Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD

Aprovechamiento de materiales locales en la estructura de pavimentos urbanos económicos

Se estudiaron las propiedades de un suelo representativo del partido de 25 de Mayo (Prov. de Buenos Aires) y su zona de influencia, con el objeto de conocer la posibilidad de utilizarlo como base y sub-base de pavimentos urbanos. Se analizó el comportamiento del suelo, realizando mezclas con emulsión bituminosa superestable EBL2, como así también mezclas de suelo-cemento. De la comparación de ambos casos surgen consideraciones técnico-económicas, en base a las cuales se dan posibles soluciones de pavimento.In this paper were studied the properties of a representative soil of 25 de Mayo district, in the Buenos Aires Province, with the object to establish the possibility of its use as a base and sub-base in urban pavements. The soil behaviour vms analyzed making mixtures with su- perstnble EBL2 bituminous emulsions and also with soil-cement mixtures. The results obtained with both mixtures were compared and technical and economical considerations were given

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Precision measurements of Linear Scattering Density using Muon Tomography

We demonstrate that muon tomography can be used to precisely measure the properties of various materials. The materials which have been considered have been extracted from an experimental blast furnace, including carbon (coke) and iron oxides, for which measurements of the linear scattering density relative to the mass density have been performed with an absolute precision of 10%. We report the procedures that are used in order to obtain such precision, and a discussion is presented to address the expected performance of the technique when applied to heavier materials. The results we obtain do not depend on the specific type of material considered and therefore they can be extended to any application.Comment: 16 pages, 4 figure

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Investigation of the Mechanism of Action of AMPs from Amphibians to Identify Bacterial Protein Targets for Therapeutic Applications

: Antimicrobial peptides (AMPs) from amphibians represent a promising source of novel antibacterial agents due to their potent and broad-spectrum antimicrobial activity, which positions them as valid alternatives to conventional antibiotics. This review provides a comprehensive analysis of the mechanisms through which amphibian-derived AMPs exert their effects against bacterial pathogens. We focus on the identification of bacterial protein targets implicated in the action of these peptides and on biological processes altered by the effect of AMPs. By examining recent advances in countering multidrug-resistant bacteria through multi-omics approaches, we elucidate how AMPs interact with bacterial membranes, enter bacterial cells, and target a specific protein. We discuss the implications of these interactions in developing targeted therapies and overcoming antibiotic resistance (ABR). This review aims to integrate the current knowledge on AMPs' mechanisms, identify gaps in our understanding, and propose future directions for research to harness amphibian AMPs in clinical applications

A critical inventory of the family Amaranthaceae s.str. in Saudi Arabia

The aims of the present study are to assess and update the floristic diversity of Amaranthaceae s.str. in Saudi Arabia. A total number of 33 taxa were indentified including 28 species, 4 subspecies, and 7 varieties. The richest genus is Amaranthus with 16 taxa (12 species); Aerva and Alternanthera have 3 species each; Achyranthes and Celosia 2 species each; 6 genera (Digera, Gomphrena, Nothosaerva, Psilotrichum, Pupalia, Saltia) include just one species each. Most of the taxa are native (18, 54.55%), 14 (42.42%) are aliens (6 casual taxa, 5 naturalized, and 1 invasive), one (Alternanthera sessilis) is here considered as doubtfully native, two (Amaranthus tricolor, Gomphrena globosa) are found only in cultivation. Two species (Amaranthus tortuosum, Pupalia lappacea var. lappacea) are excluded from the national flora. Diagnostic keys at genus, species, and infraspecific ranks are provided. The following names are lectotypified: Achyranthes argentea var. obovata (G; isolectotype at HBG), Achyranthes fruticosa var. pubescens (G), Achyranthes papposa (C; isolectotypes at C and BM), Achyranthes polystachya (BM), Aerva javanica var. bovei (FI), Achyranthes lanata (illustration by Burman), Digera arvensis (C; isolectotype at C), Psilostachys gnaphalobryum (TUB; isolectotypes at GOET, HBG, HEID, JE, MEL, MPU, P, and TUB), Telanthera bettzickiana (LE)