LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

Molecular characterisation of the caprine (Capra hircus) lymphocyte function-associated antigen-1 alpha subunit-encoding cDNA

BACKGROUND: Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alpha L beta 2) is required for many cellular adhesive interactions during the immune response. RESULTS: The Capra hircus CD11a-encoding cDNA was sequenced and compared with its human, murine, rat, bovine and ovine counterparts. Despite some focal differences, it shares all the main characteristics of its known mammalian homologues. CONCLUSION: Therefore, along with the caprine CD18-encoding cDNA, which has been available for a few months, the sequence data revealed here will allow the Capra hircus LFA-1 expression in vitro as a tool to explore the specificities of inflammation in the caprine species

History of discovery of the patagonian lizards

Knowledge of the history is necessary to understand why things are today as they are. Argentinean and Chilean Patagonia have a very interesting story about the native fauna and its discovery. The main character of this story is an adventurer spirit wanting to increase knowledge by traveling to the “end of the world”, ignoring barriers only to search and see what is beyond. Many well-known naturalists have visited this land eager and willing to find new species never seen before, while others have made some amazing contributions while never setting one foot on Patagonian soil. In this chapter, we intend to summarize how Patagonian herpetofauna was discovered, described and studied over time. In addition, we want to mention important scientists, whose work led the way for the future researchers to come.Fil: Williams, Jorge Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Zoología de Vertebrados. Sección Herpetología; ArgentinaFil: Kass, Camila Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Zoología de Vertebrados. Sección Herpetología; ArgentinaFil: Avila, Luciano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentin

EDGEdb: a transcription factor-DNA Interaction database for the analysis of C. elegans differential gene expression

BACKGROUND: Transcription regulatory networks are composed of protein-DNA interactions between transcription factors and their target genes. A long-term goal in genome biology is to map protein-DNA interaction networks of all regulatory regions in a genome of interest. Both transcription factor -and gene-centered methods can be used to systematically identify such interactions. We use high-throughput yeast one-hybrid assays as a gene-centered method to identify protein-DNA interactions between regulatory sequences (e.g. gene promoters) and transcription factors in the nematode Caenorhabditis elegans. We have already mapped several hundred protein-DNA interactions and analyzed the transcriptional consequences of some by examining differential gene expression of targets in the presence or absence of an upstream regulator. The rapidly increasing amount of protein-DNA interaction data at a genome scale requires a database that facilitates efficient data storage, retrieval and integration. DESCRIPTION: Here, we report the implementation of a C. elegans differential gene expression database (EDGEdb). This database enables the storage and retrieval of protein-DNA interactions and other data that relate to differential gene expression. Specifically, EDGEdb contains: i) sequence information of regulatory elements, including gene promoters, ii) sequence information of all 934 predicted transcription factors, their DNA binding domains, and, where available, their dimerization partners and consensus DNA binding sites, iii) protein-DNA interactions between regulatory elements and transcription factors, and iv) expression patterns conferred by regulatory elements, and how such patterns are affected by interacting transcription factors. CONCLUSION: EDGEdb provides a protein-DNA -and protein-protein interaction resource for C. elegans transcription factors and a framework for similar databases for other organisms. The database is available at

The wild boar (Sus scrofa) Lymphocyte function-associated antigen-1 (CD11a/CD18) receptor: cDNA sequencing, structure analysis and comparison with homologues

BACKGROUND: The most predominant beta2-integrin lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), expressed on all leukocytes, is essential for many adhesive functions of the immune system. Interestingly, RTX toxin-producing bacteria specifically target this leukocyte beta2-integrin which exacerbates lesions and disease development. RESULTS: This study reports the sequencing of the wild boar beta2-integrin CD11a and CD18 cDNAs. Predicted CD11a and CD18 subunits share all the main structural characteristics of their mammalian homologues, with a larger interspecies conservation for the CD18 than the CD11a. Besides these strong overall similarities, wild boar and domestic pig LFA-1 differ by 2 (CD18) and 1 or 3 (CD11a) substitutions, of which one is located in the crucial I-domain (CD11a, E168D). CONCLUSION: As most wild boars are seropositive to the RTX toxin-producing bacterium Actinobacillus pleuropneumoniae and because they have sustained continuous natural selection, future studies addressing the functional impact of these polymorphisms could bring interesting new information on the physiopathology of Actinobacillus pleuropneumoniae-associated pneumonia in domestic pigs

