Nanomaterials: Strenght in numbers

Self-assembly of proteins commonly associated with neurodegenerative diseases can be exploited to make well-ordered and strong functional macroscopic materials

Quantum flutter of supersonic particles in one-dimensional quantum liquids

The non-equilibrium dynamics of strongly correlated many-body systems exhibits some of the most puzzling phenomena and challenging problems in condensed matter physics. Here we report on essentially exact results on the time evolution of an impurity injected at a finite velocity into a one-dimensional quantum liquid. We provide the first quantitative study of the formation of the correlation hole around a particle in a strongly coupled many-body quantum system, and find that the resulting correlated state does not come to a complete stop but reaches a steady state which propagates at a finite velocity. We also uncover a novel physical phenomenon when the impurity is injected at supersonic velocities: the correlation hole undergoes long-lived coherent oscillations around the impurity, an effect we call quantum flutter. We provide a detailed understanding and an intuitive physical picture of these intriguing discoveries, and propose an experimental setup where this physics can be realized and probed directly.Comment: 13 pages, 9 figure

Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction

The overall effect of brain zinc (Zn2+) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn2+ can exacerbate the pathological features of AD, a deficit of Zn2+ intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn2+ supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both β amyloid (Aβ)- and tau-dependent pathology. We found that Zn2+ supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aβ and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn2+ supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn2+ supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn2+ homeostasis may be beneficial in the treatment of AD

Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

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Fine mapping of the 9q31 Hirschsprung’s disease locus

Hirschsprung’s disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 × 10−6 [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system

Comprehensive Analysis of NRG1 Common and Rare Variants in Hirschsprung Patients

Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. Many other genes have been described to be associated with the pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in the development of the enteric nervous system (ENS), and seems to contribute by both common and rare variants. Here we present the results of a comprehensive analysis of the NRG1 gene in the context of the disease in a series of 207 Spanish HSCR patients, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which we have functionally characterized. All of them were found to be associated with a significant reduction of the normal NRG1 protein levels. The fact that those mutations analyzed alter NRG1 protein would suggest that they would be related with HSCR disease not only in Chinese but also in a Caucasian population, which reinforces the implication of NRG1 gene in this pathology

Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila brain, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkably, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42, while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo

Fine Mapping of the NRG1 Hirschsprung's Disease Locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR

"A spanner in the works..." International action of US unionism in Spain, 1945-1975

La derrota republicana en la guerra civil española generó una especie de «sentimiento de culpabilidad» en buena parte de la izquierda europea y estadounidense. Durante la II Guerra Mundial el interés del sindicalismo internacional por España no desapareció, pero quedó en un segundo plano. Tras la derrota de Hitler, el sindicalismo estadounidense impulsó numerosas campañas de ayuda a quienes luchaban contra la dictadura franquista, considerada vestigio del fascismo derrotado. Pero tal solidaridad trasatlántica se produjo en un contexto desfavorable. La politizada atmósfera de la guerra fría cercenó la acción exterior de los sindicatos estadounidenses. Algo que no siempre comprendieron sus homólogos europeos. Pese a ello, aquella ayuda del otro lado del Atlántico contribuyó a la supervivencia del sindicalismo antifranquista; fue importante para denunciar la represión franquista en distintos foros internacionales. En las páginas siguientes intento explicar los pormenores de lo sucedido en el período 1945-1975, contrastando documentación inédita de archivos estadounidenses con fuentes españolas.The Republican defeat in the Spanish Civil War generated a kind of “feeling of remorse” across much of the European and American left. During World War II, international unionism did not lose interest in Spain, but it was relegated in importance. After the defeat of Hitler, American unionism promoted numerous aid campaigns to support those who fought against the Franco dictatorship, which was considered a remaining vestige after the defeat of fascism elsewhere. But this Transatlantic solidarity took place in an adverse context. The politicized atmosphere of the Cold War hindered the foreign action of US unions, a circumstance which their European counterparts sometimes failed to understand. Nevertheless, support from the other side of the Atlantic contributed to the survival of anti-Franco trade unionism and was important in denouncing the repression exercised by the Franco regime in a number of international forums. The following pages seek to clarify what happened during the 1945-1975 period, comparing unpublished documentation from US archives with Spanish sources.Ministerio de Economía y Competitividad (España). Proyecto HAR2013-44849-P (I+D+i)peerReviewe