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Foust et al. describe a viral vector that crosses the blood-brain barrier, providing a non-invasive method for delivering therapeutic genes to the central nervous system. A single intravascular injection of AAV9 results in widespread transduction of astrocytes in adult mice and of astrocytes and neurons in neonatal mice.
Cox and Mann describe MaxQuant, a suite of algorithms for the analysis of high-resolution mass spectrometry data. The approach achieves substantial improvements in the accuracy of mass measurements and the peptide identification rate.
Analyzing the massive and heterogenous datasets from genome-wide chromatin immunoprecipitation (ChIP) datasets presents several computational and statistical challenges. Ji et al. present a software suite that integrates all steps in ChIP-chip and ChIP-seq data analyses and illustrate the use of these tools by comparing the ability of the two platforms to identify transcription factor binding sites.
The picomolar sensitivity of fluorescence-based protein detection limits the use of protein arrays in research and clinical diagnosis. Chen et al. use antibody-tagged single-walled carbon nanotubes as multicolor Raman labels to detect femtomolar levels of serum analytes over a wide dynamic range.
Aasen et al. boost the efficiency of human induced pluripotent stem (iPS) cell generation 100-fold by starting with keratinocytes rather than fibroblasts. They also produce iPS cells from plucked adult hair, an easily accessible source of cells that avoids the need for a biopsy.
One strategy for advancing induced pluripotent stem (iPS) cell technology toward the clinic is to replace the reprogramming genes with small molecules. Huangfu et al. show that the HDAC inhibitor valproic acid can substitute for the reprogramming gene Klf4, allowing human iPS cells to be generated with only two transgenes, Oct4 and Sox2.
The development of effective methods for generating cardiomyocytes from embryonic stem cells may prove useful in cell replacement therapies and drug screening. Chen et al. show that activation of Notch signaling efficiently converts hematopoietic progenitors derived from mouse embryonic stem cells into cardiovascular progenitors that give rise to large numbers of cardiomyocytes.
Munger et al. show that infection with human cytomegalovirus upregulates fatty acid biosynthesis and that pharmacological inhibition of this pathway inhibits replication of both this virus and influenza A. This approach, the first to reliably map major carbon fluxes in mammalian cells, extends the promise of metabolomics from diagnostic applications to identification of new therapeutic concepts.
Penicillins and derived β-lactam antibiotics are essential in healthcare. To gain more insight into penicillin synthesis van den Berg and colleagues sequence and analyze the genome and transcriptome of the filamentous fungus Penicillium chrysogenum.
New hepatitis C treatments are urgently needed. Working with a high-throughput microfluidic affinity assay for RNA-protein interactions, Quake and colleagues identify a small molecule that negatively affects HCV replication in cell culture by inhibiting the binding between the nonstructural protein 4B and the viral RNA genome.
Biological control of the root-knot nematode Meloidogyne incognita, one of the world's most destructive crop pathogens, presents a major opportunity for safely improving global agricultural yields. Its 86-Mb genome—the first to be sequenced for a strictly parthenogenetic species—provides a blueprint to design new strategies for plant protection.
Systemic toxicity associated with heterogeneity in the stoichiometries and sites of drug attachment is a major hurdle to developing antibody-drug conjugates (ADCs) for cancer therapy. Junutula et al. engineer cysteine residues in constant domains to produce near-homogenous ADCs that are better tolerated than conventional ADCs, without any loss of antitumor activity.
Little is known about the regulation of RNA interference (RNAi). Shan et al. constructed a reporter system to monitor RNAi activity and identified a small molecule that increases RNAi by facilitating the interaction between small RNAs and a protein involved in small RNA loading and processing.
Generating induced pluripotent stem (iPS) cells is still an inefficient process, in part because the delivery of reprogramming factors by retroviral vectors yields cell populations that are genetically heterogeneous. Wernig et al. increase efficiency by producing iPS-cell chimeric mice from which they isolate cells bearing identical proviral insertions that support drug-inducible reprogramming.
Therapies that target only one inflammatory cytokine such as tumor necrosis factor α are often insufficient to treat rheumatoid arthritis. Aikawa et al. show that a small molecule targeting c-Fos/AP-1, a transcription factor that regulates both inflammatory cytokines and matrix metalloproteinases, inhibits type II collagen-induced arthritis in mice.
Widespread use of antiangiogenic drugs for cancer therapy is limited in part by the requirement for intravenous injection. Benny et al. describe an oral formulation of an antiangiogenic small molecule that inhibits tumor growth and prevents liver metastases in mice.