Upwelling-Level Acidification and pH/pCO2 Variability Moderate Effects of Ocean Acidification on Brain Gene Expression in the Temperate Surfperch, Embiotoca jacksoni

Acidification-induced changes in neurological function have been documented in several tropical marine fishes. Here, we investigate whether similar patterns of neurological impacts are observed in a temperate Pacific fish that naturally experiences regular and often large shifts in environmental pH/pCO2. In two laboratory experiments, we tested the effect of acidification, as well as pH/pCO2 variability, on gene expression in the brain tissue of a common temperate kelp forest/estuarine fish, Embiotoca jacksoni. Experiment 1 employed static pH treatments (target pH = 7.85/7.30), while Experiment 2 incorporated two variable treatments that oscillated around corresponding static treatments with the same mean (target pH = 7.85/7.70) in an eight-day cycle (amplitude ± 0.15). We found that patterns of global gene expression differed across pH level treatments. Additionally, we identified differential expression of specific genes and enrichment of specific gene sets (GSEA) in comparisons of static pH treatments and in comparisons of static and variable pH treatments of the same mean pH. Importantly, we found that pH/pCO2 variability decreased the number of differentially expressed genes detected between high and low pH treatments, and that interindividual variability in gene expression was greater in variable treatments than static treatments. These results provide important confirmation of neurological impacts of acidification in a temperate fish species and, critically, that natural environmental variability may mediate the impacts of ocean acidification

A unifying framework for understanding ecological and evolutionary population connectivity

Although the concept of connectivity is ubiquitous in ecology and evolution, its definition is often inconsistent, particularly in interdisciplinary research. In an ecological context, population connectivity refers to the movement of individuals or species across a landscape. It is measured by locating organisms and tracking their occurrence across space and time. In an evolutionary context, connectivity is typically used to describe levels of current and past gene flow, calculated from the degree of genetic similarity between populations. Both connectivity definitions are useful in their specific contexts, but rarely are these two perspectives combined. Different definitions of connectivity could result in misunderstandings across subdisciplines. Here, we unite ecological and evolutionary perspectives into a single unifying framework by advocating for connectivity to be conceptualized as a generational continuum. Within this framework, connectivity can be subdivided into three timescales: (1) within a generation (e.g., movement), (2) across one parent-offspring generation (e.g., dispersal), and (3) across two or more generations (e.g., gene flow), with each timescale determining the relevant context and dictating whether the connectivity has ecological or evolutionary consequences. Applying our framework to real-world connectivity questions can help to identify sampling limitations associated with a particular methodology, further develop research questions and hypotheses, and investigate eco-evolutionary feedback interactions that span the connectivity continuum. We hope this framework will serve as a foundation for conducting and communicating research across subdisciplines, resulting in a more holistic understanding of connectivity in natural systems

The hydrogen-poor superluminous supernova iPTF 13ajg and its host galaxy in absorption and emission

We present imaging and spectroscopy of a hydrogen-poor superluminous supernova (SLSN) discovered by the intermediate Palomar Transient Factory, iPTF 13ajg. At a redshift of z = 0.7403, derived from narrow absorption lines, iPTF 13ajg peaked at an absolute magnitude of M u, AB = -22.5, one of the most luminous supernovae to date. The observed bolometric peak luminosity of iPTF 13ajg is 3.2 × 1044 erg s-1, while the estimated total radiated energy is 1.3 × 1051 erg. We detect narrow absorption lines of Mg I, Mg II, and Fe II, associated with the cold interstellar medium in the host galaxy, at two different epochs with X-shooter at the Very Large Telescope. From Voigt profile fitting, we derive the column densities log N(Mg I) =11.94 ± 0.06, log N(Mg II) =14.7 ± 0.3, and log N(Fe II) =14.25 ± 0.10. These column densities, as well as the Mg I and Mg II equivalent widths of a sample of hydrogen-poor SLSNe taken from the literature, are at the low end of those derived for gamma-ray bursts (GRBs) whose progenitors are also thought to be massive stars. This suggests that the environments of hydrogen-poor SLSNe and GRBs are different. From the nondetection of Fe II fine-structure absorption lines, we derive a lower limit on the distance between the supernova and the narrow-line absorbing gas of 50 pc. The neutral gas responsible for the absorption in iPTF 13ajg exhibits a single narrow component with a low velocity width, ΔV = 76 km s-1, indicating a low-mass host galaxy. No host galaxy emission lines are detected, leading to an upper limit on the unobscured star formation rate (SFR) of SFR. Late-time imaging shows the iPTF 13ajg host galaxy to be faint, with g AB 27.0 and R AB ≥ 26.0 mag, corresponding to M B, Vega ≳ -17.7 mag. © 2014. The American Astronomical Society. All rights reserved.

