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Telomerase-independent telomere lengthening is a potential target for cancer therapy, but molecules specific to this pathway have remained elusive. Henson et al. show that DNA circles of (CCCTAA)n are specific intermediates of alternative lengthening of telomeres and present a sensitive assay to detect them.
Patwardhan et al. describe a high-throughput approach for analyzing at single-nucleotide resolution the DNA regulatory sequences that control gene expression. Characterizing these sequences in a massively parallel manner will be useful for deciphering the regulatory logic of the cell and for synthetic biology.
The feasibility of recycling CO2 to biofuels in photosynthetic organisms will depend on advances in productivity and product-purification efficiency. Atsumi et al. improve the direct conversion of CO2 by engineering Synechococcus elongatus to produce isobutyraldehyde, which can be easily recovered from the production medium.
Rapid clearance frequently complicates therapeutic use of proteins and peptides. Schellenberger et al. demonstrate that genetic fusion of an unstructured polypeptide offers a general strategy to extend peptide or protein half-life in vivo in a tunable manner.
Cho et al. reconstruct the regulatory and functional architecture of the E. coli genome by integrating data from several high-throughput measurements. The detailed map will allow the development of improved models of the networks that control the bacterium's transcription and translation.
With a flood of cancer genome sequences expected soon, distinguishing 'driver' from 'passenger' mutations will be an important task. Wang et al. describe a bioinformatic method for identifying cancer-associated fusions and apply it to discover a recurrent rearrangement in lung cancer.
In many sequencing applications, it is sufficient to sequence selected portions of a genome rather than the complete genome. Tewhey et al. describe an approach for massively parallel genome targeting that relies on PCR in microdroplets generated by a microfluidic device.
Cytochrome P450 enzymes metabolize drugs and contribute to harmful drug-drug interactions. To decipher p450 activities, Veith et al. screen ∼17,000 compounds, including >1,000 FDA-approved drugs, against five important P450 isozymes and identify chemical structures that are enriched in compounds active against specific isozymes.
Cells that have been purified by FACS using intracellular markers are not amenable to gene expression analysis by conventional methods. Pechhold et al. solve this problem with the quantitative nuclease protection assay and apply the approach to study subsets of islet cells.
Methods for reprogramming human cells are unable to prospectively distinguish bona fide induced pluripotent stem (iPS) cells from partially reprogrammed cells. Using live imaging to monitor cell fate, Chan et al. identify a set of markers that allows identification of rare iPS cells within a heterogeneous cell population.
Controlling protein-protein interaction with high temporal and spatial resolution is essential for understanding many cellular processes. Yazawa et al. present genetically encoded tags that can induce protein dimer formation upon stimulation with blue light.
Kubota et al. describe a sensitive mass spectrometric method for generating signatures of kinase activity characteristic of specific cell types. They also identify kinases responsible for phosphorylating substrates of interest.
Salis et al. design precisely tuned ribosome binding sites that allow rational control over the rate of protein translation. This technology should facilitate the design of synthetic genetic circuits and metabolic pathways.
Nonribosomal peptides and polyketides constitute a large fraction of antibiotic, antitumor and immunosuppressant drugs. Bumpus et al. present a proteomic strategy to identify new natural products and their biosynthetic pathways.
Tumors generate microenvironments that actively suppress the body's anti-tumor immune response. Kortylewski et al. restore immunity by delivering an siRNA against Stat3, a regulator of immune suppression, to myeloid and B cells using a CpG oligonucleotide that targets toll-like receptor 9.
Modulatory proteins ensure that transcription factors are active when and where they should be. Wang et al. describe an algorithm for identifying modulators from a compendium of gene expression profiles and experimentally validate four diverse modulators of the MYC oncogene in human B cells.
Systemic delivery remains a major obstacle in therapeutic applications of siRNAs. Using RNA aptamer–siRNA chimeras with enhanced silencing activity and specificity, Dassie et al. achieve regression of xenograft prostate tumors by intraperitoneal injection.
Gene-specific changes in DNA methylation are promising biomarkers, but sensitive quantitative detection of these epigenetic marks remains challenging. Li et al. adapt the so-called BEAMing technology to enable high-throughput digital quantification of gene methylation in clinical samples.
Hockemeyer et al. demonstrate targeted genetic modification of three genes in human embryonic stem cells and induced pluripotent stem cells using zinc-finger nucleases delivered on plasmids. They use the approach to generate a reporter cell line that monitors the pluripotent state, a drug-inducible overexpression system, and a reporter cell line for a gene that is not expressed in pluripotent stem cells.
Pushkarev et al. present the first human genome sequence obtained using single-molecule sequencing technology. These results demonstrate that human genome sequencing—previously the turf of large sequencing centers—is now within reach of an individual lab in a matter of weeks.