Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer's mouse model

Background Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased A beta pathology and increased expression of glial activation markers in APPswe/PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Methods To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. Results Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1 alpha, MIP-1 beta, and MCP-1) and pro-inflammatory cytokines, including IL-1 alpha, IFN-gamma, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of A beta 1-40, A beta 1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, A beta and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD

Utilidade da PET/CT, (18F-FDG), no estudo do linfoma Hodgkin e linfoma não Hodgkin

Os linfomas são tumores estabelecidos a nível do sistema linfático. Devido à sua heterogeneidade classificam-se como Linfoma Hodgkin (LH) e Linfoma não Hodgkin (LNH), apresentando diferente prognóstico e seguimento quimioterapêutico. Actualmente, a Photon Emission Tomography/Computed Tomography (PET/CT, do acrónimo inglês) é considerada “imagem” de excelência no estudo desta patologia. Neste contexto, é objectivo deste artigo verificar a utilidade da técnica PET/CT e correlacionar o valor de Standard Uptake Value (SUV), obtido pela PET, com o estadio histológico do linfoma e com a resposta ao tratamento quimioterapêutico. Metodologia - Analisaram-se retrospectivamente 356 estudos respeitantes a 231 pacientes, aos quais se realizou uma PET/CT para estadiamento, estudo de massa ou avaliação da resposta ao tratamento. Após a administração de uma actividade média de 18F-FDG de 288,6 MBq, foram adquiridas imagens numa PET/CT GE Discovery ST. Os resultados obtidos foram comparados com os dados clínicos dos pacientes. Resultados - Foram encontradas diferenças significativas entre a idade Vs tipo de linfoma. Não foram encontradas diferenças significativas entre: valor de SUVmáx ganglionar, lesões extra-ganglionares e seu valor de SUV relativamente ao tipo de linfoma. Comprovou-se a influência da PET/CT na alteração do estadio do linfoma e atitude terapêutica. Em última análise, obtiveram-se respectivamente os seguintes valores de sensibilidade, especificidade e exactidão: 98%, 79% e 88%. Conclusões - Os resultados obtidos permitem verificar a importância da imagem PET/CT no estadiamento, monitorização e alteração da atitude terapêutica dos LH e LNH

Using Rules to Adapt Applications for Business Models with High Evolutionary Rates

Nowadays, business models are in permanent evolution since the requirements belongs to a rapidly evolving world. In a context where communications all around the world travel so fast the business models need to be adapted permanently to the information the managers receive. In such world, traditional software development, needed for adapting software to changes, do not work properly since business changes need to be in exploitation in shorter times. In that situation, it is needed to go quicker from the business idea to the exploitation environment. This issue can be solved accelerating the development speed: from the expert to the customer, with no –or few, technical intervention. This paper proposes an approach to empower domain experts in developing adaptability solutions by using automated sets of production rules in a friendly way. Furthermore, a use case that implements this kind of development was used in a real problem prototype

Effect of dietary vitamin A on Senegalese sole (Solea senegalensis) skeletogenesis and larval quality

16 páginas, 12 figuras, 4 tablas.The effects of different levels of vitamin A (VA) in Senegalese sole larval performance and development were evaluated by means of a dietary dose–response experiment using enriched Artemia metanauplii as a carrier of this micronutrient. Larvae were fed from 6 to 27 days post hatch (dph) with enriched Artemia containing graded levels of total VA (1.3, 2.1, 4.5 and 12.9 µg VA mg− 1 DW). The content of VA in live prey directly affected its accumulation in larvae and early juveniles. Retinyl palmitate accumulated during larval ontogeny, whereas retinol showed the opposite trend, decreasing from hatching until 41 dph and then remaining constant until the end of the study. In metamorphic larvae (10 and 15 dph), VA did not affect the number of thyroid follicles or the intensity of the immunoreactive staining of T3 and T4. However, at older stages of development (post-metamorphic larvae: 20, 30, 41 and 48 dph), VA decreased the number of thyroid follicles but increased their mean size and enhanced T3 and T4 immunoreactive staining. A dietary excess of VA did not affect either larval performance in terms of growth and survival or the maturation of the digestive system. However, the most remarkable impact of this morphogenetic nutrient was detected during skeletal morphogenesis. Dietary VA accelerated the intramembranous ossification of vertebral centrums, which led to the formation of a supranumerary haemal vertebra and a high incidence of fused and compressed vertebrae in fish fed 2.1, 4.5 and 12.9 mg VA mg− 1 DW. In addition, VA also affected those structures from vertebrae and caudal fin formed by chondral ossification, leading to defects in their shape and fusions with adjacent skeletal elements. In particular, the caudal fin was the region most affected by the dietary treatments. In order of importance, the bones with more developmental anomalies were the modified neural and haemal spines, epural, hypurals and parahypural. The impact of systemic factors such as thyroidal hormones in skeletogenesis should not be neglected since present results revealed that an excess of dietary VA affected the levels of T3 and T4, which might have affected bone formation and remodelling, leading to skeletal deformities.This work was funded by the Ministry of Education and Culture (MEC) of the Spanish Government (project AGL2005-02478).Peer reviewe

Estudio anatomopatológico de aislados de Leptospira spp., provenientes de Nicaragua en Mesocricetus auratus como biomodelo

