Hot off the presses! Jun 01 Nat Methods

The Jun 01 issue of the Nat Methods is now up on Pubget (About Nat Methods): 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:

• No fruit fly an island?
  - Nat Methods 6(6):395 (2009)
  Methods to study the behavior of Drosophila sp. in the context of a group may deepen our understanding of the neural mechanisms underlying social behavior.
• Predicting microRNA targets and functions: traps for the unwary
  - Nat Methods 6(6):397-398 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Methods Select this option to purchase a personal subscription to Nature Methods.
• Snapshots of the cell surface
  - Nat Methods 6(6):401 (2009)
  Researchers develop an approach to selectively isolate and profile cell-surface proteins by targeting the glycopeptides, a strategy that could be used to generate an atlas of cell-surface protein 'barcodes'.
• Micro-reprogramming
  - Nat Methods 6(6):402-403 (2009)
  Researchers use microRNAs to more efficiently generate induced pluripotent stem cells in the mouse.
• A functional blueprint of E. coli
  - Nat Methods 6(6):402-403 (2009)
  Researchers integrate proteomics data with genomic-context analysis and develop a protein-function prediction tool to annotate functional orphans in Escherichia coli.
• News in brief
  - Nat Methods 6(6):403 (2009)
  
• Nature's pH meter
  - Nat Methods 6(6):404 (2009)
  A new pH nanosensor changes color in acidic cell compartments by forming an unusual four-stranded DNA structure.
• TACLing rare genetic variants
  - Nat Methods 6(6):406 (2009)
  By combining methods for selective genome capture, allele enrichment and array resequencing, researchers create a pipeline for high-throughput variant detection.
• Flight patterns
  - Nat Methods 6(6):408 (2009)
  Flying animals ranging from bugs to bats use a common mechanism to maintain control in turns a discovery that reveals hidden advantages of flapping-wing flight.
• A stress test for mass spectrometry–based proteomics
  - Nat Methods 6(6):411-412 (2009)
  A multilaboratory study attempts to dispel some of the notions of the irreproducibility of mass spectrometry–based proteomics by pinpointing where the methodological problems are and where challenges remain.
• The ethomics era?
  - Nat Methods 6(6):413-414 (2009)
  Applying modern machine-vision techniques to the study of animal behavior, two groups developed systems that quantify many aspects of the complex social behaviors of Drosophila melanogaster. These software tools will enable high-throughput screens that seek to uncover the cellular and molecular underpinnings of behavior.
• Transposon-mediated genome manipulation in vertebrates
  - Nat Methods 6(6):415-422 (2009)
  Transposable elements are DNA segments with the unique ability to move about in the genome. This inherent feature can be exploited to harness these elements as gene vectors for genome manipulation. Transposon-based genetic strategies have been established in vertebrate species over the last decade, and current progress in this field suggests that transposable elements will serve as indispensable tools. In particular, transposons can be applied as vectors for somatic and germline transgenesis, and as insertional mutagens in both loss-of-function and gain-of-function forward mutagenesis screens. In addition, transposons will gain importance in future cell-based clinical applications, including nonviral gene transfer into stem cells and the rapidly developing field of induced pluripotent stem cells. Here we provide an overview of transposon-based methods used in vertebrate model organisms with an emphasis on the mouse system and highlight the most important considerations! concerning genetic applications of the transposon systems.
• A HUPO test sample study reveals common problems in mass spectrometry–based proteomics
  - Nat Methods 6(6):423-430 (2009)
  We performed a test sample study to try to identify errors leading to irreproducibility, including incompleteness of peptide sampling, in liquid chromatography–mass spectrometry–based proteomics. We distributed an equimolar test sample, comprising 20 highly purified recombinant human proteins, to 27 laboratories. Each protein contained one or more unique tryptic peptides of 1,250 Da to test for ion selection and sampling in the mass spectrometer. Of the 27 labs, members of only 7 labs initially reported all 20 proteins correctly, and members of only 1 lab reported all tryptic peptides of 1,250 Da. Centralized analysis of the raw data, however, revealed that all 20 proteins and most of the 1,250 Da peptides had been detected in all 27 labs. Our centralized analysis determined missed identifications (false negatives), environmental contamination, database matching and curation of protein identifications as sources of problems. Improved search engines and databases ar! e needed for mass spectrometry–based proteomics.
• Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster
  - Nat Methods 6(6):431-434 (2009)
  We constructed Drosophila melanogaster bacterial artificial chromosome libraries with 21-kilobase and 83-kilobase inserts in the P[acman] system. We mapped clones representing 12-fold coverage and encompassing more than 95% of annotated genes onto the reference genome. These clones can be integrated into predetermined attP sites in the genome using PhiC31 integrase to rescue mutations. They can be modified through recombineering, for example, to incorporate protein tags and assess expression patterns.
