Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these 'last resort' treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.

http://research1t.imb.uq.edu.au/conoserver/.

Ischemia-reperfusion injury (IRI) is a common occurrence following myocardial infarction, transplantation, stroke, and trauma that can lead to multiple organ failure, which remains the foremost cause of death in critically ill patients. Current therapeutic strategies for IRI are mainly palliative, and there is an urgent requirement for a therapeutic that could prevent or reverse tissue damage caused by IRI. Neutrophils are the primary responders following ischemia and reperfusion and represent important components in the protracted inflammatory response and severity associated with IRI. Experimental studies demonstrate neutrophil infiltration at the site of ischemia and show that inducing neutropenia can protect organs from IRI. In this review, we highlight the mechanisms involved in neutrophil recruitment, activation, and adherence and how this contributes to disease severity in IRI. Inhibiting neutrophil mobilization, tissue recruitment, and ultimately neutrophil-associated activation of local and systemic inflammatory responses may have therapeutic potential in the amelioration of local and remote tissue damage following IRI.

Vc1.1 is a disulfide-rich peptide inhibitor of nicotinic acetylcholine receptors that has stimulated considerable interest in these receptors as potential therapeutic targets for the treatment of neuropathic pain. Here we present an extensive series of mutational studies in which all residues except the conserved cysteines were mutated separately to Ala, Asp, or Lys. The effect on acetylcholine (ACh)-evoked membrane currents at the ␣9␣10 nicotinic acetylcholine receptor (nAChR), which has been implicated as a target in the alleviation of neuropathic pain, was then observed. The analogs were characterized by NMR spectroscopy to determine the effects of mutations on structure. The structural fold was found to be preserved in all peptides except where Pro was substituted. Electrophysiological studies showed that the key residues for functional activity are Asp 5 -Arg 7 and Asp 11 -Ile 15 , because changes at these positions resulted in the loss of activity at the ␣9␣10 nAChR. Interestingly, the S4K and N9A analogs were more potent than Vc1.1 itself. A second generation of mutants was synthesized, namely N9G, N9I, N9L, S4R, and S4K؉N9A, all of which were more potent than Vc1.1 at both the rat ␣9␣10 and the human ␣9/rat ␣10 hybrid receptor, providing a mechanistic insight into the key residues involved in eliciting the biological function of Vc1.1. The most potent analogs were also tested at the ␣3␤2, ␣3␤4, and ␣7 nAChR subtypes to determine their selectivity. All mutants tested were most selective for the ␣9␣10 nAChR. These findings provide valuable insight into the interaction of Vc1