Antimicrobial activity of an iron triple helicate

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe2L3]4+ and [Cu2(L’)2]2+ as antibacterial agents. Both molecules have been shown to bind DNA; [Fe2L3]4+ binds in the major groove and causes DNA coiling, whilst [Cu2(L’)2]2+ can act as an artificial nuclease. The work described here shows that only [Fe2L3]4+ is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe2L3]4+ binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly

Synthetic metallomolecules as agents for the control of DNA structure

This tutorial review summarises B-DNA structure and metallomolecule binding modes and illustrates some DNA structures induced by molecules containing metallic cations. The effects of aquated metal ions, cobalt amines, ruthenium octahedral metal complexes, metallohelicates and platinum complexes such as cis-platin are discussed alongside the techniques of NMR, X-ray crystallography, gel electrophoresis, circular dichroism, linear dichroism and molecular dynamics. The review will be of interest to people interested in both DNA structure and roles of metallomolecules in biological systems

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures

Parallel derivation of isogenic human primed and naive induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) have considerably impacted human developmental biology and regenerative medicine, notably because they circumvent the use of cells from embryonic origin and offer the potential to generate patient-specific pluripotent stem cells. However, conventional reprogramming protocols produce developmentally advanced, or primed, human iPSCs (hiPSCs), restricting their use to postimplantation human development modeling. Hence, there is a need for hiPSCs resembling preimplantation naive epiblast. Here, we develop a method to generate naive hiPSCs directly from somatic cells, using OKMS overexpression and specific culture conditions, further enabling parallel generation of their isogenic primed counterparts. We benchmark naive hiPSCs against human preimplantation epiblast and reveal a remarkable concordance in their transcriptome, dependency on mitochondrial respiration and X chromosome status. Collectively, our results are essential for the understanding of pluripotency regulation throughout preimplantation development and generate new opportunities for disease modeling and regenerative medicine.status: publishe

MALDI-In Source Decay Applied to Mass Spectrometry Imaging: A New Tool for Protein Identification.

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging is a powerful technique giving access to the distribution of a large range of biomolecules directly from a tissue section, allowing, for example, the discovery of new pathological biomarkers. Nevertheless, one main difficulty lies in the identification of the detected species, especially proteins. MALDI-in source decay (ISD) is used to fragment ions directly in the mass spectrometer ion source. This technique does not require any special sample treatment but only the use of a specific MALDI matrix such as 2,5-dihydroxybenzoic acid or 1,5-diaminonaphthalene. MALDI-ISD is generally employed on classical, purified samples, but here we demonstrate that ISD can also be performed directly on mixtures and on a tissue slice leading to fragment ions, allowing the identification of major proteins without any further treatment. On a porcine eye lens slice, de novo sequencing was even performed. Crystallins not yet referenced in databases were identified by sequence homology with other mammalian species. On a mouse brain slice, we demonstrate that results obtained with ISD are comparable and even better than those obtained with a classical in situ digestion

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.ISSN:2041-172