The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

(276–279) Proposals to provide for registration of new names and nomenclatural acts

The Melbourne Congress of 2011 authorized a Special Committee on Registration of Algal and Plant Names (including fossils), which was established the following year (Wilson in Taxon 61: 878–879. 2012). Its explicit mandate was “to consider what would be involved in registering algal and plant names (including fossils), using a procedure analogous to that for fungal names agreed upon in Melbourne and included in the Code as Art. 42”, but expectations at the Nomenclature Section in Melbourne went farther than that. There was the hope that registration systems for at least some of the main groups would soon be set up, to be used and tested on a voluntary basis and, if found to be generally accepted, would persuade the subsequent Congress in Shenzhen, in 2017, to declare registration of new names an additional requirement for valid publication. The Melbourne Congress also approved mandatory registration of nomenclatural novelties in fungi, starting on 1 Jan 2013. The new Art. 42 of the Code (McNeill & al. in Regnum Veg. 154. 2012) requires authors to register any fungal nomenclatural novelty, prior to publication, with a recognized repository, whereupon they are provided with a unique identifier for each name, to be included in the protologue along with other Code-mandated information. Years before registration became mandatory, mycologists had been encouraged, often prompted by journal editors, to register their nomenclatural novelties prior to publication. Most complied. Consequently, when mandatory registration was proposed, it had strong support from the mycological community. There are currently three recognized repositories for fungal names. They vary somewhat in how they operate, but they share records of their registered novelties as soon as publication has been effected. One consequence of implementing mandatory registration is that locating new fungal names and combinations and associated protologue information is much simpler now than it was before. This makes it easier to incorporate the information into taxonomic studies and to update taxonomic treatments, inventories, and indices. A corollary is that, no matter what publication outlet an author chooses, the name cannot fail to be noticed. The positive experience in mycology makes extension of the registration concept to plants and algae a compelling idea. That experience shows that the best way to make mandatory registration of nomenclatural novelties palatable to botanists and phycologists is the establishment of trial registration at repositories with a history of involvement in and commitment to the indexing of names. Trial registration enables users to acquaint themselves with registration procedures, make suggestions on how they might be improved, and appreciate, by personal experience, the benefits of registration. Unfortunately, the task of establishing such repositories proved to be more complex and time-consuming than had been foreseen. Substantial progress has been made in the establishment of such centres (Barkworth & al., in this issue, pp. 670–672) but the Committee is not in a position to make firm proposals to regulate registration procedures, even less to make registration mandatory from a concrete future date. Nevertheless, the Committee sees it as imperative that the Shenzhen Congress be offered the opportunity to move forward with registration without having to wait six more years. In this spirit, we offer the proposals below. Proposal (276) would declare registration an ongoing concern of the botanical, mycological, and phycological community and provide the basic structure for making it possible. Proposal (277) and Prop. (278) would, in addition, define a flexible framework within which a system of voluntary registration could be developed for various categories of organisms. Proposal (279) would provide for future mandatory registration in a way that does not depend on the six-year intervals between International Botanical Congresses. Presentation of each proposal is followed by a summary of the support received from members of the Committee.Fil: Barkworth, Mary E.. State University of Utah; Estados UnidosFil: Watson, Mark. Royal Botanic Gardens; Reino UnidoFil: Barrie, Fred R.. Missouri Botanical Garden; Estados Unidos. Field Museum Of Natural History; Estados UnidosFil: Belyaeva, Irina V.. Royal Botanic Gardens; Reino UnidoFil: Chung, Richard C. K.. Forest Research Institute ; MalasiaFil: Dasková, Jirina. Národní Muzeum; República ChecaFil: Davidse, Gerrit. Missouri Botanical Garden; Estados UnidosFil: Dönmez, Ali A.. Hacettepe Üniversitesi; TurquíaFil: Doweld, Alexander B.. National Institute Of Carpology; RusiaFil: Dressler, Stefan. Senckenberg Forschungsinstitut Und Naturmuseum; AlemaniaFil: Flann, Christina. Naturalis Biodiversity Center; Países BajosFil: Gandhi, Kanchi. Harvard University; Estados UnidosFil: Geltman, Dmitry. Russian Academy of Science; RusiaFil: Glen, Hugh F.. Forest Hills; SudáfricaFil: Greuter, Werner. Freie Universität Berlin; AlemaniaFil: Head, Martin J.. Brock University; CanadáFil: Jahn, Regine. Freie Universität Berlin; AlemaniaFil: Janarthanam, Malapati K.. Goa University; IndiaFil: Katinas, Liliana. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División de Plantas Vasculares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Kirk, Paul M.. Royal Botanic Gardens; Reino UnidoFil: Klazenga, Niels. Royal Botanic Gardens Victoria; AustraliaFil: Kusber, Wolf-Henning. Freie Universität Berlin; AlemaniaFil: Kvacek, Jirí. Národní Muzeum; República ChecaFil: Malécot, Valéry. Universite D'angers; FranciaFil: Mann, David G.. Royal Botanic Gardens; Reino UnidoFil: Marhold, Karol. Charles University; República ChecaFil: Nagamasu, Hidetoshi. Kyoto University; JapónFil: Nicolson, Nicky. Royal Botanic Gardens; Reino UnidoFil: Paton, Alan. Royal Botanic Gardens; Reino UnidoFil: Patterson, David J.. The University Of Sydney; AustraliaFil: Price, Michelle J.. Conservatoire et Jardin botaniques de la Ville de Genève; SuizaFil: van Reine, Willem F Prud' Homme. Naturalis Biodiversity Center; Países BajosFil: Schneider, Craig W.. Trinity College Hartford; Estados UnidosFil: Sennikov, Alexander. Russian Academy Of Sciences; RusiaFil: Smith, Gideon F.. Nelson Mandela Metropolitan University; Sudáfrica. Universidad de Coimbra; PortugalFil: Stevens, Peter F.. Missouri Botanical Garden; Estados Unidos. University of Missouri; Estados UnidosFil: Yang, Zhu-Liang. Kunming Institute Of Botany Chinese Academy Of Sciences; ChinaFil: Zhang, Xian-Chun. Chinese Academy of Sciences; República de ChinaFil: Zuccarello, Giuseppe C.. Victoria University Of Wellington; Nueva Zeland