| 1. |
- Abu-Raya, Bahaa, et al.
(författare)
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Antibody and B-cell Immune Responses Against Bordetella Pertussis Following Infection and Immunization
- 2023
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Ingår i: Journal of Molecular Biology. - 0022-2836 .- 1089-8638. ; 435:24
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Forskningsöversikt (refereegranskat)abstract
- Neither immunization nor recovery from natural infection provides life-long protection against Bordetella pertussis. Replacement of a whole-cell pertussis (wP) vaccine with an acellular pertussis (aP) vaccine, mutations in B. pertussis strains, and better diagnostic techniques, contribute to resurgence of number of cases especially in young infants. Development of new immunization strategies relies on a comprehensive understanding of immune system responses to infection and immunization and how triggering these immune components would ensure protective immunity. In this review, we assess how B cells, and their secretory products, antibodies, respond to B. pertussis infection, current and novel vaccines and highlight similarities and differences in these responses. We first focus on antibody-mediated immunity. We discuss antibody (sub)classes, elaborate on antibody avidity, ability to neutralize pertussis toxin, and summarize different effector functions, i.e. ability to activate complement, promote phagocytosis and activate NK cells. We then discuss challenges and opportunities in studying B-cell immunity. We highlight shared and unique aspects of B-cell and plasma cell responses to infection and immunization, and discuss how responses to novel immunization strategies better resemble those triggered by a natural infection (i.e., by triggering responses in mucosa and production of IgA). With this comprehensive review, we aim to shed some new light on the role of B cells and antibodies in the pertussis immunity to guide new vaccine development.
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| 2. |
- Arike, Liisa, et al.
(författare)
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The Densely O-Glycosylated MUC2 Mucin Protects the Intestine and Provides Food for the Commensal Bacteria.
- 2016
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Ingår i: Journal of molecular biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 428:16, s. 3221-3229
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Forskningsöversikt (refereegranskat)abstract
- All mucins are highly O-glycosylated by variable glycans depending on species, histoblood group and organ. This makes the intestinal main mucin MUC2 non-degradable by the host digestive system but well by both commensal and pathogenic bacteria. The MUC2 glycans are important for selection of the commensal bacteria and act as a nutritional source for the bacteria; this also helps the host to recover some of the energy spent on constantly renewing the protective mucus layer. Glycosylation is the most diverse and common posttranslational modification of cell surfaces and secreted proteins. N-Glycosylation is most well studied and predictable, whereas O-glycosylation is more diverse and less well understood. O-Glycosylation is also often called mucin-type glycosylation as it is typical for mucins that often have more than 80% of the mass as O-glycans. This review will discuss the mucin-type O-glycosylation and especially the O-glycosylation of human and mice intestinal mucin MUC2 in relation to bacteria and disease.
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| 3. |
- Cymer, Florian, et al.
(författare)
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Mechanisms of Integral Membrane Protein Insertion and Folding
- 2015
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 427:5, s. 999-1022
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Forskningsöversikt (refereegranskat)abstract
- The biogenesis, folding, and structure of alpha-helical membrane proteins (MPs) are important to understand because they underlie virtually all physiological processes in cells including key metabolic pathways, such as the respiratory chain and the photosystems, as well as the transport of solutes and signals across membranes. Nearly all MPs require translocons-often referred to as protein-conducting channels-for proper insertion into their target membrane. Remarkable progress toward understanding the structure and functioning of translocons has been made during the past decade. Here, we review and assess this progress critically. All available evidence indicates that MPs are equilibrium structures that achieve their final structural states by folding along thermodynamically controlled pathways. The main challenge for cells is the targeting and membrane insertion of highly hydrophobic amino acid sequences. Targeting and insertion are managed in cells principally by interactions between ribosomes and membrane-embedded translocons. Our review examines the biophysical and biological boundaries of MP insertion and the folding of polytopic MPs in vivo. A theme of the review is the under-appreciated role of basic thermodynamic principles in MP folding and assembly. Thermodynamics not only dictates the final folded structure but also is the driving force for the evolution of the ribosome-translocon system of assembly. We conclude the review with a perspective suggesting a new view of translocon-guided MP insertion. (C) 2014 Elsevier Ltd. All rights reserved.
