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David J Koss, Glynn Jones, Anna Cranston, Heidi Gardner, Nicholas M Kanaan, Bettina Platt
Post-mortem investigations of human Alzheimer's disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities...
October 21, 2016: Acta Neuropathologica
Natalia Eliza Domeradzka, Marc W T Werten, Frits A de Wolf, Renko de Vries
Previously, we developed triblock protein polymers that form fibrillar hydrogels at low protein polymer concentrations (denoted C2-SH48-C2). We here demonstrate that the structure of these hydrogels can be tuned via heterodimeric coiled coils that cross-link and bundle the self-assembled protein-polymer fibrils. We fused well-characterized, 47 amino acids-long heterodimeric coiled coil "linkers" (DA or DB) to the C-terminus of the triblock polymer. The resulting C2-SH48-C2-DA and C2-SH48-C2-DB polymers, were successfully produced as secreted proteins in Pichia pastoris, with titers of purified protein in the order of g L-1 of clarified broth...
October 21, 2016: Biomacromolecules
Bruce Wen, Kirby R Campbell, Karissa Tilbury, Oleg Nadiarnykh, Molly A Brewer, Manish Patankar, Vikas Singh, Kevin W Eliceiri, Paul J Campagnola
Remodeling of the collagen architecture in the extracellular matrix (ECM) has been implicated in ovarian cancer. To quantify these alterations we implemented a form of 3D texture analysis to delineate the fibrillar morphology observed in 3D Second Harmonic Generation (SHG) microscopy image data of normal (1) and high risk (2) ovarian stroma, benign ovarian tumors (3), low grade (4) and high grade (5) serous tumors, and endometrioid tumors (6). We developed a tailored set of 3D filters which extract textural features in the 3D image sets to build (or learn) statistical models of each tissue class...
October 21, 2016: Scientific Reports
Akihiko Hosoi, Yu Su, Masaharu Torikai, Hirofumi Jono, Daisuke Ishikawa, Kenji Soejima, Hirofumi Higuchi, Jianying Guo, Mitsuharu Ueda, Genki Suenaga, Hiroaki Motokawa, Tokunori Ikeda, Satoru Senju, Toshihiro Nakashima, Yukio Ando
Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death approximately 10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very important for amyloid formation and deposition in the organs, no effective therapy targeting this step is available. In this study, we generated a mouse monoclonal antibody T24 which recognized the cryptic epitope of conformationally-changed TTR...
October 7, 2016: Journal of Biological Chemistry
Jack R Staunton, Wilfred Vieira, King Leung Fung, Ross Lake, Alexus Devine, Kandice Tanner
One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue's mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs...
September 2016: Cellular and Molecular Bioengineering
Cuilian Liu, Halei Zhai, Zhisen Zhang, Yaling Li, Xurong Xu, Ruikang Tang
Hydroxyapatite (HAP) nanocrystallites in all types of bones are distinguished by their ultrathin characteristics, which are uniaxially oriented with fibrillar collagen to uniquely expose the (100) faces. We speculate that living organisms prefer the specific crystal morphology and orientation of HAP because of the interactions between cells and crystals at the mineral-cell interface. Here, bone-like platy HAP (p-HAP) and two different rod-like HAPs were synthesized to investigate the ultrathin mineral modulating effect on cell bioactivity and bone generation...
October 18, 2016: ACS Applied Materials & Interfaces
Tiernan Thomas O'Malley, William M Wittbold, Sara Linse, Dominic M Walsh
Extracts of Alzheimer's disease (AD) brain that contain what appear to be SDS-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated from Aβ monomer, consist primarily of Aβ42 and resist denaturation by powerful chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in only one of two different ways - either by the formation of a dityrosine (DiY) or an isopeptide ε-(γ-glutamyl)-lysine (Q-K) bond...
October 17, 2016: Biochemistry
Jimmy Tat, Aaron M Kociolek, Peter J Keir
The most common finding in carpal tunnel syndrome is fibrosis and thickening of the subsynovial connective tissue (SSCT). While the SSCT mediates tendon gliding in the carpal tunnel, this histopathology suggests excessive shear forces are involved in injury development. Ultrasound is often used to quantify relative motion between the finger flexor tendons and SSCT as an indirect measure of "shear-strain"; however, the underlying mechanical implications of using ultrasound are not well understood. The middle flexor digitorum superficialis (FDS) tendon of 8 cadavers was moved in a combination of 2 wrist postures (neutral, flexed), 3 velocities (5, 10, 15cm/s), and 3 forces (10, 20, 30N) to assess ultrasound-based FDS-SSCT relative displacement while simultaneously quantifying tendon frictional work in the carpal tunnel...
October 6, 2016: Journal of Biomechanics
Heidrun Maja Ries, Carmen Nussbaum-Krammer
A particular subgroup of protein-misfolding diseases, comprising Alzheimer's and Parkinson's disease, involves amyloidogenic proteins that can form alternative pathogenic conformations with a high tendency to self-assemble into oligomeric and fibrillar species. Although misfolded proteins have been clearly linked to disease, the exact nature of the toxic species remains highly controversial. Increasing evidence suggests that there is little correlation between the occurrence of macroscopic protein deposits and toxic phenotypes in affected cells and tissues...
October 15, 2016: Essays in Biochemistry
Ximena Zottig, Mathieu Laporte Wolwertz, Makan Golizeh, Leanne Ohlund, Lekha Sleno, Steve Bourgault
Light chain amyloidosis (AL) originates from the deposition of immunoglobulin light chains (LCs) as amyloid fibrils in the extracellular space of vital organs. Although non-enzymatic post-translational modifications (PTMs) have been shown to contribute to protein misfolding diseases, little is known about their contributions to LC amyloidogenicity. In this study, we investigated the effects of three oxidative PTMs, carbonylation by hydroxynonenal (HNE), oxidation and nitration, on the structure, thermodynamic stability and self-assembly propensity of a LC variable domain from the λ6 germline, Wil...