The CD11a partner in Sus scrofa lymphocyte function-associated antigen-1 (LFA-1): mRNA cloning, structure analysis and comparison with mammalian homologues

BACKGROUND: Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), the most abundant and widely expressed beta2-integrin, is required for many cellular adhesive interactions during the immune response. Many studies have shown that LFA-1 is centrally involved in the pathogenesis of several diseases caused by Repeats-in-toxin (RTX) -producing bacteria. RESULTS: The porcine-LFA-1 CD11a (alpha) subunit coding sequence was cloned, sequenced and compared with the available mammalian homologues in this study. Despite some focal differences, it shares all the main characteristics of these latter. Interestingly, as in sheep and humans, an allelic variant with a triplet insertion resulting in an additional Gln-744 was consistently identified, which suggests an allelic polymorphism that might be biologically relevant. CONCLUSION: Together with the pig CD18-encoding cDNA, which has been available for a long time, the sequence data provided here will allow the successful expression of porcine CD11a, thus giving the first opportunity to express the Sus scrofa beta2-integrin LFA-1 in vitro as a tool to examine the specificities of inflammation in the porcine species

Peptidomic Analysis of Skin Secretions of the Caribbean Frogs Leptodactylus insularum and Leptodactylus nesiotus (Leptodactylidae) Identifies an Ocellatin with Broad Spectrum Antimicrobial Activity

International audienceOcellatins are peptides produced in the skins of frogs belonging to the genus Leptodactylus that generally display weak antimicrobial activity against Gram-negative bacteria only. Peptidomic analysis of norepinephrine-stimulated skin secretions from Leptodactylus insularum Barbour 1906 and Leptodactylus nesiotus Heyer 1994, collected in the Icacos Peninsula, Trinidad, led to the purification and structural characterization of five ocellatin-related peptides from L. insularum (ocellatin-1I together with its (1-16) fragment, ocellatin-2I and its (1-16) fragment, and ocellatin-3I) and four ocellatins from L. nesiotus (ocellatin-1N,-2N,-3N, and-4N). While ocellatins-1I,-2I, and-1N showed a typically low antimicrobial potency against Gram-negative bacteria, ocellatin-3N (GIFDVLKNLAKGVITSLAS.NH 2) was active against an antibiotic-resistant strain of Klebsiella pneumoniae and reference strains of Escherichia coli, K. pneumoniae, Pseudomonas aeruginosa, and Salmonella typhimurium (minimum inhibitory concentrations (MICs) in the range 31.25-62.5 µM), and was the only peptide active against Gram-positive Staphylococcus aureus (MIC = 31.25 µM) and Enterococcus faecium (MIC = 62.5 µM). The therapeutic potential of ocellatin-3N is limited by its moderate hemolytic activity (LC 50 = 98 µM) against mouse erythrocytes. The peptide represents a template for the design of long-acting, non-toxic, and broad-spectrum antimicrobial agents for targeting multidrug-resistant pathogens

Thermodynamics, kinetics, and mechanics of cesium sorption in cement paste: A multiscale assessment

