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“The APOBEC3 cytidine deaminases are potent antiviral Buparlisib factors that restrict the replication
of human immunodeficiency virus type 1 (HIV-1). In HIV-1-infected CD4(+) T cells, the viral accessory protein Vif binds to APOBEC3G (A3G), APOBEC3F (A3F), and APOBEC3C (A3C) and targets these proteins for polyubiquitination by forming an E3 ubiquitin ligase with cullin 5. Previous studies identified regions of HIV-1 Vif, (40)YRHHY(44) and (12)QVDRMR(17), which are important for interaction with A3G and A3F, respectively, and showed that Vif residues 54 to 71 are sufficient for A3G binding. Here, we identify (69)YXXL(72) as a novel conserved motif in HIV-1 Vif that mediates binding to human A3G and its subsequent degradation. Studies on other APOBEC3 proteins revealed that Tyr69 and Leu72 are important for the degradation of A3F and A3C as well. Similar to A3F, A3C regulation is also mediated by Vif residues (12)QVDRMR(17). Simian immunodeficiency virus (SIV) Vif was shown to bind and degrade African green monkey A3G (agmA3G) and, unexpectedly, human A3C. The YXXL motif of SIVagm Vif was important for the inactivation of agmA3G and human A3C. Unlike HIV- 1 Vif, however, SIVagm Vif does not require Tyr40 and His43 for agmA3G degradation. Tyr69 in the YXXL motif was critical for binding of recombinant glutathione S- transferase-Vif(1-94) to A3G in
vitro. These results suggest that the YXXL motif in Vif is a potential target for small- molecule inhibitors to block Vif interaction with A3G, A3F, and A3C, and thereby protect cells GDC-0449 cell line against HIV- 1 infection.”
“The Symbol IMP dehydrogenase Digit Modalities Test is an easy test
used to assess cognitive impairment in a wide range of neurological diseases, like multiple sclerosis. We adapted the oral version of this cognitive task making it suitable for functional Magnetic Resonance Imaging studies. Symbol Digit Modalities Test performance was associated with increased brain activity in frontal and parietal areas involved in selective attention and working memory functions. These may provide the basis for future studies assessing potential abnormal cortical activations in multiple sclerosis patients and other clinical populations. Published by Elsevier Ireland Ltd.”
“Protein accumulation and aggregation are signatures of several major neurodegenerative diseases. Proteasomal- and lysosomal-mediated protein degradation pathways are the two major pathways for intracellular protein degradation. Cross-regulation between these two pathways may be important for protein homeostasis. Pharmacological inhibition of proteasomal activities has been shown to up-regulate the levels of lysosomal enzymes. To determine whether the reverse regulatory mechanism also occurs in the cell, we investigated the effects of inhibition of lysosomal function on proteasomal activities.