scholarly journals NKNK: a New Essential Motif in the C-Terminal Domain of HIV-1 Group M Integrases

2020 ◽  
Vol 94 (20) ◽  
Author(s):  
Marine Kanja ◽  
Pierre Cappy ◽  
Nicolas Levy ◽  
Oyndamola Oladosu ◽  
Sylvie Schmidt ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Viral Evolution ◽  
Purifying Selection ◽  
The Other ◽  
Functional Motif ◽  
Multiple Functions ◽  
Terminal Domain ◽  
Per Se ◽  
Infectious Cycle ◽  
Hiv 1

ABSTRACT Using coevolution network interference based on comparison of two phylogenetically distantly related isolates, one from the main group M and the other from the minor group O of HIV-1, we identify, in the C-terminal domain (CTD) of integrase, a new functional motif constituted by four noncontiguous amino acids (N222K240N254K273). Mutating the lysines abolishes integration through decreased 3′ processing and inefficient nuclear import of reverse-transcribed genomes. Solution of the crystal structures of wild-type (wt) and mutated CTDs shows that the motif generates a positive surface potential that is important for integration. The number of charges in the motif appears more crucial than their position within the motif. Indeed, the positions of the K’s could be permutated or additional K’s could be inserted in the motif, generally without affecting integration per se. Despite this potential genetic flexibility, the NKNK arrangement is strictly conserved in natural sequences, indicative of an effective purifying selection exerted at steps other than integration. Accordingly, reverse transcription was reduced even in the mutants that retained wt integration levels, indicating that specifically the wt sequence is optimal for carrying out the multiple functions that integrase exerts. We propose that the existence of several amino acid arrangements within the motif, with comparable efficiencies of integration per se, might have constituted an asset for the acquisition of additional functions during viral evolution. IMPORTANCE Intensive studies of HIV-1 have revealed its extraordinary ability to adapt to environmental and immunological challenges, an ability that is also at the basis of antiviral treatment escape. Here, by deconvoluting the different roles of the viral integrase in the various steps of the infectious cycle, we report how the existence of alternative equally efficient structural arrangements for carrying out one function opens up the possibility of adapting to the optimization of further functionalities exerted by the same protein. Such a property provides an asset to increase the efficiency of the infectious process. On the other hand, though, the identification of this new motif provides a potential target for interfering simultaneously with multiple functions of the protein.

scholarly journals Genetically flexible but conserved: a new essential motif in the C-ter domain of HIV-1 group M integrases

2020 ◽  
Author(s):  
Marine Kanja ◽  
Pierre Cappy ◽  
Nicolas Levy ◽  
Oyndamola Oladosu ◽  
Sylvie Schmidt ◽  
...  
Keyword(s):  
Amino Acids ◽  
Viral Evolution ◽  
Purifying Selection ◽  
The Other ◽  
Functional Motif ◽  
Multiple Functions ◽  
Per Se ◽  
Integration Levels ◽  
Infectious Cycle ◽  
Hiv 1

ABSTRACTUsing coevolution-network interference based on the comparison of two phylogenetically distantly related isolates, one from the main group M and the other from the minor group O of HIV-1, we identify, in the C-terminal domain (CTD) of integrase, a new functional motif constituted by four non-contiguous amino acids (N222K240N254K273). Mutating the lysines abolishes integration through decreased 3’-processing and inefficient nuclear import of reverse transcribed genomes. Solution of the crystal structures of wt and mutated CTDs shows that the motif generates a positive surface potential that is important for integration. The number of charges in the motif appears more crucial than their position within the motif. Indeed, the positions of the K could be permutated or additional K could be inserted in the motif, generally without affecting integration per se. Despite this potential genetic flexibility, the NKNK arrangement is strictly conserved in natural sequences, indicative of an effective purifying selection exerted at steps other than integration. Accordingly, reverse transcription was reduced even in the mutants that retained wt integration levels, indicating that specifically the wt sequence is optimal for carrying out the multiple functions integrase exerts. We propose that the existence of several amino acids arrangements within the motif, with comparable efficiencies of integration per se, might have constituted an asset for the acquisition of additional functions during viral evolution.IMPORTANCEIntensive studies on HIV-1 have revealed its extraordinary ability to adapt to environmental and immunological challenges, an ability that is also at the basis of antiviral treatments escape. Here, by deconvoluting the different roles of the viral integrase in the various steps of the infectious cycle, we report how the existence of alternative equally efficient structural arrangements for carrying out one function opens on the possibility of adapting to the optimisation of further functionalities exerted by the same protein. Such property provides an asset to increase the efficiency of the infectious process. On the other hand, though, the identification of this new motif provides a potential target for interfering simultaneously with multiple functions of the protein.

Crime, Responsibility, Culpability, and Wrongdoing

2021 ◽  
pp. 3-25
Author(s):  
A P Simester
Keyword(s):  
Criminal Justice ◽  
Moral Responsibility ◽  
Criminal Justice System ◽  
Criminal Law ◽  
Justice System ◽  
The Other ◽  
Multiple Functions ◽  
Primary Function ◽  
Per Se ◽  
Theoretical Overview

This chapter provides a theoretical overview of criminal law, claiming that it has multiple functions. Among other things, the criminal law operates to prevent certain kinds of wrongs, and to punish them when they occur. Those functions are compatible; but they are often thought to be in tension. Whether preventive, interrogative, or punitive, all parts of the criminal justice system need justification. The chapter then briefly introduces at five foundational principles for criminal law: culpability, legitimate enactment, moral responsibility, wrongdoing, and ascriptive responsibility. Culpability is served by moral responsibility, and it is entwined with wrongdoing: but the latter principles, and the doctrines they govern, are independently significant. The principle of ascriptive responsibility, on the other hand, is related more closely to wrongdoing and legitimate enactment than to culpability per se. Its primary function is to moderate the state’s generic prohibition by identifying those defendants who fall within its scope. As such, it is primarily a criminalization principle.

The Problem of the Typology of Rationality in Muslim Culture

2019 ◽  
Vol 62 (6) ◽  
pp. 88-99
Author(s):  
Andrey A. Lukashev
Keyword(s):  
Modern Philosophy ◽  
Theoretical Basis ◽  
Theoretical Models ◽  
The Other ◽  
Common Denominator ◽  
Islamic Culture ◽  
The Common ◽  
Per Se ◽  
The One ◽  
Muslim Culture

The typology of rationality is one of major issues of modern philosophy. In an attempt to provide a typology to Oriental materials, a researcher faces additional problems. The diversity of the Orient as such poses a major challenge. When we say “Oriental,” we mean several cultures for which we cannot find a common denominator. The concept of “Orient” involves Arabic, Indian, Chinese, Turkish and other cultures, and the only thing they share is that they are “non-Western.” Moreover, even if we focus just on Islamic culture and look into rationality in this context, we have to deal with a conglomerate of various trends, which does not let us define, with full confidence, a common theoretical basis and treat them as a unity. Nevertheless, we have to go on trying to find common directions in thought development, so as to draw conclusions about types of rationality possible in Islamic culture. A basis for such a typology of rationality in the context of the Islamic world was recently suggested in A.V. Smirnov’s logic of sense theory. However, actual empiric material cannot always fit theoretical models, and the cases that do not fit the common scheme are interesting per se. On the one hand, examination of such cases gives an opportunity to specify certain provisions of the theory and, on the other hand, to define the limits of its applicability.

Genetic Flexibility of the NKNK Motif in HIV-1 Integrases Allows Its Involvement in Multiple Functions During Infection

2018 ◽  
Author(s):  
Marine Kanja ◽  
Pierre Cappy ◽  
Guillermo Blanco-Rodriguez ◽  
Nicolas Levy ◽  
Oyndamola Oladosu ◽  
...  
Keyword(s):  
Multiple Functions ◽  
Hiv 1

Expansion of CD56− NK cells in chronic HCV/HIV-1 co-infection: Reversion by antiviral treatment with pegylated IFNα and ribavirin

2008 ◽  
Vol 128 (1) ◽  
pp. 46-56 ◽  
Author(s):  
Veronica D. Gonzalez ◽  
Karolin Falconer ◽  
Jakob Michaëlsson ◽  
Markus Moll ◽  
Olle Reichard ◽  
...  
Keyword(s):  
Nk Cells ◽  
Antiviral Treatment ◽  
Chronic Hcv ◽  
Hiv 1

scholarly journals Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

2015 ◽  
Vol 89 (20) ◽  
pp. 10303-10318 ◽  
Author(s):  
Justine E. Sunshine ◽  
Brendan B. Larsen ◽  
Brandon Maust ◽  
Ellie Casey ◽  
Wenje Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Evolution ◽  
T Cell Responses ◽  
Fitness Cost ◽  
Viral Population ◽  
Cell Responses ◽  
Founder Virus ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

ABSTRACTTo understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and the mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with host CTL responses in six linked transmission pairs. HIV-1 sequences corresponding to full-length p17 and p24gagwere generated by 454 pyrosequencing for all pairs near the time of transmission, and seroconverting partners were followed for a median of 847 days postinfection. T-cell responses were screened by gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present in at least 5% of sequence reads in the individual's viral population. While we found little evidence for the occurrence of CTL reversions, CTL escape processes were found to be highly dynamic, with multiple epitope variants emerging simultaneously. We found a correlation between epitope entropy and the number of epitope variants per response (r= 0.43;P= 0.05). In cases in which multiple escape mutations developed within a targeted epitope, a variant with no fitness cost became fixed in the viral population. When multiple mutations within an epitope achieved fitness-balanced escape, these escape mutants were each maintained in the viral population. Additional mutations found to confer escape but undetected in viral populations incurred high fitness costs, suggesting that functional constraints limit the available sites tolerable to escape mutations. These results further our understanding of the impact of CTL escape and reversion from the founder virus in HIV infection and contribute to the identification of immunogenic Gag regions most vulnerable to a targeted T-cell attack.IMPORTANCERapid diversification of the viral population is a hallmark of HIV-1 infection, and understanding the selective forces driving the emergence of viral variants can provide critical insight into the interplay between host immune responses and viral evolution. We used deep sequencing to comprehensively follow viral evolution over time in six linked HIV transmission pairs. We then mapped T-cell responses to explore if mutations arose due to adaption to the host and found that escape processes were often highly dynamic, with multiple mutations arising within targeted epitopes. When we explored the impact of these mutations on replicative capacity, we found that dynamic escape processes only resolve with the selection of mutations that conferred escape with no fitness cost to the virus. These results provide further understanding of the complicated viral-host interactions that occur during early HIV-1 infection and may help inform the design of future vaccine immunogens.

HALF-WAY TECHNOLOGIES ARE PROFITABLE

PEDIATRICS ◽  
1995 ◽  
Vol 95 (5) ◽  
pp. 681-681
Keyword(s):  
The Other ◽  
Other Hand ◽  
Per Se ◽  
Commercial Organizations

Decisive interventions, like vaccines, can be quite inexpensive. But commercial organizations make money by selling commodities; they cannot produce and sell "health" per se. The most profitable commodities are those embodying the "half-way" technologies, for those with the means to pay for them-again and again and again. Vaccines, on the other hand, "may never prove as enticing as drugs for pharmaceutical makers. They can be quite expensive to develop, and they produce less income-repeated refills not required ... "

The relationship among freezing tolerance, vernalization requirement, Ppd alleles and winter hardiness in European wheat cultivars

2017 ◽  
Vol 155 (9) ◽  
pp. 1353-1370 ◽  
Author(s):  
A. GORASH ◽  
R. ARMONIENĖ ◽  
Ž. LIATUKAS ◽  
G. BRAZAUSKAS
Keyword(s):  
Molecular Markers ◽  
Western Europe ◽  
Complex Trait ◽  
Winter Hardiness ◽  
Photoperiod Sensitivity ◽  
The Other ◽  
Wheat Cultivars ◽  
Crucial Component ◽  
Per Se ◽  
The Relationship

SUMMARYWinter hardiness of wheat is a complex trait involving a system of structural, regulatory and developmental genes, which interact in a complex pathway. The objective of the present work was to study the relationship among the main traits determining the level of adaptation and the possibility for target manipulation of breeding material by using molecular markers and phenological parameters. Wheat cultivars from different ecoclimatic environments of Europe were included for analysis. Gene-specific assay showed that photoperiod sensitivity of the studied cultivars was determined by polymorphism in the Ppd-D1 allele. The study established the relationship among winter hardiness, LT50 (the temperature at which 50% of plants are killed), photoperiod sensitivity, vernalization duration and earliness per se genes in the environment of Lithuania. The cultivars from Northern and Western Europe exhibited stronger requirement for vernalization and photoperiod. Although the group of cultivars from the southern latitudes were characterized by earliness, they possessed a stronger level of LT50. The level of LT50 was found to be the most crucial component of winter hardiness, the other traits served as supplementary components.

Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

2018 ◽  
Vol 16 (3) ◽  
pp. 184-207 ◽  
Author(s):  
Vanessa D`Urbano ◽  
Elisa De Crignis ◽  
Maria Carla Re
Keyword(s):  
Mammalian Cells ◽  
Viral Evolution ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Immunodeficiency Virus ◽  
Lentiviral Infection ◽  
Specific Proteins ◽  
Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

Semantic Congruency Improves Recognition Memory Performance for Both Audiovisual and Visual Stimuli

2017 ◽  
Vol 30 (7-8) ◽  
pp. 763-781 ◽  
Author(s):  
Jenni Heikkilä ◽  
Kimmo Alho ◽  
Kaisa Tiippana
Keyword(s):  
Recognition Memory ◽  
Congruency Effect ◽  
Memory Performance ◽  
Visual Stimuli ◽  
The Other ◽  
Memory Encoding ◽  
Semantic Congruency ◽  
Recognition Memory Performance ◽  
Visual Encoding ◽  
Per Se

Audiovisual semantic congruency during memory encoding has been shown to facilitate later recognition memory performance. However, it is still unclear whether this improvement is due to multisensory semantic congruency or just semantic congruencyper se. We investigated whether dual visual encoding facilitates recognition memory in the same way as audiovisual encoding. The participants memorized auditory or visual stimuli paired with a semantically congruent, incongruent or non-semantic stimulus in the same modality or in the other modality during encoding. Subsequent recognition memory performance was better when the stimulus was initially paired with a semantically congruent stimulus than when it was paired with a non-semantic stimulus. This congruency effect was observed with both audiovisual and dual visual stimuli. The present results indicate that not only multisensory but also unisensory semantically congruent stimuli can improve memory performance. Thus, the semantic congruency effect is not solely a multisensory phenomenon, as has been suggested previously.

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