Brain Virome in Neurodegenerative Disorders: Insights from Transcriptomic Data Analysis.

Neurodegenerative disorders (NDs) are chronic ailments of the central nervous system that gradually deteriorate the structures and functions of neurons. The etiologies of NDs include genetic factors, aging, infections, starvation, brain trauma, and spinal cord injury, among others. However, it is unclear whether viral infections impact the prognosis of NDs or contribute to their development. Hence, we investigated the prevalence of neurotropic viruses in brain samples by using transcriptomic data. A total of 1635 viral isolates with complete genomic information was used to investigate the incidence of 18 distinct viruses across 129 data sets from healthy and ND subjects. Our findings support the evidence pointing to the existence of a brain virome where certain viruses co-occur. We further hypothesize that distinct virome profiles are linked to different forms of NDs.

Molecular dynamics of the membrane interaction and localisation of prodigiosin.

The tripyrrolic antibiotic prodigiosin causes diverse reactions on its targets like energy spilling, membrane leakage, loss of motility and phototoxicity. It has bacteriostatic, bactericidal, anti-fungal, anti-cancer and immunosuppressive properties. Most of the functions suggest the role of prodigiosin in membrane disruption but the exact mechanism remains unknown. A molecular dynamics study was performed to understand the interactions of prodigiosin with the membrane. It was seen that prodigiosin from the solvent enters the membrane immediately either individually or as small clusters. Prodigiosin clusters with more than eight molecules do not appear to enter the membrane. Upon entry, the molecules orient themselves along the membrane-water interface with the pyrrole rings interacting with lipid head groups and with water. This orientation is stabilised by hydrogen bonding and hydrophobic interactions. The presence of prodigiosin molecules in the membrane changes the local lipid architecture and reduces the solvent accessibility of the membrane. The membrane fluidity, thickness or area per lipid head are largely unaffected. This suggests that prodigiosin could cause most damage in the vicinity of a membrane protein and thus could also explain the reason for varied effects on the targets.

Phylogenetic Studies on the Prodigiosin Biosynthetic Operon.

Prodigiosin and undecylprodigiosin are tripyrrolic red pigmented antibiotics produced by certain bacteria. Many strains of Serratia and certain other Gammaproteobacteria produce prodigiosin and undecylprodigiosin is produced by certain strains of Streptomyces. This is a multistage process which involves the synthesis of a bipyrrolic compound from L-proline and its subsequent condensation with a mono pyrrole synthesized from 2-octenal in the case of prodigiosin and malonyl-CoA in the case of undecylprodigiosin respectively. We have carried out sequence analysis of the genes involved in the pathway and identified the distribution of the prodigiosin producing genes amongst the various bacteria which have been fully sequenced. The presence of the operon was clearly seen in certain clustered branches suggesting inheritance from a common ancestor. This was further confirmed by the absence of traits observed in horizontally acquired genes like, GC content variation, codon bias or the presence of mobile elements. Multiple sequence alignment of the promoter of the prodigiosin operon in seven fully sequenced Serratia marcescens strains showed excellent homology. Putative regulatory elements in this region were identified by sequence analysis studies and many of them have been found to influence pigment production. The undecylprodigiosin gene cluster on the other hand, shows homology to other gene clusters involved in the production of other pyrrole-containing antibiotics of the genus Streptomyces. This coupled with the presence of ORFs with three different promoters could indicate lateral gene transfer. Hence the evolution of undecylprodigiosin operon could be an example of convergent evolution.

Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression.

Histone acetylation is a diagnostic feature of transcriptionally active genes. The proper recruitment and function of histone acetyltransferases (HATs) and deacetylases (HDACs) are key regulatory steps for gene expression and cell cycle. Functional defects of either of these enzymes may lead to several diseases, including cancer. HATs and HDACs thus are potential therapeutic targets. Here we report that garcinol, a polyisoprenylated benzophenone derivative from Garcinia indica fruit rind, is a potent inhibitor of histone acetyltransferases p300 (IC50 approximately 7 microm) and PCAF (IC50 approximately 5 microm) both in vitro and in vivo. The kinetic analysis shows that it is a mixed type of inhibitor with an increased affinity for PCAF compared with p300. HAT activity-dependent chromatin transcription was strongly inhibited by garcinol, whereas transcription from DNA template was not affected. Furthermore, it was found to be a potent inducer of apoptosis, and it alters (predominantly down-regulates) the global gene expression in HeLa cells.