232 research outputs found

    Monitoring phagocytic uptake of amyloid beta into glial cell lysosomes in real time

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    Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ_{1-42} analogue (Aβ^{pH}) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of Aβ^{pH} in real time in live animals. We find that microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. Aβ^{pH} can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD

    Monopolin subunit Csm1 associates with MIND complex to establish monopolar attachment of sister kinetochores at meiosis I

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    Sexually reproducing organisms halve their cellular ploidy during gametogenesis by undergoing a specialized form of cell division known as meiosis. During meiosis, a single round of DNA replication is followed by two rounds of nuclear divisions (referred to as meiosis I and II). While sister kinetochores bind to microtubules emanating from opposite spindle poles during mitosis, they bind to microtubules originating from the same spindle pole during meiosis I. This phenomenon is referred to as mono-orientation and is essential for setting up the reductional mode of chromosome segregation during meiosis I. In budding yeast, mono-orientation depends on a four component protein complex referred to as monopolin which consists of two nucleolar proteins Csm1 and Lrs4, meiosis-specific protein Mam1 of unknown function and casein kinase Hrr25. Monopolin complex binds to kinetochores during meiosis I and prevents bipolar attachments. Although monopolin associates with kinetochores during meiosis I, its binding site(s) on the kinetochore is not known and its mechanism of action has not been established. By carrying out an imaging-based screen we have found that the MIND complex, a component of the central kinetochore, is required for monopolin association with kinetochores during meiosis. Furthermore, we demonstrate that interaction of monopolin subunit Csm1 with the N-terminal domain of MIND complex subunit Dsn1, is essential for both the association of monopolin with kinetochores and for monopolar attachment of sister kinetochores during meiosis I. As such this provides the first functional evidence for a monopolin-binding site at the kinetochore

    Scalability approaches for causal multicast: a survey

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    The final publication is available at Springer via http://dx.doi.org/10.1007/s00607-015-0479-0Many distributed services need to be scalable: internet search, electronic commerce, e-government... In order to achieve scalability, high availability and fault tolerance, such applications rely on replicated components. Because of the dynamics of growth and volatility of customer markets, applications need to be hosted by adaptive, highly scalable systems. In particular, the scalability of the reliable multicast mechanisms used for supporting the consistency of replicas is of crucial importance. Reliable multicast might propagate updates in a pre-determined order (e.g., FIFO, total or causal). Since total order needs more communication rounds than causal order, the latter appears to be the preferable candidate for achieving multicast scalability, although the consistency guarantees based on causal order are weaker than those of total order. This paper provides a historical survey of different scalability approaches for reliable causal multicast protocols.This work was supported by European Regional Development Fund (FEDER) and Ministerio de Economia y Competitividad (MINECO) under research Grant TIN2012-37719-C03-01.Juan Marín, RD.; Decker, H.; Armendáriz Íñigo, JE.; Bernabeu Aubán, JM.; Muñoz Escoí, FD. (2016). Scalability approaches for causal multicast: a survey. Computing. 98(9):923-947. https://doi.org/10.1007/s00607-015-0479-0S923947989Adly N, Nagi M (1995) Maintaining causal order in large scale distributed systems using a logical hierarchy. In: IASTED Intnl Conf on Appl Inform, pp 214–219Aguilera MK, Chen W, Toueg S (1997) Heartbeat: a timeout-free failure detector for quiescent reliable communication. In: 11th Intnl Wshop on Distrib Alg (WDAG), Saarbrücken, pp 126–140Almeida JB, Almeida PS, Baquero C (2004) Bounded version vectors. 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    Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

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    During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

    Neutrino emission from dense matter, and neutron star thermal evolution

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    A brief review is given of neutrino emission processes in dense matter, with particular emphasis on recent developments. These include direct Urca processes for nucleons and hyperons, which can give rise to rapid energy loss from the stellar core without exotic matter, and the effect of band structure on neutrino bremsstrahlung from electrons in the crust, which results in much lower energy losses by this process than had previously been estimated

    Prediction of Liver-Related Events Using Fibroscan in Chronic Hepatitis B Patients Showing Advanced Liver Fibrosis