• A toolkit for high-throughput, cross-species gene engineering in Drosophila
  - Nat Methods 6(6):435-437 (2009)
  We generated two complementary genomic fosmid libraries for Drosophila melanogaster and Drosophila pseudoobscura that permit seamless modification of large genomic clones by high-throughput recombineering and direct transgenesis. The fosmid transgenes recapitulated endogenous gene expression patterns. These libraries, in combination with recombineering technology, will be useful to rescue mutant phenotypes, allow imaging of gene products in living flies and enable systematic analysis and manipulation of gene activity across species.
• TU-tagging: cell type–specific RNA isolation from intact complex tissues
  - Nat Methods 6(6):439-441 (2009)
  We found that the combination of spatially restricted uracil phosphoribosyltransferase (UPRT) expression with 4-thiouracil delivery can be used to label and purify cell type–specific RNA from intact complex tissues in Drosophila melanogaster. This method is useful for isolating RNA from cell types that are difficult to isolate by dissection or dissociation methods and should work in many organisms, including mammals and other vertebrates.
• Rapid creation and quantitative monitoring of high coverage shRNA libraries
  - Nat Methods 6(6):443-445 (2009)
  Short hairpin RNA libraries are limited by low efficacy of many shRNAs and by off-target effects, which give rise to false negatives and false positives, respectively. Here we present a strategy for rapidly creating expanded shRNA pools (approx30 shRNAs per gene) that are analyzed by deep sequencing (EXPAND). This approach enables identification of multiple effective target-specific shRNAs from a complex pool, allowing a rigorous statistical evaluation of true hits.
• Automated unrestricted multigene recombineering for multiprotein complex production
  - Nat Methods 6(6):447-450 (2009)
  Structural and functional studies of many multiprotein complexes depend on recombinant-protein overexpression. Rapid revision of expression experiments and diversification of the complexes are often crucial for success of these projects; therefore, automation is increasingly indispensable. We introduce Acembl, a versatile and automatable system for protein-complex expression in Escherichia coli that uses recombineering to facilitate multigene assembly and diversification. We demonstrated protein-complex expression using Acembl, including production of the complete prokaryotic holotranslocon.
• High-throughput ethomics in large groups of Drosophila
  - Nat Methods 6(6):451-457 (2009)
  We present a camera-based method for automatically quantifying the individual and social behaviors of fruit flies, Drosophila melanogaster, interacting in a planar arena. Our system includes machine-vision algorithms that accurately track many individuals without swapping identities and classification algorithms that detect behaviors. The data may be represented as an ethogram that plots the time course of behaviors exhibited by each fly or as a vector that concisely captures the statistical properties of all behaviors displayed in a given period. We found that behavioral differences between individuals were consistent over time and were sufficient to accurately predict gender and genotype. In addition, we found that the relative positions of flies during social interactions vary according to gender, genotype and social environment. We expect that our software, which permits high-throughput screening, will complement existing molecular methods available in Drosophila, ! facilitating new investigations into the genetic and cellular basis of behavior.
• Tissue tectonics: morphogenetic strain rates, cell shape change and intercalation
  - Nat Methods 6(6):458-464 (2009)
  The dynamic reshaping of tissues during morphogenesis results from a combination of individual cell behaviors and collective cell rearrangements. However, a comprehensive framework to unambiguously measure and link cell behavior to tissue morphogenesis is lacking. Here we introduce such a kinematic framework, bridging cell and tissue behaviors at an intermediate, mesoscopic, level of cell clusters or domains. By measuring domain deformation in terms of the relative motion of cell positions and the evolution of their shapes, we characterized the basic invariant quantities that measure fundamental classes of cell behavior, namely tensorial rates of cell shape change and cell intercalation. In doing so we introduce an explicit definition of cell intercalation as a continuous process. We mapped strain rates spatiotemporally in three models of tissue morphogenesis, gaining insight into morphogenetic mechanisms. Our quantitative approach has broad relevance for the precise c! haracterization and comparison of morphogenetic phenotypes.
• In vivo molecular imaging: the inside job
  - Nat Methods 6(6):465-469 (2009)
  In a short period of time, in vivo molecular imaging systems have become indispensable research tools in many clinical and basic research laboratories. But developers are now pushing the technology further in the hopes of making a new generation of platforms with greater accuracy and sensitivity for a wider array of applications.

Hot off the presses! Jun 01 Nat Genet

The Jun 01 issue of the Nat Genet is now up on Pubget (About Nat Genet): 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:

• The cup half empty
  - Nat Genet 41(6):635 (2009)
  One-sixth of the world's population does not have enough food to sustain life, and the world's food supply needs to double by 2050 without increasing demand for water or fuel. Agricultural genetics is one of the easier parts of the solution.
• Genetics of reproductive lifespan
  - Nat Genet 41(6):637-638 (2009)
  Five genome-wide association studies of the timing of menarche and menopause have now taken us beyond the range of candidate gene and linkage studies. The list of new genetic associations identified for these two traits should shed light on the mechanisms of ovarian aging, as well as breast cancer and other diseases associated with reproductive lifespan.
• Diversifying microtubules in brain development
  - Nat Genet 41(6):638-640 (2009)
  Tubulins are key structural components of all cells. A new study reveals roles in brain development for a specific beta-tubulin isoform and highlights potential for functional diversity in the beta-tubulin gene family.
• Narcolepsy and the T-cell receptor
  - Nat Genet 41(6):640-641 (2009)
  The etiology of the sleep disorder narcolepsy has not been firmly established, although an autoimmune pathogenesis has been proposed and is supported by a strong genetic association with the HLA. A new genome-wide association study provides further support for the autoimmune basis of narcolepsy by uncovering a robust association at the T-cell receptor alpha locus.
• Research highlights
  - Nat Genet 41(6):642 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Genetics Select this option to purchase a personal subscription to Nature Genetics.
• Loci at chromosomes 13, 19 and 20 influence age at natural menopause
  - Nat Genet 41(6):645-647 (2009)
  We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 times 10-11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 times 10-11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 times 10-8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.
• Meta-analysis of genome-wide association data identifies two loci influencing age at menarche
  - Nat Genet 41(6):648-650 (2009)
  We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 times 10-9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 times 10-9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.
• Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia
  - Nat Genet 41(6):651-653 (2009)
  The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts—bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, we define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes.
• SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy
  - Nat Genet 41(6):654-656 (2009)
  We report mutations in SDHAF1, encoding a new LYR-motif protein, in infantile leukoencephalopathy with defective succinate dehydrogenase (SDH, complex II). Disruption of the yeast homolog or expression of variants corresponding to human mutants caused SDH deficiency and failure of OXPHOS-dependent growth, whereas SDH activity and amount were restored in mutant fibroblasts proportionally with re-expression of the wild-type gene. SDHAF1 is the first bona fide SDH assembly factor reported in any organism.
• Genome-wide and fine-resolution association analysis of malaria in West Africa
  - Nat Genet 41(6):657-665 (2009)
  We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 times 10-7 to P = 4 times 10-14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing! data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
• Genome-wide association study identifies eight loci associated with blood pressure
  - Nat Genet 41(6):666-676 (2009)
  Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N less than or equal to 71,225 European ancestry, N less than or equal to 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 times 10-24), CYP1A2 (P = 1 times 10-23), FGF5 (P = 1 times 10-21), SH2B3 (P = 3 times 10-18), MTHFR (P = 2 times 10-13), c10orf107 (P = 1 times 10-9), ZNF652 (P = 5 times 10-9) and PLCD3 (P = 1 times 10-8) genes. All variants associated with continuous blood pressur! e were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
• Genome-wide association study of blood pressure and hypertension
  - Nat Genet 41(6):677-687 (2009)
  Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 times 10-7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 times 10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure a! dvances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
• Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests
  - Nat Genet 41(6):688-695 (2009)
  The tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility in inescapable situations. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on chromosome 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase were significantly decreased in the Usp46 mutant mice compared to control mice. These phenotypes were rescued in transge! nic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.
• Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2
  - Nat Genet 41(6):696-702 (2009)
  Here we show that the cytosine-5 methyltransferase DNMT2 controls retrotransposon silencing in Drosophila somatic cells. In Drosophila, significant DNMT2-dependent DNA methylation occurs during early embryogenesis. Suppression of white gene silencing by Mt2 (Dnmt2) null mutations in variegated P[w+] element insertions identified functional targets of DNMT2. The enzyme controls DNA methylation at retrotransposons in early embryos and initiates histone H4K20 trimethylation catalyzed by the SUV4-20 methyltransferase. In somatic cells, loss of DNMT2 eliminates H4K20 trimethylation at retrotransposons and impairs maintenance of retrotransposon silencing. In Dnmt2 and Suv4-20 null genotypes, retrotransposons are strongly overexpressed in somatic but not germline cells, where retrotransposon silencing depends on an RNAi mechanism. DNMT2 also controls integrity of chromosome 2R and 3R telomeres. In Dnmt2 null strains, we found stable loss of the subtelomeric clusters of defect! ive Invader4 elements. Together, these results demonstrate a previously unappreciated role of DNA methylation in retrotransposon silencing and telomere integrity in Drosophila.
• Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes
  - Nat Genet 41(6):703-707 (2009)
  Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10-6). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 times 10-8) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.
