The Devil Dwells in the Tails A Quantile Regression Approach to Firm Growth

This paper explores the firm growth rate distribution in a Gibrat’s Law context. The aim is to provide an empirical exploration of the determinants of firm growth. The work is novel in two respects. First, rather than limiting the analysis to focus on the conditional mean growth level, we investigate the complete shape of the distribution. Second, we show that the differences in the firm growth rate process between large and small firms are highly circumstantial. That industry dynamics have a substantial influence on the relationship between firm size and firm growth. The data used includes more than 9000 Danish firms from manufacturing, services and construction. We provide robust evidence indicating that firm growth studies should be less obsessed with explaining means and instead look to other parts of the firm growth rate distribution.Firm growth; quantile regression; distribution shape

Evolutionarily stable gene clusters shed light on the common grounds of pathogenicity in the Acinetobacter calcoaceticus-baumannii complex

Nosocomial pathogens of the Acinetobacter calcoaceticus-baumannii (ACB) complex are a cautionary example for the world-wide spread of multi- and pan-drug resistant bacteria. Aiding the urgent demand for novel therapeutic targets, comparative genomics studies between pathogens and their apathogenic relatives shed light on the genetic basis of human-pathogen interaction. Yet, existing studies are limited in taxonomic scope, sensing of the phylogenetic signal, and resolution by largely analyzing genes independent of their organization in functional gene clusters. Here, we explored more than 3,000 Acinetobacter genomes in a phylogenomic framework integrating orthology-based phylogenetic profiling and microsynteny conservation analyses. We delineate gene clusters in the type strain A. baumannii ATCC 19606 whose evolutionary conservation indicates a functional integration of the subsumed genes. These evolutionarily stable gene clusters (ESGCs) reveal metabolic pathways, transcriptional regulators residing next to their targets but also tie together sub-clusters with distinct functions to form higher-order functional modules. We shortlisted 150 ESGCs that either co-emerged with the pathogenic ACB clade or are preferentially found therein. They provide a high-resolution picture of genetic and functional changes that coincide with the manifestation of the pathogenic phenotype in the ACB clade. Key innovations are the remodeling of the regulatory-effector cascade connecting LuxR/LuxI quorum sensing via an intermediate messenger to biofilm formation, the extension of micronutrient scavenging systems, and the increase of metabolic flexibility by exploiting carbon sources that are provided by the human host. We could show experimentally that only members of the ACB clade use kynurenine as a sole carbon and energy source, a substance produced by humans to fine-tune the antimicrobial innate immune response. In summary, this study provides a rich and unbiased set of novel testable hypotheses on how pathogenic Acinetobacter interact with and ultimately infect their human host. It is a comprehensive resource for future research into novel therapeutic strategies.Peer Reviewe

Evolutionarily stable gene clusters shed light on the common grounds of pathogenicity in the Acinetobacter calcoaceticus-baumannii complex

Nosocomial pathogens of the Acinetobacter calcoaceticus-baumannii (ACB) complex are a cautionary example for the world-wide spread of multi- and pan-drug resistant bacteria. Aiding the urgent demand for novel therapeutic targets, comparative genomics studies between pathogens and their apathogenic relatives shed light on the genetic basis of human-pathogen interaction. Yet, existing studies are limited in taxonomic scope, sensing of the phylogenetic signal, and resolution by largely analyzing genes independent of their organization in functional gene clusters. Here, we explored more than 3,000 Acinetobacter genomes in a phylogenomic framework integrating orthology-based phylogenetic profiling and microsynteny conservation analyses. We delineate gene clusters in the type strain A. baumannii ATCC 19606 whose evolutionary conservation indicates a functional integration of the subsumed genes. These evolutionarily stable gene clusters (ESGCs) reveal metabolic pathways, transcriptional regulators residing next to their targets but also tie together sub-clusters with distinct functions to form higher-order functional modules. We shortlisted 150 ESGCs that either co-emerged with the pathogenic ACB clade or are preferentially found therein. They provide a high-resolution picture of genetic and functional changes that coincide with the manifestation of the pathogenic phenotype in the ACB clade. Key innovations are the remodeling of the regulatory-effector cascade connecting LuxR/LuxI quorum sensing via an intermediate messenger to biofilm formation, the extension of micronutrient scavenging systems, and the increase of metabolic flexibility by exploiting carbon sources that are provided by the human host. We could show experimentally that only members of the ACB clade use kynurenine as a sole carbon and energy source, a substance produced by humans to fine-tune the antimicrobial innate immune response. In summary, this study provides a rich and unbiased set of novel testable hypotheses on how pathogenic Acinetobacter interact with and ultimately infect their human host. It is a comprehensive resource for future research into novel therapeutic strategies

