MOVEMENT BEHAVIOR AND METAPOPULATION CONNECTIVITY OF STREAM SALAMANDERS IN RESPONSE TO DISTURBANCE EVENTS

Metapopulations are shaped by the dispersal between populations in a landscape. Disturbance events can disrupt this connectivity resulting in local population extinction. For my dissertation, I used a combination of empirical and theoretical techniques to examine dispersal in response to disturbance and assessed it’s population-level consequences. My research used capture-mark-recapture sampling techniques to evaluate stream salamander movement in response to (1) a supraseasonal drought and (2) mountaintop-removal-mining (MTR) and valley-filling (VF) and (3) agent-based simulation modeling to evaluate population extinction risk in response to varying dispersal and mortality rates. First, I evaluated the effects of a supraseasonal drought, a severe drought that occurs outside of predictable seasonal dry periods for an extended period of time, on the movement frequency distribution, survival, and growth rates of adult Desmognathus fuscus. I found that salamanders were more likely to move immediately after the supraseasonal drought compared to before or during the drought. Salamanders who moved experienced slightly higher growth rates post-drought. Although movement frequency was low during the drought, survival was higher for individuals who moved in comparison to individuals who remained in their original capture location. My results suggest that adult salamanders were potentially displaying an adaptive movement strategy to resist drought conditions by moving away from affected (i.e., dry) areas within the study stream during the drought and moving towards replenished resources in other areas after the drought ended. Next, I evaluated movement pathways (e.g. within-stream, overland), movement frequency distribution curves, individual body condition, and dispersal rates for two common stream salamander species (D. fuscus and D. monticola) within a reclaimed MTR and VF landscape and compared these populations with populations from an undisturbed, reference landscape. I found that stream salamanders utilized within-stream dispersal pathways in the reference and MTR and VF landscape. However, overland movement was only detected in the reference landscape, not in the MTR and VF landscape. Body condition was a potential driver for individuals engaging in dispersal and was overall lower for individuals in the MTR and VF landscape compared to the reference landscape. My results indicated that overland connectivity between salamander populations in the MTR and VF landscape was disrupted compared to the undisturbed landscape and resulted in population isolation, which, if left unchanged, could result in local population extirpation. Finally, I constructed two agent-based models with different metapopulation structures and investigated how differences in extinction risk was affected by differences in dispersal and mortality probabilities between populations and between areas. I found that differences in dispersal and mortality did influence population extinction risk. My models demonstrated that increased dispersal into a population decreased it’s extinction risk but only when population differences in mortality was low. In addition, when mortality was higher for an area, populations located on the fringe of the metapopulation network had a higher extinction risk compared to the populations that bordered other populations. My results indicated that maintaining connectivity between populations lowers population extinction risk, especially in areas of lower habitat quality resulting from a disturbance event. This research demonstrates that long-distance movement allows populations to resist the negative effects of environmental and anthropogenic disturbance. Therefore, maintaining and, when applicable, restoring both aquatic and terrestrial habitat is likely vital for stream salamander population persistence

Comparing marine survival among Chinook and coho salmon and steelhead trout in the Salish Sea

Recent work on marine survival in Chinook and coho salmon and steelhead trout has shown a decline in marine survival in the Salish Sea that was not evident in other regions. For Chinook, the decline was not explained well by oceanographic patterns, and for coho, regional-scale patterns were suggested as important in understanding survival. Recent work on the development of indicators of Puget Sound steelhead survival has shown that predator abundance and patterns in hatchery releases, as well as oceanographic conditions are informative in predicting marine survival. While the three species of focus for the Salish Sea Marine Survival Project have different life-histories, and are therefore subjected to variable pressures at multiple scales, this current analysis aims to answer three questions: 1.) Are there similarities in survival trends among the three species? 2.) Do regional patterns in survival emerge when survival trends are evaluated concurrently across the three species? 3.) Does release strategy (yearling or subyearling) confer a survival advantage, and if so, is this consistent across all species? To evaluate survival time series, we used multivariate time series analysis with multiple groupings (species, spatial, and release strategy) to identify commonalities among species. Observed commonalities will aid in the development of indicators of marine survival for coho and Chinook by focusing efforts on appropriate spatial or temporal attributes. A hypothesis-driven approach similar to that employed for the development of indicators for steelhead survival will be used to relate coho and Chinook to environmental, biological, and anthropogenic factors influencing survival

