scholarly journals Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

2021 ◽  
Author(s):  
Nikolaos N Louros ◽  
Meine Ramakers ◽  
Emiel Michiels ◽  
Katerina Konstantoulea ◽  
Chiara Morelli ◽  
...  
Keyword(s):  
Sequence Homology ◽  
Protein Sequences ◽  
Sequence Specificity ◽  
Structural Mechanism ◽  
Structural Rules ◽  
Amyloidogenic Proteins ◽  
Systematic Understanding ◽  
Fibril Morphology ◽  
Amyloid Assembly

Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using this knowledge, we demonstrate, using tau as a model system, that predicted cross-interactions driven by sequence homology indeed can modify nucleation, fibril morphology, kinetic assembly and cellular spreading of aggregates. We also find that these heterotypic amyloid interactions can result in the mis-localisation of brain-expressed protein sequences with prevalent activities in neurodegenerative disorders. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.

scholarly journals Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β40 (Aβ40) by the peptide fragment Aβ16–22

2019 ◽  
Vol 5 (6) ◽  
pp. eaav8216 ◽  
Author(s):  
Samuel J. Bunce ◽  
Yiming Wang ◽  
Katie L. Stewart ◽  
Alison E. Ashcroft ◽  
Sheena E. Radford ◽  
...  
Keyword(s):  
Random Coil ◽  
Peptide Fragments ◽  
Secondary Nucleation ◽  
Dynamic Interactions ◽  
Structural Mechanism ◽  
Dynamics Simulations ◽  
Transient Intermediates ◽  
Amyloid Assembly ◽  
Amyloid Diseases

Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ40 and Aβ16–22, two widely studied peptide fragments of Aβ42 implicated in Alzheimer’s disease. We demonstrate that Aβ16–22 increases the aggregation rate of Aβ40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ40 monomers/oligomers on the surface of preformed Aβ16–22 fibrils nucleate Aβ40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.

Big Data and Sustainable Consumption: A Review and Research Agenda

2021 ◽  
pp. 097226292110225
Author(s):  
Shobhana Chandra ◽  
Sanjeev Verma
Keyword(s):  
Big Data ◽  
Consumer Behaviour ◽  
Business Models ◽  
Sustainable Consumption ◽  
Big Data Analytics ◽  
Consumption Behaviour ◽  
Consumer Experiences ◽  
Systematic Understanding ◽  
The Impact

Big data (BD) is making advances in promoting sustainable consumption behaviour and has attracted the attention of researchers worldwide. Despite the increased focus, the findings of studies on this topic are fragmented, and future researchers need a systematic understanding of the existing literature for identification of the research scope. This study offers a systematic review of the role of BD in promoting sustainable-consumption behaviour with the help of a bibliometric analysis, followed by a thematic analysis. The findings suggest that businesses deploy BD to create sustainable consumer experiences, predict consumer buying patterns, design and alter business models and create nudges for sustainable consumption, while consumers are forcing businesses to develop green operations and supply chains to reduce the latter’s carbon footprint. The major research gaps for future researchers are in the following areas: the impact of big data analytics (BDA) on consumerism, the role of BD in the formation of sustainable habits and consumer knowledge creation for sustainable consumption and prediction of green consumer behaviour.

scholarly journals Heparan sulfate and heparin interactions with proteins

2015 ◽  
Vol 12 (110) ◽  
pp. 20150589 ◽  
Author(s):  
Maria C. Z. Meneghetti ◽  
Ashley J. Hughes ◽  
Timothy R. Rudd ◽  
Helena B. Nader ◽  
Andrew K. Powell ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Ex Vivo ◽  
Sequence Specificity ◽  
Structure Activity ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Heparin Activity

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro , ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed.

scholarly journals Genomic imprinting in germ cells: imprints are under control

Reproduction ◽  
2010 ◽  
Vol 140 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Philippe Arnaud
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Germ Cells ◽  
Imprinted Genes ◽  
Regulatory Sequences ◽  
Sequence Specificity ◽  
Maternal Allele ◽  
Primary Sequence ◽  
Chromatin Configuration

The cis-acting regulatory sequences of imprinted gene loci, called imprinting control regions (ICRs), acquire specific imprint marks in germ cells, including DNA methylation. These epigenetic imprints ensure that imprinted genes are expressed exclusively from either the paternal or the maternal allele in offspring. The last few years have witnessed a rapid increase in studies on how and when ICRs become marked by and subsequently maintain such epigenetic modifications. These novel findings are summarised in this review, which focuses on the germline acquisition of DNA methylation imprints and particularly on the combined role of primary sequence specificity, chromatin configuration, non-histone proteins and transcriptional events.

