Faster juvenile growth promotes earlier sex change in a protandrous hermaphrodite (barramundi Lates calcarifer)

The relationship between growth and sexual maturation is central to understanding the dynamics of animal populations which exhibit indeterminate growth. In sequential hermaphrodites, which undergo post-maturation sex change, the size and age at which sex change occurs directly affects reproductive output and hence population productivity. However, these traits are often labile, and may be strongly influenced by heterogenous growth and mortality rates. We analysed otolith microstructure of a protandrous (i.e., male-to-female) fish (barramundi Lates calcarifer) to examine growth in relation to individual variation in the timing of sex change. Growth trajectories of individuals with contrasting life histories were examined to elucidate the direction and extent to which growth rate influences the size and age individuals change sex. Then, the relationships between growth rate, maturation schedules and asymptotic maximum size were explored to identify potential trade-offs between age at female maturity and growth potential. Rapid growth was strongly associated with decreased age at sex change, but this was not accompanied by a decrease in size at sex change. Individuals that were caught as large females grew faster than those caught as males, suggesting that fast-growing individuals ultimately obtain higher fitness and therefore make a disproportionate contribution to population fecundity. These results indicate that individual-level variation in maturation schedules is not reflective of trade-offs between growth and reproduction. Rather, we suggest that conditions experienced during the juvenile phase are likely to be a key determinant of post-maturation fitness. These findings highlight the vulnerability of sex-changing species to future environmental change and harvest

A local infrared perspective to deeper ISO surveys

We present new techniques to produce IRAS 12 micron samples of galaxies andstars. We show that previous IRAS 12 micron samples are incompatible fordetailed comparison with ISO surveys and review their problems. We provide astellar infrared diagnostic diagram to distinguish galaxies from stars withoutusing longer wavelength IRAS colour criteria and produce complete 12 micronsamples of galaxies and stars. This new technique allows us to estimate thecontribution of non-dusty galaxies to the IRAS 12 micron counts and produce atrue local mid-infrared extragalactic sample compatible with ISO surveys. Wepresent our initial analysis and results

Modelling ponatinib resistance in tyrosine kinase inhibitor-naive and dasatinib resistant BCR-ABL1+ cell lines

TKI resistance remains a major impediment to successful treatment of CML. In this study, we investigated the emerging modes of ponatinib resistance in TKI-naïve and dasatinib resistant BCR-ABL1+ cell lines. To investigate potential resistance mechanisms, ponatinib resistance was generated in BCR-ABL1+ cell-lines by long-term exposure to increasing concentrations of ponatinib. Two cell lines with prior dasatinib resistance demonstrated BCR-ABL1 kinase domain (KD) mutation(s) upon exposure to ponatinib. In one of these cell lines the T315I mutation had emerged during dasatinib exposure. When further cultured with ponatinib, the T315I mutation level and BCR-ABL1 mRNA expression level were increased. In the other cell line, compound mutations G250E/E255K developed with ponatinib exposure. In contrast, the ponatinib resistant cell lines that had no prior exposure to other TKIs (TKI-naïve) did not develop BCR-ABL1 KD mutations. Rather, both of these cell lines demonstrated Bcr-Abl-independent resistance via Axl overexpression. Axl, a receptor tyrosine kinase, has previously been associated with imatinib and nilotinib resistance. Ponatinib sensitivity was restored following Axl inhibition or shRNA-mediated-knockdown of Axl, suggesting that Axl was the primary driver of resistance and a potential target for therapy in this setting.Liu Lu, Chung Hoow Kok, Verity Ann Saunders, Jueqiong Wang, Jennifer Anne McLean, Timothy Peter Hughes, and Deborah Lee Whit

Polyurethane Elastomers as Maxillofacial Prosthetic Materials

A series of polyurethane elastomers based on an aliphatic diisocyanate and a polyether macroglycol was polymerized with various crosslink densities and OH/NCO ratios. Stoichiometries yielding between 8,600 and 12,900 gm/ mole/crosslink and an OH/NCO ratio of 1.1 resulted in polymers with the low modulus, yet high strength and elongation necessary for maxillofacial applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68299/2/10.1177_00220345780570040501.pd

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

Accurate quantification of minimal residual disease during treatment of chronic myeloid leukaemia guides clinical decisions. The conventional minimal residual disease method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first 3 months of treatment BCR-ABL1 mRNA values declined more rapidly than DNA. By 6 months the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in minimal residual disease being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first 3 months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond 3 months falling levels of BCR-ABL1 mRNA are predominantly due to depletion of leukaemic cells.Ilaria S. Pagani, Phuong Dang, Ivar O. Kommers, Jarrad M. Goyne, Mario Nicola, Verity A. Saunders, Jodi Braley, Deborah L. White, David T. Yeung, Susan Branford, Timothy P. Hughes, and David M. Ros

Planck 2015 results. XXVII. The Second Planck Catalogue of Sunyaev-Zeldovich Sources

We present the all-sky Planck catalogue of Sunyaev-Zeldovich (SZ) sources detected from the 29 month full-mission data. The catalogue (PSZ2) is the largest SZ-selected sample of galaxy clusters yet produced and the deepest all-sky catalogue of galaxy clusters. It contains 1653 detections, of which 1203 are confirmed clusters with identified counterparts in external data-sets, and is the first SZ-selected cluster survey containing > $10^3$ confirmed clusters. We present a detailed analysis of the survey selection function in terms of its completeness and statistical reliability, placing a lower limit of 83% on the purity. Using simulations, we find that the Y5R500 estimates are robust to pressure-profile variation and beam systematics, but accurate conversion to Y500 requires. the use of prior information on the cluster extent. We describe the multi-wavelength search for counterparts in ancillary data, which makes use of radio, microwave, infra-red, optical and X-ray data-sets, and which places emphasis on the robustness of the counterpart match. We discuss the physical properties of the new sample and identify a population of low-redshift X-ray under- luminous clusters revealed by SZ selection. These objects appear in optical and SZ surveys with consistent properties for their mass, but are almost absent from ROSAT X-ray selected samples

Widespread aberrant alternative splicing despite molecular remission in chronic myeloid leukaemia patients

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.Ulf Schmitz, Jaynish S. Shah, Bijay P. Dhungel, Geoffray Monteuuis, Phuc-Loi Luu, Veronika Petrova, Cynthia Metierre, Shalima S. Nair, Charles G. Bailey, Verity A. Saunders, Ali G. Turhan, Deborah L. White, Susan Branford, Susan J. Clark, Timothy P. Hughes, Justin J.-L. Wong, and John E.J. Rask

Therapeutic options for mucinous ovarian carcinoma

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition

Association of a novel mutation in the plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity

Background. Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine. Methods. Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33 716 genomewide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin- piperaquine treatment outcomes in an independent dataset. Results. Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90, including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity. Conclusions. Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance