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TALEs (transcription activator-like effectors) are transcription factors from the plant pathogen Xanthomonas that can be readily engineered to bind new DNA sequences of interest. Miller et al. use a truncated TALE linked to a nuclease domain to edit and regulate endogenous genes in human cells.
Antibodies that modulate the activity of a target are difficult to discover with display-based approaches, which select only high-affinity binders. Mao et al. identify antibodies with a range of affinities using a small-molecule discovery method that involves one-by-one screening of an optimized small library of antibody fragments with known sequences.
Degeneration of articular cartilage in the joints may be amenable to tissue engineering solutions. Oldershaw et al. present an efficient, chemically defined protocol for differentiating human ES cells to chondrocyte-like cells.
The grading systems used by in vitro fertilization clinics cannot determine reliably whether a given embryo will lead to a successful pregnancy. Wong et al. address one part of this problem by showing that development of an embryo to the blastocyst stage can be predicted with high confidence at day 2 post fertilization.
Castor beans are best known as a source of industrial lubricants and the toxic bioterror threat, ricin, and they have potential to provide biofuel. Chan et al. present the draft sequence of the Ricinus communis genome, the first for a member of the Euphorbiaceae.
The Microarray Quality Control consortium pitted 36 teams against each other to evaluate methods for creating genomic classifiers, computational tools for interpreting gene expression profiles. The performance of the classifiers on blinded validation data—and metadata on the analytic methods—reveal the challenges facing the field.
Polo et al. show that early-passage induced pluripotent stem cells retain an epigenetic memory of their cell type of origin. These epigenetic differences affect the cells’ differentiation potential and might be exploited to generate particular cell types of interest.
To identify genes affecting traits of interest in E. coli, Warner et al. describe a method to rapidly create and assay rationally mutated versions of every gene. The approach is applied to several traits, including tolerance to cellulosic hydrolysate, a biofuel precursor.
Much remains to be learned about the biology of mushrooms, which are an important source of food as well as secondary metabolites and enzymes of biotechnological importance. Ohm et al. report the sequence of the genetically tractable species Schizophyllum commune and identify genes involved in the formation of fruiting bodies and the degradation of lignocellulose.
Holt et al. describe an anti-HIV strategy in which human hematopoietic stem/progenitor cells are modified with zinc-finger nucleases to knock out the viral co-receptor CCR5. Transplantation of these cells into mice confers resistance to HIV, as shown by higher human T-cell counts and lower viral loads compared with animals that received unmodified cells.
Genetically engineered mouse models of cancer simulate the spontaneous development of tumors in their native tissue environment. Singh et al. establish their ability to predict the efficacy of different treatment regimens by comparing clinical trial results to equivalent experiments in mutated KRAS-driven mouse models of pancreatic and lung cancer.
A panel of urinary biomarkers enables the progression of renal injury and subsequent repair and recovery to be monitored after exposure of rats to either carbapenem A or gentamicin. The authors complement this study by demonstrating that serum cystatin C is more sensitive and specific than serum creatinine and blood urea nitrogen in monitoring generalized renal function after exposure to nephrotoxicants.
Current biomarkers for detecting kidney damage, such as serum creatinine (SCr) and blood urea nitrogen (BUN), lack the sensitivity needed for use in drug development. Urinary clusterin outperforms SCr and BUN in detecting proximal tubular injury, and urinary total protein, cystatin C and β2-microglobulin each outperform either SCr or BUN in detecting glomerular injury.
Exposure of rats to kidney toxicants reduces levels of urinary trefoil factor 3 (TFF3) and increases levels of urinary albumin. Whereas urinary albumin outperforms either serum creatinine (SCr) or blood urea nitrogen (BUN) for detecting kidney tubule damage, urinary TFF3 abundance complements the capacity of combined SCr and BUN levels to detect renal injury.
Urinary kidney injury-1 (Kim-1) outperforms serum creatinine, blood urea nitrogen and urinary N-acetyl-β-D-glucosaminidase in detecting kidney damage induced in rats by a range of nephrotoxicants. Earlier detection of renal injury, enabled by monitoring levels of urinary Kim-1, should enable elimination of nephrotoxic candidates sooner in the drug development pipeline.
High-throughput sequencing of total cellular RNA by RNA-Seq promises rapid reconstruction of spliced transcripts in a cell population. Guttman et al. accomplish this using only paired-end RNA-seq data and an unannotated genome sequence, and apply the method to better define many new, conserved long intergenic noncoding RNAs (lincRNAs).
Efforts to develop drugs that would prevent a primary tumor from spreading to new sites have been hampered by a lack of metastasis-specific targets. Working with a mouse model of breast cancer, Ma et al. show for the first time that metastasis formation can be substantially reduced by inhibition of a pro-metastatic microRNA.
High-throughput imaging generates massive data sets that are difficult to quantitatively analyze by hand. Peng et al. describe customizable software for visualizing and working with multi-gigabyte three-dimensional images in real time.
Decreasing levels of mutant, but not normal, huntingtin (HTT) protein remains a major obstacle to treating Huntington's disease (HD). Bauer et al. show that a fusion of polyglutamine-and HSC70–binding motifs specifically targets mutant HTT for degradation by chaperone-mediated autophagy and ameliorates the phenotype of a mouse model of HD.
Magnetic resonance imaging of hemoglobin in the brain can detect blood flow associated with neural activity, but direct imaging of neurotransmitters would provide a more sensitive measure of neural signal processing. Shapiro et al. use directed evolution to generate a protein probe that enables magnetic resonance imaging of the neurotransmitter dopamine.