We used DNA microarrays to profile gene expression patterns in the C. elegans germline and identified 1416 germline-enriched transcripts that define three groups. The sperm-enriched group contains an unusually large number of protein kinases and phosphatases. The oocyte-enriched group includes potentially new components of embryonic signaling pathways. The germline-intrinsic group, defined as genes expressed similarly in germlines making only sperm or only oocytes, contains a family of piwi-related genes that may be important for stem cell proliferation. Finally, examination of the chromosomal location of germline transcripts revealed that sperm-enriched and germline-intrinsic genes are nearly absent from the X chromosome, but oocyte-enriched genes are not.

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Background-We previously showed that a selective activator peptide of ⑀-protein kinase C (PKC), ⑀RACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of ⑀RACK confers sustained cardioprotection against ischemiareperfusion in isolated mouse hearts and whether ⑀RACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo. Methods and Results-After ⑀RACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas ⑀RACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with ⑀RACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of ⑀PKC, and no adverse effects after sustained ⑀RACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and ⑀RACK was administered by intracoronary injection during the first 10 minutes of ischemia. ⑀RACK treatment reduced infarct size (34Ϯ2% versus 14Ϯ1%, control versus ⑀RACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus ⑀RACK). Conclusions-The ⑀PKC activator ⑀RACK induced cardioprotection both in vivo and ex vivo, reduced the incidence of lethal arrhythmia during ischemia-reperfusion, and did not cause desensitization or downregulation of ⑀PKC after sustained delivery. Thus, ⑀RACK may be useful for patients with ischemic heart disease. In addition, the ⑀RACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of ⑀PKC in vivo is needed. (Circulation. 2005;111:44-50.)

Background Treatment with vesatolimod, an investigational oral toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a phase 1 study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with HIV-1. Methods In this double-blind, multicentre, placebo-controlled trial (ClinicalTrials.gov NCT02858401), participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose escalation cohorts. Primary study objectives included safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. Findings A total of 48 individuals were randomly assigned to vesatolimod (n=36) or placebo (n=12). Vesatolimod was generally well tolerated with no study drug-related serious adverse events or adverse events leading to study discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups compared to placebo. Vesatolimod plasma exposures increased dose-proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours post 6 mg dose were >3·9-fold for IP-10, IL-1Ra, and ITAC when compared to baseline values. Interpretation Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation observed at doses above 4 mg, providing rationale for future combination trials in people with HIV.