October 11, 2016: Biophysical Chemistry
Yan Zhang, Richard G Weiss
The structural and dynamic properties of molecular gels, made from 9 structurally-related mono-, di, and tri-hydroxymethylated alkanamide gelators, have been examined at different distance scales. The subtle changes in the gelator structures, in terms of the number of hydroxymethyl groups and the length of the alkanamide chain, have been correlated with the type of the self-assembled fibrillar networks and the viscoelasticity of the gels as well as the characteristics of the liquid as indicated by Hansen solubility parameters...
October 5, 2016: Journal of Colloid and Interface Science
Marta Mikolajczak, Timothy Goodman, Mohammad K Hajihosseini
Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb (FGFR2-IIIb) result in two human syndromes - LADD (lacrimo-auriculo-dento-digital) and ALSG (Aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells. However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic...
October 14, 2016: Biochemical Journal
Kerstin Kick, Katharina Nekolla, Markus Rehberg, Angelika M Vollmar, Stefan Zahler
OBJECTIVE: Cell-matrix interactions are crucial for regulating cellular activities, such as migration. This is of special importance for morphogenic processes, such as angiogenesis (the development of new blood vessels). Most of our understanding of cell migration relies on 2-dimensional (2D) experiments. However, the awareness that 3D settings might elicit different results has increased. Knowledge about endothelial cell (EC) behavior in 3D environments and the influence of matrix composition on EC migration, in particular, is still limited...
October 13, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Luiz Alexandre Chisini, Marcus Cristian Muniz Conde, Jose Carlos Bernedo Alcázar, Adriana Fernandes da Silva, Jacques Eduardo Nör, Sandra Beatriz Chaves Tarquinio, Flávio Fernando Demarco
The aim of the present study was to evaluate the expression of transforming growth factor-β1 (TGF-β1) and osteonectin (ON) in pulp-like tissues developed by tissue engineering and to compare it with the expression of these proteins in pulps treated with Ca(OH)2 therapy. Tooth slices were obtained from non-carious human third molars under sterile procedures. The residual periodontal and pulp soft tissues were removed. Empty pulp spaces of the tooth slice were filled with sodium chloride particles (250-425 µm)...
October 10, 2016: Brazilian Oral Research
Neal K Bennett, Rebecca Chmielowski, Dalia S Abdelhamid, Jonathan J Faig, Nicola Francis, Jean Baum, Zhiping P Pang, Kathryn E Uhrich, Prabhas V Moghe
Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers...
December 2016: Biomaterials
Deep Sankar Pal, Haridas Kar, Suhrit Ghosh
Photo-initiated supramolecular polymerization of a naphthalenediimide (NDI-1) derivative containing an ortho-nitrobenzyl (ONB)-protected amide group is demonstrated. In a hydrocarbon solvent (methylcyclohexane), it remains as monomer. Upon photo-irradiation, deprotection of the ONB group produces NDI-2 with a free amide group, which drives supramolecular polymerization by self-complementary H-bonding between the amide groups, leading to gelation. The polymerization rate can be controlled by tuning the energy of the light source...
October 13, 2016: Chemistry: a European Journal
Susanne Wegmann, Samantha Nicholls, Shuko Takeda, Zhanyun Fan, Bradley T Hyman
Tau is a neuronal microtubule binding protein that, in Alzheimer's disease and other neurodegenerative diseases, can form oligomeric and large fibrillar aggregates, which deposit in neurofibrillary tangles. Tau's physiological state of multimerization appears to vary across conditions, and a stable dimeric form of soluble tau has been suggested from experiments using recombinant tau in vitro. We tested if tau dimerization, or oligomerization, also occurs in cells, and if soluble tau oligomers are relevant for the release and internalization of tau...
October 12, 2016: Journal of Neurochemistry
Chen Hongbo, Duo Yanhong, Hu Bo, Wang Zhiwei, Zhang Fang, Tsai Hsiangi, Zhang Jianping, Zhou Lanzhen, Wang Lijun, Wang Xinyu, Huang Laiqiang
PICT-1 was originally identified as a tumor suppressor. Here, we found that PICT-1 overexpression triggered pro-death autophagy without nucleolar disruption or p53 accumulation in U251 and MCF7 cells. Truncated PICT-1 fragments 181-346 and 1-346, which partly or totally lack nucleolar localization, showed weaker autophagy-inducing effects than full-length PICT-1 and a well-defined nucleolar mutant (181-479). Furthermore, PICT-1 partly localizes to the nucleolar fibrillar center (FC) and directly binds to ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF)...
September 27, 2016: Oncotarget
Olivera Evrova, Vahid Hosseini, Vincent Milleret, Gemma Palazzolo, Marcy Zenobi-Wong, Tullio Sulser, Johanna Buschmann, Daniel Eberli
Cellular responses are regulated by their microenvironments and engineered synthetic scaffolds can offer control over different microenvironment properties. This important relationship can be used as a tool to manipulate cell fate and cell responses for different biomedical applications. We showed for the first time in this study how blending of poly(ethylene oxide) (PEO) to poly(lactic-co-glycolic acid) (PLGA) fibers to yield hybrid scaffolds changes physical and mechanical properties of PLGA fibrous scaffolds and in turn affects cellular response...
October 11, 2016: ACS Applied Materials & Interfaces
Xiaohui Zhao, Linda A Kotilinek, Benjamin Smith, Chris Hlynialuk, Kathleen Zahs, Martin Ramsden, James Cleary, Karen H Ashe
In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD...
October 10, 2016: Nature Medicine
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