Institute for Information Transmission Problems

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Click to increase image sizeClick to decrease image size *Here and in what follows f≈g indicates that the differencef—g is bounded, while f∼g indicates that the ratio f:g approaches one Notes *Here and in what follows f≈g indicates that the differencef—g is bounded, while f∼g indicates that the ratio f:g approaches one

The equilibrium control hypothesis (lambda model) is considered with special reference to the following concepts: (a) the length-force invariant characteristic (IC) of the muscle together with central and reflex systems subserving its activity; (b) the tonic stretch reflex threshold (lambda) as an independent measure of central commands descending to alpha and gamma motoneurons; (c) the equilibrium point, defined in terms of lambda, IC and static load characteristics, which is associated with the notion that posture and movement are controlled by a single mechanism; and (d) the muscle activation area (a reformulation of the "size principle")--the area of kinematic and command variables in which a rank-ordered recruitment of motor units takes place. The model is used for the interpretation of various motor phenomena, particularly electromyographic patterns. The stretch reflex in the lambda model has no mechanism to follow-up a certain muscle length prescribed by central commands. Rather, its task is to bring the system to an equilibrium, load-dependent position. Another currently popular version defines the equilibrium point concept in terms of alpha motoneuron activity alone (the alpha model). Although the model imitates (as does the lambda model) spring-like properties of motor performance, it nevertheless is inconsistent with a substantial data base on intact motor control. An analysis of alpha models, including their treatment of motor performance in deafferented animals, reveals that they suffer from grave shortcomings. It is concluded that parameterization of the stretch reflex is a basis for intact motor control. Muscle deafferentation impairs this graceful mechanism though it does not remove the possibility of movement.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Arabidopsis thaliana is a long established model species for plant molecular biology, genetics and genomics, and studies of A. thaliana gene function provide the basis for formulating hypotheses and designing experiments involving other plants, including economically important species. A comprehensive understanding of the A. thaliana genome and a detailed and accurate understanding of the expression of its associated genes is therefore of great importance for both fundamental research and practical applications. Such goal is reliant on the development of new genetic and genomic resources, involving new methods of data acquisition and analysis. We present here the genome-wide analysis of A. thaliana gene expression profiles across different organs and developmental stages using high-throughput transcriptome sequencing. The expression of 25 706 protein-coding genes, as well as their stability and their spatiotemporal specificity, was assessed in 79 organs and developmental stages. A search for alternative splicing events identified 37 873 previously unreported splice junctions, approximately 30% of them occurred in intergenic regions. These potentially represent novel spliced genes that are not included in the TAIR10 database. These data are housed in an open-access web-based database, TraVA (Transcriptome Variation Analysis, http://travadb.org/), which allows visualization and analysis of gene expression profiles and differential gene expression between organs and developmental stages.

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors into young germ-free mice that were fed a Malawian diet revealed that immature microbiota from undernourished infants and children transmit impaired growth phenotypes. The representation of several age-discriminatory taxa in recipient animals correlated with lean body mass gain; liver, muscle, and brain metabolism; and bone morphology. Mice were cohoused shortly after receiving microbiota from healthy or severely stunted and underweight infants; age- and growth-discriminatory taxa from the microbiota of the former were able to invade that of the latter, which prevented growth impairments in recipient animals. Adding two invasive species, Ruminococcus gnavus and Clostridium symbiosum, to the microbiota from undernourished donors also ameliorated growth and metabolic abnormalities in recipient animals. These results provide evidence that microbiota immaturity is causally related to undernutrition and reveal potential therapeutic targets and agents.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

A combination is presented of all inclusive deep
\ninelastic cross sections previously published by the H1 and
\nZEUS collaborations at HERA for neutral and charged current e± p scattering for zero beam polarisation. The datawere
\ntaken at proton beam energies of 920, 820, 575 and 460GeV
\nand an electron beam energy of 27.5GeV. The data correspond
\nto an integrated luminosity of about 1 fb−1 and span
\nsix orders ofmagnitude in negative four-momentum-transfer
\nsquared, Q2, and Bjorken x. The correlations of the systematic
\nuncertainties were evaluated and taken into account for
\nthe combination. The combined cross sections were input
\nto QCD analyses at leading order, next-to-leading order and
\nat next-to-next-to-leading order, providing a new set of parton
\ndistribution functions, called HERAPDF2.0. In addition
\nto the experimental uncertainties, model and parameterisation
\nuncertainties were assessed for these parton distribution
\nfunctions. Variants of HERAPDF2.0 with an alternative
\ngluon parameterisation, HERAPDF2.0AG, and using fixedflavour-
\nnumber schemes, HERAPDF2.0FF, are presented.
