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81.
Reinier Oropesa-Nuñez Sandeep Keshavan Silvia Dante Alberto Diaspro Benedetta Mannini Claudia Capitini Cristina Cecchi Massimo Stefani Fabrizio Chiti Claudio Canale 《Biophysical journal》2018,114(6):1357-1367
The deposition of fibrillar protein aggregates in human organs is the hallmark of several pathological states, including highly debilitating neurodegenerative disorders and systemic amyloidoses. It is widely accepted that small oligomers arising as intermediates in the aggregation process, released by fibrils, or growing in secondary nucleation steps are the cytotoxic entities in protein-misfolding diseases, notably neurodegenerative conditions. Increasing evidence indicates that cytotoxicity is triggered by the interaction between nanosized protein aggregates and cell membranes, even though little information on the molecular details of such interaction is presently available. In this work, we propose what is, to our knowledge, a new approach, based on the use of single-cell force spectroscopy applied to multifunctional substrates, to study the interaction between protein oligomers, cell membranes, and/or the extracellular matrix. We compared the interaction of single Chinese hamster ovary cells with two types of oligomers (toxic and nontoxic) grown from the N-terminal domain of the Escherichia coli protein HypF. We were able to quantify the affinity between both oligomer type and the cell membrane by measuring the mechanical work needed to detach the cells from the aggregates, and we could discriminate the contributions of the membrane lipid and protein fractions to such affinity. The fundamental role of the ganglioside GM1 in the membrane-oligomers interaction was also highlighted. Finally, we observed that the binding of toxic oligomers to the cell membrane significantly affects the functionality of adhesion molecules such as Arg-Gly-Asp binding integrins, and that this effect requires the presence of the negatively charged sialic acid moiety of GM1. 相似文献
82.
Inhibition of tumour necrosis factor (TNF)-alpha with biological molecules has proven an effective treatment for rheumatoid
arthritis, achieving a 20% improvement in American College of Rheumatology score in up to 65% of patients. The main drawback
to these and many other biological treatments has been their expense, which has precluded their widespread application. Biological
molecules could alternatively be delivered by gene therapy as the encoding DNA. We have developed novel plasmid vectors termed
pGTLMIK and pGTTMIK, from which luciferase and a dimeric TNF receptor II (dTNFR) are respectively expressed in a doxycycline
(Dox)-regulated manner. Regulated expression of luciferase from the self-contained plasmid pGTLMIK was examined in vitro in a variety of cell lines and in vivo following intramuscular delivery with electroporation in DBA/1 mice. Dox-regulated expression of luciferase from pGTLMIK
of approximately 1,000-fold was demonstrated in vitro, and efficient regulation was observed in vivo. The vector pGTTMIK encoding dTNFR was delivered by the same route with and without administration of Dox to mice with collagen-induced
arthritis. When pGTTMIK was delivered after the onset of arthritis, progression of the disease in terms of both paw thickness
and clinical score was inhibited when Dox was also administered. Vectors with similar regulation characteristics may be suitable
for clinical application. 相似文献
83.
Wilfried Thuiller Luigi Maiorano Florent Mazel Fran?ois Guilhaumon Gentile Francesco Ficetola Sébastien Lavergne Julien Renaud Cristina Roquet David Mouillot 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2015,370(1662)
Protected areas (PAs) are pivotal tools for biodiversity conservation on the Earth. Europe has had an extensive protection system since Natura 2000 areas were created in parallel with traditional parks and reserves. However, the extent to which this system covers not only taxonomic diversity but also other biodiversity facets, such as evolutionary history and functional diversity, has never been evaluated. Using high-resolution distribution data of all European tetrapods together with dated molecular phylogenies and detailed trait information, we first tested whether the existing European protection system effectively covers all species and in particular, those with the highest evolutionary or functional distinctiveness. We then tested the ability of PAs to protect the entire tetrapod phylogenetic and functional trees of life by mapping species'' target achievements along the internal branches of these two trees. We found that the current system is adequately representative in terms of the evolutionary history of amphibians while it fails for the rest. However, the most functionally distinct species were better represented than they would be under random conservation efforts. These results imply better protection of the tetrapod functional tree of life, which could help to ensure long-term functioning of the ecosystem, potentially at the expense of conserving evolutionary history. 相似文献
84.
Mayor F Lucas E Jurado-Pueyo M Garcia-Guerra L Nieto-Vazquez I Vila-Bedmar R Fernández-Veledo S Murga C 《Archives of physiology and biochemistry》2011,117(3):125-130
G protein-coupled receptor kinase 2 (GRK2) is emerging as a key, integrative node in many signalling pathways. Besides its canonical role in the modulation of the signalling mediated by many G protein-coupled receptors (GPCR), this protein can display a very complex network of functional interactions with a variety of signal transduction partners, in a stimulus, cell type, or context-specific way. We review herein recent data showing that GRK2 can regulate insulin-triggered transduction cascades at different levels and that this protein plays a relevant role in insulin resistance and obesity in vivo, what uncovers GRK2 as a potential therapeutic target in the treatment of these disorders. 相似文献
85.
