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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.
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.
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.
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.
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.
Although never demonstrated in humans, exchange of the antigen-binding regions of IgG4 antibodies with different specificities could complicate certain antibody therapies. Labrijn et al. show that Fab-arm exchange occurs in patients and propose that a single mutation can inhibit the process.
Until now, determining the sequences recognized by an RNA-binding protein has been time and labor intensive. Ray et al. use a custom pool of >210,000 oligos that encode linear and stem-loop RNAs to rapidly determine the sequences bound by nine RNA-binding proteins.
Traditional methods for modifying viruses to produce live attenuated vaccines are being updated with molecularly targeted approaches. Perez et al. attenuate influenza A viruses by introducing miRNA target sites into the coding region of the viral genome.
The delivery to primary cells is a major challenge in the application of siRNAs in biological research. Using a fusion protein consisting of a double-stranded RNA binding domain and a protein transduction domain, Eguchi et al. are able to transfect siRNAs into a wide variety of cells with very high efficiency without cytotoxicity.
Strategies for allele-specific knockdown of the mutant genes in triplet-repeat disorders have relied on point or deletion mutations that differ among affected individuals. Hu et al. show that antisense oligomers can selectively recognize expanded CAG repeats in mRNAs, allowing silencing of mutant but not wild-type alleles.
Single-nucleotide polymorphisms in microRNA target sites can disrupt the effects of the microRNA. Kim and Bartel use sequencing to investigate this phenomenon on a large scale and find that such polymorphisms generate gene-regulatory diversity in mice.
Chambers et al. present an improved method for neural differentiation of human pluripotent stem cells that avoids the use of stromal feeder cells and embryoid bodies. By combining two inhibitors of SMAD signaling, the protocol generates neural cells with an efficiency of >80%.
Teratoma formation is a safety concern for any therapeutic strategy involving human embryonic stem cells. Blum et al. characterize teratomas derived from mouse and human embryonic stem cells and uncover a key role for the oncofetal gene survivin.
Lam and Joyce describe a new approach to ligand detection based on two cross-replicating RNA ligases with allosteric ligand-binding domains. The ligases amplify exponentially at a rate dependent on ligand concentration—a system analogous to qPCR for detection of small molecules and proteins.