Hypermutable Non-Synonymous Sites Are under Stronger Negative Selection

Mutation rate varies greatly between nucleotide sites of the human genome and depends both on the global genomic location and the local sequence context of a site. In particular, CpG context elevates the mutation rate by an order of magnitude. Mutations also vary widely in their effect on the molecular function, phenotype, and fitness. Independence of the probability of occurrence of a new mutation's effect has been a fundamental premise in genetics. However, highly mutable contexts may be preserved by negative selection at important sites but destroyed by mutation at sites under no selection. Thus, there may be a positive correlation between the rate of mutations at a nucleotide site and the magnitude of their effect on fitness. We studied the impact of CpG context on the rate of human–chimpanzee divergence and on intrahuman nucleotide diversity at non-synonymous coding sites. We compared nucleotides that occupy identical positions within codons of identical amino acids and only differ by being within versus outside CpG context. Nucleotides within CpG context are under a stronger negative selection, as revealed by their lower, proportionally to the mutation rate, rate of evolution and nucleotide diversity. In particular, the probability of fixation of a non-synonymous transition at a CpG site is two times lower than at a CpG site. Thus, sites with different mutation rates are not necessarily selectively equivalent. This suggests that the mutation rate may complement sequence conservation as a characteristic predictive of functional importance of nucleotide sites

Left atrial appendage volume is an independent predictor of atrial arrhythmia recurrence following cryoballoon pulmonary vein isolation in persistent atrial fibrillation

PurposePulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation in persistent AF (persAF), and cryoballoon PVI emerged as an initial ablation strategy. Symptomatic atrial arrhythmia recurrence following successful PVI in persAF is observed more frequently than in paroxysmal AF. Predictors for arrhythmia recurrence following cryoballoon PVI for persAF are not well described, and the role of left atrial appendage (LAA) anatomy is uncertain.MethodsPatients with symptomatic persAF and pre-procedural cardiac computed tomography angiography (CCTA) images undergoing initial second-generation cryoballoon (CBG2) were enrolled. Left atrial (LA), pulmonary vein (PV) and LAA anatomical data were assessed. Clinical outcome and predictors for atrial arrhythmia recurrence were evaluated by univariate and multivariate regression analysis.ResultsFrom May 2012 to September 2016, 488 consecutive persAF patients underwent CBG2-PVI. CCTA with sufficient quality for measurements was available in 196 (60.4%) patients. Mean age was 65.7 ± 9.5 years. Freedom from arrhythmia was 58.2% after a median follow-up of 19 (13; 29) months. No major complications occurred. Independent predictors for arrhythmia recurrence were LAA volume (HR 1.082; 95% CI, 1.032 to 1.134; p = 0.001) and mitral regurgitation ≥ grade 2 (HR, 2.49; 95% CI 1.207 to 5.126; p = 0.013). LA volumes ≥110.35 ml [sensitivity: 0.81, specificity: 0.40, area under the curve (AUC) = 0.62] and LAA volumes ≥9.75 ml (sensitivity: 0.56, specificity 0.70, AUC = 0.64) were associated with recurrence. LAA-morphology, classified as chicken-wing (21.9%), windsock (52.6%), cactus (10.2%) and cauliflower (15.3%), did not predict outcome (log-rank, p = 0.832).ConclusionLAA volume and mitral regurgitation were independent predictors for arrhythmia recurrence following cryoballoon ablation in persAF. LA volume was less predictive and correlated with LAA volume. LAA morphology did not predict the clinical outcome. To improve outcomes in persAF ablation, further studies should focus on treatment strategies for persAF patients with large LAA and mitral regurgitation

A new measurement of direct CP violation in two pion decays of the neutral kaon

The NA48 experiment at CERN has performed a new measurement of direct CP violation, based on data taken in 1997 by simultaneously collecting K_L and K_S decays into pi0pi0 and pi+pi-. The result for the CP violating parameter Re(epsilon'/epsilon) is (18.5 +/- 4.5(stat)} +/- 5.8 (syst))x10^{-4}.Comment: 18 pages, 6 figure

Hypermutable Non-Synonymous Sites Are under Stronger Negative Selection

Mutation rate varies greatly between nucleotide sites of the human genome and depends both on the global genomic location and the local sequence context of a site. In particular, CpG context elevates the mutation rate by an order of magnitude. Mutations also vary widely in their effect on the molecular function, phenotype, and fitness. Independence of the probability of occurrence of a new mutation's effect has been a fundamental premise in genetics. However, highly mutable contexts may be preserved by negative selection at important sites but destroyed by mutation at sites under no selection. Thus, there may be a positive correlation between the rate of mutations at a nucleotide site and the magnitude of their effect on fitness. We studied the impact of CpG context on the rate of human–chimpanzee divergence and on intrahuman nucleotide diversity at non-synonymous coding sites. We compared nucleotides that occupy identical positions within codons of identical amino acids and only differ by being within versus outside CpG context. Nucleotides within CpG context are under a stronger negative selection, as revealed by their lower, proportionally to the mutation rate, rate of evolution and nucleotide diversity. In particular, the probability of fixation of a non-synonymous transition at a CpG site is two times lower than at a CpG site. Thus, sites with different mutation rates are not necessarily selectively equivalent. This suggests that the mutation rate may complement sequence conservation as a characteristic predictive of functional importance of nucleotide sites