\nThe analysiswas extended by includingHERAdata on charm
\nand jet production, resulting in the variant HERAPDF2.0Jets.
\nThe inclusion of jet-production cross sections made a simultaneous
\ndetermination of these parton distributions and the
\nstrong coupling constant possible, resulting in αs (M2Z
\n) =
\n0.1183±0.0009(exp)±0.0005(model/parameterisation)±
\n0.0012(hadronisation)
\n+0.0037
\n−0.0030(scale).An extraction of xFγ Z
\n3
\nand results on electroweak unification and scaling violations
\nare also presented.

Here, we study deformations of 2D Integrable Quantum Field Theories (IQFT) which preserve integrability (the existence of infinitely many local integrals of motion). The IQFT are understood as “effective field theories”, with finite ultraviolet cutoff. We show that for any such IQFT there are infinitely many integrable deformations generated by scalar local fields X_s, which are in one-to-one correspondence with the local integrals of motion; moreover, the scalars X_s are built from the components of the associated conserved currents in a universal way. The first of these scalars, X₁, coincides with the composite field View the MathML source(TT¯) built from the components of the energy–momentum tensor. The deformations of quantum field theories generated by X₁ are “solvable” in a certain sense, even if the original theory is not integrable. In a massive IQFT the deformations X_s are identified with the deformations of the corresponding factorizable S-matrix via the CDD factor. The situation is illustrated by explicit construction of the form factors of the operators X_s in sine-Gordon theory. Lastly, we also make some remarks on the problem of UV completeness of such integrable deformations.

While celebrating the 21st year since the very first IEEE 802.11 “legacy” 2 Mbit/s wireless local area network standard, the latest Wi-Fi newborn is today reaching the finish line, topping the remarkable speed of 10 Gbit/s. IEEE 802.11ax was launched in May 2014 with the goal of enhancing throughput-per-area in high-density scenarios. The first 802.11ax draft versions, namely, D1.0 and D2.0, were released at the end of 2016 and 2017. Focusing on a more mature version D3.0, in this tutorial paper, we help the reader to smoothly enter into the several major 802.11ax breakthroughs, including a brand new orthogonal frequency-division multiple access-based random access approach as well as novel spatial frequency reuse techniques. In addition, this tutorial will highlight selected significant improvements (including physical layer enhancements, multi-user multiple input multiple output extensions, power saving advances, and so on) which make this standard a very significant step forward with respect to its predecessor 802.11ac.

BACKGROUND: Genome-scale prediction of gene regulation and reconstruction of transcriptional regulatory networks in prokaryotes is one of the critical tasks of modern genomics. Bacteria from different taxonomic groups, whose lifestyles and natural environments are substantially different, possess highly diverged transcriptional regulatory networks. The comparative genomics approaches are useful for in silico reconstruction of bacterial regulons and networks operated by both transcription factors (TFs) and RNA regulatory elements (riboswitches). DESCRIPTION: RegPrecise (http://regprecise.lbl.gov) is a web resource for collection, visualization and analysis of transcriptional regulons reconstructed by comparative genomics. We significantly expanded a reference collection of manually curated regulons we introduced earlier. RegPrecise 3.0 provides access to inferred regulatory interactions organized by phylogenetic, structural and functional properties. Taxonomy-specific collections include 781 TF regulogs inferred in more than 160 genomes representing 14 taxonomic groups of Bacteria. TF-specific collections include regulogs for a selected subset of 40 TFs reconstructed across more than 30 taxonomic lineages. Novel collections of regulons operated by RNA regulatory elements (riboswitches) include near 400 regulogs inferred in 24 bacterial lineages. RegPrecise 3.0 provides four classifications of the reference regulons implemented as controlled vocabularies: 55 TF protein families; 43 RNA motif families; ~150 biological processes or metabolic pathways; and ~200 effectors or environmental signals. Genome-wide visualization of regulatory networks and metabolic pathways covered by the reference regulons are available for all studied genomes. A separate section of RegPrecise 3.0 contains draft regulatory networks in 640 genomes obtained by an conservative propagation of the reference regulons to closely related genomes. CONCLUSIONS: RegPrecise 3.0 gives access to the transcriptional regulons reconstructed in bacterial genomes. Analytical capabilities include exploration of: regulon content, structure and function; TF binding site motifs; conservation and variations in genome-wide regulatory networks across all taxonomic groups of Bacteria. RegPrecise 3.0 was selected as a core resource on transcriptional regulation of the Department of Energy Systems Biology Knowledgebase, an emerging software and data environment designed to enable researchers to collaboratively generate, test and share new hypotheses about gene and protein functions, perform large-scale analyses, and model interactions in microbes, plants, and their communities.

