Chaperones in Polyglutamine Aggregation:Beyond the Q-Stretch

Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level

Clinical and molecular characterization of a brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46,XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

Objective: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design. Methods: Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length. Results: On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression. Interpretation: Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2020

Funções de agregação baseadas em integral de Choquet aplicadas em redimensionalização de imagens

O crescente aumento do volume de dados, juntamente com a alta complexidade destes, tem gerado a necessidade de se desenvolver técnicas de extração de conhecimento cada vez mais eficientes, tanto em custo computacional quanto em precisão. A maioria dos problemas que são tratados por esses técnicas tem informações complexas a serem identificadas. Para isso são utilizados métodos de aprendizado de máquina, onde esses métodos usam uma variedade de funções dentro das diferentes etapas que são empregadas em suas arquiteturas. Uma dessas consiste no uso de funções de agregação para redimensionar imagens. Neste contexto, apresenta-se um estudo de funções de agregação baseadas na integral de Choquet, onde a principal característica da integral do Choquet, em comparação com outras funções de agregação, reside no fato de que ela considera, por meio da medida fuzzy, a interação entre os elementos a serem agregados. Logo, apresenta-se um estudo avaliativo do desempenho das funções integral de Choquet clássica, integral de Choquet baseada em Cópula em relação as funções máximo e média, procurando resultados que podem ser melhores do que as funções de agregação usualmente aplicadas. Os resultados de tais comparações são promissores, quando avaliados através de medidas de qualidade de imagem

Quantifying and mapping species threat abatement opportunitiesto support national target setting

The successful implementation of the Convention on Biological Diversity’s post-2020Global Biodiversity Framework will rely on effective translation of targets from global tonational level and increased engagement across diverse sectors of society. Species conserva-tion targets require policy support measures that can be applied to a diversity of taxonomicgroups, that link action targets to outcome goals, and that can be applied to both global andnational data sets to account for national context, which the species threat abatement andrestoration (STAR) metric does. To test the flexibility of STAR, we applied the metric to vascular plants listed on national red lists of Brazil, Norway, and South Africa. The STARmetric uses data on species’ extinction risk, distributions, and threats, which we obtainedfrom national red lists to quantify the contribution that threat abatement and habitatrestoration activities could make to reducing species’ extinction risk. Across all 3 coun-tries, the greatest opportunity for reducing plant species’ extinction risk was from abatingthreats from agricultural activities, which could reduce species’ extinction risk by 54% inNorway, 36% in South Africa, and 29% in Brazil. Species extinction risk could be reducedby a further 21% in South Africa by abating threats from invasive species and by 21% inBrazil by abating threats from urban expansion. Even with different approaches to red-listing among countries, the STAR metric yielded informative results that identified wherethe greatest conservation gains could be made for species through threat-abatement andrestoration activities. Quantifiably linking local taxonomic coverage and data collection toglobal processes with STAR would allow national target setting to align with global targetsand enable state and nonstate actors to measure and report on their potential contributionsto species conservation. habitat restoration, national red lists, species’ extinction risk, threat reduction, threatened species, vascular plantspublishedVersio

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. RESULTS: Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. CONCLUSIONS: NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts