Evolutionary descent of prion genes from a ZIP metal ion transport ancestor

In the more than 20 years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into the function of PrP may be obtained through a characterization of its molecular neighborhood. Quantitative interactome data revealed the spatial proximity of a subset of metal ion transporters of the ZIP family to mammalian prion proteins. A subsequent bioinformatic analysis revealed the presence of a prion-like protein sequence within the N-terminal, extracellular domain of a phylogenetic branch of ZIPs. Additional structural threading and ortholog sequence alignment analyses consolidated the conclusion that the prion protein gene family is phylogenetically derived from a ZIP-like ancestor molecule. Our data explain structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The connection to ZIP proteins is expected to open new avenues to elucidate the biology of the prion protein in health and disease

Fermentability of whole oat flour, PeriTec flour and bran by Lactobacillus plantarum

4 páginas, 2 tablas, 1 figuraWhole oat flour obtained by hammer milling was fermented with Lactobacillus plantarum along with white flour and bran in order to compare the suitability of these substrates for the production of a probiotic beverage. The three substrates show a viable cell concentration at the end of fermentation above the minimum required in a probiotic product. The highest cell concentration was observed in white flour (9.16 Log10 CFU/mL) and the lowest in the bran sample (8.17 Log10 CFU/mL)Peer reviewe

The prion 2018 round tables (I): the structure of PrP Sc

Understanding the structure of PrPSc is without doubt a sine qua non to understand not only PrPSc propagation, but also critical features of that process such as the strain phenomenon and transmission barriers. While elucidation of the PrPSc structure has been full of difficulties, we now have a large amount of structural information that allows us to begin to understand it. This commentary article summarizes a round table that took place within the Prion 2018 meeting held in Santiago de Compostela to discuss the state of the art in this matter. Two alternative models of PrPSc exist: the PIRIBS and the 4-rung β-solenoid models. Both of them have relevant features. The 4-rung β-solenoid model agrees with experimental constraints of brain derived PrPSc obtained from cryo-EM and X-ray fiber diffraction studies. Furthermore, it allows facile accommodation of the bulky glycans that decorate brain-derived PrPSc. On the other hand, the infectious PrP23-144 amyloid exhibits a PIRIBS architecture. Perhaps, both types of structure co-exist.Supported by grants BFU2013-48436-C2-1-P and BFU2017- 86692-P from the Spanish Ministries of Economy and Competitiveness and Science, Innovation and Universities, respectively, to JRR and grant 201600029 from the Alberta Prion Research Institute to HW. This work was also supported in part by the Intramural Research Program of the NIAID (BC) and by the National Institute of Health grants R01 NS045585 (IVB), P01 AI106705 (WKS), R01 NS083687 (WKS) and R01 NS103848 (WKS)S

Full atomistic model of prion structure and conversion

Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) of the cellular prion protein (PrPC), caused epidemic and epizootic episodes [1]. Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register- β-Sheet (PIRIBS) [2] or β-solenoid conformations [3]. Similar folding models have also been proposed for PrPSc, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrPSc is structured as a 4-rung β-solenoid (4RβS) [4, 5]. Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrPSc, based on the 4RβS architecture. The stability of this new PrPSc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring β-solenoid. Importantly, the 4RβS arrangement allowed the first simulation of the sequence of events underlying PrPC conversion into PrPSc. This study provides the most updated, experimentally- driven and physically-coherent model of PrPSc, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions.JRR was funded by grants BFU2017-86692-P and BFU2013-48436-C2-1-P from the Spanish Ministries of Economy and Competitiveness, and Education and Science, respectively, both partially including FEDER funds from the European Union. This work was also supported by a grant from Fondazione Telethon (Italy, TCP14009). GS is a recipient of a fellowship from Fondazione Telethon. EB is an Assistant Telethon Scientist at the Dulbecco Telethon Institute. HW acknowledges support through grant 201600029 from the Alberta Prion Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptS

Standards – An important step for the (public) use of lidars

Lidar standards are needed to ensure quality and lidar product control at the interface between lidar manufacturers and lidar users. Meanwhile three lidar standards have been published by German and international standardization organizations. This paper describes the cooperation between the lidar technique inventors, lidar instrument constructors, and lidar product users to establish useful standards. Presently a backscatter lidar standard is elaborated in Germany. Key points of this standard are presented here. Two German standards were already accepted as international standards by the International Organization for Standardization (ISO). Hence, German and international organizations for the establishment of lidar standards are introduced to encourage a cooperative work on lidar standards by lidar scientists

Менеджмент

Присвячується нашому вчителю - професору Саллі В.І. та академіку Амоші О.І. - мудрому наставнику і колезі.Навчальний посібник призначений для формування у майбутніх менеджерів управлінського мислення та системи спеціальних знань у галузі менеджменту, формування розуміння концептуальних основ системного управління організаціями, набуття умінь аналізу середовища діяльності організації, прийняття адекватних управлінських рішень

In vitro and in vivo evidence towards fibronectin’s protective effects against prion infection

A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrPSc, in the central nervous system of prion-affected humans and animals. PrPSc is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrPSc. Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrPSc is tightly associated with proteins found in the systemic extracellular matrix, mostly fibronectin (FN). The interaction of PrPSc with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich extracellular matrix while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrPSc deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues

Machine learning based prediction of COVID-19 mortality suggests repositioning of anticancer drug for treating severe cases

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19

Design of a dual species atom interferometer for space

Atom interferometers have a multitude of proposed applications in space including precise measurements of the Earth's gravitational field, in navigation & ranging, and in fundamental physics such as tests of the weak equivalence principle (WEP) and gravitational wave detection. While atom interferometers are realized routinely in ground-based laboratories, current efforts aim at the development of a space compatible design optimized with respect to dimensions, weight, power consumption, mechanical robustness and radiation hardness. In this paper, we present a design of a high-sensitivity differential dual species $^{85}$Rb/$^{87}$Rb atom interferometer for space, including physics package, laser system, electronics and software. The physics package comprises the atom source consisting of dispensers and a 2D magneto-optical trap (MOT), the science chamber with a 3D-MOT, a magnetic trap based on an atom chip and an optical dipole trap (ODT) used for Bose-Einstein condensate (BEC) creation and interferometry, the detection unit, the vacuum system for $10^{-11}$ mbar ultra-high vacuum generation, and the high-suppression factor magnetic shielding as well as the thermal control system. The laser system is based on a hybrid approach using fiber-based telecom components and high-power laser diode technology and includes all laser sources for 2D-MOT, 3D-MOT, ODT, interferometry and detection. Manipulation and switching of the laser beams is carried out on an optical bench using Zerodur bonding technology. The instrument consists of 9 units with an overall mass of 221 kg, an average power consumption of 608 W (819 W peak), and a volume of 470 liters which would well fit on a satellite to be launched with a Soyuz rocket, as system studies have shown.Comment: 30 pages, 23 figures, accepted for publication in Experimental Astronom

STE-QUEST - Test of the Universality of Free Fall Using Cold Atom Interferometry

In this paper, we report about the results of the phase A mission study of the atom interferometer instrument covering the description of the main payload elements, the atomic source concept, and the systematic error sources