“Transcription factor Histone Nuclear Factor P (HiNF-P; gene symbol Hinfp) mediates cell cycle
control of histone H4 gene expression to support the packaging of newly replicated DNA as chromatin. The HiNF-P/p220(NPAT) complex controls multiple H4 genes in established human cell lines and is critical for cell proliferation. The mouse Hinfp(LacZ) null allele causes early embryonic lethality due to a blastocyst defect. However, neither Hinfp function nor its temporal expression relative to histone H4 genes during fetal development has been explored. Here, we establish that expression of Hinfp is biologically coupled with expression of twelve functional mouse H4 genes during pre- and post-natal tissue-development. Both Hinfp and H4 genes are robustly expressed at multiple embryonic (E) days (from E5.5 to E15.5), coincident with ubiquitous LacZ staining driven by the Hinfp promoter. Selleckchem CHIR 99021 Five highly expressed mouse H4 genes (Hist1h4d, Histh4f, Hist1h4m selleck products and Hist2h4) account for >90% of total histone H4 mRNA throughout development. Post-natal expression of H4 genes in mice is most evident in lung, spleen, thymus and intestine, and with few exceptions (e.g., adult liver) correlates with Hinfp gene expression. Histone H4 gene expression decreases but Hinfp levels remain constitutive upon cell growth inhibition in culture. The in vivo co-expression
of Hinfp and histone H4 genes is consistent with the biological function of Hinfp as a principal transcriptional regulator of histone H4 gene expression during mouse development. (C) 2011 Elsevier B.V. All rights reserved.”
“Metabolic activation of new chemical entities to reactive intermediates is routinely monitored in drug discovery and development. Reactive intermediates may bind to cellular macromolecules such as proteins, DNA and may eventually lead to cell death via necrosis, apoptosis or oxidative stress. The evidence that the ultimate outcome of metabolic activation is an adverse drug reaction manifested as in vivo
toxicity, is at best circumstantial. However, understanding the process of bioactivation of structural alerts by trapping the reactive intermediates is critical to guide medicinal chemistry efforts in quest for safer and potent molecules. This commentary provides a brief introduction to adverse drug Fosbretabulin reactions and mechanisms of reactive intermediate formation for various functional groups, followed by a review of chemical design approaches, examples of such strategies, possible isosteric replacements for structural alerts and rationalization of laboratory approaches to determine reactive intermediates, as a guide to today’s medicinal chemist.”
“The development of alternative, non-fluorinated membranes for polymer electrolyte membrane fuel cells necessitates the co-development of a non-fluorinated electrode catalyst binder to ensure compatibility between membrane and electrode.