species level, restoration of cellular membrane integrity, decreasing pro-apoptotic signaling molecules, and modulating cellular levels of stress-related proteins. it has also been shown that the production of infective viral particles from previously infected neuroblastoma cells is reduced, which is achieved by inhibition of the ubiquitin-proteasome system. minocycline in mice resulted in marked decreases in the levels of several markers, viral titer, and the level of proinflammatory mediators and also prevented blood–brain barrier damage. evolution it is theorized that the virus may have originated from an ancestral virus in the mid-1500s in the malay archipelago region and evolved there into five different genotypes which spread across asia. the mean evolutionary rate has been estimated to be 4.35×10−4 (range: 3.49×10−4 to 5.30×10−4) nucleotide substitutions per site per year.