Grammar of Ambel, an Austronesian language of Raja Ampat, west New Guinea

This thesis is a descriptive grammar of Ambel [wgo], an endangered Austronesian (South Halmahera-West New Guinea) language. Ambel is spoken by approximately 1600 people on Waigeo, the largest island in the Raja Ampat archipelago (West Papua province, Indonesia). This grammar is based on naturalistic and elicited data, collected by the author from native speakers of Ambel. Ambel is a head-marking language, with basic SV/AVO constituent order. There are 14 native consonant phonemes and five vowel phonemes. Ambel has a tone system, in which /H/ syllables contrast with toneless syllables. Neither stress nor vowel length are contrastive. In verbal clauses, the subject of the clause is marked on the verb. This system makes a four-way number distinction (singular, dual, paucal, and plural), an animacy distinction in the third person, and a clusivity distinction in the non-singular first person. The Ambel noun phrase is mainly head-initial. There are five distinct morphosyntactic possessive constructions, the choice of which is primarily determined by a lexical specification on the possessed noun. Some nouns (including most body parts and some kin terms) are possessed in one of three constructions in which the person, number, and animacy of the possessor is marked directly on the possessed noun, while most other nouns are possessed in one of two constructions in which the possessor is marked on a prenominal possessive classifier. Within the clause, all negation particles and most aspect and mode particles are clause-final. There is no passive construction. Ambel has a rich system of spatial deixis, in which six different classes of deictic words (such as demonstratives, deictic prepositions, and deictic nouns) are derived from one of four demonstrative roots or 28 directional stems. Verb serialisation is used to express, among other things, purposive motion and changes of state. This thesis is the first major description and documentation of the Ambel language. As such, it will be of considerable interest to typologists and historical linguists, as well as others interested in the languages, cultures, and history of New Guinea. All of the data on which this grammar is based have been archived with both the Endangered Languages Archive, and the Center for Endangered Languages Documentation at Universitas Papua in Manokwari. The data will thus be available to future generations, including the Ambel community themselves

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

ASIRI : an ocean–atmosphere initiative for Bay of Bengal

Author Posting. © American Meteorological Society, 2016. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 97 (2016): 1859–1884, doi:10.1175/BAMS-D-14-00197.1.Air–Sea Interactions in the Northern Indian Ocean (ASIRI) is an international research effort (2013–17) aimed at understanding and quantifying coupled atmosphere–ocean dynamics of the Bay of Bengal (BoB) with relevance to Indian Ocean monsoons. Working collaboratively, more than 20 research institutions are acquiring field observations coupled with operational and high-resolution models to address scientific issues that have stymied the monsoon predictability. ASIRI combines new and mature observational technologies to resolve submesoscale to regional-scale currents and hydrophysical fields. These data reveal BoB’s sharp frontal features, submesoscale variability, low-salinity lenses and filaments, and shallow mixed layers, with relatively weak turbulent mixing. Observed physical features include energetic high-frequency internal waves in the southern BoB, energetic mesoscale and submesoscale features including an intrathermocline eddy in the central BoB, and a high-resolution view of the exchange along the periphery of Sri Lanka, which includes the 100-km-wide East India Coastal Current (EICC) carrying low-salinity water out of the BoB and an adjacent, broad northward flow (∼300 km wide) that carries high-salinity water into BoB during the northeast monsoon. Atmospheric boundary layer (ABL) observations during the decaying phase of the Madden–Julian oscillation (MJO) permit the study of multiscale atmospheric processes associated with non-MJO phenomena and their impacts on the marine boundary layer. Underway analyses that integrate observations and numerical simulations shed light on how air–sea interactions control the ABL and upper-ocean processes.This work was sponsored by the U.S. Office of Naval Research (ONR) in an ONR Departmental Research Initiative (DRI), Air–Sea Interactions in Northern Indian Ocean (ASIRI), and in a Naval Research Laboratory project, Effects of Bay of Bengal Freshwater Flux on Indian Ocean Monsoon (EBOB). ASIRI–RAWI was funded under the NASCar DRI of the ONR. The Indian component of the program, Ocean Mixing and Monsoons (OMM), was supported by the Ministry of Earth Sciences of India.2017-04-2

Male breast cancer in BRCA1 and BRCA2 mutation carriers : pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 x 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 x 10(-12)). Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.Peer reviewe

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 Pediatric Cell Atlas:Defining the Growth Phase of Human Development at Single-Cell Resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

​​Observing Antarctic Bottom Water in the Southern Ocean​

Dense, cold waters formed on Antarctic continental shelves descend along the Antarctic continental margin, where they mix with other Southern Ocean waters to form Antarctic Bottom Water (AABW). AABW then spreads into the deepest parts of all major ocean basins, isolating heat and carbon from the atmosphere for centuries. Despite AABW’s key role in regulating Earth’s climate on long time scales and in recording Southern Ocean conditions, AABW remains poorly observed. This lack of observational data is mostly due to two factors. First, AABW originates on the Antarctic continental shelf and slope where in situ measurements are limited and ocean observations by satellites are hampered by persistent sea ice cover and long periods of darkness in winter. Second, north of the Antarctic continental slope, AABW is found below approximately 2 km depth, where in situ observations are also scarce and satellites cannot provide direct measurements. Here, we review progress made during the past decades in observing AABW. We describe 1) long-term monitoring obtained by moorings, by ship-based surveys, and beneath ice shelves through bore holes; 2) the recent development of autonomous observing tools in coastal Antarctic and deep ocean systems; and 3) alternative approaches including data assimilation models and satellite-derived proxies. The variety of approaches is beginning to transform our understanding of AABW, including its formation processes, temporal variability, and contribution to the lower limb of the global ocean meridional overturning circulation. In particular, these observations highlight the key role played by winds, sea ice, and the Antarctic Ice Sheet in AABW-related processes. We conclude by discussing future avenues for observing and understanding AABW, impressing the need for a sustained and coordinated observing system

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

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

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