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

Development of New Deoxycytidine Kinase Inhibitors and Noninvasive in Vivo Evaluation Using Positron Emission Tomography

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2′-deoxy-2′-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC(50) = ∼1 – 12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies

Adaptation Genomics of Surfperch Populations in the Context of Rapid Environmental Change

While the immediate impacts of global climate change are of serious concern, the outcomes of these environmental changes for populations will ultimately play out over multiple generations. Despite this, our understanding of the evolutionary impacts of climate-related environmental change is still in its early stages, particularly in the marine realm. Furthermore, evolutionary processes can act over short, ecological timescales, such that they may play a key role in both the short-term resistance and long-term resilience of natural populations. Therefore, the objective of this dissertation is to better incorporate evolutionary processes into the developing understanding of the ecological effects of global change. In particular, I focus my investigations on the relationships between genetic diversity, local adaptation, and environmental change to better understand the evolutionary factors that contribute to a population’s adaptive capacity and resilience. A population’s genetic diversity may translate to response (phenotypic) diversity, the level of which will determine the likelihood of evolutionary rescue via the portfolio effect. Adaptation of subpopulations to their local conditions (local adaptation) has the potential to enhance broad-scale genetic diversity within a species, potentially increasing resilience in the face of environmental change, but can simultaneously reduce local diversity, increasing the risk of extinction for subpopulations if gene flow is low. In this dissertation, I use a pair of marine fish species with unique life-histories (Embiotoca jacksoni and Brachyistius frenatus; family Embiotocidae) to 1) test the molecular impact of environmental change on an important temperate fish group, 2) investigate the scale of genetic diversity and admixture along the Pacific coast of North America, 3) provide evidence of local adaptation among subpopulations, and 4) associate genomic differences between subpopulations with regional environmental differences to better understand the physiological pressures imposed by climate variables and form hypotheses for the genetic mechanisms that may underlie ongoing adaptation to climate change

A high-quality reference genome of the kelp surfperch, Brachyistius frenatus (Embiotocidae), a wide-ranging Eastern Pacific reef fish with no pelagic larval stage

The surfperches (family Embiotocidae) are a unique group of mostly marine fishes whose phylogenetic position within the Ovalentaria clade (Percomorpha) is still unresolved. As a result of their viviparity and lack of a dispersive larval stage, surfperches are an excellent model for the study of speciation, gene flow, and local adaptation in the ocean. They are also the target of an immensely popular recreational fishery. Very few high-quality molecular resources, however, are available for this group and only for a single species. Here, we describe a highly complete reference genome for the kelp surfperch, Brachyistius frenatus, assembled using a combination of short-read (Illumina, ~47× coverage) and long-read (Oxford Nanopore Technologies, ~27× coverage) sequencing. The 596 Mb assembly has a completeness level of 98.1% (BUSCO), a contig N50 of 2.6 Mb (n = 56), and a contig N90 of 406.6 kb (n = 293). Comparative analysis revealed a high level of synteny between B. frenatus and its close relative, Embiotoca jacksoni. This assembly will serve as a valuable molecular resource upon which future evolutionary dynamics research will build, such as the investigation of local adaptation and the genomic potential for climate adaptation in wild populations

Upwelling-level acidification and pH/pCO2 variability moderate effects of ocean acidification on brain gene expression in the temperate surfperch, Embiotoca jacksoni.

Acidification-induced changes in neurological function have been documented in several tropical marine fishes. Here, we investigate whether similar patterns of neurological impacts are observed in a temperate Pacific fish that naturally experiences regular and often large shifts in environmental pH/pCO2 . In two laboratory experiments, we tested the effect of acidification, as well as pH/pCO2 variability, on gene expression in the brain tissue of a common temperate kelp forest/estuarine fish, Embiotoca jacksoni. Experiment 1 employed static pH treatments (target pH = 7.85/7.30), while Experiment 2 incorporated two variable treatments that oscillated around corresponding static treatments with the same mean (target pH = 7.85/7.70) in an eight-day cycle (amplitude ± 0.15). We found that patterns of global gene expression differed across pH level treatments. Additionally, we identified differential expression of specific genes and enrichment of specific gene sets (GSEA) in comparisons of static pH treatments and in comparisons of static and variable pH treatments of the same mean pH. Importantly, we found that pH/pCO2 variability decreased the number of differentially expressed genes detected between high and low pH treatments, and that interindividual variability in gene expression was greater in variable treatments than static treatments. These results provide important confirmation of neurological impacts of acidification in a temperate fish species and, critically, that natural environmental variability may mediate the impacts of ocean acidification