An Update on Autophagy in Prion Diseases

Autophagy is a dynamic intracellular mechanism involved in protein and organelle turnover through lysosomal degradation. When properly regulated, autophagy supports normal cellular and developmental processes, whereas defects in autophagic degradation have been associated with several pathologies, including prion diseases. Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurodegenerative disorders characterized by the accumulation of the pathological misfolded isoform (PrPSc) of the physiological cellular prion protein (PrPc) in the central nervous system. Autophagic vacuoles have been described in experimental models of TSE and in the natural disease in humans. The precise connection of this process with prion-related neuropathology, or even whether autophagy is completely beneficial or pathogenic during neurodegeneration, is poorly understood. Thus, the biological role of autophagy in these diseases is still open to debate. During the last years, researchers have used a wide range of morphological, genetic and biochemical methods to monitor and manipulate the autophagic pathway and thus determine the specific role of this process in TSE. It has been suggested that PrPc could play a crucial role in modulating the autophagic pathway in neuronal cells, and the presence of abnormal autophagic activity has been frequently observed in several models of TSE both in vitro and in vivo, as well as in human prion diseases. Altogether, these findings suggest that autophagy is implicated in prion neuropathology and points to an impairment or failure of the process, potentially contributing to the pathogenesis of the disease. Additionally, autophagy is now emerging as a host defense response in controlling prion infection that plays a protective role by facilitating the clearance of aggregation-prone proteins accumulated within neurons. Since autophagy is one of the pathways of PrPSc degradation, and drug-induced stimulation of autophagic flux (the dynamic process of autophagic degradation activity) produces anti-prion effects, new treatments based on its activation have been tested to develop therapeutic strategies for prion diseases. In this review, we summarize previous and recent findings concerning the role of autophagy in TSE

Easy access to modified cyclodextrins by an intramolecular radical approach

A simple method to modify the primary face of cyclodextrins (CDs) is described. The 6I-O-yl radical of a-, b-, and g-CDs regioselectively abstracts the H5II, located in the adjacent d-glucose unit, by an intramolecular 1,8-hydrogenatom-transfer reaction through a geometrically restricted ninemembered transition state to give a stable 1,3,5-trioxocane ring. The reaction has been extended to the 1,4-diols of a- and b-CD to give the corresponding bis(trioxocane)s. The C2-symmetric bis(trioxocane) corresponding to the a-CD is a stable crystalline solid whose structure was confirmed by X-ray diffraction analysis. The calculated geometric parameters confirm that the primary face is severely distorted toward a narrower elliptical shape for this rim

Radical-mediated C–H functionalization : a strategy for access to modified cyclodextrins

A simple and efficient radical C–H functionalization to access modified cyclodextrins (CDs) has been developed. The well-defined conformation of glycosidic and aglyconic bonds in α-, β-, and γ-CDs favors the intramolecular 1,8-hydrogen atom transfer (HAT) promoted by the 6I-O-yl radical, which abstracts regioselectively the hydrogen at C5II of the contiguous pyranose. The C5II-radical evolves by a polar crossover mechanism to a stable 1,3,5-trioxocane ring between two adjacent glucoses or alternatively triggers the inversion of one α-d-glucose into a 5-C-acetoxy-β-l-idose unit possessing a 1C4 conformation. The 6I,IV- and 6I,III-diols of α- and β-CDs behave similarly to the monoalcohols, forming mostly compounds originating from two 1,8-HAT consecutive processes. In the case of 6I,II-diols the proximity of the two 6-O-yl radicals in adjacent sugar units allows the formation of unique lactone rings within the CD framework via a 1,8-HAT−β-scission tandem mechanism. X-ray diffraction carried out on the crystalline 1,4-bis(trioxocane)-α-CD derivative shows a severe distortion toward a narrower elliptical shape for the primary face

Crossed-ratchet effects and domain wall geometrical pinning

The motion of a domain wall in a two dimensional medium is studied taking into account the internal elastic degrees of freedom of the wall and geometrical pinning produced both by holes and sample boundaries. This study is used to analyze the geometrical conditions needed for optimizing crossed ratchet effects in periodic rectangular arrays of asymmetric holes, recently observed experimentally in patterned ferromagnetic films. Geometrical calculations and numerical simulations have been used to obtain the anisotropic critical fields for depinning flat and kinked walls in rectangular arrays of triangles. The aim is to show with a generic elastic model for interfaces how to build a rectifier able to display crossed ratchet effects or effective potential landscapes for controlling the motion of interfaces or invasion fronts.Comment: 13 pages, 18 figure