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    Liver stiffness measurement (LSM) using transient elastography (FibroScan®) can assess liver fibrosis noninvasively. This study investigated whether LSM can predict the development of liver-related events (LREs) in chronic hepatitis B (CHB) patients showing histologically advanced liver fibrosis.Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB) before starting nucleot(s)ide analogues and showed histologically advanced fibrosis (≥F3) with a high viral loads [HBV DNA ≥2,000 IU/mL] were enrolled. All patients were followed regularly to detect LRE development, including hepatic decompensation (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome) and hepatocellular carcinoma (HCC).The mean age of the patient (72 men, 56 women) was 52.2 years. During the median follow-up period [median 27.8 (12.6-61.6) months], LREs developed in 19 (14.8%) patients (five with hepatic decompensation, 13 with HCC, one with both). Together with age, multivariate analysis identified LSM as an independent predictor of LRE development [P<0.044; hazard ratio (HR), 1.038; 95% confidence interval (CI), 1.002-1.081]. When the study population was stratified into two groups using the optimal cutoff value (19 kPa), which maximized the sum of sensitivity (61.1%) and specificity (86.2%) from a time-dependent receiver operating characteristic curve, patients with LSM>19 kPa were at significantly greater risk than those with LSM≤19 kPa for LRE development (HR, 7.176; 95% CI, 2.257-22.812; P = 0.001).LSM can be a useful predictor of LRE development in CHB patients showing histologically advanced liver fibrosis

    Physics of Neutron Star Crusts

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    The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10

    Genetic analysis of scattered populations of the Indian eri silkworm, Samia cynthia ricini Donovan: Differentiation of subpopulations

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    Deforestation and exploitation has led to the fragmentation of habitats and scattering of populations of the economically important eri silkworm, Samia cynthia ricini, in north-east India. Genetic analysis of 15 eri populations, using ISSR markers, showed 98% inter-population, and 23% to 58% intra-population polymorphism. Nei’s genetic distance between populations increased significantly with altitude (R2 = 0.71) and geographic distance (R2 = 0.78). On the dendrogram, the lower and upper Assam populations were clustered separately, with intermediate grouping of those from Barpathar and Chuchuyimlang, consistent with geographical distribution. The Nei’s gene diversity index was 0.350 in total populations and 0.121 in subpopulations. The genetic differentiation estimate (Gst) was 0.276 among scattered populations. Neutrality tests showed deviation of 118 loci from Hardy-Weinberg equilibrium. The number of loci that deviated from neutrality increased with altitude (R2 = 0.63). Test of linkage disequilibrium showed greater contribution of variance among eri subpopulations to total variance. D’2IS exceeded D’2ST, showed significant contribution of random genetic drift to the increase in variance of disequilibrium in subpopulations. In the Lakhimpur population, the peripheral part was separated from the core by a genetic distance of 0.260. Patchy habitats promoted low genetic variability, high linkage disequilibrium and colonization by new subpopulations. Increased gene flow and habitat-area expansion are required to maintain higher genetic variability and conservation of the original S. c. ricini gene pool

    MRI of Arterial Flow Reserve in Patients with Intermittent Claudication: Feasibility and Initial Experience

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    Objectives: The aim of this work was to develop a MRI method to determine arterial flow reserve in patients with intermittent claudication and to investigate whether this method can discriminate between patients and healthy control subjects. Methods: Ten consecutive patients with intermittent claudication and 10 healthy control subjects were included. All subjects underwent vector cardiography triggered quantitative 2D cine MR phase-contrast imaging to obtain flow waveforms of the popliteal artery at rest and during reactive hyperemia. Resting flow, maximum hyperemic flow and absolute flow reserve were determined and compared between the two groups by two independent MRI readers. Also, interreader reproducibility of flow measures was reported. Results: Resting flow was lower in patients compared to controls (4.961.6 and 11.163.2 mL/s in patients and controls, respectively (p,0.01)). Maximum hyperemic flow was 7.362.9 and 16.463.2 mL/s (p,0.01) and the absolute flow reserve was 2.461.6 and 5.361.3 mL/s (p,0.01), respectively in patients and controls. The interreader coefficient of variation was below 10 % for all measures in both patients and controls. Conclusions: Quantitative 2D MR cine phase-contrast imaging is a promising method to determine flow reserve measures in patients with peripheral arterial disease and can be helpful to discriminate patients with intermittent claudication fro
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