Hot off the presses! Sep 01 Nat Biotechnol

The Sep 01 issue of the Nat Biotechnol is now up on Pubget (About Nat Biotechnol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• DNA confidential
  - Nat Biotechnol 27(9):777 (2009)
  As the cost of human genome sequencing plunges and large-scale genome-phenotype studies become possible, society should do more to reward those individuals who choose to disclose their data, despite the risks.
• Human Genome Sciences trial data wow lupus community
  - Nat Biotechnol 27(9):779-780 (2009)
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• Bristol-Myers Squibb swallows last of antibody pioneers
  - Nat Biotechnol 27(9):781-783 (2009)
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• Big oil bucks for algae
  - Nat Biotechnol 27(9):783 (2009)
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• PARP inhibitors blaze a trail in difficult-to-treat cancers
  - Nat Biotechnol 27(9):784-786 (2009)
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• VC firms push for REMS
  - Nat Biotechnol 27(9):785 (2009)
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• Alnylam casts IP into pool
  - Nat Biotechnol 27(9):785 (2009)
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• Consumer genomics battle lines drawn
  - Nat Biotechnol 27(9):786 (2009)
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• Biocon, Mylan in pan-biogenerics deal
  - Nat Biotechnol 27(9):786 (2009)
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• China tightens IP protection, but concerns linger
  - Nat Biotechnol 27(9):787-788 (2009)
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• Canada ends EU row over GM products
  - Nat Biotechnol 27(9):788 (2009)
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• Pakistan's first biotech plant
  - Nat Biotechnol 27(9):788 (2009)
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• Trends in biotech literature 2008
  - Nat Biotechnol 27(9):789 (2009)
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• Trading on hope
  - Nat Biotechnol 27(9):790-792 (2009)
  Jane Qiu investigates the thriving business of selling stem cell transplants as cure-alls for debilitating diseases.
• Playing to win
  - Nat Biotechnol 27(9):793-796 (2009)
  
• Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray
  - Nat Biotechnol 27(9):797-799 (2009)
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• Preventing the misuse of gene synthesis
  - Nat Biotechnol 27(9):800-801 (2009)
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• Reply to Preventing the misuse of gene synthesis
  - Nat Biotechnol 27(9):801 (2009)
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• Commercialized GM crops and yield
  - Nat Biotechnol 27(9):801-802 (2009)
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• Commercialized GM crops and yield
  - Nat Biotechnol 27(9):802-803 (2009)
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• Reply to Commercialized GM crops and yield
  - Nat Biotechnol 27(9):803 (2009)
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• Commercialized GM crops and yield
  - Nat Biotechnol 27(9):803-804 (2009)
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• The neonatal blood-brain barrier is functionally effective, and immaturity does not explain differential targeting of AAV9
  - Nat Biotechnol 27(9):804-805 (2009)
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• Reply to The neonatal blood-brain barrier is functionally effective, and immaturity does not explain differential targeting of AAV9
  - Nat Biotechnol 27(9):805 (2009)
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• Globetrotting firms: Canada's health biotechnology collaborations with developing countries
  - Nat Biotechnol 27(9):806-814 (2009)
  A survey of Canadian biotech firms reveals that their biotech collaborations with developing countries are not only significant but also increasingly reciprocal in terms of the exchange of financial resources and technological know-how.
• Accelerated patent examination procedures spur Japanese university innovation
  - Nat Biotechnol 27(9):815-818 (2009)
  Two recent events—the issuance of the world's first patent for induced pluripotent stem cells and, under a pilot system, the issuance of the fastest patent ever granted—signal a watershed in Japanese academia's transition from gown to town.
• Recent patent applications in drug screening
  - Nat Biotechnol 27(9):819 (2009)
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• Faster human genome sequencing
  - Nat Biotechnol 27(9):820-821 (2009)
  Advances in parallelization allow a human genome to be sequenced using single-molecule technology.
• Silencing prostate cancer
  - Nat Biotechnol 27(9):821-823 (2009)
  Systemic delivery of an siRNA–aptamer chimera leads to prostate cancer regression in mice.
• Reshaping pluripotent stem cells
  - Nat Biotechnol 27(9):823-824 (2009)
  Engineered zinc-finger nucleases are used to generate several genetically modified pluripotent stem cell lines.
• Absolute abundance for the masses
  - Nat Biotechnol 27(9):825-826 (2009)
  Mass spectrometry can now measure the absolute concentrations of the majority of cellular proteins without labeling.
• Combinatorics and next-generation sequencing
  - Nat Biotechnol 27(9):826-827 (2009)
  The massive capacity of today's sequencing machines can be harnessed efficiently by sequencing pooled samples and decoding the results.
• Research highlights
  - Nat Biotechnol 27(9):828 (2009)
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• Genome-wide identification of post-translational modulators of transcription factor activity in human B cells
  - Nat Biotechnol 27(9):829-837 (2009)
  The ability of a transcription factor (TF) to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms, resulting in highly context-dependent regulatory networks. However, high-throughput methods for the identification of proteins that affect TF activity are still largely unavailable. Here we introduce an algorithm, modulator inference by network dynamics (MINDy), for the genome-wide identification of post-translational modulators of TF activity within a specific cellular context. When used to dissect the regulation of MYC activity in human B lymphocytes, the approach inferred novel modulators of MYC function, which act by distinct mechanisms, including protein turnover, transcription complex formation and selective enzyme recruitment. MINDy is generally applicable to study the post-translational modulation of mammalian TFs in any cellular context. As such it can be used to dissect context-specific signaling pathways and combinatorial transcr! iptional regulation.
• Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors
  - Nat Biotechnol 27(9):839-846 (2009)
  Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer–small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery. These included adding 2-nucleotide 3'-overhangs and optimizing the thermodynamic profile and structure of the duplex to favor processing of the siRNA guide strand. We also truncated the aptamer portion of the chimeras to facilitate large-scale chemical synthesis. The optimized chimeras resulted in pronounced regression of PSMA-expressing tumors in athymic mice after systemic administration. Anti-! tumor activity was further enhanced by appending a polyethylene glycol moiety, which increased the chimeras' circulating half-life.
• Single-molecule sequencing of an individual human genome
  Pushkarev D Neff NF Quake SR - Nat Biotechnol 27(9):847-850 (2009)
  Recent advances in high-throughput DNA sequencing technologies have enabled order-of-magnitude improvements in both cost and throughput. Here we report the use of single-molecule methods to sequence an individual human genome. We aligned billions of 24- to 70-bp reads (32 bp average) to 90% of the National Center for Biotechnology Information (NCBI) reference genome, with 28 average coverage. Our results were obtained on one sequencing instrument by a single operator with four data collection runs. Single-molecule sequencing enabled analysis of human genomic information without the need for cloning, amplification or ligation. We determined 2.8 million single nucleotide polymorphisms (SNPs) with a false-positive rate of less than 1% as validated by Sanger sequencing and 99.8% concordance with SNP genotyping arrays. We identified 752 regions of copy number variation by analyzing coverage depth alone and validated 27 of these using digital PCR. This milestone should allow! widespread application of genome sequencing to many aspects of genetics and human health, including personal genomics.
• Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases
  - Nat Biotechnol 27(9):851-857 (2009)
  Realizing the full potential of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) requires efficient methods for genetic modification. However, techniques to generate cell type–specific lineage reporters, as well as reliable tools to disrupt, repair or overexpress genes by gene targeting, are inefficient at best and thus are not routinely used. Here we report the highly efficient targeting of three genes in human pluripotent cells using zinc-finger nuclease (ZFN)–mediated genome editing. First, using ZFNs specific for the OCT4 (POU5F1) locus, we generated OCT4-eGFP reporter cells to monitor the pluripotent state of hESCs. Second, we inserted a transgene into the AAVS1 locus to generate a robust drug-inducible overexpression system in hESCs. Finally, we targeted the PITX3 gene, demonstrating that ZFNs can be used to generate reporter cells by targeting non-expressed genes in hESCs and hiPSCs.
• Sensitive digital quantification of DNA methylation in clinical samples
  Li M Chen WD Papadopoulos N Goodman SN Bjerregaard NC Laurberg S Levin B Juhl H Arber N Moinova H Durkee K Schmidt K He Y Diehl F Velculescu VE Zhou S Diaz LA Kinzler KW Markowitz SD Vogelstein B - Nat Biotechnol 27(9):858-863 (2009)
  Analysis of abnormally methylated genes is increasingly important in basic research and in the development of cancer biomarkers1, 2. We have developed methyl-BEAMing technology to enable absolute quantification of the number of methylated molecules in a sample. Individual DNA fragments are amplified and analyzed either by flow cytometry3 or next-generation sequencing. We demonstrate enumeration of as few as one methylated molecule in 5,000 unmethylated molecules in DNA from plasma or fecal samples. Using methylated vimentin as a biomarker in plasma samples, methyl-BEAMing detected 59% of cancer cases. In early-stage colorectal cancers, this sensitivity was four times more than that obtained by assaying serum-carcinoembryonic antigen (CEA). With stool samples, methyl-BEAMing detected 41% of cancers and 45% of advanced adenomas. In addition to diagnostic and prognostic applications, this digital quantification of rare methylation events should be applicable to preclinica! l assessment of new epigenetic biomarkers and quantitative analyses in epigenetic research.
• Corrigendum: Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins
  - Nat Biotechnol 27(9):864 (2009)
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• Corrigendum: Multi-site assessment of the precision and reproducibility of multiple reaction monitoring–based measurements of proteins in plasma
  - Nat Biotechnol 27(9):864 (2009)
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• Erratum: Synergistic drug combinations tend to improve therapeutically relevant selectivity
  - Nat Biotechnol 27(9):864 (2009)
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• Erratum: The Systems Biology Graphical Notation
  - Nat Biotechnol 27(9):864 (2009)
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• Erratum: Table of Contents
  - Nat Biotechnol 27(9):864 (2009)
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• Interview essentials for executives: beyond the basics
  - Nat Biotechnol 27(9):865-866 (2009)
  Tips for competing successfully for a senior position in a biotech company.
• People
  - Nat Biotechnol 27(9):868 (2009)
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