Modulation of Molecular Chaperones in Huntington's Disease and Other Polyglutamine Disorders

Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here, we provide a focused review on Hsp90, Hsp70, and their co-chaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences

Non-adiabatic radiative collapse of a relativistic star under different initial conditions

We examine the role of space-time geometry in the non-adiabatic collapse of a star dissipating energy in the form of radial heat flow, studying its evolution under different initial conditions. The collapse of a star with interior comprising of a homogeneous perfect fluid is compared with that of a star filled with inhomogeneous imperfect fluid with anisotropic pressure. Both the configurations are spherically symmetric, however, in the latter case, the physical space $t= constant$ of the configurations is assumed to be inhomogeneous endowed with spheroidal or pseudo-spheroidal geometry. It is observed that as long as the collapse is shear-free, its evolution depends only on the mass and size of the star at the onset of collapse.Comment: To appear in Pramana- j. of physic

Flexible temperature sensor integration into e-textiles using different industrial yarn fabrication processes

Textiles enhanced with thin-film flexible sensors are well-suited for unobtrusive monitoring of skin parameters due to the sensors’ high conformability. These sensors can be damaged if they are attached to the surface of the textile, also affecting the textiles’ aesthetics and feel. We investigate the effect of embedding flexible temperature sensors within textile yarns, which adds a layer of protection to the sensor. Industrial yarn manufacturing techniques including knit braiding, braiding, and double covering were utilised to identify an appropriate incorporation technique. The thermal time constants recorded by all three sensing yarns was <10 s. Simultaneously, effective sensitivity only decreased by a maximum of 14% compared to the uncovered sensor. This is due to the sensor being positioned within the yarn instead of being in direct contact with the measured surface. These sensor yarns were not affected by bending and produced repeatable measurements. The double covering method was observed to have the least impact on the sensors’ performance due to the yarn’s smaller dimensions. Finally, a sensing yarn was incorporated in an armband and used to measure changes in skin temperature. The demonstrated textile integration techniques for flexible sensors using industrial yarn manufacturing processes enable large-scale smart textile fabrication

Targeting the proteostasis network in Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the huntingtin protein. Expansions above 40 polyglutamine repeats are invariably fatal, following a symptomatic period characterised by choreiform movements, behavioural abnormalities, and cognitive decline. While mutant huntingtin (mHtt) is widely expressed from early life, most patients with HD present in mid-adulthood, highlighting the role of ageing in disease pathogenesis. mHtt undergoes proteolytic cleavage, misfolding, accumulation, and aggregation into inclusion bodies. The emerging model of HD pathogenesis proposes that the chronic production of misfolded mHtt overwhelms the chaperone machinery, diverting other misfolded clients to the proteasome and the autophagy pathways, ultimately leading to a global collapse of the proteostasis network. Multiple converging hypotheses also implicate ageing and its impact in the dysfunction of organelles as additional contributing factors to the collapse of proteostasis in HD. In particular, mitochondrial function is required to sustain the activity of ATP-dependent chaperones and proteolytic machinery. Recent studies elucidating mitochondria-endoplasmic reticulum interactions and uncovering a dedicated proteostasis machinery in mitochondria, suggest that mitochondria play a more active role in the maintenance of cellular proteostasis than previously thought. The enhancement of cytosolic proteostasis pathways shows promise for HD treatment, protecting cells from the detrimental effects of mHtt accumulation. In this review, we consider how mHtt and its post translational modifications interfere with protein quality control pathways, and how the pharmacological and genetic modulation of components of the proteostasis network impact disease phenotypes in cellular and in vivo HD models

Microdevices for extensional rheometry of low viscosity elastic liquids : a review

Extensional flows and the underlying stability/instability mechanisms are of extreme relevance to the efficient operation of inkjet printing, coating processes and drug delivery systems, as well as for the generation of micro droplets. The development of an extensional rheometer to characterize the extensional properties of low viscosity fluids has therefore stimulated great interest of researchers, particularly in the last decade. Microfluidics has proven to be an extraordinary working platform and different configurations of potential extensional microrheometers have been proposed. In this review, we present an overview of several successful designs, together with a critical assessment of their capabilities and limitations

Valuation of the quality attributes of tomato for fresh market: a study with CEAGESP wholesalers