• Narcolepsy is strongly associated with the T-cell receptor alpha locus
  - Nat Genet 41(6):708-711 (2009)
  Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals1, 2. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported7, 8. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10-21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders! 9; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders9.
• Multiple loci associated with indices of renal function and chronic kidney disease
  - Nat Genet 41(6):712-717 (2009)
  Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity1. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m2) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 times 10-8) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein2, and rare mutations in UMOD cause mendelian forms of kidney disease3. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic! variants influencing renal function and disease.
• Common variations in BARD1 influence susceptibility to high-risk neuroblastoma
  - Nat Genet 41(6):718-723 (2009)
  We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma1. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma2, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (Pallelic = 2.35 times 10-9–2.25 times 10-8). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (Pallelic = 7.90 times 10-7–2.77 times 10-4). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 times 10-18 and 2.74 times 10-16, respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of ! the aggressive and most clinically relevant subset of human neuroblastoma.
• Genome-wide association studies identify loci associated with age at menarche and age at natural menopause
  - Nat Genet 41(6):724-728 (2009)
  Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 times 10-7–3 times 10-13) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 times 10-7–1 times 10-21) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.
• Genetic variation in LIN28B is associated with the timing of puberty
  - Nat Genet 41(6):729-733 (2009)
  The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 times 10-8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 times 10-10; combined P = 3.6 times 10-16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 times 10-7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA pro! cessing2, as the first genetic determinant regulating the timing of human pubertal growth and development.
• Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche
  - Nat Genet 41(6):734-738 (2009)
  Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 times 10-14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3, 4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height3, 4, 5, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass i! ndex (BMI)6, 7, 8, 9, 10, 11 and 5 of those associated with earlier AAM.
• A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies
  - Nat Genet 41(6):739-745 (2009)
  Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromis! es this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.
• Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria
  - Nat Genet 41(6):746-752 (2009)
  Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissen! cephaly and pachygyria, but also polymicrogyria malformations.
• Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates
  Mátés L Chuah MK Belay E Jerchow B Manoj N Acosta-Sanchez A Grzela DP Schmitt A Becker K Matrai J Ma L Samara-Kuko E Gysemans C Pryputniewicz D Miskey C Fletcher B Vandendriessche T Ivics Z Izsvák Z - Nat Genet 41(6):753-761 (2009)
  The Sleeping Beauty (SB) transposon is a promising technology platform for gene transfer in vertebrates; however, its efficiency of gene insertion can be a bottleneck in primary cell types. A large-scale genetic screen in mammalian cells yielded a hyperactive transposase (SB100X) with approx100-fold enhancement in efficiency when compared to the first-generation transposase. SB100X supported 35–50% stable gene transfer in human CD34+ cells enriched in hematopoietic stem or progenitor cells. Transplantation of gene-marked CD34+ cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution. In addition, SB100X supported sustained (>1 year) expression of physiological levels of factor IX upon transposition in the mouse liver in vivo. Finally, SB100X reproducibly resulted in 45% stable transgenesis frequencies by pronuclear microinjection into mouse zygotes. The newly developed transposase yields unprecedented stable gene transfer effic! iencies following nonviral gene delivery that compare favorably to stable transduction efficiencies with integrating viral vectors and is expected to facilitate widespread applications in functional genomics and gene therapy.
• Corrigendum: Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study
  - Nat Genet 41(6):762 (2009)
  Introduction Nat. Genet. 41, 216–220 (2009), published online 4 January 2009; corrected after print 28 April 2009 ADVERTISEMENT Advertisement In the first paragraph of the second column on the third page, rs11209026 A allele was incorrectly listed as rs111209026 A allele. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis
  - Nat Genet 41(6):762 (2009)
  Introduction Nat. Genet. 41, 228–233 (2009), published online 4 January 2009; corrected after print 28 April 2009 ADVERTISEMENT Advertisement The affiliation of the 24th author, Alessandro Terrinoni, was listed incorrectly. It should read IDI-IRCCS Biochemistry Laboratory c/o Univ. Tor Vergata, 00133 Rome, Italy. The error has been corrected in the HTML and PDF versions of this article.
• Corrigendum: Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants
  - Nat Genet 41(6):762 (2009)
  Introduction Nat. Genet. 41, 334–341 (2009); published online 8 February 2009; corrected after print 27 May 2009 ADVERTISEMENT Advertisement In the version of this article initially published, the names of four co-authors (Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser) were omitted from the author list. The error has been corrected in the HTML and PDF versions of the article.
• Addendum: Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing
  - Nat Genet 41(6):762 (2009)
  Introduction Nat. Genet. 40, 1413–1415 (2008), published online 2 November 2008; addendum published after print 28 April 2009 The GEO accession number for the mRNA-Seq datasets is GSE13652.

