The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria

BACKGROUND: The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. RESULTS: Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. CONCLUSIONS: Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12934-015-0284-7) contains supplementary material, which is available to authorized users

An open secret in porcine acute myocardial infarction models: The relevance of anaesthetic regime and breed in ischaemic outcomes.

Large animal models of acute myocardial infarction (AMI) play a crucial role in translating novel therapeutic approaches to patients as denoted by their use in the right-before-human testing platform. At present, the porcine model of AMI is used most frequently as it mimics the human condition and its anatomopathological features accurately. We want to describe to, and share with, the translational research community our experience of how different anaesthetic protocols (sevoflurane, midazolam, ketamine+xylazine+midazolam, and propofol) and pig breeds [Large White and Landrace x Large White (LLW)] can dramatically modify the outcomes of a well-established porcine model of closed-chest AMI. Our group has extensive experience with the porcine model of reperfused AMI and, over time, we reduced the time of ischaemia used to induce the disease from 90 to 50 min to increase the salvageable myocardium for cardioprotection studies. For logistical reasons, we changed both the anaesthetic protocol and the pig breed used, but these resulted in a dramatic reduction in the size of the myocardial infarct, to almost zero in some cases (sevoflurane, 50-min ischaemia, LLW, 2.4 ± 3.9% infarct size), and the cardiac function was preserved. Therefore, we had to re-validate the model by returning to 90 min of ischaemia. Here, we report the differences in infarct size and cardiac function, measured by different modalities, for each combination of anaesthetic protocol and pig breed we have used. Furthermore, we discuss these combinations and the limited literature pertaining to how these two factors influence cardiac function and infarct size in the porcine model of AMI.This research was funded by a grant (PI18/00277) from Instituto de Salud Carlos III (ISCIII), Spain—Fondo Europeo de Desarrollo Regional (FEDER). FJ is the recipient of the Ayudas para la formación de profesorado Universitario (FPU19/04925) grant from the Spanish Ministry of Science and Innovation. IDIBAPS belongs to the CERCA Programme and receives partial funding from the Generalitat de Catalunya.S

Vessel Shrinkage as a Sign of Atherosclerosis Progression in Type 2 Diabetes : A Serial Intravascular Ultrasound Analysis

OBJECTIVE—The aim of this study was to determine the natural history of vascular remodeling of atherosclerotic plaques in patients with type 2 diabetes and the predictors of vessel shrinkage

Study of cosolvent-induced α-chymotrypsin fibrillogenesis: Does protein surface hydrophobicity trigger early stages of aggregation reaction?

The misfolding of specific proteins is often associated with their assembly into fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterize amyloid formation in vitro, there is no deep knowledge about the environment (in which aggregation occurs) as well as mechanism of this type of protein aggregation. Alpha-chymotrypsin was recently driven toward amyloid aggregation by the addition of intermediate concentrations of trifluoroethanol. In the present study, approaches such as turbidimetric, thermodynamic, intrinsic fluorescence and quenching studies as well as chemical modification have been successfully used to elucidate the underlying role of hydrophobic interactions (involved in early stages of amyloid formation) in α-chymotrypsin-based experimental system. © 2009 Springer Science+Business Media, LLC

Spanish validation of Bad Sobernheim Stress Questionnaire (BSSQ (brace).es) for adolescents with braces

