Comparative Studies on Retroviral Proteases: Substrate Specificity

Exogenous retroviruses are subclassified into seven genera and include viruses that cause diseases in humans. The viral Gag and Gag-Pro-Pol polyproteins are processed by the retroviral protease in the last stage of replication and inhibitors of the HIV-1 protease are widely used in AIDS therapy. Resistant mutations occur in response to the drug therapy introducing residues that are frequently found in the equivalent position of other retroviral proteases. Therefore, besides helping to understand the general and specific features of these enzymes, comparative studies of retroviral proteases may help to understand the mutational capacity of the HIV-1 protease

The functional O-mannose glycan on adystroglycan contains a phospho-ribitol primed for matriglycan addition

This work was supported in part by grants from NIGMS/NIH (R01GM111939 to LW, P01GM107012, KWM and LW co-PIs), technology resource grants from NIGMS/NIH (P41GM103490, LW and KWM co-PIs and P41GM103390, KWM, PI), a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (1U54NS053672, KPC, SAM and TW), a MDA grant (238219, KPC and TW) and an ARRA Go Grant (1 RC2 NS069521- 01, KPC and TW). KPC is an investigator of the Howard Hughes Medical Institute. Additional funding information P.2

A switch-on mechanism to activate maize ribosome-inactivating protein for targeting HIV-infected cells

Maize ribosome-inactivating protein (RIP) is a plant toxin that inactivates eukaryotic ribosomes by depurinating a specific adenine residue at the α-sarcin/ricin loop of 28S rRNA. Maize RIP is first produced as a proenzyme with a 25-amino acid internal inactivation region on the protein surface. During germination, proteolytic removal of this internal inactivation region generates the active heterodimeric maize RIP with full N-glycosidase activity. This naturally occurring switch-on mechanism provides an opportunity for targeting the cytotoxin to pathogen-infected cells. Here, we report the addition of HIV-1 protease recognition sequences to the internal inactivation region and the activation of the maize RIP variants by HIV-1 protease in vitro and in HIV-infected cells. Among the variants generated, two were cleaved efficiently by HIV-1 protease. The HIV-1 protease-activated variants showed enhanced N-glycosidase activity in vivo as compared to their un-activated counterparts. They also possessed potent inhibitory effect on p24 antigen production in human T cells infected by two HIV-1 strains. This switch-on strategy for activating the enzymatic activity of maize RIP in target cells provides a platform for combating pathogens with a specific protease

HIV-1 protease inhibitors: effects on HIV-2 replication and resistance

Novel antiretroviral drugs include protease (PR) inhibitors (e.g. atazanavir, tipranavir and darunavir) that block HIV-1 maturation and show remarkable antiviral potency on drug-resistant isolates. However, the strains used as prototypes in the design of the novel drugs belong to a specific clade (i.e. HIV-1 group M subtype B), which is the most prevalent in developed countries. At the same time, there is an increasing concern about the expansion of other HIV-1 clades as well as other related retroviruses, such as HIV-2. The HIV-2 PR is weakly inhibited by some PR inhibitors (e.g. amprenavir), and little is known of the mutational pathways leading to drug resistance in this virus. The design of specific PR inhibitors targeting HIV-2, or potent drugs showing broad specificity on HIV-1 and HIV-2 clades, remains a major challenge for the futureGrants from the Spanish-Hungarian Intergovernmental Science and Technology Cooperation Program (HH2005–0020), the Hungarian Science and Research Fund (OTKA K68288), and the Spanish Ministry of Health (Instituto de Salud Carlos III, RD06/0006/0025), as well as an institutional grant of Fundación Ramón Areces are acknowledgedPeer reviewe

The phenomenological argument for the disjunctive theory of perception

According to the phenomenological argument for disjunctivism, the reasons why we should prefer the disjunctive theory over its rivals is that (1) the disjunctive theory conforms the most to our pretheoretical or natural convic- tions about perception (what Michael Martin calls naïve realism), and (2) we should commit ourselves to naïve realism because it conforms the most to the phenomenology of the perceptual experience of objects. In this paper I try to explain why is the phenomenal argument exceptionally strong argument for disjunctivism and at the same time against sense-datum and intentional theories. Furthermore I try to show that the disjunctivist’s explanation of hallucination (which is allegedly the weak point of the theory) is as plausible as its rivals’

Mental Fictionalism As an Undermotivated Theory

Our paper consists of three parts. In the first part we explain the concept of mental fictionalism. In the second part, we present the various versions of fictionalism and their main sources of motivation.We do this because in the third part we argue that mental fictionalism, as opposed to other versions of fictionalism, is a highly undermotivated theory