Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

SummaryPeptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here, we focus on islet amyloid polypeptide (IAPP) mediated loss of insulin secreting cells in diabetics. Newly developed methods enable structure-function inquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two class of pores coexist; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilizing non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalizable approach for inquiry applicable to other partially ordered protein assemblies.HighlightsThe peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.The two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.A drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.The mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.

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Toxic and Non-Toxic Forms of Membrane Poration are Mediated by Structurally Distinct States of Islet Amyloid Polypeptide

Biophysical Journal ◽

10.1016/j.bpj.2016.11.2724 ◽

2017 ◽

Vol 112 (3) ◽

pp. 503a

Author(s):

Melissa Birol ◽

Sunil Kumar ◽

Elizabeth Rhoades ◽

Andrew Miranker

Keyword(s):

Islet Amyloid Polypeptide ◽

Islet Amyloid ◽

Membrane Poration

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Effect of Vibration on Rapeseed Header Loss and Optimization of Header Frame

Transactions of the ASABE ◽

10.13031/trans.13299 ◽

2021 ◽

Vol 64 (4) ◽

pp. 1247-1258

Author(s):

Yang Li ◽

Lizhang Xu ◽

Zhipeng Gao ◽

En Lu ◽

Yaoming Li

Keyword(s):

Modal Analysis ◽

Engine Speed ◽

Vibration Measurement ◽

List Type ◽

Positive Correlation ◽

Combine Harvester ◽

Analysis System ◽

Combine Harvesters ◽

Relationship Of ◽

The Relationship

HighlightsThe relationship of vibration and header loss was studied by multi-point vibration measurement and loss collection test.There was an approximately linear positive correlation between total header vibration and total rapeseed header loss.The header frame was analyzed and optimized through modal simulation and testing.The total rapeseed header loss of the improved header was reduced by 33.2% to 46.9%.Abstract. In view of the current large rapeseed header losses of rape combine harvesters, the effects of the header on rapeseed header loss were studied from the perspective of vibration. First, the vibrations at various measuring points on the header during rape harvest were studied using a data acquisition and analysis system while performing collection tests of rapeseed header loss with the sample slot method. The relationships between total header vibration and total rapeseed header loss and between vertical cutter vibration and rapeseed vertical cutter loss were shown to have a positive correlation, and they all increased with the increase in engine speed. Vertical cutter loss accounted for 31.2% to 42.4% of the total rapeseed header loss. Modal analysis and optimization of the header frame were then performed by simulation and test. The natural frequencies of the first-order and second-order modes of the optimized header were increased, and the possibility of resonance with other working parts was eliminated. Finally, the improved header was tested during rape harvest. The results showed that the total vibration of the improved header was reduced by 19.9% to 43.9%, and the total rapeseed header loss was reduced by 33.2% to 46.9%. The vertical cutter vibration was reduced by 30.5% to 49.8%, and the rapeseed vertical cutter loss was reduced by 20.8% to 34.7%. In addition, the vibration and rapeseed loss of the improved header had relatively slow rates of increase with the increase in engine speed. The method of reducing rapeseed loss by reducing the header vibration achieved an obvious and positive effect. Keywords: Frame optimization, Modal analysis, Rape combine harvester, Rapeseed header loss, Vibration.

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Kinetic and Conformational Insights into Islet Amyloid Polypeptide Self-Assembly Using a Biarsenical Fluorogenic Probe

Bioconjugate Chemistry ◽

10.1021/acs.bioconjchem.7b00827 ◽

2018 ◽

Vol 29 (2) ◽

pp. 517-527 ◽

Cited By ~ 6

Author(s):

Noé Quittot ◽

Mathew Sebastiao ◽

Soultan Al-Halifa ◽

Steve Bourgault

Keyword(s):

Self Assembly ◽

Islet Amyloid Polypeptide ◽

Islet Amyloid ◽

Fluorogenic Probe

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Human Islet Amyloid Polypeptide N-Terminus Fragment Self-Assembly: Effect of Conserved Disulfide Bond on Aggregation Propensity

Journal of the American Society for Mass Spectrometry ◽

10.1007/s13361-016-1347-7 ◽

2016 ◽

Vol 27 (6) ◽

pp. 1010-1018 ◽

Cited By ~ 15

Author(s):

Alexandre I. Ilitchev ◽

Maxwell J. Giammona ◽

Thanh D. Do ◽

Amy G. Wong ◽

Steven K. Buratto ◽

...

Keyword(s):

Disulfide Bond ◽

Self Assembly ◽

Islet Amyloid Polypeptide ◽

Human Islet ◽

Islet Amyloid ◽

Aggregation Propensity ◽

Human Islet Amyloid Polypeptide ◽

N Terminus

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Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach

Journal of The Royal Society Interface ◽

10.1098/rsif.2012.0368 ◽

2012 ◽

Vol 9 (76) ◽

pp. 3118-3128 ◽

Cited By ~ 16

Author(s):

Shanghao Li ◽

Miodrag Micic ◽

Jhony Orbulescu ◽

Jeffrey D. Whyte ◽

Roger M. Leblanc

Keyword(s):

Self Assembly ◽

Islet Amyloid Polypeptide ◽

Langmuir Monolayer ◽

Human Islet ◽

Diabetic Patients ◽

Brewster Angle Microscopy ◽

Islet Amyloid ◽

Type 2 Diabetic Patients ◽

Human Islet Amyloid Polypeptide ◽

Time Zero

Human islet amyloid polypeptide (hIAPP) is the source of the major component of the amyloid deposits found in the islets of Langerhans of around 95 per cent type 2 diabetic patients. The formation of aggregates and mature fibrils is thought to be responsible for the dysfunction and death of the insulin-producing pancreatic β-cells. Investigation on the conformation, orientation and self-assembly of the hIAPP at time zero could be beneficial for our understanding of its stability and aggregation process. To obtain these insights, the hIAPP at time zero was studied at the air–aqueous interface using the Langmuir monolayer technique. The properties of the hIAPP Langmuir monolayer at the air–aqueous interface on a NaCl subphase with pH 2.0, 5.6 and 9.0 were examined by surface pressure- and potential-area isotherms, UV–Vis absorption, fluorescence spectroscopy and Brewster angle microscopy. The conformational and orientational changes of the hIAPP Langmuir monolayer under different surface pressures were characterized by p-polarized infrared-reflection absorption spectroscopy, and the results did not show any prominent changes of conformation or orientation. The predominant secondary structure of the hIAPP at the air–aqueous interface was α-helix conformation, with a parallel orientation to the interface during compression. These results showed that the hIAPP Langmuir monolayer at the air–aqueous interface was stable, and no aggregate or domain of the hIAPP at the air–aqueous interface was observed during the time of experiments.

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Self-Assembly Micro-Nanostructures of Discotic Organic Molecules

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.331.567 ◽

2013 ◽

Vol 331 ◽

pp. 567-571

Author(s):

Yong Sheng Mi ◽

Zhou Yang ◽

Dong Wang ◽

Peng Xia Liang ◽

Zhao Kui Jin

Keyword(s):

Self Assembly ◽

Organic Molecules ◽

Molecular Design ◽

Fluorescence Emission ◽

Cyclic Voltammogram ◽

H Nmr ◽

Ft Ir ◽

Assembly Behavior ◽

Relationship Of ◽

The Relationship

A series of discotic organic molecules with different substituents have been successfully synthesized. The structures of these compounds were fully characterized by 1H-NMR, FT-IR and MS. Their optical and electrical properties were investigated by means of Uv-vis absorption, fluorescence emission and cyclic voltammogram. By exploring the self-assembly behavior of different substituted discotic molecules through method of solvent exchange-evaporation, organic micro-nanostructures such as nanoparticles, nanotubes and nanorods were obtained through supramolecular self-assembly. In order to investigate the applications of these discotic organic molecules, the relationship of molecular design, structural design and material properties has been studied based on the experimental work.

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White matter correlates of hemi-face dominance in happy and sad expression

10.1101/232926 ◽

2017 ◽

Cited By ~ 1

Author(s):

Stefano Ioannucci ◽

Nathalie George ◽

Patrick Friedrich ◽

Leonardo Cerliani ◽

Michel Thiebaut de Schotten

Keyword(s):

White Matter ◽

Emotional Expression ◽

Individual Variability ◽

Cerebral White Matter ◽

List Type ◽

Brain Hemispheres ◽

Neural Underpinnings ◽

Human Participants ◽

Relationship Of ◽

The Relationship

AbstractThe neural underpinnings of human emotional expression are thought to be unevenly distributed among the two brain hemispheres. However, little is known on the anatomy supporting this claim, particularly in the cerebral white matter. Here, we explored the relationship between hemi-face dominance in emotional expression and cerebral white matter asymmetries in 33 healthy participants. Measures of emotional expression were derived from pictures of the participant’s faces in a ‘happy smiling’ and a ‘sad frowning’ conditions. Chimeric faces were constructed by mirroring right and left hemi-faces, as done in previous studies, resulting in a left mirrored and right mirrored chimeric face per picture. To gain measures of hemi-face dominance per participant, a jury of 20 additional participants rated which chimeric face shows higher intensity of emotional expressivity, by marking a 155mm line between the two versions. Measures of the asymmetry of the uncinate, the cingulum and the three branches of superior longitudinal fasciculi were derived from diffusion weighted imaging tractography dissections. Group effect analyses indicated that the degree of asymmetry in emotional expression was not as prominent as reported in the literature and showed a large inter-individual variability. The degree of asymmetry in emotional expression was, however, significantly associated with the asymmetries in connective properties of the fronto-temporal and fronto-parietal tracts, specifically the uncinate fasciculus and the first branch of the superior longitudinal fasciculus. Therefore, this result raises novel hypotheses on the relationship of specific white matter tracts and emotional expression, especially their role in mood disorders.Ethical statementNone of the authors have a conflict of interestData collection from human participants was approved by the Comité de Protection des Personnes “CPP Ile de France V”All participants provided written informed consentFunding from ERC (grant agreement No. 818521) and “Agence Nationale de la Recherche” [grants numbers ANR-13-JSV4-0001-01 an ANR-10-IAIHU-06]

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