The novel MAPT mutation K298E:mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem

Comparing Beerkan infiltration tests with rainfall simulation experiments for hydraulic characterization of a sandy-loam soil

[EN] Saturated soil hydraulic conductivity, K-s, data collected by ponding infiltrometer methods and usual experimental procedures could be unusable for interpreting field hydrological processes and particularly rainfall infiltration. The K-s values determined by an infiltrometer experiment carried out by applying water at a relatively large distance from the soil surface could however be more appropriate to explain surface runoff generation phenomena during intense rainfall events. In this study, a link between rainfall simulation and ponding infiltrometer experiments was established for a sandy-loam soil. The height of water pouring for the infiltrometer run was chosen, establishing a similarity between the gravitational potential energy of the applied water, E-p, and the rainfall kinetic energy, E-k. To test the soundness of this procedure, the soil was sampled with the Beerkan estimation of soil transfer parameters procedure of soil hydraulic characterization and two heights of water pouring (0.03m, i.e., usual procedure, and 0.34m, yielding E-p=E-k). Then, a comparison between experimental steady-state infiltration rates, i(sR), measured with rainfall simulation experiments determining runoff production and K-s values for the two water pouring heights was carried out in order to discriminate between theoretically possible (i(sR)K(s)) and impossible (i(sR)3.0.co;2-vCerdà, A. (1999). Seasonal and spatial variations in infiltration rates in badland surfaces under Mediterranean climatic conditions. Water Resources Research, 35(1), 319-328. doi:10.1029/98wr01659Cerdà, A. (2000). Aggregate stability against water forces under different climates on agriculture land and scrubland in southern Bolivia. Soil and Tillage Research, 57(3), 159-166. doi:10.1016/s0167-1987(00)00155-0Cerdà, A. (2001). Effects of rock fragment cover on soil infiltration, interrill runoff and erosion. European Journal of Soil Science, 52(1), 59-68. doi:10.1046/j.1365-2389.2001.00354.xCerdà, A., & Doerr, S. H. (2007). Soil wettability, runoff and erodibility of major dry-Mediterranean land use types on calcareous soils. Hydrological Processes, 21(17), 2325-2336. doi:10.1002/hyp.6755Cerdà, A., Ibáñez, S., & Calvo, A. (1997). Design and operation of a small and portable rainfall simulator for rugged terrain. Soil Technology, 11(2), 163-170. doi:10.1016/s0933-3630(96)00135-3Di Prima, S. (2015). Automated single ring infiltrometer with a low-cost microcontroller circuit. Computers and Electronics in Agriculture, 118, 390-395. doi:10.1016/j.compag.2015.09.022Di Prima, S., Lassabatere, L., Bagarello, V., Iovino, M., & Angulo-Jaramillo, R. (2016). Testing a new automated single ring infiltrometer for Beerkan infiltration experiments. Geoderma, 262, 20-34. doi:10.1016/j.geoderma.2015.08.006Diodato, N., Verstraeten, G., & Bellocchi, G. (2012). DECADAL MODELLING OF RAINFALL EROSIVITY IN BELGIUM. Land Degradation & Development, 25(6), 511-519. doi:10.1002/ldr.2168Gee GW Bauder JW 1986 Particle-size analysis SSSA Book Series 383 411Haverkamp, R., Ross, P. J., Smettem, K. R. J., & Parlange, J. Y. (1994). Three-dimensional analysis of infiltration from the disc infiltrometer: 2. Physically based infiltration equation. Water Resources Research, 30(11), 2931-2935. doi:10.1029/94wr01788Iovino, M., Castellini, M., Bagarello, V., & Giordano, G. (2013). Using Static and Dynamic Indicators to Evaluate Soil Physical Quality in a Sicilian Area. Land Degradation & Development, 27(2), 200-210. doi:10.1002/ldr.2263Iserloh, T., Ries, J. B., Arnáez, J., Boix-Fayos, C., Butzen, V., Cerdà, A., … Wirtz, S. (2013). European small portable rainfall simulators: A comparison of rainfall characteristics. CATENA, 110, 100-112. doi:10.1016/j.catena.2013.05.013Iserloh, T., Ries, J. B., Cerdà, A., Echeverría, M. T., Fister, W., Geißler, C., … Seeger, M. (2013). Comparative measurements with seven rainfall simulators on uniform bare fallow land. Zeitschrift für Geomorphologie, Supplementary Issues, 57(1), 11-26. doi:10.1127/0372-8854/2012/s-00085Keesstra, S., Pereira, P., Novara, A., Brevik, E. C., Azorin-Molina, C., Parras-Alcántara, L., … Cerdà, A. (2016). Effects of soil management techniques on soil water erosion in apricot orchards. Science of The Total Environment, 551-552, 357-366. doi:10.1016/j.scitotenv.2016.01.182B. A. King, & D. L. Bjorneberg. (2012). Transient Soil Surface Sealing and Infiltration Model for Bare Soil under Droplet Impact. Transactions of the ASABE, 55(3), 937-945. doi:10.13031/2013.41525Lado, M., Paz, A., & Ben-Hur, M. (2004). Organic Matter and Aggregate-Size Interactions in Saturated Hydraulic Conductivity. Soil Science Society of America Journal, 68(1), 234-242. doi:10.2136/sssaj2004.2340Lassabatere, L., Angulo-Jaramillo, R., Goutaland, D., Letellier, L., Gaudet, J. P., Winiarski, T., & Delolme, C. (2010). Effect of the settlement of sediments on water infiltration in two urban infiltration basins. Geoderma, 156(3-4), 316-325. doi:10.1016/j.geoderma.2010.02.031Lassabatère, L., Angulo-Jaramillo, R., Soria Ugalde, J. M., Cuenca, R., Braud, I., & Haverkamp, R. (2006). Beerkan Estimation of Soil Transfer Parameters through Infiltration Experiments-BEST. Soil Science Society of America Journal, 70(2), 521-532. doi:10.2136/sssaj2005.0026Lassabatere, L., Angulo-Jaramillo, R., Soria-Ugalde, J. M., Šimůnek, J., & Haverkamp, R. (2009). Numerical evaluation of a set of analytical infiltration equations. Water Resources Research, 45(12). doi:10.1029/2009wr007941Lassabatere, L., Yilmaz, D., Peyrard, X., Peyneau, P. E., Lenoir, T., Šimůnek, J., & Angulo-Jaramillo, R. (2014). New Analytical Model for Cumulative Infiltration into Dual-Permeability Soils. Vadose Zone Journal, 13(12), vzj2013.10.0181. doi:10.2136/vzj2013.10.0181Lassu, T., Seeger, M., Peters, P., & Keesstra, S. D. (2015). The Wageningen Rainfall Simulator: Set-up and Calibration of an Indoor Nozzle-Type Rainfall Simulator for Soil Erosion Studies. Land Degradation & Development, 26(6), 604-612. doi:10.1002/ldr.2360BISSONNAIS, Y. (1996). Aggregate stability and assessment of soil crustability and erodibility: I. Theory and methodology. European Journal of Soil Science, 47(4), 425-437. doi:10.1111/j.1365-2389.1996.tb01843.xLi, X.-Y., González, A., & Solé-Benet, A. (2005). Laboratory methods for the estimation of infiltration rate of soil crusts in the Tabernas Desert badlands. CATENA, 60(3), 255-266. doi:10.1016/j.catena.2004.12.004Lilliefors, H. W. (1967). On the Kolmogorov-Smirnov Test for Normality with Mean and Variance Unknown. Journal of the American Statistical Association, 62(318), 399-402. doi:10.1080/01621459.1967.10482916Liu, H., Lei, T. W., Zhao, J., Yuan, C. P., Fan, Y. T., & Qu, L. Q. (2011). Effects of rainfall intensity and antecedent soil water content on soil infiltrability under rainfall conditions using the run off-on-out method. Journal of Hydrology, 396(1-2), 24-32. doi:10.1016/j.jhydrol.2010.10.028Mualem, Y., Assouline, S., & Rohdenburg, H. (1990). Rainfall induced soil seal (A) A critical review of observations and models. CATENA, 17(2), 185-203. doi:10.1016/0341-8162(90)90008-2Mubarak, I., Angulo-Jaramillo, R., Mailhol, J. C., Ruelle, P., Khaledian, M., & Vauclin, M. (2010). Spatial analysis of soil surface hydraulic properties: Is infiltration method dependent? Agricultural Water Management, 97(10), 1517-1526. doi:10.1016/j.agwat.2010.05.005Nunes, A. N., Lourenço, L., Vieira, A., & Bento-Gonçalves, A. (2014). Precipitation and Erosivity in Southern Portugal: Seasonal Variability and Trends (1950-2008). Land Degradation & Development, 27(2), 211-222. doi:10.1002/ldr.2265Prosdocimi, M., Jordán, A., Tarolli, P., Keesstra, S., Novara, A., & Cerdà, A. (2016). The immediate effectiveness of barley straw mulch in reducing soil erodibility and surface runoff generation in Mediterranean vineyards. Science of The Total Environment, 547, 323-330. doi:10.1016/j.scitotenv.2015.12.076Reynolds, W. D., Bowman, B. T., Brunke, R. R., Drury, C. F., & Tan, C. S. (2000). Comparison of Tension Infiltrometer, Pressure Infiltrometer, and Soil Core Estimates of Saturated Hydraulic Conductivity. Soil Science Society of America Journal, 64(2), 478-484. doi:10.2136/sssaj2000.642478xRockström, J., Jansson, P.-E., & Barron, J. (1998). Seasonal rainfall partitioning under runon and runoff conditions on sandy soil in Niger. On-farm measurements and water balance modelling. Journal of Hydrology, 210(1-4), 68-92. doi:10.1016/s0022-1694(98)00176-0Shainberg, I., & Singer, M. J. (1988). Drop Impact Energy-Soil Exchangeable Sodium Percentage Interactions in Seal Formation. Soil Science Society of America Journal, 52(5), 1449-1452. doi:10.2136/sssaj1988.03615995005200050046xShaver, T. M., Peterson, G. A., Ahuja, L. R., & Westfall, D. G. (2013). Soil sorptivity enhancement with crop residue accumulation in semiarid dryland no-till agroecosystems. Geoderma, 192, 254-258. doi:10.1016/j.geoderma.2012.08.014Somaratne, N. M., & Smettem, K. R. J. (1993). Effect of cultivation and raindrop impact on the surface hydraulic properties of an Alfisol under wheat. Soil and Tillage Research, 26(2), 115-125. doi:10.1016/0167-1987(93)90038-qSouza, E. S., Antonino, A. C. D., Heck, R. J., Montenegro, S. M. G. L., Lima, J. R. S., Sampaio, E. V. S. B., … Vauclin, M. (2014). Effect of crusting on the physical and hydraulic properties of a soil cropped with Castor beans (Ricinus communis L.) in the northeastern region of Brazil. Soil and Tillage Research, 141, 55-61. doi:10.1016/j.still.2014.04.004Tricker, A. S. (1979). The design of a portable rainfall simulator infiltrometer. Journal of Hydrology, 41(1-2), 143-147. doi:10.1016/0022-1694(79)90111-2Turner, R. K., van den Bergh, J. C. J. M., Söderqvist, T., Barendregt, A., van der Straaten, J., Maltby, E., & van Ierland, E. C. (2000). Ecological-economic analysis of wetlands: scientific integration for management and policy. Ecological Economics, 35(1), 7-23. doi:10.1016/s0921-8009(00)00164-6Van De Giesen, N. C., Stomph, T. J., & de Ridder, N. (2000). Scale effects of Hortonian overland flow and rainfall-runoff dynamics in a West African catena landscape. Hydrological Processes, 14(1), 165-175. doi:10.1002/(sici)1099-1085(200001)14:13.0.co;2-1Vandervaere, J.-P., Vauclin, M., Haverkamp, R., Peugeot, C., Thony, J.-L., & Gilfedder, M. (1998). PREDICTION OF CRUST-INDUCED SURFACE RUNOFF WITH DISC INFILTROMETER DATA. Soil Science, 163(1), 9-21. doi:10.1097/00010694-199801000-00003White, I., Sully, M. J., & Melville, M. D. (1989). Use and Hydrological Robustness of Time-to-Incipient-Ponding. Soil Science Society of America Journal, 53(5), 1343-1346. doi:10.2136/sssaj1989.03615995005300050007xXu, X., Kiely, G., & Lewis, C. (2009). Estimation and analysis of soil hydraulic properties through infiltration experiments: comparison of BEST and DL fitting methods. Soil Use and Management, 25(4), 354-361. doi:10.1111/j.1475-2743.2009.00218.xYilmaz, D., Lassabatere, L., Angulo-Jaramillo, R., Deneele, D., & Legret, M. (2010). Hydrodynamic Characterization of Basic Oxygen Furnace Slag through an Adapted BEST Method. Vadose Zone Journal, 9(1), 107. doi:10.2136/vzj2009.0039YOUNGS, E. G. (1987). Estimating hydraulic conductivity values from ring infiltrometer measurements. Journal of Soil Science, 38(4), 623-632. doi:10.1111/j.1365-2389.1987.tb02159.xZimmermann, A., Schinn, D. S., Francke, T., Elsenbeer, H., & Zimmermann, B. (2013). Uncovering patterns of near-surface saturated hydraulic conductivity in an overland flow-controlled landscape. Geoderma, 195-196, 1-11. doi:10.1016/j.geoderma.2012.11.00

A global descriptor of spatial pattern interaction in the galaxy distribution

We present the function J as a morphological descriptor for point patterns formed by the distribution of galaxies in the Universe. This function was recently introduced in the field of spatial statistics, and is based on the nearest neighbor distribution and the void probability function. The J descriptor allows to distinguish clustered (i.e. correlated) from ``regular'' (i.e. anti-correlated) point distributions. We outline the theoretical foundations of the method, perform tests with a Matern cluster process as an idealised model of galaxy clustering, and apply the descriptor to galaxies and loose groups in the Perseus-Pisces Survey. A comparison with mock-samples extracted from a mixed dark matter simulation shows that the J descriptor can be profitably used to constrain (in this case reject) viable models of cosmic structure formation.Comment: Significantly enhanced version, 14 pages, LaTeX using epsf, aaspp4, 7 eps-figures, accepted for publication in the Astrophysical Journa

Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy

Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem-like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression. © 2013 American Association for Cancer Research

European HYdropedological Data Inventory (EU-HYDI)

There is a common need for reliable hydropedological information in Europe. In the last decades research institutes, universities and government agencies have developed local, regional and national datasets containing soil physical, chemical, hydrological and taxonomic information often combined with land use and landform data. A hydrological database for western European soils was also created in the mid-1990s. However, a comprehensive European hydropedological database, with possible additional information on chemical parameters and land use is still missing. A comprehensive joint European hydropedological inventory can serve multiple purposes, including scientific research, modelling and application of models on different geographical scales. The objective of the joint effort of the participants is to establish the European Hydropedological Data Inventory (EU-HYDI). This database holds data from European soils focusing on soil physical, chemical and hydrological properties. It also contains information on geographical location, soil classification and land use/cover at the time of sampling. It was assembled with the aim of encompassing the soil variability in Europe. It contains data from 18 countries with contributions from 29 institutions. This report presents an overview of the database, details the individual contributed datasets and explains the quality assurance and harmonization process that lead to the final database

Hematopoietic cell transplantation comorbidity index and risk of developing invasive fungal infections after allografting

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CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6- progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. © 2014 Elsevier Inc