Customisation of the Exome Data Analysis Pipeline Using a Combinatorial Approach

The advent of next generation sequencing (NGS) technologies have revolutionised the way biologists produce, analyse and interpret data. Although NGS platforms provide a cost-effective way to discover genome-wide variants from a single experiment, variants discovered by NGS need follow up validation due to the high error rates associated with various sequencing chemistries. Recently, whole exome sequencing has been proposed as an affordable option compared to whole genome runs but it still requires follow up validation of all the novel exomic variants. Customarily, a consensus approach is used to overcome the systematic errors inherent to the sequencing technology, alignment and post alignment variant detection algorithms. However, the aforementioned approach warrants the use of multiple sequencing chemistry, multiple alignment tools, multiple variant callers which may not be viable in terms of time and money for individual investigators with limited informatics know-how. Biologists often lack the requisite training to deal with the huge amount of data produced by NGS runs and face difficulty in choosing from the list of freely available analytical tools for NGS data analysis. Hence, there is a need to customise the NGS data analysis pipeline to preferentially retain true variants by minimising the incidence of false positives and make the choice of right analytical tools easier. To this end, we have sampled different freely available tools used at the alignment and post alignment stage suggesting the use of the most suitable combination determined by a simple framework of pre-existing metrics to create significant datasets

Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq: PQ-2017#305529/2017-0Deutsche Forschungsgemeinschaft, DFG: MA 1876/12-1Alexander von Humboldt-Stiftung: 88881.136091/2017-01RVO-VFN64165, 26/203.214/20172018.070.1Associazione Italiana per la Ricerca sul Cancro, AIRC: IG2015, 17593Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPESCancer Australia: PdCCRS1128727CancerfondenBarncancerfondenVetenskapsrÃ¥det, VRCrafoordska StiftelsenKnut och Alice Wallenbergs StiftelseLund University Medical Faculty FoundationXiamen University, XMU2014S0617-74-30019C7838/A15733Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNSF: 31003A_140913CNIBInstitut National Du Cancer, INCaR01 NCI CA167824National Institutes of Health, NIH: S10OD0185222016/2017, 02R/2016AU 525/1-1Deutschen Konsortium für Translationale Krebsforschung, DKTK70112951Smithsonian Institution, SIIsrael Science Foundation, ISFAustrian Science Fund, FWF: W1212SFB-F06107, SFB-F06105Acknowledgements BAL received a fellowship provided by CAPES and the Alexander von Humboldt Foundation (#88881.136091/2017-01). ME is supported by CNPq (PQ-2017#305529/2017-0) and FAPERJ-JCNE (#26/203.214/2017) research scholarships, and ZZ by grant RVO-VFN64165. GC is supported by the AIRC Investigator grant IG2015 grant no. 17593 and RS by Cancer Australia grant PdCCRS1128727. This work was supported by grants to RM from the “Georg und Franziska Speyer’sche Hochsschulstiftung”, the “Wilhelm Sander foundation” (grant 2018.070.1) and DFG grant MA 1876/12-1.Acknowledgements This work was supported by The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, The Knut and Alice Wallenberg Foundation, BioCARE, The Crafoord Foundation, The Per-Eric and Ulla Schyberg Foundation, The Nilsson-Ehle Donations, The Wiberg Foundation, and Governmental Funding of Clinical Research within the National Health Service. Work performed at the Center for Translational Genomics, Lund University has been funded by Medical Faculty Lund University, Region Skåne and Science for Life Laboratory, Sweden.Acknowledgements This work was supported by the Fujian Provincial Natural Science Foundation 2016S016 China and Putian city Natural Science Foundation 2014S06(2), Fujian Province, China. Alexey Ste-panov and Alexander Gabibov were supported by Russian Scientific Foundation project No. 17-74-30019. Jinqi Huang was supported by a doctoral fellowship from Xiamen University, China.Acknowledgments This work was supported by the Swiss National Science Foundation (grant 31003A_140913; OH) and the Cancer Research UK Experimental Cancer Medicine Centre Network, Cardiff ECMCI, grant C7838/A15733. We thank N. Carpino for the Sts-1/2 double-KO mice.Acknowledgements This work was supported by the French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.We are indebted to all members of our groups for useful discussions and for their critical reading of the manuscript. Special thanks go to Silke Furlan, Friederike Opitz and Bianca Killing. F.A. is supported by the Deutsche For-schungsgemeinschaft (DFG, AU 525/1-1). J.H. has been supported by the German Children’s Cancer Foundation (Translational Oncology Program 70112951), the German Carreras Foundation (DJCLS 02R/2016), Kinderkrebsstiftung (2016/2017) and ERA PerMed GEPARD. Support by Israel Science Foundation, ERA-NET and Science Ministry (SI). A. B. is supported by the German Consortium of Translational Cancer Research, DKTK. We are grateful to the Jülich Supercomputing Centre at the Forschungszemtrum Jülich for granting computing time on the supercomputer JURECA (NIC project ID HKF7) and to the “Zentrum für Informations-und Medientechnologie” (ZIM) at the Heinrich Heine University Düsseldorf for providing computational support to H. G. The study was performed in the framework of COST action CA16223 “LEGEND”.Funding The work was supported by the Austrian Science Fund FWF grant SFB-F06105 to RM and SFB-F06107 to VS and FWF grant W1212 to VS