Promotion of activated human B cell apoptosis and inhibition of Ig production by soluble CD95 ligand: CD95-based downregulation of Ig production need not culminate in activated B cell death

CD95/CD95L interactions are vital to normal lymphoid homeostasis and in the protection against autoimmunity. To directly assess the effects of CD95L on activated B cell survival and Ig responses, purified human peripheral blood B cells, activated in vitro with SAC + rIL2, were incubated with a soluble CD95L fusion protein (fp) and assayed for apoptosis and IgG/IgM production. CD95L fp reproducibly increased apoptosis of these activated B cells and inhibited their Ig production. However, CD95L fp-mediated effects on activated B cell survival could be uncoupled from those on Ig production in that a soluble CD40L fp was incapable of reversing CD95L fp-mediated downregulation of Ig responses despite inhibiting CD95L fp-mediated apoptosis. Moreover, despite the specific caspase-8 inhibitor z-IETD-fmk substantially protecting transformed CL-01 B cells from CD95L fp-mediated apoptosis and permitting their ongoing proliferation, caspase-8 inhibition had no protective effects on CD95L fp-mediated inhibition of constitutive IgM production by CL-01 B cells. Collectively, these results point to a CD95-based downregulatory pathway in activated B cells that need not necessarily culminate in their death.     

Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure-activity relationships

A series of fused pyrimidine based inhibitors of PDE7 have been derived from an earlier screening lead 1. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members are described.     

Micronuclei monitoring of fishes from Lake Paranoá, under influence of sewage treatment plant discharges

Fish micronuclei tests (MN) were used to evaluate the ability of wastewater from two municipal sewage treatment plants that empty into Lake Paranoá to cause genetic damage. There were no significant differences in the frequencies of micronuclei between the control and hypertrophic areas. In contrast, cyclophosphamide and mitomycin C, used to test the sensitivity of the biological assay, significantly increased the micronuclei counts in Tilapia rendalli, Oreochromis niloticus and Cyprinus carpio, T. rendalli was the most sensitive specie to both clastogens and C. carpio, the most resistant.     

Prevalence of non-strongyle gastrointestinal parasites of horses in Riyadh region of Saudi Arabia

This study aimed to provide recent data on the occurrence of non-strongyle intestinal parasite infestation in horses in the Riyadh region of Saudi Arabia as a basis for developing parasite control strategies. We conducted necropsy for 45 horses from September 2006 to November 2007 in the Riyadh region, Saudi Arabia. 39 out of 45 horses were infected with intestinal parasites with an infestation rate of 86.6%. Infestations with seven nematode species and two species of Gasterophilus larva were found. The most prevalent parasites were Strongyloides westeri (64.4%) and Parascaris equorum (28.8%) followed by Habronema muscae (22.2%). Trichostrongylus axei and Oxyuris equi were less common at (11.1%) and (8.8%), respectively. Habronema megastoma and Setaria equine were found in two horses only (4.4%). Gasterophilus intestinalis larvae were recovered from 39 horses (86.6%) and Gasterophilus nasalis larvae were found in 17 horses (37.7%). Season had a significant effect on the prevalence of P. equorum and G. nasalis, while age of horses had a significant effect only on the prevalence of P. equorum. The husbandry in Saudi Arabia appears to be conductive to parasites transmitted in stables or by insects rather than in pasture.     

NONO enhances mRNA processing of super‐enhancer‐associated GATA2 and HAND2 genes in neuroblastoma

High‐risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA‐binding protein, NONO, in neuroblastoma is associated with poor patient outcome; however, there is little understanding of the mechanism of NONO‐dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biochemical and genome‐wide molecular analysis to reveal complex NONO‐dependent regulation of gene expression. NONO forms RNA‐ and DNA‐tethered condensates throughout the nucleus and undergoes phase separation in vitro, modulated by nucleic acid binding. CLIP analyses show that NONO mainly binds to the 5′ end of pre‐mRNAs and modulates pre‐mRNA processing, dependent on its RNA‐binding activity. NONO regulates super‐enhancer‐associated genes, including HAND2 and GATA2. Abrogating NONO RNA binding, or phase separation activity, results in decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA‐binding activity of NONO may have therapeutic potential in this cancer context.     

Die chemische Koordination der Funktionen des K?rpers

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