivity C-reactive protein were measured from 1047 subjects. Endothelial function was assessed by measuring reactive hyperemia pulse amplitude tonometry from 66 subjects with borderline peripheral arterial disease. In this study, smoking was a crucial risk factor for peripheral arterial disease. Subclinical peripheral arterial disease seems to be more common in hypertensive patients even without comorbidities. The measurement of the ankle brachial index is an efficient method to identify patients at an increased cardiovascular risk. High-sensitivity C-reactive protein did not correlate with the ankle brachial index or peripheral arterial disease. Instead, it correlated with measures of obesity. In a cardiovascular risk population with borderline peripheral arterial disease, nearly every fourth subject had endothelial dysfunction. This might point out a subgroup of individuals in need of more intensive treatment for their risk factors.

Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation

Objective: To evaluate the influence of end-stage liver disease and orthotopic liver transplantation in the pituitary function and hormone metabolism before and after liver transplantation.Methods: In a prospective study, serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) of 30 male patients with cirrhosis were determined two to four hours before and six months after liver transplantation. The results were compared according to the Model for End-stage Liver Disease (MELD).Results: male patients with liver cirrhosis have hypogonadism. FSH was normal, but inappropriately low due to androgen failure; E2 and PRL, on their turn, were high. After liver transplantation, FSH and LH levels increased (p < 0.05), whereas E2 and PRL normalized (p < 0.05). The MELD score did not influence changes in FSH, PRL and LH, however, the more severe the cirrhosis was, the more significant was the normalization of E2 (p = 0.01).Conclusion: Patients with cirrhosis and male hypogonadism have inappropriately normal levels of FSH and LH, associated with an increase in E2 and LRP. After liver transplantation, FSH and LH increased, while E2 and PRL returned to normal. Changes in E2 levels were most pronounced in patients with MELD > 18. The severity of cirrhosis had no influence on FSH, PRL and LH.

The Structure and Function of αI Domains in Collagen Receptor and Leukocyte Integrins

Integrins are heterodimeric, signaling transmembrane adhesion receptors that connect the intracellular actin microfilaments to the extracellular matrix composed of collagens and other matrix molecules. Bidirectional signaling is mediated via drastic conformational changes in integrins. These changes also occur in the integrin αI domains, which are responsible for ligand binding by collagen receptor and leukocyte specific integrins. Like intact integrins, soluble αI domains exist in the closed, low affinity form and in the open, high affinity form, and so it is possible to use isolated αI domains to study the factors and mechanisms involved in integrin activation/deactivation. Integrins are found in all mammalian tissues and cells, where they play crucial roles in growth, migration, defense mechanisms and apoptosis. Integrins are involved in many human diseases, such as inflammatory, cardiovascular and metastatic diseases, and so plenty of effort has been invested into developing integrin specific drugs. Humans have 24 different integrins, four of which are collagen receptor (α1β1, α2β1, α10β1, α11β1) and five leukocyte specific integrins (αLβ2, αMβ2, αXβ2, αDβ2, αEβ7). These two integrin groups are quite unselective having both primary and secondary ligands. This work presents the first systematic studies performed on these integrin groups to find out how integrin activation affects ligand binding and selectivity. These kinds of studies are important not only for understanding the partially overlapping functions of integrins, but also for drug development. In general, our results indicated that selectivity in ligand recognition is greatly reduced upon integrin activation. Interestingly, in some cases the ligand binding properties of integrins have been shown to be cell type specific. The reason for this is not known, but our observations suggest that cell types with a higher integrin activation state have lower ligand selectivity, and vice versa. Furthermore, we solved the three-dimensional structure for the activated form of the collagen receptor α1I domain. This structure revealed a novel intermediate conformation not previously seen with any other integrin αI domain. This is the first 3D structure for an activated collagen receptor αI domain without ligand. Based on the differences between the open and closed conformation of the αI domain we set structural criteria for a search for effective collagen receptor drugs. By docking a large number of molecules into the closed conformation of the α2I domain we discovered two polyketides, which best fulfilled the set structural criteria, and by cell adhesion studies we showed them to be specific inhibitors of the collagen receptor integrins.

Tradução para português, adaptação cultural e validação do Female Sexual Function Index

OBJETIVO: traduzir para o português, adaptar culturalmente e validar o questionário Female Sexual Function Index (FSFI). MÉTODOS: dois tradutores brasileiros, cientes dos objetivos desta pesquisa, preparam duas versões do FSFI para o português, as quais foram retro-traduzidas por outros dois tradutores ingleses. As diferenças foram harmonizadas e pré-testadas em um estudo piloto. As versões finais do FSFI e de outro questionário, o Short-Form Health Survey, já vertido e publicado em português, foram simultaneamente administradas a cem pacientes. Foram testadas as propriedades psicométricas do FSFI, como confiabilidade (consistência interna e teste-reteste) e validades de construto. O reteste foi realizado após quatro semanas, a partir da primeira entrevista. RESULTADOS: o processo de adaptação cultural não alterou a versão em português do FSFI comparado ao original. O alfa de Cronbach padronizado do questionário foi 0,96; avaliado por domínios, variou de 0,31 a 0,97. Como medida de confiabilidade teste-reteste, foi aplicado o coeficiente de correlação intra-classes, que foi considerado forte e idêntico (1,0). O coeficiente de correlação de Pearson entre o FSFI e o Short-Form Health Survey foi positivo, mas fraco na maioria dos domínios afins, variando de 0,017 a 0,036. CONCLUSÕES: a versão do FSFI foi traduzida para o português e adaptada culturalmente e é válida para avaliação da resposta sexual das mulheres brasileiras.