Induction of chronic human immunodeficiency virus infection is blocked in vitro by a methylphosphonate oligodeoxynucleoside targeted to a U3 enhancer element.

Oligodeoxynucleosides with internucleoside methylphosphonate linkages complementary to regions within U3 of human immunodeficiency virus type 1 were evaluated for their ability to block phorbol myristate acetate upregulation of virus in chronically infected promonocytic and T-lymphoblastoid cell lines. One such oligomer, targeted to an NF-kappa B enhancer element, inhibited phorbol myristate acetate induction of viral replication and tat-mediated trans activation of the human immunodeficiency virus long terminal repeat. The effect of this construct is contrasted with classical antisense methylphosphonate-derivatized oligomers complementary to initiation codon and splice acceptor sites of human immunodeficiency virus structural and regulatory genes. Its activity suggests a novel application of the modified oligonucleotide strategy in the blockade of viral induction from latently infected cells.     

Proteoglycans: key partners in bone cell biology

The diversity of bone proteoglycan (PG) structure and localisation (pericellular, extracellular in the organic bone matrix) reflects a broad spectrum of biological functions within a unique tissue. PGs play important roles in organizing the bone extracellular matrix, taking part in the structuring of the tissue itself as active regulators of collagen fibrillogenesis. PGs also display selective patterns of reactivity with several constituents including cytokines and growth factors, such as transforming growth factor-beta or osteoprotegerin thereby modulating their bio-availability and biological activity in the bone tissue. In this review, the complex PG composition in bone will be addressed together with the specific role played by PGs (or their GAGs chains) in bone biology, as regulatory molecules for bone resorption and their involvement in bone tumor development. These roles have been determined after modulation of PG expression or mutations in their corresponding genes, which revealed specific roles for these compounds in bone pathologies (e.g. perlecan or glypican-3 mutations observed respectively in chondrodysplasia or dysmorphic syndrome). Finally, the potential therapeutic interest of PGs is discussed based on recent data, more particularly on bone tumor-associated osteolysis as these molecules are involved both in bone resorption and tumor development.     

Toxins-antitoxins: diversity, evolution and function

Genes for toxin-antitoxin (TA) complexes are widespread in prokaryote genomes, and species frequently possess tens of plasmid and chromosomal TA loci. The complexes are categorized into three types based on genetic organization and mode of action. The toxins universally are proteins directed against specific intracellular targets, whereas the antitoxins are either proteins or small RNAs that neutralize the toxin or inhibit toxin synthesis. Within the three types of complex, there has been extensive evolutionary shuffling of toxin and antitoxin genes leading to considerable diversity in TA combinations. The intracellular targets of the protein toxins similarly are varied. Numerous toxins, many of which are sequence-specific endoribonucleases, dampen protein synthesis levels in response to a range of stress and nutritional stimuli. Key resources are conserved as a result ensuring the survival of individual cells and therefore the bacterial population. The toxin effects generally are transient and reversible permitting a set of dynamic, tunable responses that reflect environmental conditions. Moreover, by harboring multiple toxins that intercede in protein synthesis in response to different physiological cues, bacteria potentially sense an assortment of metabolic perturbations that are channeled through different TA complexes. Other toxins interfere with the action of topoisomersases, cell wall assembly, or cytoskeletal structures. TAs also play important roles in bacterial persistence, biofilm formation and multidrug tolerance, and have considerable potential both as new components of the genetic toolbox and as targets for novel antibacterial drugs.