Hot off the presses! Jun 01 Nat Neurosci

The Jun 01 issue of the Nat Neurosci is now up on Pubget (About Nat Neurosci): 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:

• Encouraging science outreach
  - Nat Neurosci 12(6):665 (2009)
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• The motor cortex re-imagined
  - Nat Neurosci 12(6):667 (2009)
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• Neurogenesis in G minor
  - Nat Neurosci 12(6):669-671 (2009)
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• Pool rules
  - Nat Neurosci 12(6):671-673 (2009)
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• How serotonin gates olfactory information flow
  - Nat Neurosci 12(6):673-675 (2009)
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• The rhythms of learning
  - Nat Neurosci 12(6):675-676 (2009)
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• Focus on hearing
  - Nat Neurosci 12(6):677 (2009)
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• Quo vadis, hair cell regeneration?
  - Nat Neurosci 12(6):679-685 (2009)
  Hearing loss is a global health problem with profound socioeconomic impact. We contend that acquired hearing loss is mainly a modern disorder caused by man-made noise and modern drugs, among other causes. These factors, combined with increasing lifespan, have exposed a deficit in cochlear self-regeneration that was irrelevant for most of mammalian evolution. Nevertheless, the mammalian cochlea has evolved from phylogenetically older structures, which do have the capacity for self-repair. Moreover, nonmammalian vertebrates can regenerate auditory hair cells that restore sensory function. We will offer a critical perspective on recent advances in stem cell biology, gene therapy, cell cycle regulation and pharmacotherapeutics to define and validate regenerative medical interventions for mammalian hair cell loss. Although these advances are promising, we are only beginning to fully appreciate the complexity of the many challenges that lie ahead.
• Beyond cochlear implants: awakening the deafened brain
  - Nat Neurosci 12(6):686-691 (2009)
  Cochlear implants have provided hearing to more than 120,000 deaf people. Recent surgical developments include direct electrical stimulation of the brain, bilateral implants and implantation in children less than 1 year old. However, research is beginning to refocus on the role of the brain in providing benefits to implant users. The auditory system is able to use the highly impoverished input provided by implants to interpret speech, but this only works well in those who have developed language before their deafness or in those who receive their implant at a very young age. We discuss recent evidence suggesting that developing the ability of the brain to learn how to use an implant may be as important as further improvements of the implant technology.
• On hearing with more than one ear: lessons from evolution
  - Nat Neurosci 12(6):692-697 (2009)
  Although ears capable of detecting airborne sound have arisen repeatedly and independently in different species, most animals that are capable of hearing have a pair of ears. We review the advantages that arise from having two ears and discuss recent research on the similarities and differences in the binaural processing strategies adopted by birds and mammals. We also ask how these different adaptations for binaural and spatial hearing might inform and inspire the development of techniques for future auditory prosthetic devices.
• Unraveling the principles of auditory cortical processing: can we learn from the visual system?
  - Nat Neurosci 12(6):698-701 (2009)
  Studies of auditory cortex are often driven by the assumption, derived from our better understanding of visual cortex, that basic physical properties of sounds are represented there before being used by higher-level areas for determining sound-source identity and location. However, we only have a limited appreciation of what the cortex adds to the extensive subcortical processing of auditory information, which can account for many perceptual abilities. This is partly because of the approaches that have dominated the study of auditory cortical processing to date, and future progress will unquestionably profit from the adoption of methods that have provided valuable insights into the neural basis of visual perception. At the same time, we propose that there are unique operating principles employed by the auditory cortex that relate largely to the simultaneous and sequential processing of previously derived features and that therefore need to be studied and understood in ! their own right.
• Linking genes underlying deafness to hair-bundle development and function
  - Nat Neurosci 12(6):703-710 (2009)
  The identification of mutations underlying monogenic, early-onset forms of deafness in humans has provided unprecedented insight into the molecular mechanisms of hearing in the peripheral auditory system. The molecules involved in the development and function of the cochlea eluded characterization until recently owing to the scarcity of the principal cell types present. The genetic approach has circumvented this problem and succeeded in identifying proteins and deciphering some of the molecular complexes that operate in these cells. In combination with mouse models, the genetic approach is now revealing some of the principles underlying the development and physiology of the cochlea. Focusing on the hair bundle, the mechanosensory device of the sensory hair cell, we highlight recent advances in understanding the way in which the hair bundle is formed, how it operates as a mechanotransducer and how it processes sound. In particular, we discuss how these findings confer a! central role on the various hair-bundle links in these processes.
• Tonotopic reorganization of developing auditory brainstem circuits
  - Nat Neurosci 12(6):711-717 (2009)
  A fundamental organizing principle of auditory brain circuits is tonotopy, the orderly representation of the sound frequency to which neurons are most sensitive. Tonotopy arises from the coding of frequency along the cochlea and the topographic organization of auditory pathways. The mechanisms that underlie the establishment of tonotopy are poorly understood. In auditory brainstem pathways, topographic precision is present at very early stages in development, which may suggest that synaptic reorganization contributes little to the construction of precise tonotopic maps. Accumulating evidence from several brainstem nuclei, however, is now changing this view by demonstrating that developing auditory brainstem circuits undergo a marked degree of refinement on both a subcellular and circuit level.
• Maps and streams in the auditory cortex: nonhuman primates illuminate human speech processing
  - Nat Neurosci 12(6):718-724 (2009)
  Speech and language are considered uniquely human abilities: animals have communication systems, but they do not match human linguistic skills in terms of recursive structure and combinatorial power. Yet, in evolution, spoken language must have emerged from neural mechanisms at least partially available in animals. In this paper, we will demonstrate how our understanding of speech perception, one important facet of language, has profited from findings and theory in nonhuman primate studies. Chief among these are physiological and anatomical studies showing that primate auditory cortex, across species, shows patterns of hierarchical structure, topographic mapping and streams of functional processing. We will identify roles for different cortical areas in the perceptual processing of speech and review functional imaging work in humans that bears on our understanding of how the brain decodes and monitors speech. A new model connects structures in the temporal, frontal and! parietal lobes linking speech perception and production.
• Intracellular zinc inhibits KCC2 transporter activity
  - Nat Neurosci 12(6):725-727 (2009)
  We found that K+/Cl- co-transporter 2 (KCC2) activity, monitored with wide-field fluorescence, was inhibited by intracellular Zn2+, a major component of neuronal injury. Zn2+-mediated KCC2 inhibition produced a depolarizing shift of GABAA reversal potentials in rat cortical neurons. Moreover, oxygen-glucose deprivation attenuated KCC2 activity in a Zn2+-dependent manner. The link between Zn2+ and KCC2 activity provides a previously unknown target for neuroprotection and may be important in activity-dependent regulation of inhibitory synaptic transmission.
• Adult neurogenesis promotes synaptic plasticity in the olfactory bulb
  - Nat Neurosci 12(6):728-730 (2009)
  To explore the functional consequences of adult neurogenesis in the mouse olfactory bulb, we investigated plasticity at glutamatergic synapses onto GABAergic interneurons. We found that one subset of excitatory synapses onto adult-born granule cells showed long-term potentiation shortly after their arrival in the bulb. This property faded as the newborn neurons matured. These results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis–dependent olfactory learning.
• Long-term plasticity of excitatory inputs to granule cells in the rat olfactory bulb
  - Nat Neurosci 12(6):731-733 (2009)
  Using two photon–guided focal stimulation, we found spike timing–dependent plasticity of proximal excitatory inputs to olfactory bulb granule cells that originated, in part, from cortical feedback projections. The protocol that potentiated proximal inputs depressed distal, dendrodendritic inputs to granule cells. Granule cell excitatory postsynaptic potentials and mitral cell inhibition were also potentiated by theta-burst stimulation. Plasticity of cortical feedback inputs to interneurons provides a mechanism for encoding information by modulating bulbar inhibition.
• Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells
  - Nat Neurosci 12(6):735-744 (2009)
  The mechanisms that regulate symmetric, proliferative divisions versus asymmetric, neurogenic divisions of mammalian neural precursors are still not well understood. We found that Lfc (Arhgef2), a Rho-specific guanine nucleotide exchange factor that interacts with spindle microtubules, and its negative regulator Tctex-1 (Dynlt1) determine the genesis of neurons from precursors in the embryonic murine cortex. Specifically, genetic knockdown of Arhgef2 in cortical precursors either in culture or in vivo inhibited neurogenesis and maintained cells as cycling radial precursors. Conversely, genetic knockdown of Dynlt1 in radial precursors promoted neurogenesis and depleted cycling cortical precursors. Coincident silencing of these two genes indicated that Tctex-1 normally inhibits the genesis of neurons from radial precursors by antagonizing the proneurogenic actions of Lfc. Moreover, Lfc and Tctex-1 were required to determine the orientation of mitotic precursor cell divis! ions in vivo. Thus, Lfc and Tctex-1 interact to regulate cortical neurogenesis, potentially by regulating mitotic spindle orientation.
• Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology
  - Nat Neurosci 12(6):745-750 (2009)
  One of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, has gone unnoticed and is the result of a Na+-activated K+ current. Previous studies of K+ currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in such studies. We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of a persistent inward sodium current (persistent INa) is highly effective at activating this large Na+-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, we identified SLO2.2 channels as being carriers of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems ne! uroscience, as well as clinical neurology and pharmacology.
• A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse
  - Nat Neurosci 12(6):751-758 (2009)
  Synapses relay information through the release of neurotransmitters stored in presynaptic vesicles. The identity, kinetics and location of the vesicle pools that are mobilized by neuronal activity have been studied using a variety of techniques. We created a genetically encoded probe, biosyn, which consists of a biotinylated VAMP2 expressed at presynaptic terminals. We exploited the high-affinity interaction between streptavidin and biotin to label biosyn with fluorescent streptavidin during vesicle fusion. This approach allowed us to tag vesicles sequentially to visualize and establish the identity of presynaptic pools. Using this technique, we were able to distinguish between two different pools of vesicles in rat hippocampal neurons: one that was released in response to presynaptic activity and another, distinct vesicle pool that spontaneously fused with the plasma membrane. We found that the spontaneous vesicles belonged to a 'resting pool' that is normally not mob! ilized by neuronal activity and whose function was previously unknown.
• Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release
  - Nat Neurosci 12(6):759-766 (2009)
  Spontaneous 'mini' release occurs at all synapses, but its nature remains enigmatic. We found that >95% of spontaneous release in murine cortical neurons was induced by Ca2+-binding to synaptotagmin-1 (Syt1), the Ca2+ sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca2+-dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca2+ dependent but was activated at lower Ca2+ concentrations and with a lower Ca2+ cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca2+ sensor for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca2+ sensor for spontaneous release that resembles the Ca2+ sensor for evoked asynchronous rel! ease. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.
• Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release
  - Nat Neurosci 12(6):767-776 (2009)