RESUMEN Objetivo. El objetivo de este trabajo fue caracterizar en el biomodelo Mesocricetus auratus la sintomatología y lesiones anatomopatológicas que provocan 5 aislados clínicos de Leptospira spp., provenientes de Nicaragua. Materiales y métodos. Con este fin se inocularon 50 hámster por vía i.p con 1mL del cultivo de cada una de las cepas en fase exponencial teniendo una concentración celular de 7.5 x 106 leptospira/mL (10 animales por cepa), evaluándose signos de la enfermedad, mortalidad durante 14 días, lesiones anatomopatológicas macroscópicas y microscópicas mediante tinción con hematoxilina-eosina y tinción de Warthyn Starryn. Resultados. Todas las cepas presentaron alta mortalidad, mostrando un cuadro tanto clínico, como lesional característico de la infección experimental. Además, causaron la muerte al 100% de los animales entre el tercer y décimo día postinfección. En el estudio anatomopatológico la cepa del serogrupo Ballum y la del serogrupo Pomona produjeron focos de hemorragias específicamente en el riñón y pulmones. De forma similar ocurrió una congestión hepática y renal, mientras que la hemorragia renal fue observada con mayor frecuencia en la cepa del serogrupo Pomona, diferenciándose del resto de las cepas que mostraron esta lesión con menos frecuencia. Conclusiones. Este trabajo permitió una mayor caracterización de estas cepas siendo utilizadas como futuras candidatas vacunales frente a una nueva epidemia de Leptospirosis en Nicaragua

The globular cluster system of NGC 1399. III. VLT spectroscopy and database

Radial velocities of 468 globular clusters around NGC 1399, the central galaxy in the Fornax cluster, have been obtained with FORS2 and the Mask Exchange Unit (MXU) at the ESO Very Large Telescope. This is the largest sample of globular cluster velocities around any galaxy obtained so far. The mean velocity uncertainty is 50 km s-1. This data sample is accurate and large enough to be used in studies of the mass distribution of NGC 1399 and the properties of its globular cluster system. Here we describe the observations and the reduction procedure, and we discuss the uncertainties of the resulting velocities. The complete sample of cluster velocities that is used in a dynamical study of NGC 1399 is tabulated. A subsample is compared with previously published values.Facultad de Ciencias Astronómicas y Geofísica

The globular cluster system of NGC 1399. III. VLT spectroscopy and database

Radial velocities of 468 globular clusters around NGC 1399, the central galaxy in the Fornax cluster, have been obtained with FORS2 and the Mask Exchange Unit (MXU) at the ESO Very Large Telescope. This is the largest sample of globular cluster velocities around any galaxy obtained so far. The mean velocity uncertainty is 50 km s-1. This data sample is accurate and large enough to be used in studies of the mass distribution of NGC 1399 and the properties of its globular cluster system. Here we describe the observations and the reduction procedure, and we discuss the uncertainties of the resulting velocities. The complete sample of cluster velocities that is used in a dynamical study of NGC 1399 is tabulated. A subsample is compared with previously published values.Facultad de Ciencias Astronómicas y Geofísica

The globular cluster system of NGC 1399. II. Kinematics of a large sample of globular clusters

We study the kinematics and dynamics of the globular cluster system of NGC 1399, the brightest elliptical galaxy near the center of the Fornax cluster of galaxies. The observational data consists of medium-resolution spectra, obtained at the Very Large Telescope with FORS2 and the Mask Exchange Unit (MXU). Our sample comprises 468 radial velocities in the magnitude range 20 R -1, significantly improving on earlier samples. The radial range is 2′ -1, while they are not found at the corresponding high-velocity side above 2000 km s-1. There is the possibility that unbound clusters and/or objects in the foreground contaminate the NGC 1399 cluster sample. Under strong error selection, practically no objects are found with velocities lower than 800 km s-1 or higher than 2000 km s-1. Since the extreme velocities influence the velocity dispersion considerably, uncertainty regarding the exact value of the dispersion remains. With the above velocity limits, we derive a projected velocity dispersion for the total sample of 274 ± 9 km s-1 which within the uncertainties remains constant over the entire radial range. Without any velocity restriction, it increases to 325 km s-1. Guided by the bimodal color distribution of clusters, we distinguish between red clusters (C-R > 1.6) and blue clusters (C-R -1, respectively, again radially constant. Any possible rotation of either of these cluster populations is below the detection limit, with the exception of a weak signature of rotation for the blue clusters more distant than 6′. Spherical models point to a circular velocity of 419 ± 30 km s-1, assuming isotropy for the red clusters. This value is constant out to 40 kpc. The inferred dark halo potential can be well represented by a logarithmic potential. A halo of the NFW type also provides a good fit to the observations. The orbital structure of the clusters can only be weakly constrained. It is consistent with isotropy for the red clusters and a slight tangential bias for the blue clusters. Some mass profiles derived from X-ray analyses do not agree with a constant circular velocity within our radial range, irrespective of its exact value. Interpreting the extreme low radial velocities as space velocities of bound clusters near their pericentric distances would require an extension of the cluster system of at least 200 kpc. Implications for formation scenarios of the cluster system are briefly commented on.Facultad de Ciencias Astronómicas y Geofísica

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours