activation response
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2022 ◽  
Vol 23 (2) ◽  
pp. 582
Author(s):  
Alice Sosic ◽  
Giulia Olivato ◽  
Caterina Carraro ◽  
Richard Göttlich ◽  
Dan Fabris ◽  
...  

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.


2022 ◽  
Author(s):  
Lin Lin ◽  
Franca Witjas ◽  
Konrad Fischer ◽  
Marten Engelse ◽  
Annemarie de Graaf ◽  
...  

Abstract Genetically tailored pigs to eliminate human immune rejection of xenografts is one promising solution to the global donor organ shortage. The development of xenograft transplantation has however been hampered by incomplete understanding of its immune rejection and the inability to test this in a human transplantation setting. Here we use an ex vivo organ perfusion system with human whole blood to assess the initial immune activation within the xenograft endothelium at single cell transcriptome level. Renal injury, complement deposition, coagulation and lymphocyte influx are all strongly reduced in genetically modified pig kidneys with porcine MHC class I and three xenoantigens (GGTA1, CMAH, B4GALNT2) eliminated (4KO) compared to wildtype (WT) pig kidneys after 6-hours human blood perfusion. Single cell RNA sequencing of endothelial cells (EC) from 4KO and WT pig kidneys respectively reveal that there is a compartment (cortex, glomeruli and medulla) specific endothelial activation, with cortical and glomeruli endothelial cells being more affected. Differential gene expression analysis shows a downregulation of endothelial transcriptome activation response to human blood perfusion in the 4KO ECs. Pathway enrichment analysis further identify the NF-kB pathway as strongly activated in human blood perfused WT ECs but diminished in the 4KO. In conclusion, the 4KO pig model has strongly reduced endothelial immune activation response when perfused with human whole blood, that goes beyond prevention of humoral rejection. Our data support further development of the 4KO for use in clinical transplantation.


Author(s):  
Alice Sosic ◽  
Giulia Olivato ◽  
Caterina Carraro ◽  
Richard Göttlich ◽  
Dan Fabris ◽  
...  

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its de-served role in the next-generation area of pharmaceutical R&D. We have recently probed the Trans-Activation Response element (TAR), a RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabiliz-ing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analyti-cal approaches for the study of multicomponent RNA-based interactions.


Author(s):  
Jorge Arede ◽  
Pedro Esteves ◽  
David Blanco ◽  
Dani Romero-Rodriguez ◽  
Nuno Leite ◽  
...  

This study sought to determine whether the inclusion of an opponent on an isoinertial crossover step task influenced the post-activation response and power production. Twenty adult male team-sports athletes participated in a randomized crossover trial. We used a novel design in which the performance of an isoinertial flywheel exercise was tested with or without the inclusion of sport-specific constraints (inclusion of an opponent vs. no opponent) in one of the two sequences (sequence one: constraint manipulation followed by no constraint manipulation; and sequence two: no constraint manipulation followed by constraint manipulation). Maximal power was recorded during exercise; then the coefficient of variation of maximal power was estimated. Post-activation responses were measured using unilateral jump height and change-of-direction time. Also, ankle dorsiflexion range of motion was measured. The use of an isoinertial flywheel resulted in improved ankle dorsiflexion and the capacity to repeat change-of-direction. Furthermore, the inclusion of an opponent was associated with a higher variability of the power output in the concentric phase of the movement. Importantly, performing the crossover step task in front of an opponent was also linked to a positive correlation between unilateral countermovement jump and power output. We conclude that the inclusion of typical constraints of the performance environment may have induced movement adaptations to accommodate the unpredictability associated with the actions of the opponent.


2021 ◽  
pp. 101390
Author(s):  
Sai Shashank Chavali ◽  
Sachitanand M. Mali ◽  
Rachel Bonn ◽  
Abhijith Saseendran ◽  
Ryan P. Bennett ◽  
...  

2021 ◽  
Author(s):  
Cecilia Rocchi ◽  
Camille Louvat ◽  
Adriana Erica Miele ◽  
Julien Batisse ◽  
Christophe Guillon ◽  
...  

Recent evidence indicated that HIV-1 Integrase (IN) binds genomic viral RNA (gRNA) playing a critical role in viral particle morphogenesis and gRNA stability in host cells. Combining biophysical and biochemical approaches we show that the C-terminal flexible 18-residues tail of IN acts as a sensor of the peculiar apical structure of trans-activation response element RNA (TAR), directly interacting with its hexaloop. We highlighted how the whole IN C-terminal domain, once bound to TAR, can change its structure assisting the binding of Tat, the HIV trans-activator protein, which finally displaces IN from TAR. Our results are consistent with the emerging role of IN in early stage of proviral transcription and suggest new steps of HIV-1 life cycle that can be considered as therapeutic targets.


2021 ◽  
Author(s):  
Rahul Kalla ◽  
Alex Adams ◽  
Jan Nowak ◽  
Daniel Bergemalm ◽  
Simen Vatn ◽  
...  

Abstract Gene-environment interactions play a pivotal role in the pathogenesis of Inflammatory Bowel Disease (IBD). Using the IBD Character inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) we confirm the presence of a highly characteristic DNA methylation profile in peripheral blood implicating 137 differentially methylated positions (DMP) in IBD, including VMP1/MIR21 (p = 9.11×10− 15) and RPS6KA2 (6.43×10− 13); with consistency seen across Scandinavia and UK. Cell of origin analysis preferentially implicated the monocyte lineage. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p = 1.53×10− 15). Age acceleration is seen in IBD (coefficient 0.94, p < 2.2x10− 16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10− 7 vs. non-IBD r -0.14, p = 0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14–12.56, logrank p = 9.70×10− 4).


Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1874
Author(s):  
Alice Sosic ◽  
Giulia Olivato ◽  
Caterina Carraro ◽  
Richard Göttlich ◽  
Dan Fabris ◽  
...  

Specific RNA sequences regulate functions essential to life. The Trans-Activation Response element (TAR) is an RNA stem–bulge–loop structure involved in several steps of HIV-1 replication. In this work, we show how RNA targeting can inhibit HIV-1 nucleocapsid (NC), a highly conserved protein known to catalyze nucleic acid melting and strand transfers during reverse transcription. Our RNA targeting strategy consists of the employment of bis-3-chloropiperidines (B-CePs) to impair RNA melting through bifunctional alkylation. Specific interactions between B-CePs and TAR RNA were analytically investigated by gel electrophoresis and mass spectrometry, allowing the elucidation of B-CePs’ recognition of TAR, and highlighting an RNA-directed mechanism of protein inhibition. We propose that B-CePs can freeze TAR tridimensional conformation, impairing NC-induced dynamics and finally inhibiting its functions in vitro.


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