Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model.

Parkinson's disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b's function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD

Academic Achievement, Self-Concept, Personality and Emotional Intelligence in Primary Education. Analysis by Gender and Cultural Group

A review of the scientific literature shows that many studies have analyzed the relationship between academic achievement and different psychological constructs, such as self-concept, personality, and emotional intelligence. The present work has two main objectives. First, to analyze the academic achievement, as well as the selfconcept, personality and emotional intelligence, according to gender and cultural origin of the participants (European vs. Amazigh). Secondly, to identify what dimensions of selfconcept, personality and emotional intelligence predict academic achievement. For this, a final sample consisting of 407 students enrolled in the last 2 years of Primary Education were utilized for the study. By gender, 192 were boys (47.2%) and 215 girls (52.8%), with an average age of 10.74 years old. By cultural group, 142 were of European origin (34.9%) and 265 of Amazigh origin (65.1%). The academic achievements were evaluated from the grades obtained in three school subjects: Natural Sciences, Spanish Language and Literature, and Mathematics, and the instruments used for data collection of the psychological constructs analyzed were the Self-Concept Test-Form 5, the Short- Form Big Five Questionnaire for Children, and the BarOn Emotional Quotient Inventory: Youth Version-Short. Based on the objectives set, first, the grades in the subject of Spanish Language and Literature varied depending on the gender of the students. Likewise, differences were found in self-concept, personality, and emotional intelligence according to gender. Also, the physical self-concept varied according to the cultural group. Regarding the second objective, in the predictive analysis for each of the subjects of the curriculum of Primary Education, the academic self-concept showed a greater predictive value. However, so did other dimensions of self-concept, personality and emotional intelligence. The need to carry out a comprehensive education in schools that addresses the promotion of not only academic but also personal and social competences is discussed. Also, that the study of the variables that affect gender differences must be deepened.This research was co-financed by the Research Group Development, Education, Diversity, and Culture: Interdisciplinary Analysis (HUM-742)

Understanding the impact of antibiotic therapies on the respiratory tract resistome: A novel pooled-template metagenomic sequencing strategy

Determining the effects of antimicrobial therapies on airway microbiology at a population-level is essential. Such analysis allows, for example, surveillance of antibiotic-induced changes in pathogen prevalence, the emergence and spread of antibiotic resistance, and the transmission of multi-resistant organisms. However, current analytical strategies for understanding these processes are limited. Culture- and PCR-based assays for specific microbes require the a priori selection of targets, while antibiotic sensitivity testing typically provides no insight into either the molecular basis of resistance, or the carriage of resistance determinants by the wider commensal microbiota. Shotgun metagenomic sequencing provides an alternative approach that allows the microbial composition of clinical samples to be described in detail, including the prevalence of resistance genes and virulence traits. While highly informative, the application of metagenomics to large patient cohorts can be prohibitively expensive. Using sputum samples from a randomised placebo-controlled trial of erythromycin in adults with bronchiectasis, we describe a novel, cost-effective strategy for screening patient cohorts for changes in resistance gene prevalence. By combining metagenomic screening of pooled DNA extracts with validatory quantitative PCR-based analysis of candidate markers in individual samples, we identify population-level changes in the relative abundance of specific macrolide resistance genes. This approach has the potential to provide an important adjunct to current analytical strategies, particularly within the context of antimicrobial clinical trials

Six-minute walking test in children with ESRD: discrimination validity and construct validity

The six-minute walking test (6MWT) may be a practical test for the evaluation functional exercise capacity in children with end-stage renal disease (ESRD). The aim of this study was to investigate the 6MWT performance in children with ESRD compared to reference values obtained in healthy children and, secondly, to study the relationship between 6MWT performance with anthropometric variables, clinical parameters, aerobic capacity and muscle strength. Twenty patients (13 boys and seven girls; mean age 14.1 ± 3.4 years) on dialysis participated in this study. Anthropometrics were taken in a standardized manner. The 6MWT was performed in a 20-m-long track in a straight hallway. Aerobic fitness was measured using a cycle ergometer test to determine peak oxygen uptake \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( {\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}} \right)$$\end{document}, peak rate (Wpeak) and ventilatory threshold (VT). Muscle strength was measured using hand-held myometry. Children with ESRD showed a reduced 6MWT performance (83% of predicted, p < 0.0001), irrespective of the reference values used. The strongest predictors of 6MWT performance were haematocrit and height. Regression models explained 59% (haematocrit and height) to 60% (haematocrit) of the variance in 6MWT performance. 6MWT performance was not associated with \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}}$$\end{document}, strength, or other anthropometric variables, but it was significantly associated with haematocrit and height. Children with ESRD scored lower on the 6MWT than healthy children. Based on these results, the 6MWT may be a useful instrument for monitoring clinical status in children with ESRD, however it cannot substitute for other fitness tests, such as a progressive exercise test to measure \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}}$$\end{document} or muscle strength tests

Transcriptional Reprogramming of CD11b+Esamhi Dendritic Cell Identity and Function by Loss of Runx3

Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esamhi DC. Ablation of Runx3 in DC progenitors led to a substantial decrease in splenic CD4+/CD11b+ DC. Combined chromatin immunoprecipitation sequencing and gene expression analysis of purified DC-subsets revealed that Runx3 is a key gene expression regulator that facilitates specification and homeostasis of CD11b+Esamhi DC. Mechanistically, loss of Runx3 alters Esamhi DC gene expression to a signature characteristic of WT Esamlow DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3-/- Esamhi DC capacity to prime CD4+ T cells, attesting to the significant role of Runx3 in specifying Esamhi DC identity and function

Elucidating the Mechanisms of Influenza Virus Recognition by Ncr1

Natural killer (NK) cells are innate cytotoxic lymphocytes that specialize in the defense against viral infection and oncogenic transformation. Their action is tightly regulated by signals derived from inhibitory and activating receptors; the later include proteins such as the Natural Cytotoxicity Receptors (NCRs: NKp46, NKp44 and NKp30). Among the NCRs, NKp46 is the only receptor that has a mouse orthologue named Ncr1. NKp46/Ncr1 is also a unique marker expressed on NK and on Lymphoid tissue inducer (LTI) cells and it was implicated in the control of various viral infections, cancer and diabetes. We have previously shown that human NKp46 recognizes viral hemagglutinin (HA) in a sialic acid-dependent manner and that the O-glycosylation is essential for the NKp46 binding to viral HA. Here we studied the molecular interactions between Ncr1 and influenza viruses. We show that Ncr1 recognizes influenza virus in a sialic acid dependent manner and that N-glycosylation is important for this binding. Surprisingly we demonstrate that none of the predicted N-glycosilated residues of Ncr1 are essential for its binding to influenza virus and we thus conclude that other, yet unidentified N-glycosilated residues are responsible for its recognition. We have demonstrated that N glycosylation play little role in the recognition of mouse tumor cell lines and also showed the in-vivo importance of Ncr1 in the control of influenza virus infection by infecting C57BL/6 and BALB/c mice knockout for Ncr1 with influenza

The Retracing Boomerang Attack

Boomerang attacks are extensions of differential attacks, that make it possible to combine two unrelated differential properties of the first and second part of a cryptosystem with probabilities $p$ and $q$ into a new differential-like property of the whole cryptosystem with probability $p^2q^2$ (since each one of the properties has to be satisfied twice). In this paper we describe a new version of boomerang attacks which uses the counterintuitive idea of throwing out most of the data (including potentially good cases) in order to force equalities between certain values on the ciphertext side. This creates a correlation between the four probabilistic events, which increases the probability of the combined property to $p^2q$ and increases the signal to noise ratio of the resultant distinguisher. We call this variant a retracing boomerang attack since we make sure that the boomerang we throw follows the same path on its forward and backward directions. To demonstrate the power of the new technique, we apply it to the case of 5-round AES. This version of AES was repeatedly attacked by a large variety of techniques, but for twenty years its complexity had remained stuck at $2^{32}$. At Crypto\u2718 it was finally reduced to $2^{24}$ (for full key recovery), and with our new technique we can further reduce the complexity of full key recovery to the surprisingly low value of $2^{16.5}$ (i.e., only 90,000 encryption/decryption operations are required for a full key recovery on half the rounds of AES). In addition to improving previous attacks, our new technique unveils a hidden relationship between boomerang attacks and two other cryptanalytic techniques, the yoyo game and the recently introduced mixture differentials

New Slide Attacks on Almost Self-Similar Ciphers

The slide attack is a powerful cryptanalytic tool which has the unusual property that it can break iterated block ciphers with a complexity that does not depend on their number of rounds. However, it requires complete self similarity in the sense that all the rounds must be identical. While this can be the case in Feistel structures, this rarely happens in SP networks since the last round must end with an additional post-whitening subkey. In addition, in many SP networks the final round has additional asymmetries -- for example, in AES the last round omits the MixColumns operation. Such asymmetry in the last round can make it difficult to utilize most of the advanced tools which were developed for slide attacks, such as deriving from one slid pair additional slid pairs by repeatedly re-encrypting their ciphertexts. In this paper we overcome this last round problem by developing four new types of slide attacks. We demonstrate their power by applying them to many types of AES-like structures (with and without linear mixing in the last round, with known or secret S-boxes, with 1,2 and 3 periodicity in their subkeys, etc). In most of these cases, the time complexity of our attack is close to $2^{n/2}$, which is the smallest possible complexity for slide attacks. Our new slide attacks have several unique properties: The first attack uses slid sets in which each plaintext from the first set forms a slid pair with some plaintext from the second set, but without knowing the exact correspondence. The second attack makes it possible to create from several slid pairs an exponential number of new slid pairs which form a hypercube spanned by the given pairs. The third attack has the unusual property that it is always successful, and the fourth attack can use known messages instead of chosen messages, with only slightly higher time complexity