Autophagy resolves early retinal inflammation in Igf1-deficient mice

Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1(-/-)), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1(-/-) mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1(-/-) mice compared to those in age-matched Igf1(+/+) controls. In 6-month-old Igf1(-/-) retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1(-/-) mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1(+/+) controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1(+/+) and Igf1(-/-) mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1(-/-) mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1(-/-) mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during agein

Mujeres en Bioquímica

We are pleased to present in the magazine "Encounters in Biology" the series of profiles published online in the «Portrait Gallery of Women in Biochemistry» on the SEBBM website, which began in 2011, with the centenary of the Nobel Prize awarded to Marie Curie, International Year of Chemistry. During the celebration of the 22nd IUBMB - 37th FEBS Congress and XXXV Congress of the SEBBM that took place in Seville from September 4 to 9, 2012, a traveling exhibition was inaugurated with this information in panel format.Tenemos el placer de presentar en la revista "Encuentros en la Biología" la serie de perfiles publicados on-li- ne en la «Galería de retratos de Mujeres en Bioquímica» de la web de la SEBBM, que comenzó en 2011, con el centenario del premio Nobel otorgado a Marie Curie, Año Internacional de la Química. Durante la celebra- ción del 22nd IUBMB - 37th FEBS Congress y XXXV Congreso de la SEBBM que tuvo lugar en Sevilla del 4 al 9 de septiembre de 2012 se inauguró una exposición itinerante con esta información en formato de paneles

Positron emission tomography of the airway distribution of intranasal challenge solutions

Abstract of: Scientific Sessions: 2007 AAAAI Annual Meeting, February 23-27, San Diego, CAIntranasal administration is one of the main routes of allergen challenge in mouse models of airway disease. Although it is widely used, it is not well established the amount of allergen that reaches the lung or is lost to the gastrointestinal tract. The local distribution of the challenge solution within the airways is also unknown. The aim of this study was to assess the distribution immediately after intranasal delivery using a Positron Emission Tomography scanner (PET)FIS 01/0598 and Foundation SEAICPublicad

Programmed cell senescence during mammalian embryonic development

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-beta/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence

Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated with plasma hyperhomocysteinemia

Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT

The Fundamental Plane of Early Type Galaxies in Nearby Clusters from the WINGS Database

By exploting the data of three large surveys (WINGS, NFPS and SDSS), we present here a comparative analysis of the Fundamental Plane (FP hereafter) of the early-type galaxies (ETGs) belonging to 59 galaxy clusters in the redshift range $0.04<z<0.07$. We show that the variances of the distributions of the FP coefficients derived for the clusters in our sample are not consistent with the hypothesis of universality of the FP relation. By investigating the origin of such remarkable variances we find that, besides a couple of obvious factors, such as the adopted fitting technique and the method used to measure the photometric and kinematic variables, the coefficients of the FP are strongly influenced by a number of things, mainly related to the distribution of photometric/kinematic properties of galaxies in the particular sample under analysis. For instance, the $a$ coefficient derived for the whole sample of ETGs, turns out to decrease when faint galaxies are progressively removed from the sample, suggesting that bright and faint ETGs have systematically different FPs, likely because of different mechanisms of galaxy formation. In general, by comparing mock cluster samples with the real one, we conclude that the observed variances of the FP coefficients cannot be attributed just to statistical uncertainties. We speculate that the FP is actually a bent surface, which is approximated by different planes when different selection criteria, either chosen or induced by observations, are acting to define galaxies samples. We also find ...Comment: 51 pages, 18 figures, ApJ submitte

Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA)

Introduction Mild cognitive impairment (MCI) is a term used to describe a level of decline in cognition which is seen as an intermediate stage between normal ageing and dementia, and which many consider to be a prodromal stage of neurodegeneration that may become dementia. That is, it is perceived as a high risk level of cognitive change. The increasing burden of dementia in our society, but also our increasing understanding of its risk factors and potential interventions, require diligent management of MCI in order to find strategies that produce effective prevention of dementia. Aim To update knowledge regarding mild cognitive impairment, and to bring together and appraise evidence about the main features of clinical interest: definitions, prevalence and stability, risk factors, screening, and management and intervention. Methods Literature review and consensus of expert opinion. Results and conclusion MCI describes a level of impairment in which deteriorating cognitive functions still allow for reasonable independent living, including some compensatory strategies. While there is evidence for some early risk factors, there is still a need to more precisely delineate and distinguish early manifestations of frank dementia from cognitive impairment that is less likely to progress to dementia, and furthermore to develop improved prospective evidence for positive response to intervention. An important limitation derives from the scarcity of studies that take MCI as an endpoint. Strategies for effective management suffer from the same limitation, since most studies have focused on dementia. Behavioural changes may represent the most cost-effective approach

AKT Signaling Mediates IGF-I Survival Actions on Otic Neural Progenitors

Background: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I), through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K). Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. Methodology/Principal Findings: By using a combination of organotypic cultures of chicken (Gallus gallus) otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1) transcription factor. By contrast, our results indicate that post-mitotic p27Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. Conclusions/Significance: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development

Geochemical vs. microbial approach to the new production of the coastal upwelling system of the Ría de Vigo (NW Spain)

Symposium GLOBEC–IMBER España, Valencia, 28-30 marzo 2007The fate of the inorganic and organic N trapped in the coastal upwelling system of Ría de Vigo (NW Spain), accumulation/export versus production/ consumption, was studied at the short time–scale (2–4 d) during July 2002. A transient geochemical box model was applied to the measured residual currents and concentrations of inorganic (NT), dissolved (DON) and particulate (PON) organic N to obtain the i) net balance of inputs minus outputs (i – o); ii) the net accumulation (V·dN/dt); and iii) the net ecosystem production (NEP) of NT, DON and PON. The average NEP during July (107 mg N m-2 d-1) indicates an autotrophic metabolism of the ría. About 25% of this material was exported to the shelf and the remaining 75% was transferred to the sediments or promoted to higher trophic levels. Measurements of oxygen production (Pg) and respiration (R) were performed in a single site twice a week at five depths. In addition, microzooplankton grazing and sedimentation rates were measured for first time in the Ría de Vigo. The high grazing rates observed reduces the efficiency of the ría to transfer organic matter directly from phytoplankton to the metazoans Comparison of the metabolic state of the Ría de Vigo derived from these in vitro measurements (Pg, R, grazing and sedimentation) and the in situ geochemical budget shows that they agree in 2 of the 3 study cases. Both methods are complementary and their simultaneous application allows obtaining a better knowledge of coastal upwelling ecosystems functioningN