Using comparative analysis of genes, operons, and regulatory elements, we describe the cobalamin (vitamin B12) biosynthetic pathway in available prokaryotic genomes. Here we found a highly conserved RNA secondary structure, the regulatory B12 element, which is widely distributed in the upstream regions of cobalamin biosynthetic/transport genes in eubacteria. In addition, the binding signal (CBL-box) for a hypothetical B12 regulator was identified in some archaea. A search for B12 elements and CBL-boxes and positional analysis identified a large number of new candidate B12-regulated genes in various prokaryotes. Among newly assigned functions associated with the cobalamin biosynthesis, there are several new types of cobalt transporters, ChlI and ChlD subunits of the CobN-dependent cobaltochelatase complex, cobalt reductase BluB, adenosyltransferase PduO, several new proteins linked to the lower ligand assembly pathway, l-threonine kinase PduX, and a large number of other hypothetical proteins. Most missing genes detected within the cobalamin biosynthetic pathways of various bacteria were identified as nonorthologous substitutes. The variable parts of the cobalamin metabolism appear to be the cobalt transport and insertion, the CobG/CbiG- and CobF/CbiD-catalyzed reactions, and the lower ligand synthesis pathway. The most interesting result of analysis of B12 elements is that B12-independent isozymes of the methionine synthase and ribonucleotide reductase are regulated by B12 elements in bacteria that have both B12-dependent and B12-independent isozymes. Moreover, B12 regulons of various bacteria are thought to include enzymes from known B12-dependent or alternative pathways. Using comparative analysis of genes, operons, and regulatory elements, we describe the cobalamin (vitamin B12) biosynthetic pathway in available prokaryotic genomes. Here we found a highly conserved RNA secondary structure, the regulatory B12 element, which is widely distributed in the upstream regions of cobalamin biosynthetic/transport genes in eubacteria. In addition, the binding signal (CBL-box) for a hypothetical B12 regulator was identified in some archaea. A search for B12 elements and CBL-boxes and positional analysis identified a large number of new candidate B12-regulated genes in various prokaryotes. Among newly assigned functions associated with the cobalamin biosynthesis, there are several new types of cobalt transporters, ChlI and ChlD subunits of the CobN-dependent cobaltochelatase complex, cobalt reductase BluB, adenosyltransferase PduO, several new proteins linked to the lower ligand assembly pathway, l-threonine kinase PduX, and a large number of other hypothetical proteins. Most missing genes detected within the cobalamin biosynthetic pathways of various bacteria were identified as nonorthologous substitutes. The variable parts of the cobalamin metabolism appear to be the cobalt transport and insertion, the CobG/CbiG- and CobF/CbiD-catalyzed reactions, and the lower ligand synthesis pathway. The most interesting result of analysis of B12 elements is that B12-independent isozymes of the methionine synthase and ribonucleotide reductase are regulated by B12 elements in bacteria that have both B12-dependent and B12-independent isozymes. Moreover, B12 regulons of various bacteria are thought to include enzymes from known B12-dependent or alternative pathways. Cobalamin (CBL), 1The abbreviations used are: CBL, cobalamin; Ado-CBL, adenosylcobalamin; Uro′III, uroporphyrinogen III; TMSs, transmembrane segments; CoA, coenzyme A; CR, corrin ring. along with chlorophyll, heme, siroheme, and coenzyme F430, constitute a class of the most structurally complex cofactors synthesized by bacteria. The distinctive feature of these cofactors is their tetrapyrrole-derived framework with a centrally chelated metal ion (cobalt, magnesium, iron, or nickel). Methylcobalamin and Ado-CBL, two derivatives of vitamin B12 (cyanocobalamin) with different upper axial ligands, are essential cofactors for several important enzymes that catalyze a variety of transmethylation and rearrangement reactions. Among the most prominent vitamin B12-dependent enzymes in bacteria and archaea are the methionine synthase isozyme MetH from enteric bacteria; the ribonucleotide reductase isozyme NrdJ from deeply rooted eubacteria and archaea; diol dehydratases and ethanolamine ammonia lyase from enteric bacteria involved in anaerobic glycerol, 1,2-propanediol, and ethanolamine fermentation; glutamate and methylmalonyl-CoA mutases from clostridia and streptomycetes; and various CBL-dependent methyltransferases from methane-producing archaea (1Banerjee R. Biochemistry. 2001; 40: 6191-6198Crossref PubMed Scopus (104) Google Scholar, 2Daniel R. Bobik T.A. Gottschalk G. FEMS Microbiol. Rev. 1999; 22: 553-566Crossref Google Scholar, 3Jordan A. Torrents E. Jeanthon C. Eliasson R. Hellman U. Wernstedt C. Barbe J. Gibert I. Reichard P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13487-13492Crossref PubMed Scopus (29) Google Scholar, 4O'Toole G.A. Rondon M.R. Trzebiatowski J.R. Suh S.-J. Escalante-Semerena J.C. Neidhardt F.C. Escherichia coli and Salmonella: Cellular and Molecular Biology. American Society for Microbiology, Washington, D. C.1994: 710-720Google Scholar, 5Sauer K. Thauer R.K. Eur. J. Biochem. 