Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies; 35244787

Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types of aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, the relationship between oligomers and fibrils in the aggregation process and spreading remains elusive. A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms. Furthermore, the lack of correlation between the presence of the typical pathological inclusions and disease sustained this debate. However, recent data show that the ß-sheet core of the a-Synuclein (aSyn) fibrils is unable to establish persistent interactions with the lipid bilayers, but they can release oligomeric species responsible for an immediate dysfunction of the recipient neurons. Reversibly, such oligomeric species could also contribute to pathogenesis via neuron-to-neuron spreading by their direct cell-to-cell transfer or by generating new fibrils, following their neuronal uptake. In this Review, we discuss the various mechanisms of cellular dysfunction caused by aSyn, including oligomer toxicity, fibril toxicity and fibril spreading. © 2022, The Author(s)

Photo-desorption of H2O:CO:NH3 circumstellar ice analogs: Gas-phase enrichment

We study the photo-desorption occurring in H$_2$O:CO:NH$_3$ ice mixtures irradiated with monochromatic (550 and 900 eV) and broad band (250--1250 eV) soft X-rays generated at the National Synchrotron Radiation Research Center (Hsinchu, Taiwan). We detect many masses photo-desorbing, from atomic hydrogen (m/z = 1) to complex species with m/z = 69 (e.g., C$_3$H$_3$NO, C$_4$H$_5$O, C$_4$H$_7$N), supporting the enrichment of the gas phase. At low number of absorbed photons, substrate-mediated exciton-promoted desorption dominates the photo-desorption yield inducing the release of weakly bound (to the surface of the ice) species; as the number of weakly bound species declines, the photo-desorption yield decrease about one order of magnitude, until porosity effects, reducing the surface/volume ratio, produce a further drop of the yield. We derive an upper limit to the CO photo-desorption yield, that in our experiments varies from 1.4 to 0.007 molecule photon$^{-1}$ in the range $\sim 10^{15} - 10^{20}$~absorbed photons cm$^{-2}$. We apply these findings to a protoplanetary disk model irradiated by a central T~Tauri star

Demography and Genealogical Analysis of Massese Sheep, a Native Breed of Tuscany

This study investigates the genealogical and demographic trends of the Massese sheep breed in Tuscany from 2001 to 2021. The Herd Book kept by the Italian Sheep and Goat Breeders Association (Asso.Na.Pa) provided the data. The descriptive statistics were analyzed using JMP software. The pedigree parameters of a total of 311,056 animals (whole population-WP) were analyzed using CFC, ENDOG, and Pedigree viewer software. A total of 24,586 animals born in the period 2007-2021 represented the Reference Population (RP), and 18,554 animals the Base Population (BP). The demographic results showed an inconsistent trend of offspring registration. This study showed a short period of productivity for both ewes and rams, with means of 1.47 and 19.2 registered newborn ewes and rams, respectively. The genealogical analysis revealed incomplete data, highlighting inaccurate assessments of the relationships among the animals, and inbreeding with large differences among provinces. The average inbreeding coefficient in the WP was 1.16%, and it was 2.26% in the RP. The total number of inbreds was 2790 in the WP, with an average FPED of 13.56%, and 2713 in the RP, with an average FPED of 12.82%. The use of pedigree data is a key and economical approach to calculating inbreeding and relationship coefficients. It is the primary step in genetic management, playing a crucial role in the preservation of a breed. The regular updating of genealogical data is the first step to ensuring the conservation of animal genetic resources, and this study is compromised by the lack of such updates

Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C

Cardiac myosin binding protein-C (cMyBP-C) is a multi-domain (C0-C10) protein that regulates heart muscle contraction through interaction with myosin, actin and other sarcomeric proteins. Several mutations of this protein cause familial hypertrophic cardiomyopathy (HCM). Domain C1 of cMyBP-C plays a central role in protein interactions with actin and myosin. Here, we studied structure-function relationship of three disease causing mutations, Arg177His, Ala216Thr and Glu258Lys of the domain C1 using computational biology techniques with its available X-ray crystal structure. The results suggest that each mutation could affect structural properties of the domain C1, and hence it's structural integrity through modifying intra-molecular arrangements in a distinct mode. The mutations also change surface charge distributions, which could impact the binding of C1 with other sarcomeric proteins thereby affecting contractile function. These structural consequences of the C1 mutants could be valuable to understand the molecular mechanisms for the disease

Simulating the High Energy Gamma-ray sky seen by the GLAST Large Area Telescope

This paper presents the simulation of the GLAST high energy gamma-ray telescope. The simulation package, written in C++, is based on the Geant4 toolkit, and it is integrated into a general framework used to process events. A detailed simulation of the electronic signals inside Silicon detectors has been provided and it is used for the particle tracking, which is handled by a dedicated software. A unique repository for the geometrical description of the detector has been realized using the XML language and a C++ library to access this information has been designed and implemented. A new event display based on the HepRep protocol was implemented. The full simulation was used to simulate a full week of GLAST high energy gamma-ray observations. This paper outlines the contribution developed by the Italian GLAST software group.Comment: 6 pages, 4 figures, to be published in the Proceedings of the 6th International Symposium ''Frontiers of Fundamental and Computational Physics'' (FFP6), Udine (Italy), Sep. 26-29, 200

Polarization squeezing with cold atoms

We study the interaction of a nearly resonant linearly polarized laser beam with a cloud of cold cesium atoms in a high finesse optical cavity. We show theoretically and experimentally that the cross-Kerr effect due to the saturation of the optical transition produces quadrature squeezing on both the mean field and the orthogonally polarized vacuum mode. An interpretation of this vacuum squeezing as polarization squeezing is given and a method for measuring quantum Stokes parameters for weak beams via a local oscillator is developed

The release of toxic oligomers from a-synuclein fibrils induces dysfunction in neuronal cells

The self-assembly of a-synuclein (aS) into intraneuronal inclusion bodies is a key characteristic of Parkinson’s disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main aS populations that have been observed to form progressively during fibril growth. The aS fibrils release soluble prefibrillar oligomeric species with cross-ß structure and solvent-exposed hydrophobic clusters. aS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released aS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that aS fibrils can spread in different brain areas, our in vitro results reveal that aS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species