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Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and T cells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity.

We reexamine commodity futures returns for evidence of fractional integration utilizing two estimators based on wavelets. We summarize basic wavelet methods for signal processing and decompose commodity futures returns by wavelet scale. We find the evidence for long memory is not conclusive based on visual inspection of the wavelet decomposition, but formal statistical tests suggest evidence of long memory, in the form of antipersistence, in about half of agricultural commodity futures. We find little evidence of long memory in metal futures. Our results are useful in interpreting previous disparate findings based on frequency domain estimators.

Since the early days of the discovery of HIV-1 protease (HIV-1 PR), this enzyme has been selected as an important target for the inhibition of viral replication. The enormous effort over the past two decades to develop effective molecules that inhibit the HIV1 PR has resulted in the discovery of drugs that have dramatically improved the quality of life and survival of the patients infected with HIV-1. To date there are six different HIV-1 PR inhibitors (PI) that are commercially available. These drugs are administered in combination with the reverse transcriptase inhibitors in what is called TMhighly active anti-retroviral therapy (HAART)∫. Unfortunately, many drug-resistant and cross-resistant mutant HIV-1 PRs have been identified, thus hampering long term suppression of the virus and resulting in return of AIDS symptoms. Therefore, the development of new protease inhibitors, which are efficacious against both the wild type and drug resistant HIV-1 PR and less prone to development of resistance, is urgently needed. During the last decade, the number and throughput of biological assays of protease activity has notably increased. However, the high rates of HIV-1 PR mutation still outpace conventional drug discovery efforts, mostly because of limitations associated with identification of the lead structures and, to a greater extent, slow structure ± activity profiling. While the former can be improved by rational design and computational studies, rapid synthesis of diverse analogues and their optimization still remains a challenge. We have recently developed a new strategy to facilitate the drug discovery process: diversityoriented organic synthesis in microtiter plates followed by in situ screening without product isolation and protecting group manipulation. This strategy was demonstrated with the use of amide-forming reaction in a rapid identification of new potent HIV protease inhibitors. Click chemistry has emerged as a strategy for the rapid and efficient assembly of molecules with diverse functionality on both laboratory and production scales. Enabled by a few nearly perfect reactions, it guarantees reliable synthesis of the desired products in high yield and purity. Modularity, selectivity, and wide scope make click chemistry ideal for achieving diversity in just a few steps and with no need for further purification. Advantages of click chemistry in biological studies have recently been demonstrated in several applications: construction of fluorescent oligonucleotides for DNA sequencing, in situ assembly of acetylcholinesterase inhibitors, chemically orthogonal high fidelity bioconjugation, and activity-based protein profiling in whole proteomes. In principle, this type of chemistry is well suited for microscale synthesis and for biological screening in situ. To demonstrate its feasibility we have used the copper(I)-catalysed triazole formation for the synthesis of sugar arrays in the above mentioned microtiter plate format, followed by in situ screening of glycosyltransferase inhibitors and enzyme glycosylation. Herein, we report an expedient approach to the discovery of novel HIV-1 PR inhibitors based on the latest advance in the copper(I)-catalyzed 1,2,3-triazole synthesis. 11] This highly reliable process, which proceeds well in aqueous solvents and tolerates virtually all functional groups without the need for protection, made it possible to quickly generate the desired libraries of potential inhibitors and to screen them directly in microtiter plates, without any purification, against HIV-1 PR and its mutants. The efficacy of hydroxyethylamine isosteres as transition-state mimics and as backbone replacements of amide bonds in the P1/P1 position of aspartyl protease inhibitors has been well documented, most notably in incorporation in the structures of three commercially available drugs, amprenavir, nelfinavir, and saquinavir. We, therefore, envisioned a library of compounds which retained this core, while diversifying the P2/P2 residues to generate new inhibitors. Starting from the optically active epoxy amine 1, two different azide cores were prepared as summarized in Scheme 1. Epoxy amine 1 in H2O/EtOH was

We have developed a series of 4-amino-3,6-disulfonato-1,8-naphthalimide (ADSN) derivatives in an attempt to create nontoxic compounds effective against lentivirus infections. The ADSN derivative Lucifer Yellow CH ([N-(hydra zinocarbonyl)amino]-4-amino-3,6-disulfonato-1,8-naphthalimid e) (LYCH) was chosen as a parent compound because of its low toxicity in vivo and in vitro and its tendency to accumulate in monocyte/macrophages, a major reservoir for lentiviruses in vivo. Several ADSN derivatives inhibited reverse transcriptases (RTs) from human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV). Viral expression in HIV-infected human peripheral blood mononuclear cells was inhibited by noncytotoxic concentrations of two ADSN derivatives, designated A4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH monohydrazone; EC50 = 29 microM after 6 days) and H4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH dihydrazone; EC50 = 5.61 microM). A4 effectively suppressed the expression of FIV in infected Crandall feline kidney fibroblasts (CRFK) at 46.2 microM, reducing the RT levels by 97% after 19 days under conditions allowing direct cell-to-cell transmission of the virus. The viability of drug-treated FIV-infected CRFK cells increased significantly in the presence of A4 relative to the viability of untreated virus-infected cells. In contrast to A4 and H4, LYCH (which lacks the appended aromatic rings characteristic of A4 and H4) had no inhibitory effects on either virus and did not inhibit RT ex vivo. However, flow cytometry studies showed that both A4 and LYCH accumulate in two cell types that can support lentiviral infections: U937 human monocytic leukemic cells that have been induced to differentiate by using tetradecanoyl phorbol acetate, and CRFK cells.

Two dual tropic recombinant murine leukemia viruses were isolated from Moloney leukemia virus passed in France for 17 years. These new isolates share most of the biological properties of previously described HIX virus isolated from a line of Moloney virus maintained in the United States. However, they differ from the HIX virus and from other recombinant viruses by the absence of a xenotropic oligopeptide thought to have been characteristic of all xenotropic and recombinant virus envelope glycoprotein.