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Rissin et al. increase the sensitivity of sandwich ELISA by segregating beads bearing a single enzyme-labeled immunoconjugate into femtoliter-volume reaction chambers. As the small volume of each well permits detection of extremely low levels of fluorescence, protein abundance is determined by counting the number of fluorescent wells as a percentage of the number of wells containing beads.
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.
Genome-wide single-gene deletion libraries can be important tools for understanding the molecular workings of an organism, but have only been created for a single eukaryotic species, Saccharomyces cerevisiae. Now, Kim et al. present a second collection of deletion mutants that covers 98.4% of the genes of Schizosaccharomyces pombe, allowing a systematic comparison of gene essentiality and knockout phenotypes between two eukaryotic species.
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).
Insects are biotechnologically important producers of recombinant proteins and materials, and their biology as crop pests has substantial economic consequences. Xiang et al. map cytosine methylation genome-wide at single-base resolution in the silkworm, opening the door for global studies of epigenetic DNA modification in insects.
ChIP-Seq data are usually analyzed with approaches developed for microarrays, which only consider binding events within a few kilobases of a gene. McLean et al. present an algorithm that takes into account more distant events, thereby improving functional annotation of regulatory regions.
Smith et al. use time-lapse imaging to study the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells. By reconstructing movies of single cells over a two-week period, they identify an early phenotypic change characteristic of cells that are successfully reprogrammed.
RNA-Seq enables rapid sequencing of total cellular RNA and should allow the reconstruction of spliced transcripts in a cell population. Trapnell et al. achieve this and transcript quantification using only paired-end RNA-Seq data and an unannotated genome sequence, and apply the approach to characterize isoform switching over a developmental time course.
Human embryonic stem cells are generally cultured as adherent monolayers, but large-scale production of these cells for clinical applications would require the development of culture conditions amenable to growth in bioreactors. Steiner et al. show that human embryonic stem cells can be derived, grown and differentiated in suspension.
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.
Cultured human embryonic stem cells often acquire chromosomal abnormalities that could be detrimental in certain applications. Närvä et al. report the highest-resolution genetic analysis of these cells to date and identify genes whose expression is altered by culture-induced genetic changes.
Synthetic genetic circuits may be used to program cells to respond to physiological conditions with predictable dynamic behaviors. Kemmer et al. describe the engineering of a mammalian circuit that maintains homeostasis of a bloodstream metabolite within a physiologically appropriate range.
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.
Plant pattern-recognition receptors (PRRs) confer resistance to infection by many microbes by recognizing conserved molecules important for pathogen viability. Lacombe et al. show that transfer of a PRR from a wild species to tobacco and tomato plants renders them resistant to several bacterial phytopathogens.
Many proteases are important drug targets, but identification of their substrates remains challenging. By using polymers to selectively isolate N-terminal peptides generated by proteolysis of complex samples, Kleifeld et al. identify substrates of clinically relevant proteases with broad specificity.
Spinal muscular atrophy is an autosomal recessive disease of motor neurons caused by lack of the SMN gene. Foust et al. achieve long-term correction of the disease phenotype in a mouse model by intravenous delivery of SMN using the viral vector scAAV9.