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)

Rock magnetism and palaeomagnetism of the Montalbano Jonico section (Italy): evidence for late diagenetic growth of greigite and implications for magnetostratigraphy

The Montalbano Jonico (MJ) section, cropping out in Southern Italy, represents a potential candidate to define the Lower/Middle Pleistocene boundary and it has been proposed as a suitable Global Stratotype Section and Point (GSSP) of the Ionian Stage (Middle Pleistocene). The MJ section is the only continuous benthic and planktonic δ18O on-land reference in the Mediterranean area for the Mid-Pleistocene transition, spanning an interval between about 1240 and 645 ka. Combined biostratigraphy and sapropel chronology, tephra stratigraphy and complete high-resolution benthic and planktonic foraminiferal stable oxygen isotope records already provide a firm chronostratigraphic framework for the MJ section. However, magnetostratigraphy was still required to precisely locate the Brunhes-Matuyama transition and to mark the GSSP for the Ionian stage. We carried out a palaeomagnetic study of a subsection (Ideale section) of the MJ composite section, sampling 61 oriented cores from 56 stratigraphic levels spread over a ca. 80-m-thick stratigraphic interval that correlates to the oxygen isotopic stage 19 and should therefore include the Brunhes-Matuyama reversal. The palaeomagnetic data indicate a stable and almost single-component natural remanent magnetization (NRM). A characteristic remanent magnetization (ChRM) was clearly identified by stepwise demagnetization of the NRM. The ChRM declination values vary around 0◦ and the ChRM inclination around the expected value (59◦) for a geocentric axial dipole field at the sampling locality. This result indicates that the section has been remagnetized during the Brunhes Chron. A preliminary study of 27 additional not azimuthally oriented hand samples, collected at various levels from other parts of the MJ composite section, indicates that all the samples are of normal polarity and demonstrates that the remagnetization is widespread across the whole exposed stratigraphic sequence. A series of specific rock magnetic techniques were then applied to investigate the nature of the main magnetic carrier in the study sediments, and they suggest that the main magnetic mineral in the MJ section is the iron sulphide greigite (Fe3S4). Scanning electron microscope observations and elemental microanalysis reveal that greigite occurs both as individual euhedral crystals and in iron sulphides aggregates filling voids in the clay matrix. Therefore, we infer that the remagnetization of the section is due to the late-diagenetic growth of greigite under reducing conditions, most likely resulting in the almost complete dissolution of the original magnetic minerals. Iron sulphide formation in the MJ section can be linked to migration of mineralized fluids. Our inferred timing of the remagnetization associated with greigite growth represents the longest remanence acquisition delay documented in greigite-bearing clays of the Italian peninsula so far

Characterization of pairs of toxic and nontoxic misfolded protein oligomers elucidates the structural determinants of oligomer toxicity in protein misfolding diseases

Conspectus: The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer’s and Parkinson’s diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies. These oligomers are small, diffusible species that can form as intermediates in the amyloid fibril formation process or be released by mature fibrils after they are formed. They have been closely associated with the induction of neuronal dysfunction and cell death. It has proven rather challenging to study these oligomeric species because of their short lifetimes, low concentrations, extensive structural heterogeneity, and challenges associated with producing stable, homogeneous, and reproducible populations. Despite these difficulties, investigators have developed protocols to produce kinetically, chemically, or structurally stabilized homogeneous populations of protein misfolded oligomers from several amyloidogenic peptides and proteins at experimentally ameneable concentrations. Furthermore, procedures have been established to produce morphologically similar but structurally distinct oligomers from the same protein sequence that are either toxic or nontoxic to cells. These tools offer unique opportunities to identify and investigate the structural determinants of oligomer toxicity by a close comparative inspection of their structures and the mechanisms of action through which they cause cell dysfunction. This Account reviews multidisciplinary results, including from our own groups, obtained by combining chemistry, physics, biochemistry, cell biology, and animal models for pairs of toxic and nontoxic oligomers. We describe oligomers comprised of the amyloid-β peptide, which underlie Alzheimer’s disease, and α-synuclein, which are associated with Parkinson’s disease and other related neurodegenerative pathologies, collectively known as synucleinopathies. Furthermore, we also discuss oligomers formed by the 91-residue N-terminal domain of [NiFe]-hydrogenase maturation factor from E. coli, which we use as a model non-disease-related protein, and by an amyloid stretch of Sup35 prion protein from yeast. These oligomeric pairs have become highly useful experimental tools for studying the molecular determinants of toxicity characteristic of protein misfolding diseases. Key properties have been identified that differentiate toxic from nontoxic oligomers in their ability to induce cellular dysfunction. These characteristics include solvent-exposed hydrophobic regions, interactions with membranes, insertion into lipid bilayers, and disruption of plasma membrane integrity. By using these properties, it has been possible to rationalize in model systems the responses to pairs of toxic and nontoxic oligomers. Collectively, these studies provide guidance for the development of efficacious therapeutic strategies to target rationally the cytotoxicity of misfolded protein oligomers in neurodegenerative conditions