1999; 261: 674-681Crossref PubMed Scopus (34) Google Scholar). Most prokaryotic organisms as well as animals (including humans) and protists have enzymes that require CBL as cofactor, whereas plants and fungi are thought not to use it. Among the CBL-utilizing organisms, some and are to CBL D. Microbiol. PubMed Scopus Google Scholar). there are two of the CBL in bacteria the well pathway in and the pathway that was in and Biochem. PubMed Google Scholar). The of from Uro′III, the of various enzymes D. Microbiol. PubMed Scopus Google and be two The the corrin is different in the anaerobic and the with the of cobalt whereas in the the corrin The of the pathway is for both anaerobic and and of CR, of the and assembly of the that the lower ligand and G.A. Rondon M.R. Trzebiatowski J.R. Suh S.-J. Escalante-Semerena J.C. Neidhardt F.C. Escherichia coli and Salmonella: Cellular and Molecular Biology. American Society for Microbiology, Washington, D. C.1994: 710-720Google Scholar). The CBL genes from S. and P. have different and S. two genes, and that and whereas in P. these functions are by we use the S. In we to genes analysis of The anaerobic and pathways several the cobalt is by the cobalt of P. which of and and two cobalt from S. and from which are associated with the anaerobic pathway D. J. J. PubMed Google Scholar, E. C. P. A. J. 1997; PubMed Google Scholar, E. R. D. C. A. Biochem. J. Google Scholar). the of the of the not pathway have the cobalt ion the the pathways use enzymes with different from P. to and is for the pathway D. J. J. PubMed Google Scholar). The of anaerobic is the cobalt which different In and are to the anaerobic of S. whereas and are to the pathway of P. In most cobalt and other metal are by the and transport J. PubMed Google Scholar). cobalt a of the was identified in with some transporters, to the of S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus (104) Google Scholar). the transport by the CBL biosynthetic in S. transport of cobalt for the B12 synthesis J.R. S. J. PubMed Google Scholar). and other are in enteric bacteria the in the complex with the transport C. E. J. PubMed Scopus Google Scholar). B12 is known to of the genes of Escherichia coli and S. J. PubMed Google and the in S. S. Microbiol. 2001; PubMed Scopus Google Scholar). genes were identified in was that is involved in the of CBL genes in A. PubMed Scopus Google Scholar). The conserved a element, a that the binding as well as several RNA is found in the regions of the CBL and is for their which is the S. Microbiol. 2001; PubMed Scopus Google Scholar). was that the Ado-CBL, and in the secondary and of the RNA and that the of of two alternative RNA A. PubMed Scopus Google Scholar). of the comparative analysis of positional of genes, and to a pathway in a variety of is a to the search of missing genes within the pathway as well as of transport genes PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Here we use comparative for the analysis of the CBL biosynthetic pathway in prokaryotes. The of genes involved in the CBL and vitamin B12 transport in eubacteria was to be regulated by a conserved RNA regulatory element, the B12 In a new regulatory signal was upstream of the of the B12 and the CBL pathway in most and we identified several new enzymes and to the CBL In new cobalt and as well as new were the vitamin B12 are widely distributed in bacteria and archaea and the B12 was to B12-independent methionine synthase and ribonucleotide reductase isozymes in bacteria that have B12-dependent isozymes. and of were from I. J. PubMed Scopus Google Scholar). were from the of the for the of for the the and the R. G. E. K. D. I. A. P. A. PubMed Scopus Google Scholar). from the and are used The of genes to be involved in the CBL metabolism have in that is available The of the and The of of was used to search for conserved RNA regulatory The RNA both the RNA secondary and the The RNA secondary was as a of the the number of the of the and of the of The RNA of the B12 was a of upstream regions of the from was with the B12 in of B12 A search was the in the Scopus Google Scholar). were 1997; PubMed Scopus Google Scholar). proteins were by the PubMed Scopus Google by of that the of used in is for genomes. The were by the in J. J. PubMed Scopus Google and the were identified S. A. J. D. 1997; PubMed Scopus Google Scholar). were the of the B12 we have two highly conserved RNA elements, and involved in the of the and biosynthetic genes in bacteria J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). B12-dependent of the and genes in their upstream regions and a of alternative RNA describe secondary of the E. coli and S. the have a number of conserved elements S. Microbiol. 