An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation

1988 ◽  
Vol 8 (2) ◽  
pp. 963-973
Author(s):  
J T Holt ◽  
R L Redner ◽  
A W Nienhuis
Keyword(s):  
Cell Growth ◽  
Protein Concentration ◽  
Myeloid Differentiation ◽  
Sequence Specificity ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Steady State Levels ◽  
Cell Growth And Differentiation ◽  
Antisense Oligomer

To study the role of a nuclear proto-oncogene in the regulation of cell growth and differentiation, we inhibited HL-60 c-myc expression with a complementary antisense oligomer. This oligomer was stable in culture and entered cells, forming an intracellular duplex. Incubation of cells with the anti-myc oligomer decreased the steady-state levels of c-myc protein by 50 to 80%, whereas a control oligomer did not significantly affect the c-myc protein concentration. Direct inhibition of c-myc expression with the anti-myc oligomer was associated with a decreased cell growth rate and an induction of myeloid differentiation. Related antisense oligomers with 2- to 12-base-pair mismatches with c-myc mRNA did not influence HL-60 cells. Thus, the effects of the antisense oligomer exhibited sequence specificity, and furthermore, these effects could be reversed by hybridization competition with another complementary oligomer. Antisense inhibition of a nuclear proto-oncogene apparently bypasses cell surface events in affecting cell proliferation and differentiation.

scholarly journals Role of maltase in the utilization of sucrose by Candida albicans

1993 ◽  
Vol 291 (3) ◽  
pp. 765-771 ◽  
Author(s):  
P R Williamson ◽  
M A Huber ◽  
J E Bennett
Keyword(s):  
Candida Albicans ◽  
Intracellular Localization ◽  
Cross Reactivity ◽  
Neutral Sugar ◽  
Sequence Specificity ◽  
Western Blots ◽  
Sds Page ◽  
Molecular Masses ◽  
Kinetics Of

Two isoenzymes of maltase (EC 3.2.1.20) were purified to homogeneity from Candida albicans. Isoenzymes I and II were found to have apparent molecular masses of 63 and 66 kDa on SDS/PAGE with isoelectric points of 5.0 and 4.6 respectively. Both isoenzymes resembled each other in similar N-terminal sequence, specificity for the alpha(1-−>4) glycosidic linkage and immune cross-reactivity on Western blots using a maltase II antigen-purified rabbit antibody. Maltase was induced by growth on sucrose whereas beta-fructofuranosidase activity could not be detected under similar conditions. Maltase I and II were shown to be unglycosylated enzymes by neutral sugar assay, and more than 90% of alpha-glucosidase activity was recoverable from spheroplasts. These data, in combination with other results from this laboratory [Geber, Williamson, Rex, Sweeney and Bennett (1992) J. Bacteriol. 174, 6992-6996] showing lack of a plausible leader sequence in genomic or mRNA transcripts, suggest an intracellular localization of the enzyme. To establish further the mechanism of sucrose assimilation by maltase, the existence of a sucrose-inducible H+/sucrose syn-transporter was demonstrated by (1) the kinetics of sucrose-induced [14C]sucrose uptake, (2) recovery of intact [14C]sucrose from ground cells by t.l.c. and (3) transport of 0.83 mol of H+/mol of [14C]sucrose. In total, the above is consistent with a mechanism whereby sucrose is transported into C. albicans to be hydrolysed by an intracellular maltase.

scholarly journals Nanostructural and mechanical changes in the sclera following proteoglycan depletion

2018 ◽  
Vol 2 (2) ◽  
pp. 14-17
Author(s):  
Zhuola Zhuola ◽  
Steve Barrett ◽  
Yalda Ashraf Kharaz ◽  
Riaz Akhtar
Keyword(s):  
Mechanical Properties ◽  
Collagen Fibril ◽  
Enzymatic Degradation ◽  
Ocular Tissues ◽  
Force Microscopy ◽  
Nanomechanical Properties ◽  
Atomic Force ◽  
Fibril Morphology

The mechanical properties of ocular tissues, such as the sclera, have a major impact on healthy eye function, and are governed by the properties and composition of the microstructural components. For example, biomechanical degradation associated with myopia occurs alongside a reduction of proteoglycans (PGs). In this study, the role of PG degradation in the nanomechanical properties of the porcine sclera is explored. In-vitro enzymatic degradation of PGs was conducted with α-amylase and chondroitinase ABC enzymes. Collagen fibril morphology and nanomechanical stiffness were measured with atomic force microscopy (AFM). The elastic modulus of the tissue was reduced in all enzyme-treated samples relative to controls. In addition, collagen fibril organization was disrupted by PG depletion. Our data demonstrate that PGs play an important role in determining not only the mechanical properties at these length scales, but also collagen fibril arrangement.

scholarly journals A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

2021 ◽  
Author(s):  
Rajasekhar Kolla ◽  
Pushparathinam Gopinath ◽  
Jonathan Ricci ◽  
Andreas Reif ◽  
Iman Rostami ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fragment Length ◽  
Neurodegenerative Disorder ◽  
Morphological Properties ◽  
Structural Determinants ◽  
Site Specific ◽  
Terminal Domain ◽  
Fibril Morphology ◽  
Insight Into

AbstractHuntington’s disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.Table of content

scholarly journals The dynamics of faculty hiring networks

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Eun Lee ◽  
Aaron Clauset ◽  
Daniel B. Larremore
Keyword(s):  
Network Models ◽  
Structural Mechanism ◽  
Faculty Hiring ◽  
Network Characteristics ◽  
Institutional Prestige ◽  
Structural Mechanisms ◽  
Global And Local ◽  
Global Placement ◽  
New Hire

AbstractFaculty hiring networks—who hires whose graduates as faculty—exhibit steep hierarchies, which can reinforce both social and epistemic inequalities in academia. Understanding the mechanisms driving these patterns would inform efforts to diversify the academy and shed new light on the role of hiring in shaping which scientific discoveries are made. Here, we investigate the degree to which structural mechanisms can explain hierarchy and other network characteristics observed in empirical faculty hiring networks. We study a family of adaptive rewiring network models, which reinforce institutional prestige within the hierarchy in five distinct ways. Each mechanism determines the probability that a new hire comes from a particular institution according to that institution’s prestige score, which is inferred from the hiring network’s existing structure. We find that structural inequalities and centrality patterns in real hiring networks are best reproduced by a mechanism of global placement power, in which a new hire is drawn from a particular institution in proportion to the number of previously drawn hires anywhere. On the other hand, network measures of biased visibility are better recapitulated by a mechanism of local placement power, in which a new hire is drawn from a particular institution in proportion to the number of its previous hires already present at the hiring institution. These contrasting results suggest that the underlying structural mechanism reinforcing hierarchies in faculty hiring networks is a mixture of global and local preference for institutional prestige. Under these dynamics, we show that each institution’s position in the hierarchy is remarkably stable, due to a dynamic competition that overwhelmingly favors more prestigious institutions. These results highlight the reinforcing effects of a prestige-based faculty hiring system, and the importance of understanding its ramifications on diversity and innovation in academia.

scholarly journals Origins of the new influenza A(H1N1) virus: time to take action

2009 ◽  
Vol 14 (22) ◽  
Author(s):  
G M Nava ◽  
M S Attene-Ramos ◽  
J K Ang ◽  
M Escorcia
Keyword(s):  
Influenza A ◽  
H1n1 Virus ◽  
Phylogenetic Analyses ◽  
Protein Sequences ◽  
Interspecies Transmission ◽  
Genetic Evolution ◽  
Protein Homology ◽  
Influenza A H1n1 ◽  
Insight Into

To gain insight into the possible origins of the 2009 outbreak of new influenza A(H1N1), we performed two independent analyses of genetic evolution of the new influenza A(H1N1) virus. Firstly, protein homology analyses of more than 400 sequences revealed that this virus most likely evolved from recent swine viruses. Secondly, phylogenetic analyses of 5,214 protein sequences of influenza A(H1N1) viruses (avian, swine and human) circulating in North America for the last two decades (from 1989 to 2009) indicated that the new influenza A(H1N1) virus possesses a distinctive evolutionary trait (genetic distinctness). This appears to be a particular characteristic in pig-human interspecies transmission of influenza A. Thus these analyses contribute to the evidence of the role of pig populations as “mixing vessels” for influenza A(H1N1) viruses.

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