Exploring Biosignals for Quantitative Pain Assessment in Cancer Patients: A Proof of Concept

Perception and expression of pain in cancer patients are influenced by distress levels, tumor type and progression, and the underlying pathophysiology of pain. Relying on traditional pain assessment tools can present limitations due to the highly subjective and multifaceted nature of the symptoms. In this scenario, objective pain assessment is an open research challenge. This work introduces a framework for automatic pain assessment. The proposed method is based on a wearable biosignal platform to extract quantitative indicators of the patient pain experience, evaluated through a self-assessment report. Two preliminary case studies focused on the simultaneous acquisition of electrocardiography (ECG), electrodermal activity (EDA), and accelerometer signals are illustrated and discussed. The results demonstrate the feasibility of the approach, highlighting the potential of EDA in capturing skin conductance responses (SCR) related to pain events in chronic cancer pain. A weak correlation (R = 0.2) is found between SCR parameters and the standard deviation of the interbeat interval series (SDRR), selected as the Heart Rate Variability index. A statistically significant (p < 0.001) increase in both EDA signal and SDRR is detected in movement with respect to rest conditions (assessed by means of the accelerometer signals) in the case of motion-associated cancer pain, thus reflecting the relationship between motor dynamics, which trigger painful responses, and the subsequent activation of the autonomous nervous system. With the objective of integrating parameters obtained from biosignals to establish pain signatures within different clinical scenarios, the proposed framework proves to be a promising research approach to define pain signatures in different clinical contexts

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

Dual-readout Calorimetry

The RD52 Project at CERN is a pure instrumentation experiment whose goal is to understand the fundamental limitations to hadronic energy resolution, and other aspects of energy measurement, in high energy calorimeters. We have found that dual-readout calorimetry provides heretofore unprecedented information event-by-event for energy resolution, linearity of response, ease and robustness of calibration, fidelity of data, and particle identification, including energy lost to binding energy in nuclear break-up. We believe that hadronic energy resolutions of {\sigma}/E $\approx$ 1 - 2% are within reach for dual-readout calorimeters, enabling for the first time comparable measurement preci- sions on electrons, photons, muons, and quarks (jets). We briefly describe our current progress and near-term future plans. Complete information on all aspects of our work is available at the RD52 website http://highenergy.phys.ttu.edu/dream/.Comment: 10 pages, 10 figures, Snowmass White pape

Integrated stratigraphy for the Late Quaternary in the eastern Tyrrhenian Sea

A high-resolution integrated stratigraphy is presented for the Late Quaternary in the southern-eastern Tyrrhenian Sea. It is based on calcareous plankton taxa (planktonic foraminifera and nannoplankton) distribution, d18OGlobigerinoides ruber record, tephrostratigraphy and radiometric dating methods (210Pb and 137Cs, AMS 14C) for a composite sediment core (from the top to the bottom, C90-1m, C90 and C836) from the continental shelf of the Salerno Gulf. High sedimentation rates from ca 1 cm/100 y for the early Holocene, to 3.45 cm/100 y for the middle Holocene to 8.78 cm/100 y from late Holocene and to 20 cm/100 y for the last 600 AD, make this area an ideal marine archive of secular paleoclimate changes. Quantitative distributional trend in planktonic foraminifera identify seven known (1Fe7F) eco-biozones, and several auxiliary bioevents of high potential for Mediterranean biostratigraphic correlation. Recognised were: the acme distribution of Neogloboquadrina pachyderma r.c. between 10.800 0.400 ka BP and 5.500 0.347 ka BP, a strong increase in abundance of Globorotalia truncatulinoides r.c. and l.c. at 5.500 0.347 ka BP and at 4.571 0.96 ka BP, respectively, an acme interval of Globigerinoides quadrilobatus (between 3.702 0.048 ka BP and 2.70 0.048 ka BP) and the acme/paracme intervals of T. quinqueloba (acme between 3.350 0.054 ka BP and 1.492 0.016 ka BP; paracme between 1.492 0.016 ka BP and 0.657 0.025 ka BP; acme beginning 0.657 0.025 ka BP). These results, integrated with trends of selected calcareous nannofossil species (Florisphaera profunda, Brarudosphaera bigelowii, Gephyrocapsa oceanica and Emiliania huxleyi) and d18OG. ruber signature, are consistent with the most important pre-Holocene and early Holocene paleoclimatic and paleoceanographic phases i.e., the BöllingeAllerod, the Younger Dryas and the time interval of Sapropel S1 deposition in the eastern Mediterranean Sea. These features revealed the high potential of this shallow water environment for high-resolution stratigraphy and correlation for the western Mediterranean. In addition, the chemical characterization of seven tephra layers supplied further data about the age and the dispersal area of some well-known Campi Flegrei explosive events, inferring the possible occurrence of explosive activity at Vesuvius around the middle of the 6th century, and contributing to refine the tephrostratigraphic framework for the last 15 ka in the south-eastern Tyrrhenian Sea.Published71-852.2. Laboratorio di paleomagnetismoJCR Journalrestricte

Solid-State 19F NMR Chemical Shift in Square-Planar Nickel-Fluoride Complexes Linked by Halogen Bonds

The halogen bond (XB) is a highly directional class of noncovalent interactions widely explored by experimental and computational studies. However, the NMR signature of the XB has attracted limited attention. The prediction and analysis of the solid-state NMR (SSNMR) chemical shift tensor provide useful strategies to better understand XB interactions. In this work, we employ a computational protocol for modeling and analyzing the 19F SSNMR chemical shifts previously measured in a family of square-planar trans NiII-L2-iodoaryl-fluoride (L = PEt3) complexes capable of forming self-complementary networks held by a NiF···I(C) halogen bond [ Thangavadivale, V. ; Chem. Sci. 2018, 9, 3767−3781 ]. To understand how the 19F NMR resonances of the nickel-bonded fluoride are affected by the XB, we investigate the origin of the shielding in trans-[NiF(2,3,5,6-C6F4I)(PEt3)2], trans-[NiF(2,3,4,5-C6F4I)(PEt3)2], and trans-[NiF(C6F5)(PEt3)2] in the solid state, where a XB is present in the two former systems but not in the last. We perform the 19F NMR chemical shift calculations both in periodic and molecular models. The results show that the crystal packing has little influence on the NMR signatures of the XB, and the NMR can be modeled successfully with a pair of molecules interacting via the XB. Thus, the observed difference in chemical shift between solid-state and solution NMR can be essentially attributed to the XB interaction. The very high shielding of the fluoride and its driving contributor, the most shielded component of the chemical shift tensor, are well reproduced at the 2c-ZORA level. Analysis of the factors controlling the shielding shows how the highest occupied Ni/F orbitals shield the fluoride in the directions perpendicular to the Ni-F bond and specifically perpendicular to the coordination plane. This shielding arises from the magnetic coupling of the Ni(3d)/F(2p lone pair) orbitals with the vacant σNi-F* orbital, thereby rationalizing the very highly upfield (shielded) resonance of the component (δ33) along this direction. We show that these features are characteristic of square-planar nickel-fluoride complexes. The deshielding of the fluoride in the halogen-bonded systems is attributed to an increase in the energy gap between the occupied and vacant orbitals that are mostly responsible for the paramagnetic terms, notably along the most shielded direction

NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene

This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The proband was subjected to NGS, utilizing a customized panel including 24 genes associated with RP and other retinal dystrophies. The NGS analysis revealed a novel missense variant (c.668T &gt; A, I223N) in PRPH2 gene, which was investigated by segregation and bioinformatic analysis. The variant is located in the D2 loop domain of PRPH2, which is critical for protein activity. Bioinformatic analysis described the c.668T &gt; A as a likely pathogenic variant. Moreover, a 3D model prediction was performed to better characterize the impact of the variant on the protein, reporting a disruption of the \u3b1-helical structures. As a result, the variant protein showed a substantially different conformation with respect to the wild-type PRPH2. The identified variant may therefore affect the oligomerization ability of the D2 loop and, ultimately, hamper PRPH2 proper functioning and localization. In conclusion, PRPH2_c.668T &gt; A provided a molecular explanation of RP symptomatology, highlighting the clinical utility of NGS panels to facilitate genotype\u2013phenotype correlations

MEG Upgrade Proposal

We propose the continuation of the MEG experiment to search for the charged lepton flavour violating decay (cLFV) \mu \to e \gamma, based on an upgrade of the experiment, which aims for a sensitivity enhancement of one order of magnitude compared to the final MEG result, down to the $6 \times 10^{-14}$ level. The key features of this new MEG upgrade are an increased rate capability of all detectors to enable running at the intensity frontier and improved energy, angular and timing resolutions, for both the positron and photon arms of the detector. On the positron-side a new low-mass, single volume, high granularity tracker is envisaged, in combination with a new highly segmented, fast timing counter array, to track positron from a thinner stopping target. The photon-arm, with the largest liquid xenon (LXe) detector in the world, totalling 900 l, will also be improved by increasing the granularity at the incident face, by replacing the current photomultiplier tubes (PMTs) with a larger number of smaller photosensors and optimizing the photosensor layout also on the lateral faces. A new DAQ scheme involving the implementation of a new combined readout board capable of integrating the diverse functions of digitization, trigger capability and splitter functionality into one condensed unit, is also under development. We describe here the status of the MEG experiment, the scientific merits of the upgrade and the experimental methods we plan to use.Comment: A. M. Baldini and T. Mori Spokespersons. Research proposal submitted to the Paul Scherrer Institute Research Committee for Particle Physics at the Ring Cyclotron. 131 Page