Neurogranin and Neurofilament Light Chain as Preclinical Biomarkers in Scrapie

Prion diseases are diagnosed in the symptomatic stage, when the neuronal damage is spread throughout the central nervous system (CNS). The assessment of biological features that allow the detection of asymptomatic cases is needed, and, in this context, scrapie, where pre-symptomatic infected animals can be detected through rectal biopsy, becomes a good study model. Neurogranin (Ng) and neurofilament light chain (NfL) are proteins that reflect synaptic and axonal damage and have been studied as cerebrospinal fluid (CSF) biomarkers in different neurodegenerative disorders. In this study, we evaluated Ng and NfL both at the protein and transcript levels in the CNS of preclinical and clinical scrapie-affected sheep compared with healthy controls and assessed their levels in ovine CSF. The correlation between these proteins and the main neuropathological events in prion diseases, PrPSc deposition and spongiosis, was also assessed. The results show a decrease in Ng and NfL at the protein and gene expression levels as the disease progresses, and significant changes between the control and preclinical animals. On the contrary, the CSF levels of NfL increased throughout the progression of the disease. Negative correlations between neuropathological markers of prion disease and the concentration of the studied proteins were also found. Although further research is needed, these results suggest that Ng and NfL could act as biomarkers for neurodegeneration onset and intensity in preclinical cases of scrapie

Increased circulating microRNAs miR-342-3p and miR-21-5p in natural sheep prion disease

Scrapie is a transmissible spongiform encephalopathy (TSE), or prion disease, of sheep and goats. As no simple diagnostic tests are yet available to detect TSEs in vivo, easily accessible biomarkers could facilitate the eradication of scrapie agents from the food chain. To this end, we analysed by quantitative reverse transcription PCR a selected set of candidate microRNAs (miRNAs) from circulating blood plasma of naturally infected, classical scrapie sheep that demonstrated clear scrapie symptoms and pathology. Significant scrapie-associated increase was repeatedly found for miR-342-3p and miR-21-5p. This is the first demonstration, to our knowledge, of circulating miRNA alterations in any animal suffering from TSE. Genome-wide expression studies are warranted to investigate the true depth of miRNA alterations in naturally occurring TSEs, especially in presymptomatic animals, as the presented study demonstrates the potential feasibility of miRNAs as circulating TSE biomarkers

Lucky Imaging Adaptive Optics of the brown dwarf binary GJ569Bab

The potential of combining Adaptive Optics (AO) and Lucky Imaging (LI) to achieve high precision astrometry and differential photometry in the optical is investigated by conducting observations of the close 0\farcs1 brown dwarf binary GJ569Bab. We took 50000 $I$-band images with our LI instrument FastCam attached to NAOMI, the 4.2-m William Herschel Telescope (WHT) AO facility. In order to extract the most of the astrometry and photometry of the GJ569Bab system we have resorted to a PSF fitting technique using the primary star GJ569A as a suitable PSF reference which exhibits an $I$-band magnitude of $7.78\pm0.03$. The AO+LI observations at WHT were able to resolve the binary system GJ569Bab located at 4\farcs 92 \pm 0\farcs05 from GJ569A. We measure a separation of $98.4 \pm 1.1$ mas and $I$-band magnitudes of $13.86 \pm 0.03$ and $14.48 \pm 0.03$ and $I-J$ colors of 2.72$\pm$0.08 and 2.83$\pm$0.08 for the Ba and Bb components, respectively. Our study rules out the presence of any other companion to GJ569A down to magnitude I$\sim$ 17 at distances larger than 1\arcsec. The $I-J$ colors measured are consistent with M8.5-M9 spectral types for the Ba and Bb components. The available dynamical, photometric and spectroscopic data are consistent with a binary system with Ba being slightly (10-20%) more massive than Bb. We obtain new orbital parameters which are in good agreement with those in the literature.Comment: 13 pages, 9 figures, 7 tables, in press in MNRA

Clinical nutrition as part of the treatment pathway of pancreatic cancer patients: an expert consensus

Purpose: Malnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients. Methods: A Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients. Results: The panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment. Conclusions: There is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patientsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Logistics of the meetings and the assistance with the medical writing have been provided by unrestricted Grant from Baxter Laboratorie