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| 4. |
- Elbahnsi, Ahmad, et al.
(författare)
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Structure and Sequence-based Computational Approaches to Allosteric Signal Transduction : Application to Electromechanical Coupling in Voltage-gated Ion Channels
- 2021
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 433:17
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Forskningsöversikt (refereegranskat)abstract
- Allosteric signaling underlies the function of many biomolecules, including membrane proteins such as ion channels. Experimental methods have enabled specific quantitative insights into the coupling between the voltage sensing domain (VSD) and the pore gate of voltage-gated ion channels, located tens of Angstrom apart from one another, as well as pinpointed specific residues and domains that participate in electromechanical signal transmission. Nevertheless, an overall atomic-level resolution picture is difficult to obtain from these methods alone. Today, thanks to the cryo-EM resolution revolution, we have access to high resolution structures of many different voltage-gated ion channels in various conformational states, putting a quantitative description of the processes at the basis of these changes within our close reach. Here, we review computational methods that build on structures to detect and characterize allosteric signaling and pathways. We then examine what has been learned so far about electromechanical coupling between VSD and pore using such methods. While no general theory of electromechanical coupling in voltage-gated ion channels integrating results from all these methods is available yet, we outline the types of insights that could be achieved in the near future using the methods that have not yet been put to use in this field of application.
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| 5. |
- Howard, Rebecca J.
(författare)
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Elephants in the Dark : Insights and Incongruities in Pentameric Ligand-gated Ion Channel Models
- 2021
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 433:17
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Forskningsöversikt (refereegranskat)abstract
- The superfamily of pentameric ligand-gated ion channels (pLGICs) comprises key players in electrochemical signal transduction across evolution, including historic model systems for receptor allostery and targets for drug development. Accordingly, structural studies of these channels have steadily increased, and now approach 250 depositions in the protein data bank. This review contextualizes currently available structures in the pLGIC family, focusing on morphology, ligand binding, and gating in three model subfamilies: the prokaryotic channel GLIC, the cation-selective nicotinic acetylcholine receptor, and the anion-selective glycine receptor. Common themes include the challenging process of capturing and annotating channels in distinct functional states; partially conserved gating mechanisms, including remodeling at the extracellular/transmembrane-domain interface; and diversity beyond the protein level, arising from post-translational modifications, ligands, lipids, and signaling partners. Interpreting pLGIC structures can be compared to describing an elephant in the dark, relying on touch alone to comprehend the many parts of a monumental beast: each structure represents a snapshot in time under specific experimental conditions, which must be integrated with further structure, function, and simulations data to build a comprehensive model, and understand how one channel may fundamentally differ from another.
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| 6. |
- Jackson, Colin, et al.
(författare)
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Adventures on the Routes of Protein Evolution-In Memoriam Dan Salah Tawfik (1955-2021)
- 2022
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Ingår i: Journal of Molecular Biology. - : Elsevier. - 0022-2836 .- 1089-8638. ; 434:7
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Forskningsöversikt (refereegranskat)abstract
- Understanding how proteins evolved not only resolves mysteries of the past, but also helps address challenges of the future, particularly those relating to the design and engineering of new protein functions. Here we review the work of Dan S. Tawfik, one of the pioneers of this area, highlighting his seminal contributions in diverse fields such as protein design, high throughput screening, protein stability, fundamental enzyme-catalyzed reactions and promiscuity, that underpin biology and the origins of life. We discuss the influence of his work on how our models of enzyme and protein function have developed and how the main driving forces of molecular evolution were elucidated. The discovery of the rugged routes of evolution has enabled many practical applications, some which are now widely used.
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| 7. |
- Koos, Björn, et al.
(författare)
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Next-Generation Pathology : Surveillance of Tumor Microecology
- 2015
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 427:11, s. 2013-2022
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Forskningsöversikt (refereegranskat)abstract
- A tumor is a heterogeneous population of cells that provides an environment in which every cell resides in a microenvironmental niche. Microscopic evaluation of tissue sections, based on histology and immunohistochemistry, has been a cornerstone in pathology for decades. However, the dawn of novel technologies to investigate genetic aberrations is currently adopted in routine molecular pathology. We herein describe our view on how recent developments in molecular technologies, focusing on proximity ligation assay and padlock probes, can be applied to merge the two branches of pathology, allowing molecular profiling under histologic observation. We also discuss how the use of image analysis will be pivotal to obtain information at a cellular level and to interpret holistic images of tissue sections. By understanding the cellular communications in the microecology of tumors, we will be at a better position to predict disease progression and response to therapy.
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| 8. |
- Ndi, Mama, et al.
(författare)
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Biogenesis of the bc(1) Complex of the Mitochondria! Respiratory Chain
- 2018
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 430:21, s. 3892-3905
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Forskningsöversikt (refereegranskat)abstract
- The oxidative phosphorylation system contains four respiratory chain complexes that connect the transport of electrons to oxygen with the establishment of an electrochemical gradient over the inner membrane for ATP synthesis. Due to the dual genetic source of the respiratory chain subunits, its assembly requires a tight coordination between nuclear and mitochondrial gene expression machineries. In addition, dedicated assembly factors support the step-by-step addition of catalytic and accessory subunits as well as the acquisition of redox cofactors. Studies in yeast have revealed the basic principles underlying the assembly pathways. In this review, we summarize work on the biogenesis of the bc(1) complex or complex III, a central component of the mitochondrial energy conversion system.
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| 9. |
- Sellin, Mikael E., et al.
(författare)
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Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens
- 2018
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 430:2, s. 193-206
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Forskningsöversikt (refereegranskat)abstract
- Inflammasome signaling impinges on the activation of inflammatory caspases (i.e., caspase-1 and caspase-4/5/11) and endows host cells with a sentinel system to sense microbial intrusion and thereby initiate appropriate immune responses. Lately, it has become evident that mammalian inflammasome-dependent responses to infection are not confined solely to cells of hematopoietic origin. Epithelial cells that line the body's mucosal surfaces use inflammasome signaling to sense and counteract pathogenic microorganisms that compromise barrier integrity. Many of the molecular mechanisms of epithelial inflammasome signaling remain unexplored. However, it now seems clear that epithelial inflammasome activation has a profound impact both on the infected cell itself and on its ability to communicate with other cell types of the mucosa. Here, we summarize current knowledge regarding the output of epithelial inflammasome activation during bacterial infection. Well-established downstream effects include epithelial cell death, release of soluble mediators, and subsequent recruitment of effector cell types, including NK cells, mast cells, and neutrophils, to sites of mucosal infection. We discuss the implications of recent findings for antibacterial defense in the mucosa and sketch out areas for future exploration.
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| 10. |
- Sohrabi, Tahereh, et al.
(författare)
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Common mechanisms underlying α-synuclein-induced mitochondrial dysfunction in Parkinson's disease
- 2023
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Ingår i: Journal of Molecular Biology. - : Elsevier. - 0022-2836 .- 1089-8638.
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is the most common neurological movement disorder characterized by the selective and irreversible loss of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. While most cases are sporadic or environmental, about 10% of patients have a positive family history with a genetic cause. The misfolding and aggregation of α-synuclein (α-syn) as a casual factor in the pathogenesis of PD has been supported by a great deal of literature. Extensive studies of mechanisms underpinning degeneration of the dopaminergic neurons induced by α-syn dysfunction suggest a complex process that involves multiple pathways, including mitochondrial dysfunction and increased oxidative stress, impaired calcium homeostasis through membrane permeabilization, synaptic dysfunction, impairment of quality control systems, disruption of microtubule dynamics and axonal transport, endoplasmic reticulum/Golgi dysfunction, nucleus malfunction, and microglia activation leading to neuroinflammation. Among them mitochondrial dysfunction has been considered as the most primary target of α-syn-induced toxicity, leading to neuronal cell death in both sporadic and familial forms of PD. Despite reviewing many aspects of PD pathogenesis related to mitochondrial dysfunction, a systemic study on how α-syn malfunction/aggregation damages mitochondrial functionality and leads to neurodegeneration is missing in the literature. In this review, we give a detailed molecular overview of the proposed mechanisms by which α-syn, directly or indirectly, contributes to mitochondrial dysfunction. This may provide valuable insights for development of new therapeutic approaches in relation to PD. Antioxidant-based therapy as a potential strategy to protect mitochondria against oxidative damage, its challenges, and recent developments in the field are discussed.
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