<p>Abstract</p> <p>Background</p> <p>As a result of scientific and medical professionals gaining interest in Stress and Health Related Quality of Life (HRQL), the aim of our research is, thus, to validate into Spanish the German questionnaire <b>Bad Sobernheim Stress Questionnaire (BSSQ) (mit Korsett)</b>, for adolescents wearing braces.</p> <p>Methods</p> <p>The methodology used adheres to literature on trans-cultural adaptation by doing a translation and a back translation; it involved 35 adolescents, ages ranging between 10 and 16, with Adolescent Idiopathic Scoliosis (AIS) and wearing the same kind of brace (Rigo System Chêneau Brace). The materials used were a socio-demographics data questionnaire, the SRS-22 and the Spanish version of BSSQ(brace).es. The statistical analysis calculated the reliability (test-retest reliability and internal consistency) and the validity (convergent and construct validity) of the BSSQ (brace).es.</p> <p>Results</p> <p>BSSQ(brace).es is reliable because of its satisfactory internal consistency (Cronbach's alpha coefficient was 0.809, p < 0.001) and temporal stability (test-retest method with a Pearson correlation coefficient of 0.902 (p < 0.01)).</p> <p>It demonstrated convergent validity with SRS-22 since the Pearson correlation coefficient was 0.656 (p < 0.01). By undertaking an Exploratory Principal Components Analysis, a latent structure was found based on two Components which explicate the variance at 60.8%.</p> <p>Conclusions</p> <p>BSSQ (brace).es is reliable and valid and can be used with Spanish adolescents to assess the stress level caused by the brace.</p

The association of health literacy with adherence in older 2 adults, and its role in interventions: a systematic meta-review

Background: Low health literacy is a common problem among older adults. It is often suggested to be associated with poor adherence. This suggested association implies a need for effective adherence interventions in low health literate people. However, previous reviews show mixed results on the association between low health literacy and poor adherence. A systematic meta-review of systematic reviews was conducted to study the association between health literacy and adherence in adults above the age of 50. Evidence for the effectiveness of adherence interventions among adults in this older age group with low health literacy was also explored. Methods: Eight electronic databases (MEDLINE, ERIC, EMBASE, PsycINFO, CINAHL, DARE, the Cochrane Library, and Web of Knowledge) were searched using a variety of keywords regarding health literacy and adherence. Additionally, references of identified articles were checked. Systematic reviews were included if they assessed the association between health literacy and adherence or evaluated the effectiveness of interventions to improve adherence in adults with low health literacy. The AMSTAR tool was used to assess the quality of the included reviews. The selection procedure, data-extraction, and quality assessment were performed by two independent reviewers. Seventeen reviews were selected for inclusion. Results: Reviews varied widely in quality. Both reviews of high and low quality found only weak or mixed associations between health literacy and adherence among older adults. Reviews report on seven studies that assess the effectiveness of adherence interventions among low health literate older adults. The results suggest that some adherence interventions are effective for this group. The interventions described in the reviews focused mainly on education and on lowering the health literacy demands of adherence instructions. No conclusions could be drawn about which type of intervention could be most beneficial for this population. Conclusions: Evidence on the association between health literacy and adherence in older adults is relatively weak. Adherence interventions are potentially effective for the vulnerable population of older adults with low levels of health literacy, but the evidence on this topic is limited. Further research is needed on the association between health literacy and general health behavior, and on the effectiveness of interventions

Cross section measurements of 155,157Gd(n, γ) induced by thermal and epithermal neutrons

© SIF, Springer-Verlag GmbH Germany, part of Springer Nature 2019Neutron capture cross section measurements on 155Gd and 157Gd were performed using the time-of-flight technique at the n_TOF facility at CERN on isotopically enriched samples. The measurements were carried out in the n_TOF experimental area EAR1, at 185 m from the neutron source, with an array of 4 C6D6 liquid scintillation detectors. At a neutron kinetic energy of 0.0253 eV, capture cross sections of 62.2(2.2) and 239.8(8.4) kilobarn have been derived for 155Gd and 157Gd, respectively, with up to 6% deviation relative to values presently reported in nuclear data libraries, but consistent with those values within 1.6 standard deviations. A resonance shape analysis has been performed in the resolved resonance region up to 181 eV and 307 eV, respectively for 155Gd and 157Gd, where on average, resonance parameters have been found in good agreement with evaluations. Above these energies and up to 1 keV, the observed resonance-like structure of the cross section has been analysed and characterised. From a statistical analysis of the observed neutron resonances we deduced: neutron strength function of 2. 01 (28) × 10 - 4 and 2. 17 (41) × 10 - 4; average total radiative width of 106.8(14) meV and 101.1(20) meV and s-wave resonance spacing 1.6(2) eV and 4.8(5) eV for n + 155Gd and n + 157Gd systems, respectively.Peer reviewedFinal Accepted Versio

