Constraining properties of the black hole population using LISA

LISA should detect gravitational waves from tens to hundreds of systems containing black holes with mass in the range from 10 thousand to 10 million solar masses. Black holes in this mass range are not well constrained by current electromagnetic observations, so LISA could significantly enhance our understanding of the astrophysics of such systems. In this paper, we describe a framework for combining LISA observations to make statements about massive black hole populations. We summarise the constraints that LISA observations of extreme-mass-ratio inspirals might be able to place on the mass function of black holes in the LISA range. We also describe how LISA observations can be used to choose between different models for the hierarchical growth of structure in the early Universe. We consider four models that differ in their prescription for the initial mass distribution of black hole seeds, and in the efficiency of accretion onto the black holes. We show that with as little as 3 months of LISA data we can clearly distinguish between these models, even under relatively pessimistic assumptions about the performance of the detector and our knowledge of the gravitational waveforms.Comment: 12 pages, 3 figures, submitted to Class. Quantum Grav. for proceedings of 8th LISA Symposium; v2 minor changes for consistency with accepted versio

Probing seed black holes using future gravitational-wave detectors

Identifying the properties of the first generation of seeds of massive black holes is key to understanding the merger history and growth of galaxies. Mergers between ~100 solar mass seed black holes generate gravitational waves in the 0.1-10Hz band that lies between the sensitivity bands of existing ground-based detectors and the planned space-based gravitational wave detector, the Laser Interferometer Space Antenna (LISA). However, there are proposals for more advanced detectors that will bridge this gap, including the third generation ground-based Einstein Telescope and the space-based detector DECIGO. In this paper we demonstrate that such future detectors should be able to detect gravitational waves produced by the coalescence of the first generation of light seed black-hole binaries and provide information on the evolution of structure in that era. These observations will be complementary to those that LISA will make of subsequent mergers between more massive black holes. We compute the sensitivity of various future detectors to seed black-hole mergers, and use this to explore the number and properties of the events that each detector might see in three years of observation. For this calculation, we make use of galaxy merger trees and two different seed black hole mass distributions in order to construct the astrophysical population of events. We also consider the accuracy with which networks of future ground-based detectors will be able to measure the parameters of seed black hole mergers, in particular the luminosity distance to the source. We show that distance precisions of ~30% are achievable, which should be sufficient for us to say with confidence that the sources are at high redshift.Comment: 14 pages, 6 figures, 2 tables, accepted for proceedings of 13th GWDAW meetin

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Identification of the keratin-associated protein 13-3 (KAP13-3) gene in sheep

Keratin-associated proteins (KAPs) are a major structural component of hair and wool fibres, and play a critical role in determining the properties of the fibre. To date, forty functional high sulphur KAP genes from fourteen families have been identified in humans, but only seven functional high sulphur KAP genes have been identified in sheep. This led us to search for the ovine KAP13-3 gene, a gene encoding a high sulphur KAP. In this study, the notional KAP13-3 gene (KRTAP13-3) was amplified using primers designed based on a reported bovine KRTAP13-3 sequence. PCR-single stranded conformational polymorphism (PCR-SSCP) analysis was used to screen amplicons derived from the gene in one hundred and forty seven New Zealand Romney cross-bred sheep. Five unique banding patterns were revealed. Either one PCR-SSCP pattern (homozygous) or a combination of two patterns (heterozygous) was observed for each sheep. Sequencing of PCR amplicons representtative of different SSCP patterns revealed five different DNA sequences. The sequences derived from the amplicons showed a low homology to other known ovine KRTAPs, but had a high homology with previous reported KRTAP13-n sequences from human and cattle, with the closest homology being with bovine KRTAP13-3, suggesting the sequences represent the ovine KRTAP13-3 locus. Among the five allele sequences, four nucleotide substitutions were identified within the coding region. Of these substitutions, three were non-synonymous and would result in amino acid changes (p.Arg79Cys, p.Arg81Gln and p.Tyr130His). This variation in the KAP13-3 gene may affect gene expression, the structure and assembly of the protein, and consequently influence wool traits, if KAP13-3 is of importance to wool fibre structure

Analysis of variation in the ovine ultra-high sulphur keratin-associated protein KAP5-4 gene using PCR-SSCP technique

Keratin-associated proteins (KAPs) are one of the main structural components of the wool fibre. Variation in the KAP genes (KRTAPs) may affect the structure of KAPs and hence wool characteristics. In this study, we used PCR-SSCP to analyse ovine KRTAP5-4, a gene encoding a member of the KAP5 family. Five different PCR-SSCP patterns were detected in the 250 sheep that were analysed. Either one or a combination of two patterns was observed for each sheep, which was consistent with these sheep being either homozygous or heterozygous at this locus. DNA sequencing revealed that these patterns represent five different DNA sequences. One of the sequences was identical to a published ovine KRTAP5-4 sequence. The remaining four were unique, but shared a high homology with the published ovine KRTAP5-4 sequence, suggesting that these sequences represent allelic variants of KRTAP5-4. There were a total of six SNPs and one length polymorphism in the sequences. Of the five SNPs found in the coding region, four were non-synonymous SNPs and would result in amino acid changes. The length polymorphism would affect the cysteine content of the putative peptide and this along with the SNPs may have an impact on the structure of KAP5-4, and hence affect wool traits. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Search for variation in the ovine KAP7-1 and KAP8-1 genes using polymerase chain reaction - single-stranded conformational polymorphism screening

Keratins and keratin-associated proteins (KAPs) are large heterogeneous groups of proteins that constitute about 90% of the wool fiber. The genes encoding the high glycine-tyrosine (HGT) KAPs are the first sub-group of KAP genes expressed in the wool follicle and just after expression of the keratin genes. Little is known about variation in these genes, which led us to investigate two HGT-KAP genes, KRTAP7-1 and KRTAP8-1. Polymerase chain reaction–single-stranded conformational polymorphism analysis was used to investigate these genes in 250 Romney-cross sheep. For KRTAP7-1, two unique banding patterns were detected for amplicons that spanned the entire coding region. Sequencing confirmed the presence of two sequences with only one nucleotide difference (c.173G/A) putatively resulting in p.Ser58Asn. One was identical to the published ovine KRTAP7-1 sequence. For KRTAP8-1, five unique banding patterns were detected in an amplicon that spanned the entire coding region. Sequencing revealed five different DNA sequences, all of which were highly homologous to the previously reported ovine KRTAP8-1 sequence. Among these five sequences, four single-nucleotide substitutions were identified and three of them were located in the coding region. One of these was nonsynonymous and would putatively result in p.Tyr34Asn. The variation detected in KRTAP7-1 and KRTAP8-1 may influence their expression or protein structure