Inhibition of HIV-1 integrase nuclear import and replication by a peptide bearing integrase putative nuclear localization signal

<p>Abstract</p> <p>Background</p> <p>The integrase (IN) of human immunodeficiency virus type 1 (HIV-1) has been implicated in different steps during viral replication, including nuclear import of the viral pre-integration complex. The exact mechanisms underlying the nuclear import of IN and especially the question of whether it bears a functional nuclear localization signal (NLS) remain controversial.</p> <p>Results</p> <p>Here, we studied the nuclear import pathway of IN by using multiple <it>in vivo </it>and <it>in vitro </it>systems. Nuclear import was not observed in an importin α temperature-sensitive yeast mutant, indicating an importin α-mediated process. Direct interaction between the full-length IN and importin α was demonstrated <it>in vivo </it>using bimolecular fluorescence complementation assay (BiFC). Nuclear import studies in yeast cells, with permeabilized mammalian cells, or microinjected cultured mammalian cells strongly suggest that the IN bears a NLS domain located between residues 161 and 173. A peptide bearing this sequence -NLS-IN peptide- inhibited nuclear accumulation of IN in transfected cell-cycle arrested cells. Integration of viral cDNA as well as HIV-1 replication in viral cell-cycle arrested infected cells were blocked by the NLS-IN peptide.</p> <p>Conclusion</p> <p>Our present findings support the view that nuclear import of IN occurs via the importin α pathway and is promoted by a specific NLS domain. This import could be blocked by NLS-IN peptide, resulting in inhibition of viral infection, confirming the view that nuclear import of the viral pre-integration complex is mediated by viral IN.</p

OCT as a monitoring tool for assessment of the stage and severity of multiple sclerosis

AIM: To identify a link between optical coherence tomography(OCT), length of multiple sclerosis(MS)and the expanded disability status scale(EDSS).METHODS: In a prospective double blind study, 29 patients with a diagnosis of MS were compared with 29 healthy patients, matched by age and sex. All participants underwent an OCT study and neurological EDSS test on the same day.RESULTS: The mean EDSS score was 3.2 in the MS group vs 0.03 in the control group, and the duration of MS was 11.7y. The mean retinal nerve fiber layer(RNFL)thickness was significantly thinner in those with MS (PCONCLUSION: RNFL is thinner in MS patients than in the general population. MS duration has a direct statistically significant effect on RNFL thickness. There seems to be a tendency of a relationship between RNFL thinning and EDSS. OCT is suggested as a monitoring and evaluation tool of MS patients

New Insights on the Nutrition Status and Antioxidant Capacity in Multiple Sclerosis Patients

Background: Multiple sclerosis (MS) is a multifactorial disease with unknown etiology. It is assumed to result from interplay between genetic and environmental factors, including nutrition. We hypothesized that there are differences in nutritional parameters between MS patients and healthy controls. Methods: We examined 63 MS patients and 83 healthy controls. Nutritional status was determined by a dietary questionnaire, blood tests, quantification of cell membrane fatty acids, and serum antioxidant capacity. Results: We found that MS patients consumed a more limited diet compared with the healthy group, indicated by a lower average of 31 nutrients and by consumption levels of zinc and thiamine below the recommended daily intake. Both consumption and measured iron values were significantly lower in MS patients, with the lowest measures in the severe MS group. Long saturated fatty acids (&gt;C16) were significantly lower in MS patients, while palmitic and palmitoleic acids were both higher. Serum total antioxidant capacity was significantly lower in the MS group compared with healthy controls, with the lowest measures in patients with severe MS. Conclusions: This study points to a possible correlation between nutritional status and MS. Understanding the clinical meaning of these findings will potentially allow for the development of future personalized dietary interventions as part of MS treatment

Patterns of salivary microbiota injury and oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation

Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Transplantation was associated with a decrease in oral α diversity in all patients. In contrast to the gut microbiome, an association with overall survival was not detected. Among 135 patients given methotrexate for graft-versus-host disease prophylaxis pre-HSCT, Kingella and Atopobium abundance correlated with future development of severe OM. Posttransplant, Methylobacterium species were significantly enriched in patients with severe OM. Moreover, the oral microbiome and metabolome of severe OM patients underwent distinct changes post-HSCT, compared with patients with no or mild OM. Changes in specific metabolites were well explained by microbial composition, and the common metabolic pathway was the polyamines pathway, which is essential for epithelial homeostasis. Together, our findings suggest that salivary microbial composition and metabolites are associated with the development of OM, offering new insights on pathophysiology and potential avenues of intervention