2001; PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar). Using the comparative analysis of regulatory regions of vitamin genes in we a highly conserved RNA the B12 PubMed Scopus Google Scholar). to the and elements, the B12 a of by a and highly conserved the known In to conserved the B12 and variable binding of to the was A. PubMed Scopus Google is interesting that of the B12 are highly conserved the be involved in to the of for and regulons J. PubMed Scopus Google Scholar, PubMed Scopus Google a of of genes of alternative RNA the B12 elements is PubMed Scopus Google Scholar). B12 of and of the cobalamin biosynthetic and transport genes in available prokaryotic were identified by search positional (including of the CBL genes are in I. The of E. which and and is by the CBL and biosynthesis, was was with other CBL and transport genes and in bacteria we the and the of a RNA PubMed Scopus Google and found B12 elements distributed in with B12 elements, CBL transport Most bacteria as well as have CBL genes B12 and B12 elements have CBL The and positional analysis of the CBL genes and the B12 elements is In to cobalamin regulons in a large B12 elements, we upstream regions of CBL genes and the signal to PubMed Scopus Google Scholar). The a with was in candidate cobalamin regulons in new of the the was used to the genomes. The cobalamin in the to include CBL and transport genes In addition, conserved CBL-boxes were identified upstream of the P. genes and and their in two other genes are to anaerobic ribonucleotide reductase two subunits of methylmalonyl-CoA synthase and methylmalonyl-CoA of these genes are to the CBL or their with the CBL genes to be of their or with B12-dependent enzymes The were for two other and not for the The CBL of A. the B12 transport and methylmalonyl-CoA Among archaea in and A. are to be to CBL and CBL to The CBL of S. in to the and genes, the genes for the CBL synthesis and cobalt that require coenzyme B12 for their we a search for known B12-dependent enzymes in prokaryotic genomes. a and as well as A. were found to have B12-dependent enzymes is in with the of the CBL biosynthetic and transport genes as well as with the of B12 elements in these two other bacteria known B12-dependent and S. were to have the B12 transport is the B12 in that B12-dependent enzymes be in these bacteria. B12 of the bacteria appear to have pathway for the CBL transport vitamin B12 or some from the The known transport for vitamin B12 is the of enteric which of two transmembrane subunits and two subunits In the of vitamin B12 the and the proteins and which are various the of the are and in and The of involved in the of heme, and vitamin B12 are and to the Microbiol. 2001; PubMed Scopus Google Scholar). a search is not to the B12 and in from enteric bacteria. a search with of highly regulatory B12 elements and with positional analysis of The for the by various of the B12 and within not The for vitamin B12 were found to be widely distributed in bacteria with were not found in and in and in In most of B12 are by of genes that are regulated by the B12 the regulatory B12 was found upstream of the from of the for and vitamin of B12 transport were in some bacteria. The genes were in and and the genes were in and The of A. and is within the which is a in the The hypothetical is not to known and transmembrane in these be a new of transmembrane of the B12 the and proteins. The of the conserved positional and hypothetical transmembrane was found in and to be involved in the transport of vitamin The of S. is of that not include a that the with some other transport transport for cobalt was identified in the from different and the and archaea In most the genes were found within large CBL or as and were by regulatory B12 bacteria in cobalt transport the of other for the CBL of and regulatory B12 elements to new candidate cobalt in the cobalt for cobalamin synthesis in cobalt in a new cobalt to from the in various and archaea. most of are for was known as a cobalt associated with S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus (104) Google Scholar). for the of cobalt are B12-regulated and with genes in eubacteria. of the with CBL genes in S. for the cobalt of as well and other B12-regulated genes, and detected in various and cobalt with genes are not to known and have B12-regulated the of which are linked to CBL In addition, is in P. with a which by a involved in metal In are to different types of cobalt and In that not have the the of the B12 is the hypothetical transmembrane with a number proteins from the are for of and and thought to be involved in transport PubMed Scopus Google Scholar). of B12 elements to cobalt to in A candidate cobalt of and by the B12-regulated and a and In the B12-regulated a cobalt with In two other and we identified candidate cobalt by the B12-regulated which and a transmembrane and A new of the B12 in a signal In in with upstream of the genes and is thought to be involved in the In addition, and have a which is B12-regulated in the In of the of of in with to be involved in cobalt of cobalt and of the CBL is by different cobalt as and are two and and of and In to the of the which is widely distributed in the and were found in and the is from other CBL genes and upstream B12 the of cobalt are missing in and genes to the were found in with various CBL genes, most with to involved in the of and and is a of E. Biochemistry. 1999; PubMed Scopus Google Scholar). The that ChlI and ChlD are the missing of the cobalt was by proteins associated with the and CBL the for both and ChlI not these we in to the cobaltochelatase complex of and of the and ChlD subunits in the cobalamin biosynthetic pathways of or in a new CBL of cobalt the hypothetical is upstream of the the of a and is to the proteins and which are involved in the of the of In addition, the variable the conserved and of a involved in metal is with cobalt in some genomes. that is for the cobalt CBL and is that the of is used to the cobalt within of the to their to the of the B12 the was found within the conserved in and is to various proteins the of E. A. A. C. Biochem. J. PubMed Scopus Google and as cobalt of the cobalt ion of is the the CBL is a for the with cobalt reductase was in P. the not identified D. J. PubMed Google Scholar). In S. in that catalyze the the is to the adenosyltransferase J. 2001; PubMed Scopus Google Scholar). Using a the was found in and as well as in the and of bacteria. was found in some CBL is to be to the B12 is with that the by several is essential in E. coli Escalante-Semerena J.C. J. 2001; PubMed Scopus Google Scholar). was not found in bacteria with the CBL biosynthetic pathway. In a candidate cobalt reductase associated with the CBL was identified in most bacteria with the CBL pathway and as well as in several other The was in R. as a of essential for the CBL synthesis P. J. PubMed Scopus Google Scholar). found that are regulated by B12 elements and with various CBL The proteins are to various from the and that catalyze the from to various The and genes in The of these bacteria have whereas is not in the of we that functions in cobalt for the CBL Moreover, was found in with CBL A. and The CBL pathways in these bacteria include genes for the of to and are involved in the of that cobalt reductase BluB, which is for these pathways as of coenzyme Ado-CBL, be by synthesis or by of require adenosyltransferase by the CBL or to The search for in that widely distributed is with other CBL genes and is B12-regulated was not found in genomes. is known two other CBL and which are associated with the CBL-dependent and ethanolamine ammonia lyase by the and G. J. PubMed Google Scholar, E. Bobik J. 2001; PubMed Scopus Google Scholar). the PduO, and of the were found within that is in the ethanolamine In to be widely distributed in in in most the in the CBL pathways The genes within the and CBL or be the of the to the and genes and to the genes not In were found in two clostridia and archaea. the have B12-dependent a and not require the of from and from appear in with B12-dependent methylmalonyl-CoA that types of are for B12-dependent enzymes or for the CBL pathways for the lower ligand synthesis of CBL known as the are thought to E. C. I. J. J. 1999; PubMed Google Scholar). have genes for the synthesis of from or have of these In two other genes of the assembly pathway, and are conserved in bacteria with the of in archaea and the have other genes for the CBL of these bacteria two hypothetical genes, and which are not to known these two genes were found in several other bacteria with The of and genes of D. and are by regulatory B12 In addition, the B12-regulated CBL of the The hypothetical transmembrane to a of new and proteins in of and A of nonorthologous of the CBL genes was found in the is by a new Escalante-Semerena J.C. I. J. 2001; PubMed Scopus Google Scholar). Here we analysis of genomes. of these appear to the and the the nonorthologous The is which both In of is linked to other CBL Here we identified of nonorthologous of CBL genes in archaea. The was found in two S. and In other A. and the hypothetical in P. was found within the CBL most linked with is to not to we that is the missing In the CBL the hypothetical nonorthologous of which is to the from in other archaea. Among S. and A. the we have found a of genes, which is with the and the have a new hypothetical which is with and The hypothetical proteins and are not to known the a a of we that and are nonorthologous of the in and of the B12 to the CBL of S. the of Escalante-Semerena J.C. J. PubMed Scopus Google Scholar). Here we found that some D. and the genes within the CBL to the Most of these are to be In addition, the by a B12 was found in S. two of and of is with the The to the kinase and is to and the CBL as a for the and the positional analysis that is we the l-threonine kinase to The of proteins not The two the B12-regulated cobalt involved in the CBL synthesis and the for the The hypothetical proteins of from and genomes. In the genes are with a new which a hypothetical with In addition, the of P. R. and are with hypothetical genes proteins to the vitamin B12 Moreover, in P. and the genes a candidate with the transport genes T.A. J. 1999; PubMed Google Scholar). The was found to various and J. PubMed Scopus Google Scholar). In the genes are linked to the a hypothetical with to that the hypothetical and of the in are involved in the transport and of various in the CBL The of the a hypothetical and be involved in the CBL biosynthesis, as the anaerobic E. A. A. C. Biochem. J. PubMed Scopus Google Scholar). of are widely distributed in some of are with CBL genes and regulated by B12 The genes are with cobalt and CBL biosynthetic genes in and and with B12 transport in and In and and the cobalt are by a the in bacteria with anaerobic CBL pathways in to most the the CBL of which is not to is to various that is the nonorthologous of The CBL of R. a of the a of the methyltransferases from archaea. a is by a from the is missing in in Cobalamin of known CBL genes and new B12-regulated genes to and the CBL pathways in various In to cobalt and the of the is highly variable in bacteria is by the or proteins and the or anaerobic of the CBL pathway, in to is Biochem. PubMed Google Scholar). and have both and the in these bacteria a large be In to other R. and R. the have involved in the CBL E. P. Biochem. PubMed Google Scholar). of we detected a the of cobalt and the of the CBL pathway. The were found in bacteria with the cobaltochelatase to the cobalt the of several we not cobaltochelatase genes, the proteins with to the cobalt In addition, C. and are to have cobalt of which are to the The is the of the in the of R. S. C. C. and with cobalt and and are with CBL genes In to the of in the CBL is Biochem. PubMed Google Scholar). of a of genes from that appear to be a within that the functions by these genes be I. 1999; PubMed Scopus Google Scholar). In to the in the CBL pathway, we The proteins appear in S. and whereas the were found in the of bacteria. we and the pathway of CBL B12-regulated in the CBL and of the regulatory B12 elements in to B12-regulated genes that are not involved in the CBL result was that most of these genes appear to to B12-dependent pathways of genes, which are not involved in the CBL and isozymes of B12-dependent ribonucleotide ribonucleotide or alternative enzymes of D. in a new in some and as well as in and B12 elements were found upstream of the the B12-independent methionine the other genes the and ribonucleotide are by B12 elements in two the and S. C. and D. there are two B12-dependent methionine synthase MetH and ribonucleotide reductase isozyme that are known to have B12-independent and G.A. Rondon M.R. Trzebiatowski J.R. Suh S.-J. Escalante-Semerena J.C. Neidhardt F.C. Escherichia coli and Salmonella: Cellular and Molecular Biology. American Society for Microbiology, Washington, D. C.1994: 710-720Google Scholar, D. Microbiol. PubMed Scopus Google Scholar). these a we for the of both B12-dependent and isozymes and found that the B12-independent isozymes are regulated by B12 elements in most bacteria that have both isozymes. regulatory B12 elements, in with both NrdJ and the genes are to be with CBL biosynthetic genes conserved CBL-boxes we that vitamin B12 is in the of B12-independent isozymes is and B12-dependent isozymes are The a glutamate upstream B12 in of the B12-dependent glutamate which is known to catalyze the of the B12-dependent pathway of glutamate Microbiol. 2001; PubMed Scopus Google Scholar). Moreover, is the B12-dependent found in to two alternative pathways of glutamate and of vitamin the the B12-independent glutamate pathway in The B12 in the and genes, which are thought to be involved in the B12-dependent pathway. In a B12 the from the B12-dependent pathway. In P. a hypothetical B12 enzymes of the B12-independent pathway of coenzyme A and several genes for B12-dependent and alternative pathways are of the vitamin B12 regulons both in eubacteria and archaea. the of B12-dependent enzymes analysis of regulatory B12 In we identified a new of the B12 in hypothetical which to the which the in the of in G. R. D. J. PubMed Scopus Google and various The was found in B12-regulated with B12-independent ribonucleotide reductase in The candidate of A. is by a B12 new of the B12 the was found in S. and R. The hypothetical and proteins are highly to the and subunits of various and from several other bacteria have upstream B12 The of B12 of the hypothetical and genes is that B12-independent of B12-dependent The of coenzyme B12 is a pathway widely distributed in bacteria and is not found in In addition, have transport for vitamin B12 and of the regulatory elements to new genes to the CBL a we and the CBL pathways in various The most variable parts of the CBL pathway are the of the corrin synthesis and cobalt that or of the pathway. The and proteins the or anaerobic types of the CBL pathway. The of a cobalt to the of cobalt and to be with of the CBL pathway we two and different cobalt transport in various of known B12-dependent enzymes in prokaryotic to coenzyme B12 for their of these are of synthesis or transport of vitamin or The is the of which CBL biosynthetic known transport genes B12-dependent methionine synthase the other there are bacteria and S. that a vitamin B12 known B12-dependent that B12-dependent enzymes in these bacteria. The a large number of missing genes in the CBL biosynthetic pathways of various bacteria. analysis of the and regulatory B12 elements to for several new genes to the CBL of various transporters, whereas the are enzymes involved in the CBL In we identified cobalt transporters, two vitamin B12 transporters, and two for various Among new we cobalt reductase to BluB, cobalt to and l-threonine kinase to as well as the of the and proteins in the corrin In addition, most functions to missing genes in several were assigned to nonorthologous Most we identified the nonorthologous for the in and missing functions in the CBL pathway are in C. in and and in P. in C. and in and in functions for involved in cobalt for for for for for for of various of various for in a new Using the analysis of the B12 elements in available we have found that conserved RNA regulatory is widely distributed in eubacteria and most CBL The B12 elements not in we identified candidate in several genomes. Among genes to the CBL biosynthesis, cobalt genes, both known and are The are the in two and and the in Most vitamin B12 transport as well as cobalt are regulated by B12 In we for the that B12 elements not genes to the CBL and transport several genes from B12-dependent pathways. that in most the B12-independent isozymes of methionine synthase and ribonucleotide reductase are regulated by B12 elements in the both B12-dependent and B12-independent isozymes. the of B12-independent enzymes by the of coenzyme B12 regulatory was not with of other B12 enzymes not to the CBL and to new B12-dependent pathways. In the in most upstream B12 in we the of a alternative to B12-dependent in these the the of comparative for of are In analysis of regulatory elements is a for of missing transport genes, as and in of other vitamin regulons J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). are to for and with

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM.

Attention helps us process potentially important objects by selectively increasing the activity of sensory neurons that represent the relevant locations and features of our environment. This selection process requires top-down feedback about what is important in our environment. We investigated how parietal cortical output influences neural activity in early sensory areas. Neural recordings were made simultaneously from the posterior parietal cortex and an earlier area in the visual pathway, the medial temporal area, of macaques performing a visual matching task. When the monkey selectively attended to a location, the timing of activities in the two regions became synchronized, with the parietal cortex leading the medial temporal area. Parietal neurons may thus selectively increase activity in earlier sensory areas to enable focused spatial attention.

We consider the asymptotics of the Plancherel measures on partitions of $n$ as $n$ goes to infinity. We prove that the local structure of a Plancherel typical partition in the middle of the limit shape converges to a determinantal point process with the discrete sine kernel. On the edges of the limit shape, we prove that the joint distribution of suitably scaled 1st, 2nd, and so on rows of a Plancherel typical diagram converges to the corresponding distribution for eigenvalues of random Hermitian matrices (given by the Airy kernel). This proves a conjecture due to Baik, Deift, and Johansson by methods different from the Riemann-Hilbert techniques used in their original papers and from the combinatorial proof given by the second author. Our approach is based on an exact determinantal formula for the correlation functions of the poissonized Plancherel measures in terms of a new kernel involving Bessel functions. Our asymptotic analysis relies on the classical asymptotic formulas for the Bessel functions and depoissonization techniques.

Abstract The following factors underlying behavioral plasticity are discussed: (1) reflex adaptability and its role in the voluntary control of movement, (2) degrees of freedom and motor equivalence, and (3) the problem of the discrete organization of motor behavior. Our discussion concerns a variety of innate motor patterns, with emphasis on the wiping reflex in the frog. It is proposed that central regulation of stretch reflex thresholds governs voluntary control over muscle force and length. This suggestion is an integral part of the equilibrium-point hypothesis, two versions of which are compared. Kinematic analysis of the wiping reflex in the spinal frog has shown that each stimulated skin site is associated with a group of different but equally effective trajectories directed to the target site. Such phenomena reflect the principle of motor equivalence -the capacity of the neuronal structures responsible for movement to select one or another of a set of possible trajectories leading to the goal. Redundancy of degrees of freedom at the neuronal level as well as at the mechanical level of the body's joints makes motor equivalence possible. This sort of equivalence accommodates the overall flexibility of motor behavior. An integrated behavioral act or a single movement consists of dynamic components. We distinguish six components for the wiping reflex, each associated with a certain functional goal, specific body positions, and motor-equivalent movement patterns. The nervous system can combine the available components in various ways in forming integrated behavioral sequences. The significance of command neuronal organization is discussed with respect to (1) the combinatory strategy of the nervous system and (2) the relation between continuous and discrete forms of motor control. We conclude that voluntary movements are effected by the central nervous system with the help of the mechanisms that underlie the variability and modifiability of innate motor patterns.