86.
Giovanni Spagna Riccardo N. Barbagallo Rosa Palmeri Cristina Restuccia Paolo Giudici 《Enzyme and microbial technology》2002,31(7):1030-1035
Three hundred sixty-one yeast strains (80 of which ascribable to Saccharomyces cerevisiae) were isolated from Sicilian musts and wines with the purpose of looking for β-glucosidase (βG, EC 3.2.1.21) activity. Of these, the AL 41 strain had highest endogenous βG activity and was identified as belonging to the species S. cerevisiae by biochemical and molecular methods. This enzyme was subsequently characterized. It had optimum effect at pH 3.5–4.0, whilst optimum temperature was 20 °C, compatible with typical wine-cellar conditions; it was not inhibited by ethanol, at concentrations of 12–14%, or fructose and glucose. The βG was also characterised in terms of the kinetic parameters Km (2.55 mM) and Vmax (1.71 U mg−1 of protein). Finally, it remained stable for at least 35 days in model solutions of must and wine. 相似文献
87.
Elena Roura Ma Pilar Almajano Ma Lourdes Mata Bilbao Cristina Andrés-Lacueva Ramon Estruch 《Free radical research》2013,47(8):943-949
Associations between cocoa consumption in humans, excreted metabolites and total antioxidant capacity (TAC) have been scarcely investigated. The aims of the study were to investigate the epicatechin (( ? )-Ec) metabolites excreted in urine samples after an intake of 40 g of cocoa powder along with the TAC of these urine samples and the relation between both the analyses. Each of the 21 volunteers received two interventions, one with a polyphenol-rich food (PRF) and one with a polyphenol-free food (PFF) in a randomized cross-over study. Urine samples were taken before and during 24 h at 0–6, 6–12 and 12–24 h periods after test intake. The excreted ( ? )-Ec metabolites and the TAC were determined in urine samples by LC-MS/MS and TEAC assay, respectively. The maximum excretion of ( ? )-Ec metabolites and the maximum TAC value were observed in urine samples excreted between 6 and 12 h after PRF consumption. Significance of TAC increase was found in urine samples excreted during 0–6 and 6–12 h (66.6 and 72.67%, respectively, with respect to the 0 h). 相似文献
88.
The species Proceratophrys cristiceps belongs to the genus Proceratophrys within the family Cycloramphidae. These amphibians are found exclusively in South America in the morphoclimatic domain of the semi-arid depression zones in northeastern Brazil known as the Caatinga. We examined intrapopulational variation using univariate and multivariate statistics with traditional and geometric morphometrics, which supported the existence of two morphotypes of this species. Our results indicated significant degrees of variation in skeletal characteristics between some natural populations of this species. Careful analyses of variability levels are fundamental to avoid taxonomic errors, principally in populations that demonstrate characteristics intimately associated with their area of occurrence, as is the case of Proceratophrys cristiceps. 相似文献
89.
90.
álvaro Javier Cruz Gómez Noelia Ventura Campos Antonio Belenguer César ávila Cristina Forn 《PloS one》2013,8(10)
Fatigue is one of the most frequent symptoms in multiple sclerosis (MS), and recent studies have described a relationship between the sensorimotor cortex and its afferent and efferent pathways as a substrate of fatigue. The objectives of this study were to assess the neural correlates of fatigue in MS through gray matter (GM) and white matter (WM) atrophy, and resting state functional connectivity (rs-FC) of the sensorimotor network (SMN). Eighteen healthy controls (HCs) and 60 relapsing-remitting patients were assessed with the Fatigue Severity Scale (FSS). Patients were classified as fatigued (F) or nonfatigued (NF). We investigated GM and WM atrophy using voxel-based morphometry, and rs-FC changes with a seed-based method and independent component analysis (ICA). F patients showed extended GM and WM atrophy focused on areas related to the SMN. High FSS scores were associated with reductions of WM in the supplementary motor area. Seed analysis of GM atrophy in the SMN showed that HCs presented increased rs-FC between the primary motor and somatosensory cortices while patients with high FSS scores were associated with decreased rs-FC between the supplementary motor area and associative somatosensory cortex. ICA results showed that NF patients presented higher rs-FC in the primary motor cortex compared to HCs and in the premotor cortex compared to F patients. Atrophy reduced functional connectivity in SMN pathways and MS patients consequently experienced high levels of fatigue. On the contrary, NF patients experienced high synchronization in this network that could be interpreted as a compensatory mechanism to reduce fatigue sensation. 相似文献