Matrix Model of Digital Systems and Its Application to Automatic Test Generation

Electrical Engineerin

Kindia (Pavetteae, Rubiaceae), a new cliff-dwelling genus with chemically profiled colleter exudate from Mt Gangan, Republic of Guinea

A new genus Kindia (Pavetteae, Rubiaceae) is described with a single species, Kindia gangan, based on collections made in 2016 during botanical exploration of Mt Gangan, Kindia, Republic of Guinea in West Africa. The Mt Gangan area is known for its many endemic species including the only native non-neotropical Bromeliaceae Pitcairnia feliciana. Kindia is the fourth endemic vascular plant genus to be described from Guinea. Based on chloroplast sequence data, the genus is part of Clade II of tribe Pavetteae. In this clade, it is sister to Leptactina sensu lato (including Coleactina and Dictyandra). K. gangan is distinguished from Leptactina s.l. by the combination of the following characters: its epilithic habit; several-flowered axillary inflorescences; distinct calyx tube as long as the lobes; a infundibular-campanulate corolla tube with narrow proximal section widening abruptly to the broad distal section; presence of a dense hair band near base of the corolla tube; anthers and style deeply included, reaching about mid-height of the corolla tube; anthers lacking connective appendages and with sub-basal insertion; pollen type 1; pollen presenter (style head) winged and glabrous (smooth and usually hairy in Leptactina); orange colleters producing a vivid red exudate, which encircle the hypanthium, and occur inside the calyx and stipules. Kindia is a subshrub that appears restricted to bare, vertical rock faces of sandstone. Fruit dispersal and pollination by bats is postulated. Here, it is assessed as Endangered EN D1 using the 2012 IUCN standard. High resolution LC-MS/MS analysis revealed over 40 triterpenoid compounds in the colleter exudate, including those assigned to the cycloartane class. Triterpenoids are of interest for their diverse chemical structures, varied biological activities, and potential therapeutic value

A key to the species of Keetia (Rubiaceae: Vanguerieae) in West Africa, with three new, threatened species from Guinea and Ivory Coast

Keetia susu Cheek and K. futa Cheek from the Republic of Guinea, and K. abouabou Cheek from Ivory Coast are described here. Each species is assessed using the IUCN standard as, respectively, Vulnerable, Endangered and Critically Endangered. Each species is illustrated and mapped. A key to the 16 species of Keetia in West Africa (Senegal to Benin) is provided. The number of species of Keetia currently accepted is now known to total 35

The SAMI Galaxy Survey: Quenching of Star Formation in Clusters I. Transition Galaxies

We use integral-field spectroscopy from the SAMI Galaxy Survey to identify galaxies that show evidence of recent quenching of star formation. The galaxies exhibit strong Balmer absorption in the absence of ongoing star formation in more than 10% of their spectra within the SAMI field of view. These Hd-strong (HDS) galaxies (HDSGs) are rare, making up only similar to 2% (25/1220) of galaxies with stellar mass log(M-*/M-circle dot) > 10. The HDSGs make up a significant fraction of nonpassive cluster galaxies (15%; 17/115) and a smaller fraction (2.0%; 8/387) of the nonpassive population in low-density environments. The majority (9/17) of cluster HDSGs show evidence of star formation at their centers, with the HDS regions found in the outer parts of the galaxy. Conversely, the HDS signal is more evenly spread across the galaxy for the majority (6/8) of HDSGs in low-density environments and is often associated with emission lines that are not due to star formation. We investigate the location of the HDSGs in the clusters, finding that they are exclusively within 0.6R(200) of the cluster center and have a significantly higher velocity dispersion relative to the cluster population. Comparing their distribution in projected phase space to those derived from cosmological simulations indicates that the cluster HDSGs are consistent with an infalling population that has entered the central 0.5r(200,3D) cluster region within the last similar to 1 Gyr. In the eight of nine cluster HDSGs with central star formation, the extent of star formation is consistent with that expected of outside-in quenching by ram pressure stripping. Our results indicate that the cluster HDSGs are currently being quenched by ram pressure stripping on their first passage through the cluster

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Peer reviewe

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification