Retromer deficiency in amyotrophic lateral sclerosis

The retromer is a protein complex whose function is to mediate the recycling of proteins from the endosome to either the plasma membrane or the trans-Golgi network. A deficit in retromer function has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In both AD and PD, deficiencies have been found in retromer expression both in patient tissues and in animal models of disease. Furthermore, mutations in the retromer and in retromer-associated genes have been strongly linked with both diseases. Despite ample evidence of the link between the retromer and neurodegeneration, little is known about the retromer in the context of amyotrophic lateral sclerosis (ALS), another common neurodegenerative disorder. ALS is an adult-onset neurodegenerative disorder of the upper and lower motor neurons (MNs) characterized by muscle wasting and weakness leading to death within 3-5 years after diagnosis. To date, the most commonly used model of ALS is a transgenic (Tg) mouse that overexpresses an ALS-causing G93A mutation in the human superoxide dismutase 1 (SOD1) gene. In this study, I first establish a link between the retromer and ALS by showing that cells from ALS patients as well as tissues and cells from SOD1G93A-Tg mice express lower protein levels of the retromer core components—vacuolar protein sorting 35 (Vps35), Vps26a, and Vps29. I then establish that deficiencies in retromer core proteins have functional consequences in an in vitro model of ALS. Having found significant deficiencies in the retromer in SOD1G93A-Tg mice, I then followed the model of studies performed in mouse models of other neurodegenerative disorders by investigating whether repletion of retromer levels, either virally or pharmacologically, in SOD1G93A-Tg mice confers a therapeutic benefit. Surprisingly, I find that rather than ameliorating disease, repletion of retromer levels in SOD1G93A-Tg mice exacerbates it, resulting in a faster decline in motor performance, earlier mortality, and a decrease in MNs in the spinal cord. Finally, since retromer repletion causes deleterious effects on SOD1G93A-Tg mouse disease progression, I study the effect of a single allele deletion of Vps35 in SOD1G93A-Tg mice and find that this depletion of the retromer results in amelioration of disease, including delayed onset of symptomatology, slower decline of motor deficits, delayed mortality, and an increase in MNs in the spinal cord. Altogether, the findings reported herein, support the notion that a mild defect in retromer develops over the course of the disease, which, rather than being deleterious may be therapeutic in mutant SOD1-induced MN degeneration. Perhaps this unexpected outcome may be explained by the fact that the observed mild nature of the defect is not sufficient to kill MNs but enough to alter the trafficking of specific cargos such as AMPA receptors, allowing MNs to better withstand the neurodegenerative process

Extraordinary Phenomenology from Warped Flavor Triviality

Anarchic warped extra dimensional models provide a solution to the hierarchy problem. They can also account for the observed flavor hierarchies, but only at the expense of little hierarchy and CP problems, which naturally require a Kaluza-Klein (KK) scale beyond the LHC reach. We have recently shown that when flavor issues are decoupled, and assumed to be solved by UV physics, the framework's parameter space greatly opens. Given the possibility of a lower KK scale and composite light quarks, this class of flavor triviality models enjoys a rather exceptional phenomenology, which is the focus of this letter. We also revisit the anarchic RS EDM problem, which requires m_{KK} > 8 TeV, and show that it is solved within flavor triviality models. Interestingly, our framework can induce a sizable differential t \bar{t} forward-backward asymmetry, and leads to an excess of massive boosted di-jet events, which may be linked to the recent findings of the CDF collaboration. This feature may be observed by looking at the corresponding planar flow distribution, which is presented here. Finally we point out that the celebrated standard model preference towards a light Higgs is significantly reduced within our framework.Comment: 6 pages, 3 figures. Updated the EDM bound on the anarchic scenario; extended discussion on the KK gluon's width, discovery potential and resulting dijet signal; matches published versio

Adapting the Web for People With Upper Body Motor Impairments Using Touch Screen Tablets

People with disabilities frequently use the Internet to perform a variety of common activities; however, they may often encounter aggravated accessibility barriers when using mobile devices to access the Web. In order to alleviate the problems faced by this group when using mobile devices, we have extended a previously developed transcoding-based system that adapts non-accessible web pages to the needs of specific users in order to enhance their accessibility. In this version, we included new adaptation techniques gathered from the literature in order to apply transcoding techniques to mobile devices. The enhanced system was evaluated with eight users with reduced mobility using tablets. The exploratory study suggests that alternative interaction methods such as the ones named 'end tap' and 'steady tap' are beneficial for some participants with reduced mobility, dexterity or strength in the upper limbs. Other results show that six of the eight users preferred the adapted version with enlarged interaction elements which required less physical effort, even if this adaptation increases the size of the page with the disadvantages associated with such a change.This research work was developed within the project eGovernability, funded by the Spanish Government, Ministry of Economy, Industry and Competitiveness (MINECO), and the European Regional Development Fund (ERDF), under grant (TIM2014-52665-C2-1-R). J.E.P. holds a PhD Scholarship from the University of the Basque Country (UPV/EHU). Some of the authors are members of the EGOKITUZ/ADIAN research team, supported by the Basque Government, Department of Education, Universities and Research under grant (IT980-16)

On the feedback from super stellar clusters. I. The structure of giant HII regions and HII galaxies

We review the structural properties of giant extragalactic HII regions and HII galaxies based on 2D hydrodynamic calculations, and propose an evolutionary sequence that accounts for their observed detailed structure. The model assumes a massive and young stellar cluster surrounded by a large collection of clouds. These are thus exposed to the most important star-formation feedback mechanisms: photoionization and the cluster wind. The models show how the two feedback mechanisms compete in the disruption of clouds and lead to two different hydrodynamic solutions: The storage of clouds into a long lasting ragged shell that inhibits the expansion of the thermalized wind, and the steady filtering of the shocked wind gas through channels carved within the cloud stratum. Both solutions are claimed to be concurrently at work in giant HII regions and HII galaxies, causing their detailed inner structure. This includes multiple large-scale shells, filled with an X-ray emitting gas, that evolve to finally merge with each other, giving the appearance of shells within shells. The models also show how the inner filamentary structure of the giant superbubbles is largely enhanced with matter ablated from clouds and how cloud ablation proceeds within the original cloud stratum. The calculations point at the initial contrast density between the cloud and the intercloud media as the factor that defines which of the two feedback mechanisms becomes dominant throughout the evolution. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.html.Comment: 28 pages, 10 figures, accepted for publication in the ApJ. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.htm

Lignin-Based Polyols with Controlled Microstructure by Cationic Ring Opening Polymerization

Lignin-based polyols (LBPs) with controlled microstructure were obtained by cationic ring opening polymerization (CROP) of oxiranes in an organosolv lignin (OL) tetrahydrofuran (THF) solution. The control on the microstructure and consequently on the properties of the LBPs such as hydroxyl number, average molecular weight, melting, crystallization and decomposition temperatures, are crucial to determine the performance and application of the derived-products. The influence of key parameters, for example, molar ratio between the oxirane and the hydroxyl groups content in OLO, initial OL concentration in THF, temperature, specific flow rate and oxirane nature has been investigated. LBPs with hydroxyl numbers from 35 to 217 mg KOH/g, apparent average Mw between 5517 and 52,900 g/mol and melting temperatures from −8.4 to 18.4 °C were obtained. The CROP procedure allows obtaining of tailor-made LBPs for specific applications in a very simple way, opening the way to introduce LBPs as a solid alternative to substitute currently used fossil-based polyols.Basque Government (grant KK-2019/00097

Potential role of the intestinal microbiota of the mother in neonatal immune education

Mucosal dendritic cells are at the heart of decision-making processes that dictate immune reactivity to intestinal microbes. They ensure tolerance to commensal bacteria and a vigorous immune response to pathogens. It has recently been demonstrated that the former involves a limited migration of bacterially loaded dendritic cells from the Peyer's patches to the mesenteric lymph nodes. During lactation, cells from gut-associated lymphoid tissue travel to the breast via the lymphatics and peripheral blood. Here, we show that human peripheral blood mononuclear cells and breast milk cells contain bacteria and their genetic material during lactation. Furthermore, we show an increased bacterial translocation from the mouse gut during pregnancy and lactation and the presence of bacterially loaded dendritic cells in lactating breast tissue. Our observations show bacterial translocation as a unique physiological event, which is increased during pregnancy and lactation. They suggest endogenous transport of intestinally derived bacterial components within dendritic cells destined for the lactating mammary gland. They also suggest neonatal immune imprinting by milk cells containing commensal-associated molecular pattern

Neuraminidase Antibodies and H5N1: Geographic-Dependent Influenza Epidemiology Could Determine Cross-Protection against Emerging Strains

Correspondencepublished_or_final_versio

Polygenic risk heterogeneity among focal epilepsies

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility.Peer reviewe