Regardless of recent advances in PAD treatment, current outcomes remain poor especially in CLI. Despite overwhelming evidence for reduction of limb loss by revascularization, CLI patients still received significantly less angiographies and revascularizations.

The initial encounter of an unrepaired DNA lesion is likely to be with a replicative DNA polymerase, and the outcome of this event determines whether an error-prone or errorfree damage avoidance pathway is taken. To understand the atomic details of this critical encounter, we have determined the crystal structures of the pol a family RB69 DNA polymerase with DNA containing the two most prevalent, spontaneously generated premutagenic lesions, an abasic site and 2 0 -deoxy-7,8-dihydro-8-oxoguanosine (8-oxodG). Identification of the interactions between these damaged nucleotides and the active site provides insight into the capacity of the polymerase to incorporate a base opposite the lesion. A novel open, catalytically inactive conformation of the DNA polymerase has been identified in the complex with a primed abasic site template. This structure provides the first molecular characterization of the DNA synthesis barrier caused by an abasic site and suggests a general mechanism for polymerase fidelity. In contrast, the structure of the ternary 8-oxodG:dCTP complex is almost identical to the replicating complex containing unmodified DNA, explaining the relative ease and fidelity by which this lesion is bypassed.

It is undisputable that the fates of metal ions and nucleic acids are inescapably interwoven. Metal ions are essential for charge compensation of the negatively charged phosphate-sugar backbone, they are instrumental for proper folding, and last but not least they are crucial cofactors for ribozyme catalysis. Considerable progress has been achieved in the past few years on the identification of metal ion binding sites in large DNA and RNA molecules, like in ribozymes including the ribosome. Hereby, most information was gained from crystallography, which fails to explain metal ion binding equilibria in solution as well as the factors that determine the coordination of a metal ion to a specific site. In contrast, such information is readily available for the low-molecular building blocks of large nucleic acids, i.e. for mononucleotides and to some extent also dinucleotides. In this review, we combine and compare for the first time both sets of information. The focus is thereby set on Mg2+, Ca2+, Mn2+, and Cd2+ because these four metal ions are either freely available in cells, have a large impact on the catalytic rate of ribozymes, and/or are often applied in RNA biochemistry. Our comparisons show that results obtained from small molecules can be directly transposed to the findings in large RNA structures like the ribosome. For example, the basic coordination-chemical properties of the different metal ions are reflected in their binding to large nucleic acid structures: macrochelate formation, e.g. the simultaneous intranucleotide coordination of a Mg2+ ion to the phosphate unit and the N7 site of a purine nucleobase (be it inner-or outersphere), is well known for mononucleotides. We show that the frequency of occurrence of this type of coordination is the same for mononucleotides and the ribosome.

This review summarizes the recent development of G4 DNA targeted metal complexes and discusses their potential as anticancer drugs.

Type 2 diabetes is associated with numerous long-term complications. This study aims to investigate whether impaired function of tissue-resident multipotent cells play role in pathogenesis of allied complications. Adipose-tissue-derived mesenchymal stem cells (ASCs) derived from nondiabetic (nASCs) and diabetic (dASCs) donors were compared with regard to glucose metabolism, cell replication, apoptosis, and differentiation potential. The data evidenced that elevation of glucose reduces proliferative capacity of both dASCs and nASCs, but impacts dASCs more significantly. Incorporation of insulin enhanced cell replication especially in nASCs. dASCs show higher levels of cellular senescence and apoptosis than nASCs. Unlike nASCs, apoptosis is induced via intrinsic pathway in dASCs. Data also evidenced that high glucose concentrations cause prominent disparities in nASCs and dASCs in expression of genes involved in insulin resistance such as adiponectin and resistin. Some changes in gene expression were irreversible in dASCs when treated with insulin. Additionally, high glucose concentrations reduce osteogenic and chondrogenic potential of ASCs, but enhance adipogenic potential. These results indicate that in addition to involvement in insulin resistance, impaired function of mesenchymal stem cells that reside in adipose tissue as one of the major sources of adult stem cells might be responsible for complications related to diabetes type 2.