  Synaptotagmin-IV (syt-IV) is a membrane trafficking protein that influences learning and memory, but its localization and role in synaptic function remain unclear. We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. Syt-IV/BDNF–harboring vesicles underwent exocytosis in both axons and dendrites, and syt-IV inhibited BDNF release at both sites. Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. Furthermore, selective loss of presynaptic syt-IV increased spontaneous quantal release, whereas a loss of postsynaptic syt-IV increased quantal amplitude. Finally, syt-IV knockout mice showed enhanced long-term potentiation (LTP), which depended entirely on disinhibition o! f BDNF release. Thus, regulation of BDNF secretion by syt-IV emerges as a mechanism for maintaining synaptic strength in a useful range during LTP.
• Ube3a is required for experience-dependent maturation of the neocortex
  - Nat Neurosci 12(6):777-783 (2009)
  Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We co! nclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.
• Serotonergic modulation of odor input to the mammalian olfactory bulb
  - Nat Neurosci 12(6):784-791 (2009)
  Centrifugal serotonergic fibers innervate the olfactory bulb, but the importance of these projections for olfactory processing is unclear. We examined serotonergic modulation of sensory input to olfactory glomeruli using mice that express synaptopHluorin in olfactory receptor neurons (ORN). Odor-evoked synaptic input to glomeruli was attenuated by increased serotonin signaling through serotonin 2C (5-HT2C) receptors and amplified by decreased serotonergic activity. Intravital multiphoton calcium imaging revealed that 5-HT2C receptor activation amplified odor-evoked activity in a subset of juxtaglomerular cells and attenuated glutamate release from ORN terminals via GABAB receptors. Endogenous serotonin released by electrical stimulation of the dorsal raphe nucleus attenuated odor-evoked responses without detectable bias in glomerular position or odor identity. Weaker glomerular responses, however, were less sensitive to raphe stimulation than strong responses. Our data! indicate that the serotonergic system regulates odor inputs in the olfactory bulb and suggest that behavioral states may alter odor processing at the earliest stages.
• Sparse temporal coding of elementary tactile features during active whisker sensation
  - Nat Neurosci 12(6):792-800 (2009)
  How the brain encodes relevant sensory stimuli in the context of active, natural sensation is not known. During active tactile sensation by rodents, whisker movement across surfaces generates complex whisker micro-motion, including discrete, transient slip-stick events, which carry information about surface properties. We simultaneously measured whisker motion and neural activity in somatosensory cortex (S1) in rats whisking across surfaces. Slip-stick motion events were prominently encoded by one or two low-probability, precisely timed spikes in S1 neurons, resulting in a probabilistically sparse ensemble code. Slips could be efficiently decoded from transient, correlated spiking (approx20-ms time scale) in small (approx100 neuron) populations. Slip responses contributed substantially to increased firing rate and transient firing synchrony on surfaces, and firing synchrony was an important cue for surface texture. Slips are thus a fundamental encoded tactile feature i! n natural whisker input streams and are represented by sparse, temporally precise, synchronous spiking in S1.
• Coherent gamma oscillations couple the amygdala and striatum during learning
  - Nat Neurosci 12(6):801-807 (2009)
  The basolateral amygdala (BLA) mediates the facilitating effects of emotions on memory. The BLA's enhancing influence extends to various types of memories, including striatal-dependent habit formation. To shed light on the underlying mechanisms, we carried out unit and local field potential (LFP) recordings in BLA, striatum, auditory cortex and intralaminar thalamus in cats trained on a stimulus-response task in which the presentation of one of two tones predicted reward delivery. The coherence of BLA, but not of cortical or thalamic, LFPs was highest with striatal gamma activity, and intra-BLA muscimol infusions selectively reduced striatal gamma power. Moreover, coupling of BLA-striatal unit activity increased when LFP gamma power was augmented. Early in training, the rewarded and unrewarded tones elicited a modest increase in coherent BLA-striatal gamma. As learning progressed, this gamma coupling selectively increased in relation to the rewarded tone. Thus, coheren! t gamma oscillations coordinate amygdalostriatal interactions during learning and might facilitate synaptic plasticity.
• Erratum: A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 387–389 (2008); published online 15 March 2009; corrected after print 15 May 2009 In the version of this article initially published, the abbreviation DLK was omitted from the abstract. The second sentence of the abstract should be "We found that dual leucine kinase (DLK) promoted degeneration of severed axons in Drosophila and mice, and that its target, c-Jun N-terminal kinase, promoted degeneration locally in axons as they committed to degenerate". The error has been corrected in the HTML and PDF versions of the article.
• Erratum: A precise form of divisive suppression supports population coding in the primary visual cortex
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 637–645 (2009); published online 26 April 2009; corrected after print 6 May 2009 In the version of this article initially published, the gray curve in Figure 1j was shifted to the left. The corrected figure is shown below. The error has been corrected in the HTML and PDF versions of the article.
• Erratum: Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, bold gamma-5
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 277–285 (2009); published online 22 February 2009; corrected after print 16 March 2009 In the version of this article initially published, the bar graphs in Figure 7c and 7d were misaligned. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 11, 1185–1192 (2008); published online 21 September 2008; corrected after print 15 January and 30 April 2009 In the version of this article initially published, two citations were inadvertently omitted. To correct this, the following two sentences were added to the second paragraph of the introduction, following the sixth sentence. "One line of work has supported the theory by demonstrating that arm movement errors evoke complex spikes51, 52 and that subsequent learned changes in motor behavior are associated with suitable changes in simple spike responses51. This work demonstrates a strong correlation, but stops short of showing cause-and-effect links between individual complex spikes, changes in simple spikes and behavioral learning." Two references were also added to the reference list as follows: In addition, the second sentence of the abstract should read "Many elements of this hypothesis have been supported by prior experiments, and correlations have been found between complex spikes, simple-spike plasticity and behavior during the learning process." The errors have been corrected in the HTML and PDF versions of the article.

Hot off the presses! Jun 01 Trends Ecol Evol

The Jun 01 issue of the Trends Ecol Evol is now up on Pubget (About Trends Ecol Evol): 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:

• Editorial Board
  - Trends Ecol Evol 24(6):i (2009)
  
• Alternative mechanisms of range expansion are associated with different changes of evolutionary potential
  - Trends Ecol Evol 24(6):289-292 (2009)
  Human-induced and natural range expansion of species are expected to lead to different patterns of genetic diversity, which might themselves be trait dependent. Recent studies examined the molecular and quantitative genetic variation following the range expansion of three plant species. The results suggest that contrasting diversity patterns among species reflect how range expansion has occurred and the level of fragmentation of the original habitat. Unexpectedly, even introductions from a homogeneous environment do not preclude a species from adapting to a new environment and becoming invasive.
• Evolution education in natural history museums
  - Trends Ecol Evol 24(6):292-293 (2009)
  
• Coping with the heat
  - Trends Ecol Evol 24(6):293-294 (2009)
  
• From natural gestures to complex grammar
  - Trends Ecol Evol 24(6):295-296 (2009)
  
• Bateman's principles and human sex roles
  - Trends Ecol Evol 24(6):297-304 (2009)
  In 1948, Angus J. Bateman reported a stronger relationship between mating and reproductive success in male fruit flies compared with females, and concluded that selection should universally favour 'an undiscriminating eagerness in the males and a discriminating passivity in the females' to obtain mates. The conventional view of promiscuous, undiscriminating males and coy, choosy females has also been applied to our own species. Here, we challenge the view that evolutionary theory prescribes stereotyped sex roles in human beings, firstly by reviewing Bateman's principles and recent sexual selection theory and, secondly, by examining data on mating behaviour and reproductive success in current and historic human populations. We argue that human mating strategies are unlikely to conform to a single universal pattern.
• Evolutionary consequences of cryptic genetic variation
  - Trends Ecol Evol 24(6):305-311 (2009)
  Phenotypic evolution depends on heritable variation in phenotypes. A central aim of evolutionary biology, therefore, is to understand how processes generating phenotypic variation interact with selection and drift to result in phenotypic evolution. Recent studies have highlighted the propensity for populations to harbor genetic variation that contributes to phenotypic variation only after some environmental or genetic change. Many authors have suggested that release of this cryptic genetic variation by stressful or novel environments can facilitate phenotypic adaptation. However, there is little empirical evidence that stressful or novel environments release cryptic genetic variation, or that, once released, it contributes to phenotypic evolution. We argue that empirical studies are needed to answer these questions, and identify the empirical approaches needed to study the relationship between environment, released cryptic genetic variation and phenotypic evolution.
• The jellyfish joyride: causes, consequences and management responses to a more gelatinous future
  - Trends Ecol Evol 24(6):312-322 (2009)
  Human-induced stresses of overfishing, eutrophication, climate change, translocation and habitat modification appear to be promoting jellyfish (pelagic cnidarian and ctenophore) blooms to the detriment of other marine organisms. Mounting evidence suggests that the structure of pelagic ecosystems can change rapidly from one that is dominated by fish (that keep jellyfish in check through competition or predation) to a less desirable gelatinous state, with lasting ecological, economic and social consequences. Management actions needed to stop such changes require tactical coping strategies and longer-term preventative responses based on fundamental and targeted research on this understudied group.
• Smelling global climate change: mitigation of function for plant volatile organic compounds
  - Trends Ecol Evol 24(6):323-331 (2009)
  Plant volatile organic compounds (VOCs) have important roles in plant adaptation to the environment and serve as infochemicals in multitrophic interactions. Global climate change factors, such as increased atmospheric carbon dioxide, ozone and temperature, could alter how insects perceive such compounds. Here we review recent research on the influence of climate change parameters on the ecological functions of VOCs, with specific focus on terpenoids, the best-characterized VOCs. We summarize how emission patterns and concentrations of VOCs could change in future environments, mainly from the perspectives of plant defense and stress responses. We discuss how higher carbon dioxide concentrations, elevated ozone levels and increased temperatures could affect the biological functions of VOCs, particularly their role in plant defense.
• Gene tree discordance, phylogenetic inference and the multispecies coalescent
  - Trends Ecol Evol 24(6):332-340 (2009)
  The field of phylogenetics is entering a new era in which trees of historical relationships between species are increasingly inferred from multilocus and genomic data. A major challenge for incorporating such large amounts of data into inference of species trees is that conflicting genealogical histories often exist in different genes throughout the genome. Recent advances in genealogical modeling suggest that resolving close species relationships is not quite as simple as applying more data to the problem. Here we discuss the complexities of genealogical discordance and review the issues that new methods for multilocus species tree inference will need to address to account successfully for naturally occurring genomic variability in evolutionary histories.
• Unicolonial ants: where do they come from, what are they and where are they going?
  - Trends Ecol Evol 24(6):341-349 (2009)
  Unicolonial ant populations are the most extensive cooperative units known in nature, forming networks of interconnected nests extending sometimes hundreds of kilometers. Within such a supercolony, worker altruistic behavior might be maladaptive, because it seems to aid random members of the population instead of relatives. However, recent genetic and behavioral data show that, viewed on a sufficiently large scale, unicolonial ants do have colony boundaries that define very large kin groups. It seems likely that they are family groups that continue to express their kin-selected behavior as they grow to extreme sizes. However, at extreme sizes, kin selection theory predicts that these behaviors are maladapted and evolutionarily unstable, a prediction that is supported by their twiggy phylogenetic distribution.