Quantitative pathophysiology in rabbit models of early onset scoliosis and expansion thoracoplasty

Thesis (Ph.D.)--Boston UniversityEarly onset deformity of the spine and chest wall (initiated <8 years of age) is associated with declining respiratory function and increased morbidity at adulthood relative to adolescent onset deformity of comparable severity. In young children it is presumed that inhibition of thoracic growth during late stage alveolarization leads to an irreversible loss of pulmonary growth and thoracic function. Consequently there is clinical incentive to treat children with growth-preserving therapies as early as possible. In particular thoracic reconstruction surgeries have gained clinical acceptance over the last 15 years with encouraging results, however due to the delicate nature of these patients and the absence of a proper untreated control population there is limited prospective evidence to objectively evaluate the benefits of these surgeries on respiratory health. Additionally, controversy remains with regard to the proper timing of surgical intervention and if greater gains in growth and function are achieved with treatment at an earlier age. Thus the primary aims of this current study were 1) to develop a surgical rabbit model representing early onset thoracic deformity (onset at 3 weeks postnatal) from which to characterize the natural progression of thoracic deformity in association with pulmonary growth and function, and 2) to use deformity rabbits from aim 1 to evaluate effectiveness of thoracic reconstruction, via expansion thoracoplasty, to preserve thoracic growth, pulmonary growth, and respiratory function with particular consideration regarding post-natal timing of intervention by evaluating separate early (7 weeks of age) and late (11 weeks of age) treatment cohorts. All rabbits were evaluated longitudinally until skeletal maturity (28 weeks of age) via pulmonary function testing and computed tomography (CT) imaging. Secondary aims were 3) to characterize the functional and structural respiratory heterogeneity occurring in these rabbits through evaluation of regional specific volume distributions via CT deformable-image-registration and through estimation of dynamic heterogeneity via inverse modeling of the respiratory input impedance, and 4) to evaluate the response of biological mechanisms in the alveolar microstructure in these rabbits through postmortem immunohistochemical assays for growth factors associated with angiogenesis (VEGF pathway) and cell proliferation (Ki-67 antibody). Our findings highlight the nature of pulmonary hypoplasia under restrictive conditions; the extent of respiratory growth and function at maturity was highly predictable from thoracic geometry measured at 6 weeks in untreated deformity rabbits. From this predictive knowledge gains in growth and function associated with expansion thoracoplasty are determined, our evidence suggests that treatment benefits to lung growth are largely offset by detrimental effects of surgery and early surgery could only provide improvements in severe cases where expected outcomes are very poor, benefits to late treatment rabbits were inconclusive. A forward-inverse modeling approach to link empirical data on specific volume and respiratory impedance shows that inherent structural heterogeneity limits the sensitive detection of heterogeneity originating from a disease process. Lastly post-mortem evidence of increased cellular proliferation is shown in the pulmonary parenchyma of thoracoplasty treated rabbits

Authigenic carbonates from the Cascadia subduction zone and their relation to gas hydrate stability

Authigenic carbonates are intercalated with massive gas hydrates in sediments of the Cascadia margin. The deposits were recovered from the uppermost 50 cm of sediments on the southern summit of the Hydrate Ridge during the RV Sonne cruise SO110. Two carbonate lithologies that differ in chemistry, mineralogy, and fabric make up these deposits. Microcrystalline high-magnesium calcite (14 to 19 mol% MgCO3) and aragonite are present in both semiconsolidated sediments and carbonate-cemented clasts. Aragonite occurs also as a pure phase without sediment impurities. It is formed by precipitation in cavities as botryoidal and isopachous aggregates within pure white, massive gas hydrate. Variations in oxygen isotope values of the carbonates reflect the mineralogical composition and define two end members: a Mg-calcite with δ18O =4.86‰ PDB and an aragonite with δ18O =3.68‰ PDB. On the basis of the ambient bottom-water temperature and accepted equations for oxygen isotope fractionation, we show that the aragonite phase formed in equilibrium with its pore-water environment, and that the Mg-calcite appears to have precipitated from pore fluids enriched in 18O. Oxygen isotope enrichment probably originates from hydrate water released during gas-hydrate destabilization

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.Cancer Research UKThis is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s10552-016-0741-

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04). Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk

Geoscience Education Perspectives on Integrated, Coordinated, Open, Networked (ICON) Science

Practitioners and researchers in geoscience education embrace collaboration applying ICON (Integrated, Coordinated, Open science, and Networked) principles and approaches ICON principles and approaches have been used to create and share large collections of educational resources, to move forward collective priorities, and to foster peer-learning among educators. These strategies can also support the advancement of coproduction between geoscientists and diverse communities. For this reason, many authors from the geoscience education community have co-created three commentaries on the use and future of ICON in geoscience education. We envision that sharing our expertise with ICON practice will be useful to other geoscience communities seeking to strengthen collaboration. Geoscience education brings substantial expertise in social science research and its application to building individual and collective capacity to address earth sustainability and equity issues at local to global scales The geoscience education community has expanded its own ICON capacity through access to and use of shared resources and research findings, enhancing data sharing and publication, and leadership development. We prioritize continued use of ICON principles to develop effective and inclusive communities that increase equity in geoscience education and beyond, support leadership and full participation of systemically non-dominant groups and enable global discussions and collaborations

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.324

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection