Fibroblast growth factors:new insights, new targets in the management of diabetes

The fibroblast growth factor (FGF) family consists of 22 evolutionarily and structurally related proteins (FGF1 to FGF23; with FGF15 being the rodent ortholog of human FGF19). Based on their mechanism of action, FGFs can be categorized into intracrine, autocrine/paracrine and endocrine subgroups. Both autocrine/paracrine and endocrine FGFs are secreted from their cells of origin and exert their effects on target cells by binding to and activating specific single-pass transmembrane tyrosine kinase receptors (FGFRs). Moreover, FGF binding to FGFRs requires specific cofactors, namely heparin/heparan sulfate proteoglycans or Klothos for autocrine/paracrine and endocrine FGF signaling, respectively. FGFs are vital for embryonic development and mediate a broad spectrum of biological functions, ranging from cellular excitability to angiogenesis and tissue regeneration. Over the past decade certain FGFs (e.g. FGF1, FGF10, FGF15/FGF19 and FGF21) have been further recognized as regulators of energy homeostasis, metabolism and adipogenesis, constituting novel therapeutic targets for obesity and obesity-related cardiometabolic disease. Until recently, translational research has been mainly focused on FGF21, due to the pleiotropic, beneficial metabolic actions and the relatively benign safety profile of its engineered variants. However, increasing evidence regarding the role of additional FGFs in the regulation of metabolic homeostasis and recent developments regarding novel, engineered FGF variants have revitalized the research interest into the therapeutic potential of certain additional FGFs (e.g. FGF1 and FGF15/FGF19). This review presents a brief overview of the FGF family, describing the mode of action of the different FGFs subgroups, and focuses on FGF1 and FGF15/FGF19, which appear to also represent promising new targets for the treatment of obesity and type 2 diabetes.

Deficit of quantal release of GABA in experimental models of temporal lobe epilepsy

Because GABA (gamma-aminobutyric acid) receptor-mediated inhibition controls the excitability of principal neurons in the brain, deficits in GABAergic inhibition have long been favored to explain seizures. In an experimental model of temporal lobe epilepsy, we have identified a deficit of inhibition in presynaptic GABAergic terminals characterized by decreased GABA quantal activity associated with reduced synaptic vesicle density. This decrease in vesicle number primarily seems to affect the reserve pool, rather than the docked or the readily releasable pool.

Bilateral force deficit in patients with haemophilic arthropathy of lower limbs: cross-sectional study

SIN FINANCIACIÓN

Microglia as therapeutic targets in retinal degeneration: role of translocator protein (18 κDa) (TSPO) and minocycline.

Microglia are the resident immune cells of the central nervous system (CNS) and play an important role in innate immune defense as well as tissue homeostasis. Chronic microglial reactivity, microgliosis, is a general hallmark of inflammatory and degenerative diseases that affect the CNS, including the retina. There is increasing evidence that chronic microgliosis is more than just a bystander effect, but rather actively contributes to progression of degeneration through processes such as toxic nitric oxide (NO) production and even phagocytosis of stressed but viable photoreceptors. Therefore immunmodulation of microglia presents a possible therapeutic strategy for retinal degenerations. Notably, the expression of the mitochondrial translocator protein 18 (κDa) (TSPO) is highly elevated in reactive microglia as seen in several neuroinflammatory diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Therefore it is used as a gliosis biomarker in the brain. Moreover TSPO ligands show potent effects in resolving neuroinflammatory brain disorders. However, TSPO expression in the eye had not been investigated before. Further, it was unknown whether TSPO ligands’ potent immunomodulatory effects could be used to treat retinal degenerations. To fill this gap, the study aimed to analyze whether TSPO is also a potential biomarker for degenerative processes in the retina. Moreover the thesis attempted to determine whether a specific TSPO ligand, XBD173, might modulate microglial reactivity and is a potent therapeutic, to treat retinal degenerative diseases. The findings revealed that TSPO is strongly upregulated in microglial cells of retinoschisin-deficient (RS1-/y) mice, a model of inherited retinal degeneration and in a murine light damage model. A co-localization of TSPO and microglia was furthermore detectable in human retinal sections, indicating a potential role for TSPO as a biomarker for retinal degenerations. In vitro assays showed that the TSPO ligand XBD173 effectively inhibited features of microglial activation such as morphological transformation into reactive phagocytes and enhanced expression of pro-inflammatory cytokines. XBD173 also reduced microglial migration and proliferation and reduced their neurotoxic potential on photoreceptor cells. In two independent mouse models of light-induced retinal degeneration, the treatment with XBD173 reduced accumulation of amoeboid, reactive microglia in the outer retina and attenuated degenerative processes, indicated by a nearly preserved photoreceptor layer. A further question addressed in this thesis was whether minocycline, an antibiotic with additional anti-inflammatory properties is able to reduce microglial neurotoxicity and to protect the retina from degeneration. Minocycline administration dampened microglial pro-inflammatory gene expression, NO production and neurotoxicity on photoreceptors. Interestingly, in addition to its immunomodulatory effect, minocycline also increased the viability of photoreceptors in a direct manner. In the light damage model, minocycline administration counter-acted microglial activation and blocked retinal degeneration. Taken together these results identified TSPO as a biomarker for microglial reactivity and as therapeutic target in the retina. Targeting TSPO with XBD173 was able to reverse microglial reactivity and could prevent degenerative processes in the retina. In addition, the study showed that the antibiotic minocycline effectively counter-regulates microgliosis and light-induced retinal degeneration. Considering that microgliosis is a major contributing factor for retinal degenerative disorders, this thesis supports the concept of a microglia-directed therapy to treat retinal degeneration.

Toward adaptive management of coastal MPAs: The influence of different conservation targets and costs on the design of no-take areas

There is still much discussion on the most appropriate location, size and shape of marine protected areas (MPAs). These three factors were analyzed for a small coastal MPA, the Luiz Saldanha Marine Park (LSMP), for which a very limited amount of local ecological information was available when implemented in 1998. Marxan was used to provide a number of near-optimal solutions considering different levels of protection for the various conservation features and different costs. These solutions were compared with the existing no-take area of the LSMP. Information on 11 habitat types and distribution models for 3 of the most important species for the local artisanal fisheries was considered. The human activities with the highest economic and ecological impact in the study area (commercial and recreational fishing and scuba diving) were used as costs. The results show that the existing no-take area is actually located in the best area. However, the no-take area offers limited protection to vagile fish and covers a very small proportion of some of the available habitats. An increase in the conservation targets led to an increase in the number of no-take areas. The comparative framework used in this study can be applied elsewhere, providing relevant information to local stakeholders and managers in order to proceed with adaptive management. (C) 2015 Elsevier B.V. All rights reserved.

Variability in the international normalised ratio (INR) in patients with antiphospholipid syndrome and positive lupus anticoagulant: should the INR targets be higher?

El síndrome antifosfolípido es un desorden autoinmune caracterizado por hipercoagulabilidad que requiere terapia anticoagulante como pilar fundamental, siendo la warfarina el tratamiento de elección en los casos que requieren manejo por largos periodos. Sin embargo, los pacientes con anticoagulante lúpico positivo representan un reto porque tienen mayor riesgo de presentar eventos trombóticos, sumado a que el seguimiento con el International Normalized Ratio (INR) no es confiable, ya que estos anticuerpos generan interferencia con las pruebas de laboratorio basadas en fosfolípidos, como es el caso del tiempo de protrombina (PT) con INR basal prolongado, incluso antes del inicio de la terapia anticoagulante. Por tal razón, se ilustra el caso de una paciente con síndrome antifosfolípido primario y anticoagulante lúpico positivo quien ha presentado múltiples episodios trombóticos, a pesar de recibir terapia anticoagulante. Además se hace una revisión de la literatura disponible y se postulan nuevas metas de INR en estos pacientes diferentes de las que se plantean actualmente.

Estado de las enfermedades raras que cursan con discapacidad intelectual en Colombia

Las enfermedades raras o huérfano son una problemática que ha tomado mucha importancia en el contexto mundial del presente siglo, estas se han definido como crónicas, de difícil tratamiento de sus síntomas y con baja prevalencia en la población; muchas de estas enfermedades cursan con varios tipos de discapacidad, siendo el objetivo del presente trabajo el enfocarse en aquellas enfermedades raras que cursan con discapacidad intelectual. Para poder profundizar en estas enfermedades se realizó una revisión teórica sobre las enfermedades raras, así como de la discapacidad psíquica y su importancia a nivel mundial y nacional. A partir de estas definiciones, se revisaron en profundidad 3 enfermedades raras que cursan con discapacidad intelectual en el contexto colombiano, como son: el síndrome de Rett, el síndrome de Prader-Willi y el síndrome de X frágil. En cada una de estas enfermedades además se explicaron los tipos de diagnóstico, intervención, prevención, grupos de apoyo y tipos de evaluación que más se usan en el contexto nacional

Self-care in older people with functional deficit: needs of long-term care.

The group of 65-year-olds is becoming more numerous and with greater needs for health care. So, is necessary the reflection about new models of provision, organization, and allocation of health resources. According to the United Nations Organization, 2015, in 2050 elderly people will reach two million people (20% of the world’s population), what mean that the number of people over 60 years old will exceed a population of young people under 15 years. Parallel to aging, less healthy lifestyles have contributed to the prevalence of chronic diseases, especially cerebrovascular diseases. Hypertension and diabetes mellitus are risk factors and increase predisposition to other diseases. With aging, there is an increased risk for developing chronic, oncological and degenerative diseases, which account for more than 50% of the burden of diseases, with profound implications on independency, use of health care and services.

Different levels of water deficit induces changes in growth pattern but not in chlorophyll fluorescence and water relations of Hancornia speciosa Gomes seedlings.

Hancornia speciosa Gomes é uma espécie conhecida popularmente no Brasil como mangabeira, cujo fruto apresenta alto valor nutricional. O conhecimento sobre a sua fisiologia é ainda escasso, principalmente no que se refere ao desenvolvimento inicial. Dessa forma, o objetivo do presente trabalho foi avaliar os efeitos de diferentes níveis de déficit hídrico sobre o padrão de crescimento, fluorescência de clorofila e relações hídricas em mudas de mangabeira. Foi utilizado um esquema fatorial (tratamentos x época de avaliação) com quatro tratamentos hídricos com base na capacidade de campo (CC) (80%, 60%, 40% e 20%), com cinco repetições. Foram avaliados a altura das plantas, número de folhas, diâmetro do caule, produção e partição de biomassa, eficiência quântica do fotossistema II (PSII), potencial hídrico (?w), teor relativo de água (TRA) e teor de carboidratos, proteínas e prolina. O déficit hídrico severo (20% CC) levou a uma redução no crescimento e alterou o padrão de partição de biomassa nas mudas. No entanto, as relações hídricas não foram significativamente afetadas, pois as mudas mantiveram altos valores de ?w e TRA, sem acúmulos significativos nos teores de solutos orgânicos quando cultivadas com 20%CC. Além do mais, a eficiência quântica do PSII não foi afetada pelos diferentes regimes hídricos, sugerindo que não houve fotoinibição devido ao estresse hídrico. A mudança no padrão de crescimento, com um incremento no aprofundamento das raízes e redução no crescimento da parte aérea parece ser a principal estratégia das mudas de H. speciosa para a manutenção da hidratação dos tecidos durante períodos de déficit hídrico.

Estimation of climatological water deficit in an experimental watershed in the brazilian cerrado.

ABSTRACT: This study aimed to estimate the probability of climatological water deficit in an experimental watershed in the Cerrado biome, located in the central plateau of Brazil. For that, it was used a time series of 31 years (1982?2012). The probable climatological water deficit was calculated by the difference between rainfall and probable reference evapotranspiration, on a decennial scale. The reference evapotranspiration (ET0) was estimated by the standard FAO-56 Penman-Monteith method. To estimate water deficit, it was used gamma distribution, time series of rainfall and reference evapotranspiration. The adherence of the estimated probabilities to the observed data was verified by the Kolmogorov-Smirnov nonparametric test, with significance level (a-0.05), which presented a good adjustment to the distribution models. It was observed a climatological water deficit, in greater or lesser intensity, between the annual decennials 2 and 32.

Identificação e avaliação da expressão de genes pertencentes a família CCCH zinc finger em duas cultivares de soja sob deficit hídrico.

2016

Respostas ecofisiológicas de acessos de mandioca (Manihot esculenta Crantz) sob deficit hídrico.

A mandioca é um alimentar tipicamente brasileiro, cultivada em várias regiões do País. Apesar de ser considerada uma planta tolerante ao deficit hídrico, sua produtividade é baixa sob certas condições edáficas e pluviométricas do Semiárido nordestino, onde é amplamente consumida na alimentação humana e animal. O objetivo deste estudo foi avaliar o crescimento inicial e a capacidade fotossintética sob déficit hídrico de dez acessos de Manihot esculenta do Banco Ativo de Germoplasma de Mandioca da Embrapa, para a identificação de materiais mais tolerantes à seca. O delineamento experimental foi realizado em blocos ao acaso, com quatro blocos por tratamento em esquema fatorial 2 (disponibilidade hídrica) x 10 (acessos), com espaçamento 0,9 m entrelinhas e 0,85 m entre plantas. O crescimento em altura foi avaliado aos 60 dias do plantio. O deficit hídrico foi induzido aos 120 dias do plantio com a suspensão da irrigação. A taxa fotossintética foi monitorada entre 90 e 111 dias após o início do deficit hídrico. Os genótipos GCP 01, 9624-09, 89, 279, Dourada, 785, 815, e cacau mostraram-se como os mais tolerantes à seca com base na menor diminuição da taxa fotossintética aos 90 dias de suspensão da irrigação, sendo os dois primeiros mais tolerantes que os acessos 163 e Formosa.

Contrasting environment targets characteristics: development of the drought phenotyping network.

Introduction. Specific sites selecting criteria. Soil characteristics for establishment of a specific site. Main steps and recommendations for a specific site selection and placement. Climatic characterization.

Searching for novel targets to control wheat Head Blight Disease-I-Protein identification, 3D modeling and virtual screening.

2016

Studies on the Hippo Pathway: new insights about a multifaceted signalling

The Hippo pathway is a well-known master regulator of cell growth and proliferation. Many studies have shed light on the centrality of Hippo functions, as this signalling is able to respond to different stimuli and translate them into distinct transcriptional outputs. Therefore, it is clearly implicated in a number of important processes, which alteration has consequences on the correct specification of the single cell, as well as the whole tissue. Even if the core of the signalling has been extensively characterized, it remains unclear which are the “co-workers” that permit the Hippo pathway to answer to so many different stimuli and act as a coordinator of the growth/differentiation balance. Taking advantage of the Drosophila model, which has witnessed most of the discoveries on this signalling pathway, this thesis aims to add some new knowledge about the Hippo pathway molecular mechanisms in different contexts, from development to disease. In the first part I studied the dynamics of the Hippo core kinase protein Warts in the development of the pupal eye. I have found out a critical time point in which the expression and the localization of Warts change suddenly, suggesting the intervention of upstream regulators modulating its activity in an extremely narrow time window. The second goal was investigating the role of the Hippo pathway in the neurodegenerative Gaucher disease. Indeed, I have produced some preliminary results which demonstrate a growth deficit associated with a massive reduction of some Yki targets, supporting a Hyper-Hippo condition underlying this neuropathic syndrome. Finally, I have evaluated the transcription factor Orthodenticle as a co-factor of Yorkie in driving tissue overgrowth, and my findings support a model of interaction of these two molecules based on Yki conformational changes. Altogether, my results lay the foundation for new important studies on the molecular mechanisms ruling Hippo pathway activity.