Cesium-137 is a common radioactive byproduct found in nuclear spent fuel. Given its 30 year half life, its interactions with potential storage materials—such as cement paste—is of crucial importance. In this paper, simulations are used to establish the interaction of calcium silicate hydrates (C-S-H)—the main binding phase of cement paste—with Cs at the nano- and mesoscale. Different C-S-H compositions are explored, including a range of Ca/Si ratios from 1.0 to 2.0. These calculations are based on a set of 150 atomistic models, which qualitatively and quantitatively reproduce a number of experimentally measured features of C-S-H—within limits intrinsic to the approximations imposed by classical molecular dynamics and the steps followed when building the models. A procedure where hydrated Ca[superscript 2+] ions are swapped for Cs[superscript 1+] ions shows that Cs adsorption in the C-S-H interlayer is preferred to Cs adsorption at the nanopore surface when Cs concentrations are lower than 0.19 Mol/kg. Interlayer sorption decreases as the Ca/Si ratio increases. The activation relaxation technique nouveau is used to access timescales out of the reach of traditional molecular dynamics (MD). It indicates that characteristic diffusion time for Cs[superscript 1+] in the C-S-H interlayer is on the order of a few hours. Cs uptake in the interlayer has little impact on the elastic response of C-S-H. It leads to swelling of the C-S-H grains, but mesoscale calculations that access length scales out of the range of MD indicate that this leads to practically negligible expansive pressures for Cs concentrations relevant to nuclear waste repositories

Phylogeny, biogeography and diversification patterns of side-necked turtles (Testudines: Pleurodira)

Pleurodires or side-necked turtles are today restricted to freshwater environments of South America, Africa– Madagascar and Australia, but in the past they were distributed much more broadly, being found also on Eurasia, India and North America, and marine environments. Two hypotheses were proposed to explain this distribution; in the first, vicariance would have shaped the current geographical distribution and, in the second, extinctions constrained a previously widespread distribution. Here, we aim to reconstruct pleurodiran biogeographic history and diversification patterns based on a new phylogenetic hypothesis recovered from the analysis of the largest morphological dataset yet compiled for the lineage, testing which biogeographical process prevailed during its evolutionary history. The resulting topology generally agrees with previous hypotheses of the group and shows that most diversification shifts were related to the exploration of new niches, e.g. littoral or marine radiations. In addition, as other turtles, pleurodires do not seem to have been much affected by either the Cretaceous– Palaeogene or the Eocene–Oligocene mass extinctions. The biogeographic analyses highlight the predominance of both anagenetic and cladogenetic dispersal events and support the importance of transoceanic dispersals as a more common driver of area changes than previously thought, agreeing with previous studies with other non-turtle lineages.Fil: Ferreira, Gabriel S.. Universidade de Sao Paulo; Brasil. Senckenberg Centre For Human Evolution And Palaeoenvironment; Alemania. Universität Tübingen; AlemaniaFil: Bronzati Filho, Mario. Bayerische Staatssammlung für Paläontologie und Geologie; AlemaniaFil: Langer, Max C.. Universidade de Sao Paulo; BrasilFil: Sterli, Juliana. Museo Paleontológico Egidio Feruglio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Simultaneous determination of wave speed and arrival time of reflected waves using the pressure-velocity loop

This is the post print version of the article. The official published version can be found at the link below.In a previous paper we demonstrated that the linear portion of the pressure–velocity loop (PU-loop) corresponding to early systole could be used to calculate the local wave speed. In this paper we extend this work to show that determination of the time at which the PU-loop first deviates from linearity provides a convenient way to determine the arrival time of reflected waves (Tr). We also present a new technique using the PU-loop that allows for the determination of wave speed and Tr simultaneously. We measured pressure and flow in elastic tubes of different diameters, where a strong reflection site existed at known distances away form the measurement site. We also measured pressure and flow in the ascending aorta of 11 anaesthetised dogs where a strong reflection site was produced through total arterial occlusion at four different sites. Wave speed was determined from the initial slope of the PU-loop and Tr was determined using a new algorithm that detects the sampling point at which the initial linear part of the PU-loop deviates from linearity. The results of the new technique for detecting Tr were comparable to those determined using the foot-to-foot and wave intensity analysis methods. In elastic tubes Tr detected using the new algorithm was almost identical to that detected using wave intensity analysis and foot-to-foot methods with a maximum difference of 2%. Tr detected using the PU-loop in vivo highly correlated with that detected using wave intensity analysis (r 2 = 0.83, P < 0.001). We conclude that the new technique described in this paper offers a convenient and objective method for detecting Tr, and allows for the dynamic determination of wave speed and Tr, simultaneously