scholarly journals The Relation Between α-Helical Conformation and Amyloidogenicity

2017 ◽  
Author(s):  
B. Haimov ◽  
S. Srebnik
Keyword(s):  
Amyloid Fibrils ◽  
Clinical Importance ◽  
Helical Structure ◽  
Data Bank ◽  
Amino Acid Sequences ◽  
Helical Conformation ◽  
Folded Proteins ◽  
Two Parameters

ABSTRACTAmyloid fibrils are stable aggregates of misfolded proteins and polypeptides that are insoluble and resistant to protease activity. Abnormal formation of amyloid fibrils in vivo may lead to neurodegenerative disorders and other systemic amyloidosis such as Alzheimer’s, Parkinson’s, and atherosclerosis. Because of their clinical importance amyloids are found under intense scientific research. Amyloidogenic sequences of short polypeptide segments within proteins are responsible for the transformation of correctly folded proteins into parts of larger amyloid fibrils. The α-helical secondary structure is believed to host many amyloidogenic sequences and be a key player in different stages of the amyloidogenesis process. Most of the studies on amyloids focus on the role of amyloidogenic sequences. The focus of this study is the relation between amyloidogenicity and the structure of the amyloidogenic α-helical sequence. We have previously shown that the α-helical conformation may be expressed by two parameters (θ and ρ) that form orthogonal coordinates based on the Ramachandran dihedrals (φ and ψ) and provide an illuminating interpretation of the α-helical conformation. By performing statistical analysis on α-helical conformations found in the protein data bank, an apparent relation between α-helical conformation, as expressed by θ and ρ, and amyloidogenicity is revealed. Remarkably, random amino acid sequences, whose helical structure was obtained from the most probably dihedral angles as obtained from PDB data, revealed the same dependency of amyloidogenicity, suggesting the importance of α-helical structure as opposed to sequence.

Oestrogens in breast tumours and fat

1989 ◽  
Vol 95 ◽  
pp. 161-168
Author(s):  
J. H. H. Thijssen ◽  
M. A. Blankenstein
Keyword(s):  
Biological Effects ◽  
Plasma Concentrations ◽  
Normal Breast ◽  
Malignant Tumours ◽  
Breast Tumours ◽  
Two Parameters ◽  
Breast Tissues

SynopsisThe levels of endogenous steroids in the target tissues are thought to be more closely related to the biological effects than their concentrations in plasma. Therefore studies on oestrogen levels in malignant and non-malignant breast tissues (expressed per g wet weight) were conducted and the following conclusions were drawn:(1) malignant tumours contained higher oestradiol levels than normal or benign breast tissues, whereas oestrone levels were more comparable;(2) in contrast to the large decrease in plasma concentrations after menopause, the levels of oestradiol in tumours and in normal breast tissue did not change with advancing age;(3) the oestradiol levels in breast tissues were lower than in uterine tissues, particularly in women before menopause; oestrone levels were very similar in all tissues studied;(4) the mean oestradiol level was higher in oestrogen-receptor-positive tumours, but no correlation between the two parameters was found;(5) preliminary results indicated lower oestradiol levels in tumours obtained from countries with a lower incidence of breast cancer;(6) as far as available, oestrone levels were comparable and those of oestradiol were lower in fat tissues than in breast tumours;(7) neither in vitro studies with breast tumours, nor in vivo results using myometrial tissues support a prominent role of the metabolism of oestrogens at the 16α-position in the development of tumours;(8) the role of local factors in the production, retention and metabolism of oestradiol in the breast remains to be elucidated.

scholarly journals Modelling approaches for evaluating multiscale tendon mechanics

2016 ◽  
Vol 6 (1) ◽  
pp. 20150044 ◽  
Author(s):  
Fei Fang ◽  
Spencer P. Lake
Keyword(s):  
Computational Models ◽  
Mechanical Response ◽  
Helical Structure ◽  
Mechanical Analysis ◽  
Hierarchical Organization ◽  
Organization Model ◽  
Tendon Mechanics ◽  
Modelling Approaches

Tendon exhibits anisotropic, inhomogeneous and viscoelastic mechanical properties that are determined by its complicated hierarchical structure and varying amounts/organization of different tissue constituents. Although extensive research has been conducted to use modelling approaches to interpret tendon structure–function relationships in combination with experimental data, many issues remain unclear (i.e. the role of minor components such as decorin, aggrecan and elastin), and the integration of mechanical analysis across different length scales has not been well applied to explore stress or strain transfer from macro- to microscale. This review outlines mathematical and computational models that have been used to understand tendon mechanics at different scales of the hierarchical organization. Model representations at the molecular, fibril and tissue levels are discussed, including formulations that follow phenomenological and microstructural approaches (which include evaluations of crimp, helical structure and the interaction between collagen fibrils and proteoglycans). Multiscale modelling approaches incorporating tendon features are suggested to be an advantageous methodology to understand further the physiological mechanical response of tendon and corresponding adaptation of properties owing to unique in vivo loading environments.

scholarly journals STIL-a novel link in Shh and Wnt signaling, endowing oncogenic and stem like attributes to colorectal cancer

2020 ◽  
Author(s):  
Tapas Pradhan ◽  
Vikas Kumar ◽  
H Evangeline Surya ◽  
R Krishna ◽  
Samu John ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Importance ◽  
Disease Free Survival ◽  
Drug Resistant ◽  
Free Survival ◽  
Over Expression ◽  
Disease Free

AbstractDiscovery of potent gene regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene, however its molecular insights and role in colorectal oncogenesis are unknown. In this study we have explored role of STIL in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 & CD44 and drug resistant markers Thymidylate synthase, ABCB1 & ABCG2 both in in-vitro and in-vivo CRC models. In addition, over expression of STIL mRNA was found to be associated with reduced disease free survival in CRC cases. To our surprise we observed an Shh independent regulation of stemness and drug resistant genes mediated by STIL. Interestingly, we found an Shh independent regulation of β-catenin mediated by STIL via p-AKT, which partially answers Shh independent regulatory mechanism of CSC markers by STIL. Our study suggest an instrumental role of STIL in molecular manifestation of CRC and progression.

scholarly journals Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Arnaud Pautrat ◽  
Marta Rolland ◽  
Margaux Barthelemy ◽  
Christelle Baunez ◽  
Valérie Sinniger ◽  
...  
Keyword(s):  
Subthalamic Nucleus ◽  
Neurological Diseases ◽  
Clinical Importance ◽  
Parabrachial Nucleus ◽  
Nociceptive Responses ◽  
Nociceptive Information ◽  
Prevalent Symptom ◽  
Deep Brain

Pain is a prevalent symptom of Parkinson’s disease, and is effectively treated by deep brain stimulation of the subthalamic nucleus (STN). However, the link between pain and the STN remains unclear. In the present work, using in vivo electrophysiology in rats, we report that STN neurons exhibit complex tonic and phasic responses to noxious stimuli. We also show that nociception is altered following lesions of the STN, and characterize the role of the superior colliculus and the parabrachial nucleus in the transmission of nociceptive information to the STN, physiologically from both structures and anatomically in the case of the parabrachial nucleus. We show that STN nociceptive responses are abnormal in a rat model of PD, suggesting their dependence on the integrity of the nigrostriatal dopaminergic system. The STN-linked nociceptive network that we reveal is likely to be of considerable clinical importance in neurological diseases involving a dysfunction of the basal ganglia.

scholarly journals Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

2015 ◽  
Vol 290 (34) ◽  
pp. 20947-20959 ◽  
Author(s):  
Chiharu Mizuguchi ◽  
Fuka Ogata ◽  
Shiho Mikawa ◽  
Kohei Tsuji ◽  
Teruhiko Baba ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Helical Structure ◽  
Lipid Binding ◽  
Fibril Formation ◽  
Random Coil ◽  
Helical Conformation ◽  
Apolipoprotein A ◽  
Terminal Fragment ◽  
Lipid Environment

The N-terminal amino acid 1–83 fragment of apolipoprotein A-I (apoA-I) has a strong propensity to form amyloid fibrils at physiological neutral pH. Because apoA-I has an ability to bind to lipid membranes, we examined the effects of the lipid environment on fibril-forming properties of the N-terminal fragment of apoA-I variants. Thioflavin T fluorescence assay as well as fluorescence and transmission microscopies revealed that upon lipid binding, fibril formation by apoA-I 1–83 is strongly inhibited, whereas the G26R mutant still retains the ability to form fibrils. Such distinct effects of lipid binding on fibril formation were also observed for the amyloidogenic prone region-containing peptides, apoA-I 8–33 and 8–33/G26R. This amyloidogenic region shifts from random coil to α-helical structure upon lipid binding. The G26R mutation appears to prevent this helix transition because lower helical propensity and more solvent-exposed conformation of the G26R variant upon lipid binding were observed in the apoA-I 1–83 fragment and 8–33 peptide. With a partially α-helical conformation induced by the presence of 2,2,2-trifluoroethanol, fibril formation by apoA-I 1–83 was strongly inhibited, whereas the G26R variant can form amyloid fibrils. These findings suggest a new possible pathway for amyloid fibril formation by the N-terminal fragment of apoA-I variants: the amyloidogenic mutations partially destabilize the α-helical structure formed upon association with lipid membranes, resulting in physiologically relevant conformations that allow fibril formation.