New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.This work was supported as part of the PhD project of K.A.G funded by the European Research Council and AstraZeneca Early Oncology TD

Reconstructing historical patterns of primary production in Puget Sound using growth increment data from shells of long-lived geoducks (Panopea generosa)

Bottom-up hypotheses predict that changes in primary production affect marine survival of species like Pacific salmon. Long term records of primary production would provide important data to test these predictions. However, direct observations of primary production (in situ fluorometers, water chemistry, and satellite observations of color back-scatter) have relatively short time series (\u3c 30 years). We investigated whether growth increments of geoduck clams (Panopea generosa) are correlated with primary production in different sub-basins of greater Puget Sound. Geoduck are long-lived (older specimens live \u3e100 years), widely distributed throughout the Salish Sea, and deposit annual growth rings in their shells. Shell samples from aged geoducks were by the Washington Department of Fish and Wildlife in four sub-basins within greater Puget Sound (Strait of Jan de Fuca, Southern Strait of Georgia, South Puget Sound, and Central Basin). Geoduck shells from Saratoga passage were provided by the Tulalip Tribe. Using growth indices, the known correlation of growth indices with sea surface temperature and other long-term measurements, and existing basin-level records of temperature and primary production, we modeled historical patterns of primary production in different regions of greater Puget Sound. Analyses show that the relationship between geoduck growth, temperature, and primary production varies between sub-basins, and stable isotope analysis suggests that geoducks may be more than just primary consumers. These issues make reconstruction of a historical record of primary production from growth increments challenging. Nevertheless, analyses suggest that residual growth (after accounting for temperature variation) can explain variation in annual marine survival of local coho and chinook salmon stocks. This indicates the method has promise for retrospective hypothesis testing

Benign tumors in myotonic dystrophy type I target disease-related cancer sites

Acknowledgments The authors thank Ms. Emily Carver, BS, and Mr. David Ruggieri, BS, both from the Information Management Services Inc. (Calverton, MD, USA) for their important contributions to database management. This study is based on data from the CPRD GOLD database October 2016 release, obtained from the UK Medicines and Healthcare Products Regulatory Agency, Hospital Episode Statistics (HES) database (Copyright © (2016)), and Office of National Statistics (ONS) database (Copyright ©(2016)) reused with the permission of The Health &Social Care Information Centre. All rights reserved. The interpretation and conclusions contained in this study are those of the authors alonePeer reviewedPublisher PD

Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors

Tidal Features at 0.05<z<0.45 in the Hyper Suprime-Cam Subaru Strategic Program: Properties and Formation Channels

We present 1,201 galaxies at $0.05<z<0.45$ that host tidal features, detected from the first $\sim\! 200$ deg$^2$ of imaging from the Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP). All galaxies in the present sample have spectroscopic observations from the Sloan Digital Sky Survey (SDSS) spectroscopic campaigns, generating a sample of 21208 galaxies. Of these galaxies, we identify 214 shell systems and 987 stream systems. For 575 of these systems, we are additionally able to measure the $(g-i)$ colors of the tidal features. We find evidence for star formation in a subset of the streams, with the exception of streams around massive ellipticals, and find that stream host galaxies span the full range of stellar masses in our sample. Galaxies which host shells are predominantly red and massive: we find that observable shells form more frequently around ellipticals than around disc galaxies of the same stellar mass. Although the majority of the shells in our sample are consistent with being formed by minor mergers, $15\% \pm 4.4\%$ of shell host galaxies have $(g-i)$ colors as red as their host galaxy, consistent with being formed by major mergers. These "red shells" are additionally preferentially aligned with the major axis of the host galaxy, as previously predicted from simulations. We suggest that although the bulk of the observable shell population originates from fairly minor mergers, which preferentially form shells that are not aligned with the major axis of the galaxy, major mergers produce a significant number of observable shells.Comment: 24 pages, 14 figures. Submitted to Ap

Invasive Group A Streptococcal Infection in Older Adults in Long-term Care Facilities and the Community, United States, 1998–20031

Invasive infection develops almost 6 times as frequently in the elderly in long-term care facilities

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations