Extracellular vesicles (EVs) are small cargo‐bearing vesicles released by cells into the extracellular space. The field of EVs has grown exponentially over the past two decades; this growth follows ...the realisation that EVs are not simply a waste disposal system as had originally been suggested by some, but also a complex cell‐to‐cell communication mechanism. Indeed, EVs have been shown to transfer functional cargo between cells and can influence several biological processes. These small biological particles are also deregulated in disease. As we approach the 75th anniversary of the first experiments in which EVs were unknowingly isolated, it seems right to take stock and look back on how the field started, and has since exploded into its current state. Here we review the early experiments, summarise key findings that have propelled the field, describe the growth of an organised EV community, discuss the current state of the field, and identify key challenges that need to be addressed.
Plasma protein factor XII (FXII) activates the procoagulant and proinflammatory contact system that drives both the kallikrein–kinin system and the intrinsic pathway of coagulation. When zymogen FXII ...comes into contact with negatively charged surfaces, it auto‐activates to the serine proteaseactivated FXII (FXIIa). Recently, various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, polyphosphate and nucleic acids. Murine models have established a central role of FXII in arterial and venous thrombosis. Despite its central function in thrombosis, deficiency in FXII does not impair haemostasis in animals and humans. In a preclinical cardiopulmonary bypass system in large animals, the FXIIa‐blocking antibody 3F7 prevented thrombosis; however, in contrast to traditional anticoagulants, bleeding was not increased. In addition to its function in thrombosis, FXIIa initiates formation of the inflammatory mediator bradykinin. This mediator increases vascular leak, causes vasodilation, and induces chemotaxis with implications for septic, anaphylactic and allergic disease states. Therefore, targeting FXIIa appears to be a promising strategy for thromboprotection without associated bleeding risks but with anti‐inflammatory properties.
We give a topological classification of quantum walks on an infinite 1D lattice, which obey one of the discrete symmetry groups of the tenfold way, have a gap around some eigenvalues at symmetry ...protected points, and satisfy a mild locality condition. No translation invariance is assumed. The classification is parameterized by three indices, taking values in a group, which is either trivial, the group of integers, or the group of integers modulo 2, depending on the type of symmetry. The classification is complete in the sense that two walks have the same indices if and only if they can be connected by a norm-continuous path along which all the mentioned properties remain valid. Of the three indices, two are related to the asymptotic behavior far to the right and far to the left, respectively. These are also stable under compact perturbations. The third index is sensitive to those compact perturbations which cannot be contracted to a trivial one. The results apply to the Hamiltonian case as well. In this case, all compact perturbations can be contracted, so the third index is not defined. Our classification extends the one known in the translation- invariant case, where the asymptotic right and left indices add up to zero, and the third one vanishes, leaving effectively only one independent index. When two translation-invariant bulks with distinct indices are joined, the left and right asymptotic indices of the joined walk are thereby fixed, and there must be eigenvalues at 1 or
-
1
(bulk-boundary correspondence). Their location is governed by the third index. We also discuss how the theory applies to finite lattices, with suitable homogeneity assumptions.
We outline a theory of symmetry protected topological phases of one-dimensional quantum walks. We assume spectral gaps around the symmetry-distinguished points +1 and −1, in which only discrete ...eigenvalues are allowed. The phase classification by integer or binary indices extends the classification known for translation invariant systems in terms of their band structure. However, our theory requires no translation invariance whatsoever, and the indices we define in this general setting are invariant under arbitrary symmetric local perturbations, even those that cannot be continuously contracted to the identity. More precisely we define two indices for every walk, characterizing the behavior far to the right and far to the left, respectively. Their sum is a lower bound on the number of eigenstates at +1 and −1. For a translation invariant system the indices add up to zero, so one of them already characterizes the phase. By joining two bulk phases with different indices we get a walk in which the right and left indices no longer cancel, so the theory predicts bound states at +1 or −1. This is a rigorous statement of bulk-edge correspondence. The results also apply to the Hamiltonian case with a single gap at zero.
The human immunodeficiency virus (HIV) envelope protein (Env) mediates viral entry into host cells and is the primary target for the humoral immune response. Env is extensively glycosylated, and ...these glycans shield underlying epitopes from neutralizing antibodies. The glycosylation of Env is influenced by the type of host cell in which the virus is produced. Thus, HIV is distinctly glycosylated by CD4+ T cells, the major target cells, and macrophages. However, the specific differences in glycosylation between viruses produced in these cell types have not been explored at the molecular level. Moreover, it remains unclear whether the production of HIV in CD4+ T cells or macrophages affects the efficiency of viral spread and resistance to neutralization. To address these questions, we employed the simian immunodeficiency virus (SIV) model. Glycan analysis implied higher relative levels of oligomannose-type N-glycans in SIV from CD4+ T cells (T-SIV) compared to SIV from macrophages (M-SIV), and the complex-type N-glycans profiles seem to differ between the two viruses. Notably, M-SIV demonstrated greater infectivity than T-SIV, even when accounting for Env incorporation, suggesting that host cell-dependent factors influence infectivity. Further, M-SIV was more efficiently disseminated by HIV binding cellular lectins. We also evaluated the influence of cell type-dependent differences on SIV's vulnerability to carbohydrate binding agents (CBAs) and neutralizing antibodies. T-SIV demonstrated greater susceptibility to mannose-specific CBAs, possibly due to its elevated expression of oligomannose-type N-glycans. In contrast, M-SIV exhibited higher susceptibility to neutralizing sera in comparison to T-SIV. These findings underscore the importance of host cell-dependent attributes of SIV, such as glycosylation, in shaping both infectivity and the potential effectiveness of intervention strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infection with cytomegalovirus (CMV) shows a worldwide high prevalence with only immunocompromised individuals or newborns to become symptomatic. The host's constitution and the pathogen's virulence ...determine whether disease occurs after infection. Mouse CMV (MCMV) is an appreciated pathogen for in vivo investigation of host-pathogen interactions. It has recently been reported that a single base pair deletion can spontaneously occur in the open reading frame of MCMV-encoded chemokine 2 (MCK2), preventing the expression of the full-length gene product. To study the consequences of this mutation, we compared the Mck2-defective reporter virus MCMV-3D with the newly generated repaired Mck2(+) mutant MCMV-3DR. Compared with MCMV-3D, neonatal mice infected with MCMV-3DR showed severe viral disease after lung infection. Viral disease coincided with high viral activity in multiple organs and increased virus replication in previously described nodular inflammatory foci (NIF) in the lung. Notably, MCMV-3DR showed tropism for alveolar macrophages in vitro and in vivo, whereas MCMV-3D did not infect this cell type. Moreover, in vivo depletion of alveolar macrophages reduced MCMV-3DR replication in the lung. We proposed an Mck2-mediated mechanism by which MCMV exploits alveolar macrophages to increase replication upon first encounter with the host's lung mucosa.
We provide a classification of translation invariant one-dimensional quantum walks with respect to continuous deformations preserving unitarity, locality, translation invariance, a gap condition, and ...some symmetry of the tenfold way. The classification largely matches the one recently obtained (arXiv:1611.04439) for a similar setting leaving out translation invariance. However, the translation invariant case has some finer distinctions, because some walks may be connected only by breaking translation invariance along the way, retaining only invariance by an even number of sites. Similarly, if walks are considered equivalent when they differ only by adding a trivial walk, i.e., one that allows no jumps between cells, then the classification collapses also to the general one. The indices of the general classification can be computed in practice only for walks closely related to some translation invariant ones. We prove a completed collection of simple formulas in terms of winding numbers of band structures covering all symmetry types. Furthermore, we determine the strength of the locality conditions, and show that the continuity of the band structure, which is a minimal requirement for topological classifications in terms of winding numbers to make sense, implies the compactness of the commutator of the walk with a half-space projection, a condition which was also the basis of the general theory. In order to apply the theory to the joining of large but finite bulk pieces, one needs to determine the asymptotic behaviour of a stationary Schrödinger equation. We show exponential behaviour, and give a practical method for computing the decay constants.
Flexible sequence-random polymers containing cationic and lipophilic subunits that act as functional mimics of host-defense peptides have recently been reported. We used bacteria and lipid vesicles ...to study one such polymer, having an average length of 21 residues, that is active against both Gram-positive and Gram-negative bacteria. At low concentrations, this polymer is able to permeabilize model anionic membranes that mimic the lipid composition of
Escherichia coli,
Staphylococcus aureus, or
Bacillus subtilis but is ineffective against model zwitterionic membranes, which explains its low hemolytic activity. The polymer is capable of binding to negatively charged vesicles, inducing segregation of anionic lipids. The appearance of anionic lipid-rich domains results in formation of phase-boundary defects through which leakage can occur. We had earlier proposed such a mechanism of membrane disruption for another antimicrobial agent. Experiments with the mutant
E. coli ML-35p indicate that permeabilization is biphasic: at low concentrations, the polymer permeabilizes the outer and inner membranes; at higher polymer concentrations, permeabilization of the outer membrane is progressively diminished, while the inner membrane remains unaffected. Experiments with wild-type
E. coli K12 show that the polymer blocks passage of solutes into the intermembrane space at high concentrations. Cell membrane integrity in
E. coli K12 and
S. aureus exhibits biphasic dependence on polymer concentration. Isothermal titration calorimetry indicates that the polymer associates with the negatively charged lipopolysaccharide of Gram-negative bacteria and with the lipoteichoic acid of Gram-positive bacteria. We propose that this polymer has two mechanisms of antibacterial action, one predominating at low concentrations of polymer and the other predominating at high concentrations.
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelope (Env) proteins are extensively decorated with N-glycans, predominantly of the high-mannose type. However, it is ...unclear how high-mannose N-glycans on Env impact viral spread. We show that exclusive modification of SIV Env with these N-glycans reduces viral infectivity and abrogates mucosal transmission, despite increasing viral capture by immune cell lectins. Thus, high-mannose N-glycans have opposed effects on SIV infectivity and lectin reactivity, and a balance might be required for efficient mucosal transmission.
Emergent Properties of Reduced-Genome Escherichia coli Pósfai, György; Plunkett, Guy III; Fehér, Tamás ...
Science (American Association for the Advancement of Science),
05/2006, Letnik:
312, Številka:
5776
Journal Article
Recenzirano
With the use of synthetic biology, we reduced the Escherichia coli K-12 genome by making planned, precise deletions. The multiple-deletion series (MDS) strains, with genome reductions up to 15%, were ...designed by identifying nonessential genes and sequences for elimination, including recombinogenic or mobile DNA and cryptic virulence genes, while preserving good growth profiles and protein production. Genome reduction also led to unanticipated beneficial properties: high electroporation efficiency and accurate propagation of recombinant genes and plasmids that were unstable in other strains. Eradication of stress-induced transposition evidently stabilized the MDS genomes and provided some of the new properties.
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