Miller Fisher syndrome: an updated narrative review

IntroductionMiller Fisher syndrome (MFS) is considered a rare variant of Guillain-Barré syndrome (GBS), a group of acute-onset immune-mediated neuropathies characterized by the classic triad of ataxia, areflexia, and ophthalmoparesis. The present review aimed to provide a detailed and updated profile of all aspects of the syndrome through a collection of published articles on the subject, ranging from the initial description to recent developments related to COVID-19.MethodsWe searched PubMed, Scopus, EMBASE, and Web of Science databases and gray literature, including references from the identified studies, review studies, and conference abstracts on this topic. We used all MeSH terms pertaining to “Miller Fisher syndrome,” “Miller Fisher,” “Fisher syndrome,” and “anti-GQ1b antibody.”ResultsAn extensive bibliography was researched and summarized in the review from an initial profile of MFS since its description to the recent accounts of diagnosis in COVID-19 patients. MFS is an immune-mediated disease with onset most frequently following infection. Anti-ganglioside GQ1b antibodies, detected in ~85% of patients, play a role in the pathogenesis of the syndrome. There are usually no abnormalities in MFS through routine neuroimaging. In rare cases, neuroimaging shows nerve root enhancement and signs of the involvement of the central nervous system. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. Although MFS is generally self-limited and has excellent prognosis, rare recurrent forms have been documented.ConclusionThis article gives an updated narrative review of MFS with special emphasis on clinical characteristics, neurophysiology, treatment, and prognosis of MFS patients

Human Stem Cell-Derived Neurons: A System to Study Human Tau Function and Dysfunction

Background: Intracellular filamentous deposits containing microtubule-associated protein tau constitute a defining characteristic of many neurodegenerative disorders. Current experimental models to study tau pathology in vitro do not usually recapitulate the tau expression pattern characteristic of adult human brain. In this study, we have investigated whether human embryonic stem cell-derived neurons could be a good model to study human tau distribution, function and dysfunction. Methodology/Principal Findings: Using RT-PCR, immunohistochemistry, western blotting and cell transfections we have investigated whether all 6 adult human brain tau isoforms are expressed in neurons derived from human embryonic and fetal stem cells and whether 4 repeat tau over-expression alone, or with the F3 tau repeat fragment, (amino acid 258–380 of the 2N4R tau isoform with the DK280 mutation) affects tau distribution. We found that the shortest 3 repeat tau isoform, similarly to human brain, is the first to be expressed during neuronal differentiation while the other 5 tau isoforms are expressed later. Over expression of tau with 4 repeats affects tau cellular distribution and the short tau F3 fragment appears to increase tau phosphorylation but this effect does not appear to be toxic for the cell. Conclusions: Our results indicate that human embryonic stem cell-derived neurons express all 6 tau isoforms and are

The mean state and variability of the North Atlantic circulation: a perspective from ocean reanalyses

The observational network around the North Atlantic has improved significantly over the last few decades with subsurface profiling floats and satellite observations, and the recent efforts to monitor the Atlantic Meridional Overturning Circulation (AMOC). These have shown decadal timescale changes across the North Atlantic including in heat content, heat transport and the circulation. However there are still significant gaps in the observational coverage. Ocean reanalyses integrate the observations with a dynamically consistent ocean model and can be used to understand the observed changes. However the ability of the reanalyses to represent the dynamics must also be assessed. We use an ensemble of global ocean reanalyses to examine the time mean state and interannual‐decadal variability of the North Atlantic ocean since 1993. We assess how well the reanalyses are able to capture processes and whether any understanding can be gained. In particular we examine aspects of the circulation including convection, AMOC and gyre strengths, and transports. We find that reanalyses show some consistency, in particular showing a weakening of the subpolar gyre and AMOC at 50oN from the mid‐90s until at least 2009 (related to decadal variability in previous studies), a strengthening and then weakening of the AMOC at 26.5oN since 2000, and impacts of circulation changes on transports. These results agree with model studies and the AMOC observations at 26.5oN since 2005. We also see less spread across the ensemble in AMOC strength and mixed layer depth, suggesting improvements as the observational coverage has improved