The great variation in the value of tomato from the same variety group, same classification and on the same day of marketing, registered by the Terminal Market of CEAGESP, were related to the difference in quality among the attributes of those fruits. The main goal of this work was to create a tool for the evaluation of the quality attributes considered important for tomatoes and from the assessment of these attributes target the most relevant for the difference in value practiced during commercialization at CEAGESP. Firstly, based on the interview with the agents of commercialization of tomatoes at CEAGESP, the main attributes seen by them, which determine the quality of tomato, were raised. Based on those answers, in a second stage, a gauge visual quality assessment was created to be used as a differential tool in the process of decision making. In a third stage, the maximum and minimum price for three classifications (big, medium and minute) were raised for lots of tomato in the same day and their quality attributes were evaluated for two systems: system I - the quality attributes were evaluated, based on banknotes of performance according to the loading gauge visual, and for system II - in addition to the assessment by notes according to the loading gauge visual, the frequency of occurrence of the attribute in a lot of tomato was measured. The attributes that determine the quality of tomato, according to the tomatoes commercialization agents from CEAGESP, are: size (type or size), fruit color, absence of defects, durability, packaging and flavor. The most important attributes to explain the variation of prices assessed by the system I are packaging that are suitable to be palletized and packaging that provides an appropriate pile, on the other hand, for system II, these attributes are: fruit without superficial skin damage and adequate protection of the package against mechanical injuries.A grande variação no valor do tomate de mesa, do mesmo grupo varietal, mesma classificação e no mesmo dia de comercialização, no mercado atacadista da CEAGESP, tem entre suas causas mais importantes a diferença de qualidade nos atributos destes frutos. O objetivo deste trabalho foi criar uma ferramenta de avaliação dos atributos de qualidade considerados importantes para o tomate de mesa e, a partir da avaliação, apontar os mais relevantes na diferença de valor praticado na comercialização da CEAGESP. Primeiramente, foram levantados os principais atributos que determinam a qualidade do tomate de mesa a partir de entrevista com agentes de comercialização de tomate da CEAGESP. A partir deste levantamento, foi criado um gabarito de avaliação visual da qualidade. Por fim, foram levantados os lotes de tomate de mesa de preço máximo e os de preço mínimo para três classificações (graúdo, médio e miúdo) comercializados no mesmo dia, avaliando-se os seus atributos de qualidade por dois sistemas: sistema I - avaliação dos atributos de qualidade por meio de notas de desempenho de acordo com o gabarito, e o sistema II - levantamento da frequência de ocorrência de cada atributo avaliado no lote de tomate. Os atributos que determinam a qualidade do tomate, segundo os agentes de comercialização de tomate da CEAGESP, são: o tamanho (tipo ou calibre), a coloração do fruto, a ausência de defeitos, durabilidade, embalagem e sabor. Os atributos determinantes na variação de preços avaliados pelo sistema I são embalagens paletizáveis e embalagens que proporcionem um adequado empilhamento, enquanto que, para o sistema II, estes atributos são: frutos sem danos superficiais de casca e proteção adequada da embalagem contra injúrias mecânicas.214219Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Emotional persistence in online chatting communities

How do users behave in online chatrooms, where they instantaneously read and write posts? We analyzed about 2.5 million posts covering various topics in Internet relay channels, and found that user activity patterns follow known power-law and stretched exponential distributions, indicating that online chat activity is not different from other forms of communication. Analysing the emotional expressions (positive, negative, neutral) of users, we revealed a remarkable persistence both for individual users and channels. I.e. despite their anonymity, users tend to follow social norms in repeated interactions in online chats, which results in a specific emotional "tone" of the channels. We provide an agent-based model of emotional interaction, which recovers qualitatively both the activity patterns in chatrooms and the emotional persistence of users and channels. While our assumptions about agent's emotional expressions are rooted in psychology, the model allows to test different hypothesis regarding their emotional impact in online communication.Comment: 34 pages, 4 main and 12 supplementary figure

Radiating Shear-Free Gravitational Collapse with Charge

We present a new shear free model for the gravitational collapse of a spherically symmetric charged body. We propose a dissipative contraction with radiation emitted outwards. The Einstein field equations, using the junction conditions and an ansatz, are integrated numerically. A check of the energy conditions is also performed. We obtain that the charge delays the black hole formation and it can even halt the collapse.Comment: 22 pages, 9 figures. It has been corrected several typos and included several references. Accepted for publication in GR

Streptomyces natalensis programmed cell death and morphological differentiation are dependenton oxidative stress

Streptomyces are aerobic Gram-positive bacteria characterized by a complex life cycle that includes hyphae differentiation and spore formation. Morphological differentiation is triggered by stressful conditions and takes place in a pro-oxidant environment, which sets the basis for an involvement of the oxidative stress response in this cellular process. Characterization of the phenotypic traits of Streptomycesnatalensis ΔkatA1 (mono-functional catalase) and ΔcatR (Fur-like repressor of katA1 expression) strains in solid medium revealed that both mutants had an impaired morphological development process. The sub-lethal oxidative stress caused by the absence of KatA1 resulted in the formation of a highly proliferative and undifferentiated vegetative mycelium, whereas de-repression of CatR regulon, from which KatA1 is the only known representative, resulted in the formation of scarce aerial mycelium. Both mutant strains had the transcription of genes associated with aerial mycelium formation and biosynthesis of the hyphae hydrophobic layer down-regulated. The first round of the programmed cell death (PCD) was inhibited in both strains which caused the prevalence of the transient primary mycelium (MI) over secondary mycelium (MII). Our data shows that the first round of PCD and morphological differentiation in S. natalensis is dependent on oxidative stress in the right amount at the right time.This work was funded by: "NORTE-07-0124-FEDER-000003 - Cell homeostasis tissue organization and organism biology" project co-funded by FEDER funds through the Operational North Region Programme (ON.2 - O Novo Norte) under National Strategic Reference Framework (QREN) and by National funds through FCT - Fundacao para a Ciencia e Tecnologia/MEC - Ministerio da Educacao e Ciencia and when applicable co-funded by FEDER funds within the partnership agreement PT2020 related with the research unit number 4293. TB was supported by a post-doctoral fellowship under the PEst-C/SAU/LA0002/2013 (FCOMP-01-0124-FEDER-037277) project; PO, MVM and SDSP were supported by the FCT fellowships SFRH/BPD/74894/2010, SFRH/BPD/95683/2013 and SFRH/BD/66367/2009, respectively. We thank Rui Fernandes, Hugo Osorio and Catarina Santos for excellent technical assistance in the preparation of samples for confocal microscopy, protein identification and in silico analysis of the S. natalensis genome, respectively