WHAT DID OUR ANCESTORS LOOK LIKE? OR, THE CAPABILITIES OF ANTHROPOLOGICAL RECONSTRUCTION

2021 ◽  
Vol 43 (3) ◽  
pp. 347-360
Author(s):  
Elizaveta VESELOVSKAYA ◽  
Keyword(s):  
Data Bank ◽  
Physical Anthropology ◽  
Current State ◽  
Historical Figures ◽  
Ancient People ◽  
Visual Reconstruction ◽  
Academy Of Sciences ◽  
Second World

Anthropological Reconstruction Laboratory of the Center for Physical Anthropology, Institute of Ethnology and Anthropology RAS. The article relates the current state of the M.M. Gerasimov Laboratory of Anthropological Reconstruction of the Center for Physical Anthropology, Institute of Ethnology and Anthropology, Russian Academy of Sciences. Emphasizing the role of the founder of the method of face reconstruction from the skull, the author discusses the latest improvements to this method. The data bank on the thickness of the facial integument in representatives of various ethnic groups, and the accumulated experience with regard to the relationships between facial features and the underlying structures of the skull, made it possible to create a program of craniofacial correspondence ‘The Algorithm of Appearance’, which significantly improves the process of reconstructing in vivo appearance based on the skull. The visual reconstruction of the appearance is supplemented by an anthropological description of the lifetime appearance, in terms of the ‘verbal portrait’ used in forensic science. A description of a unique collection of more than 300 sculptural and graphic portraits made on the basis of the skulls of ancient people and historical figures is given. Based on the examples of specific projects, the possibilities of anthropological reconstruction for solving applied and theoretical problems of science are shown. The reconstruction of the appearance of soldiers killed in the Second World War is the key patriotic direction of the Laboratory s work. Based on the results of these reconstructions, several fi were identifi Th Laboratory is currently at work on reconstructing the lifetime appearance of A.V. Suvorov on the basis of a death mask.

scholarly journals Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

2017 ◽  
Vol 37 (17) ◽  
Author(s):  
Therese Jacobson ◽  
Smriti Priya ◽  
Sandeep K. Sharma ◽  
Stefanie Andersson ◽  
Sofia Jakobsson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cadmium Toxicity ◽  
Cytosolic Proteins ◽  
Content Type ◽  
Folded Proteins ◽  
Protein Folding Disorders ◽  
Induced Aggregation

ABSTRACT Cadmium is a highly poisonous metal and is classified as a human carcinogen. While its toxicity is undisputed, the underlying in vivo molecular mechanisms are not fully understood. Here, we demonstrate that cadmium induces aggregation of cytosolic proteins in living Saccharomyces cerevisiae cells. Cadmium primarily targets proteins in the process of synthesis or folding, probably by interacting with exposed thiol groups in not-yet-folded proteins. On the basis of in vitro and in vivo data, we show that cadmium-aggregated proteins form seeds that increase the misfolding of other proteins. Cells that cannot efficiently protect the proteome from cadmium-induced aggregation or clear the cytosol of protein aggregates are sensitized to cadmium. Thus, protein aggregation may contribute to cadmium toxicity. This is the first report on how cadmium causes misfolding and aggregation of cytosolic proteins in vivo. The proposed mechanism might explain not only the molecular basis of the toxic effects of cadmium but also the suggested role of this poisonous metal in the pathogenesis of certain protein-folding disorders.

scholarly journals STIL Endows Oncogenic and Stem-Like Attributes to Colorectal Cancer Plausibly by Shh and Wnt Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Tapas Pradhan ◽  
Vikas Kumar ◽  
Evangeline Surya H ◽  
R. Krishna ◽  
Samu John ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Importance ◽  
Disease Free Survival ◽  
Drug Resistant ◽  
Free Survival ◽  
Shh Pathway ◽  
Disease Free

The discovery of a potent gene regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene; however, its molecular associations and role in colorectal oncogenesis are unknown. In this study, we have explored the role of STIL gene in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 and CD44 and drug resistant markers thymidylate synthase, ABCB1, and ABCG2 both in in-vitro and in-vivo CRC models. In addition, high expression of STIL mRNA was found to be associated with reduced disease-free survival in CRC cases. Interestingly, we observed that STIL-mediated regulation of stemness and drug resistant genes is not exclusively governed by Sonic hedgehog (Shh) signaling. Remarkably, we found STIL regulate β-catenin levels through p-AKT, independent of Shh pathway. This partially answers Shh independent regulatory mechanism of cancer stem cell (CSC) markers by STIL. Our study suggests an instrumental role of STIL in molecular manifestation of CRC and progression.

scholarly journals Conservation of Structure and Protein-Protein Interactions Mediated by the Secreted Mycobacterial Proteins EsxA, EsxB, and EspA

2009 ◽  
Vol 192 (1) ◽  
pp. 326-335 ◽  
Author(s):  
Brian Callahan ◽  
Kiet Nguyen ◽  
Alissa Collins ◽  
Kayla Valdes ◽  
Michael Caplow ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Helical Structure ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Structures And Properties ◽  
Virulence Protein ◽  
Single Polypeptide ◽  
Specific Association

ABSTRACT Mycobacterium tuberculosis EsxA and EsxB proteins are founding members of the WXG100 (WXG) protein family, characterized by their small size (∼100 amino acids) and conserved WXG amino acid motif. M. tuberculosis contains 11 tandem pairs of WXG genes; each gene pair is thought to be coexpressed to form a heterodimer. The precise role of these proteins in the biology of M. tuberculosis is unknown, but several of the heterodimers are secreted, which is important for virulence. However, WXG proteins are not simply virulence factors, since nonpathogenic mycobacteria also express and secrete these proteins. Here we show that three WXG heterodimers have structures and properties similar to those of the M. tuberculosis EsxBA (MtbEsxBA) heterodimer, regardless of their host species and apparent biological function. Biophysical studies indicate that the WXG proteins from M. tuberculosis (EsxG and EsxH), Mycobacterium smegmatis (EsxA and EsxB), and Corynebacterium diphtheriae (EsxA and EsxB) are heterodimers and fold into a predominately α-helical structure. An in vivo protein-protein interaction assay was modified to identify proteins that interact specifically with the native WXG100 heterodimer. MtbEsxA and MtbEsxB were fused into a single polypeptide, MtbEsxBA, to create a biomimetic bait for the native heterodimer. The MtbEsxBA bait showed specific association with several esx-1-encoded proteins and EspA, a virulence protein secreted by ESX-1. The MtbEsxBA fusion peptide was also utilized to identify residues in both EsxA and EsxB that are important for establishing protein interactions with Rv3871 and EspA. Together, the results are consistent with a model in which WXG proteins perform similar biological roles in virulent and nonvirulent species.

scholarly journals The Human NUP58 Nucleoporin Can Form Amyloids In Vitro and In Vivo

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1451
Author(s):  
Lavrentii G. Danilov ◽  
Svetlana E. Moskalenko ◽  
Andrew G. Matveenko ◽  
Xenia V. Sukhanova ◽  
Mikhail V. Belousov ◽  
...  
Keyword(s):  
Phase Separation ◽  
Disulfide Bonds ◽  
Amyloid Fibrils ◽  
Bioinformatic Analysis ◽  
Amyloid Formation ◽  
Amyloid Aggregates ◽  
Protease Treatment

Amyloids are fibrillar protein aggregates with a cross-β structure and unusual features, including high resistance to detergent or protease treatment. More than two hundred different proteins with amyloid or amyloid-like properties are already known. Several examples of nucleoporins (e.g., yeast Nup49, Nup100, Nup116, and human NUP153) are supposed to form amyloid fibrils. In this study, we demonstrated an ability of the human NUP58 nucleoporin to form amyloid aggregates in vivo and in vitro. Moreover, we found two forms of NUP58 aggregates: oligomers and polymers stabilized by disulfide bonds. Bioinformatic analysis revealed that all known orthologs of this protein are potential amyloids which possess several regions with conserved ability to aggregation. The biological role of nucleoporin amyloid formation is debatable. We suggest that it is a rather abnormal process, which is characteristic for many proteins implicated in phase separation.

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