Investigation of the Pu 240 (n,f) reaction at the n_TOF/EAR2 facility in the 9 meV-6 MeV range

Background: Nuclear waste management is considered amongst the major challenges in the field of nuclear energy. A possible means of addressing this issue is waste transmutation in advanced nuclear systems, whose operation requires a fast neutron spectrum. In this regard, the accurate knowledge of neutron-induced reaction cross sections of several (minor) actinide isotopes is essential for design optimization and improvement of safety margins of such systems. One such case is 240 Pu, due to its accumulation in spent nuclear fuel of thermal reactors and its usage in fast reactor fuel. The measurement of the 240 Pu (n,f) cross section was previously attempted at the CERN n_TOF facility EAR1 measuring station using the time-of-flight technique. Due to the low amount of available material and the given flux at EAR1, the measurement had to last several months to achieve a sufficient statistical accuracy. This long duration led to detector deterioration due to the prolonged exposure to the high α activity of the fission foils, therefore the measurement could not be successfully completed. Purpose: It is aimed to determine whether it is feasible to study neutron-induced fission at n_TOF/EAR2 and provide data on the 240 Pu(n,f) reaction in energy regions requested for applications. Methods: The study of the 240 Pu(n,f) reaction was made at a new experimental area (EAR2) with a shorter flight path which delivered on average 30 times higher flux at fast neutron energies. This enabled the measurement to be performed much faster, thus limiting the exposure of the detectors to the intrinsic activity of the fission foils. The experimental setup was based on microbulk Micromegas detectors and the time-of-flight data were analyzed with an optimized pulse-shape analysis algorithm. Special attention was dedicated to the estimation of the non-negligible counting loss corrections with the development of a new methodology, and other corrections were estimated via Monte Carlo simulations of the experimental setup. Results: This new measurement of the 240Pu(n,f) cross section yielded data from 9meV up to 6 MeV incident neutron energy and fission resonance kernels were extracted up to 10 keV. Conclusions: Neutron-induced fission of high activity samples can be successfully studied at the n_TOF/EAR2 facility at CERN covering a wide range of neutron energies, from thermal to a few MeV

22^{22}Na Activation Level Measurements of Fused Silica Rods in the LHC Target Absorber for Neutrals (TAN) Compared to FLUKA Simulations

The Target Absorbers for Neutrals (TANs) are located in a high-intensity radiation environment inside the tunnel of the Large Hadron Collider (LHC). TANs are positioned about $140$ m downstream from the beam interaction points. Seven $40$ cm long fused silica rods with different dopant specifications were irradiated in the TAN by the Beam RAte of Neutrals (BRAN) detector group during $p$+$p$ data taking from 2016 to 2018 at the LHC. The peak dose delivered to the fused silica rods was $18$ MGy. We report measurements of the $^{22}$Na activation of the fused silica rods carried out at the University of Illinois at Urbana-Champaign and Argonne National Laboratory. At the end of the irradiation campaign, the maximum $^{22}$Na activity observed was $A=21$ kBq$/{\rm cm^3}$ corresponding to a density, $\rho= 2.5\times 10^{12} /{\rm cm^3}$, of $^{22}$Na nuclei. FLUKA Monte Carlo simulations have been performed by the CERN FLUKA team to estimate $^{22}$Na activities for the irradiated BRAN rod samples. The simulations reproduce the $^{22}$Na activity profile measured along the rods, with a 35% underestimation of the experimental measurement results.Comment: 11 pages, 14 figures, to be submitted to PRA