Environmental drivers of deer population dynamics and spatial selection in Southeast Alaska

Thesis (Ph.D.) University of Alaska Fairbanks, 2015The coastal temperate rainforest is one of the rarest ecosystems in the world, and a major portion of the global total is found in Southeast Alaska. In this ecosystem, Sitka black-tailed deer are the dominant large herbivore, influencing large carnivores that prey on deer such as wolves and bears, as well as plant species and communities through browsing. In addition, deer play an important economic and cultural role for humans in Southeast Alaska, making up the large majority of terrestrial subsistence protein harvested each year as well as providing the backbone of a thriving tourism industry built around sport hunting. Given the importance of deer in this system, there remain a surprisingly large number of key gaps in our knowledge of deer ecology in Southeast Alaska. These knowledge gaps are potentially troubling in light of ongoing industrial timber-harvest across the region, which greatly alters habitat characteristics and value to wildlife. This dissertation research project was undertaken with the aim of filling several connected needs for further understanding deer ecology, specifically 1) patterns of reproduction and fawn survival, 2) population dynamics in response to environmental variability, and the underlying drivers of spatial selection during 3) reproduction and 4) winter. To fill these knowledge gaps, I developed robust statistical tools for estimating rates of fawn survival, and found that fawns must be captured at birth, rather than within several days of birth, in order to produce unbiased estimates because highly vulnerable individuals died quickly and were thus absent from the latter sample. I then use this robust approach to estimate vital rates, including fawn survival in winter and summer, and developed a model of population dynamics for deer. I found that winter weather had the strongest influence on population dynamics, via reduced over-winter fawn survival, with mass at birth and gender ratio of fawns important secondary drivers. To better understand deer-habitat relationships, I examined both summer and winter habitat selection patterns by female deer. Using summer-only data, I asked how reproductive female deer balance wolf and bear predation risk against access to forage over time. Predation risks and forage were strong drivers of deer spatial selection during summer, but reproductive period and time within reproductive period determined deer reaction to these drivers. To ensure adequate reproductive habitat for deer, areas with low predation risk and high forage should be conserved. Focusing on winter, I evaluated deer spatial selection during winter as a response to snow depth, vegetation classes, forage, and landscape features. I allowed daily snow depth measures to interact with selection of other covariates, and found strong support for deer avoidance of deep snow, as well as changes in deer selection of old-growth and second-growth habitats and landscape features with increasing snow depth. Collectively, this dissertation greatly improves our understanding of deer ecology in Alaska, and suggests habitat management actions that will help ensure resilient deer populations in the future

A consecutive process for C–C and C–N bond formation with high enantio-and diastereocontrol : direct reductive amination of chiral ketones using hydrogenation catalysts

Authors thank the University of St Andrews, and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT) for financial support [PhD studentship to SG; Grant code: EP/L016419/1].High diastereoselectivity was observed in the Rh-catalysed reductive amination of 3-arylcyclohexanones to form tertiary amines. This was incorporated into a one-pot enantioselective conjugate addition and diastereoselective reductive amination, including an example of assisted tandem catalysis.PostprintPeer reviewe

Investigating genome reduction of Bordetella pertussis using a multiplex PCR-based reverse line blot assay (mPCR/RLB)

BACKGROUND: The genetic composition of the bacterium causing whooping cough, Bordetella pertussis, has been investigated using microarray studies in order to examine potential genetic contributors to the disease re-emergence in the past decade. Regions of difference (RDs) have been previously identified as clusters of genes flanked by insertion sequences which are variably present in different sets of isolates, and have also been shown to be potential markers of B. pertussis evolution. This study used microarray data to identify and select a panel of RDs; primers and probes for these RDs were then designed to test for the presence or absence of these regions in a novel and less expensive multiplex PCR-based reverse line blot (mPCR/RLB) assay. By comparing the presence or absence of RDs, we aimed to determine the genomic variability of a diverse collection of B. pertussis strains and how they have changed over time. RESULTS: A B. pertussis specific mPCR/RLB using 43 genes representing 30 RDs, was developed and used to characterise a set of 42 B. pertussis isolates. When mapped against the previously identified evolutionary relationships of the strains, the losses of two RDs - BP0910A - BP00930 and BP1948-BP1962 - were found to be associated with significant events in B. pertussis history: the loss of BP0910A - BP00930 coincided with introduction of whole cell vaccines in the 1950s while that of BP1948-BP1962 occurred after the introduction of acellular vaccines. The loss of BP1948-BP1962 also coincided with expansion of the most recent B. pertussis strains. CONCLUSIONS: The mPCR/RLB assay offers an inexpensive and fast method of determining the gene content of B. pertussis strains and also confirms that gene losses are an ongoing feature of B. pertussis evolution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1756-0500-7-727) contains supplementary material, which is available to authorized users

Tragic trade-offs accompany carnivore coexistence in the modern world

Two vital policy aims—biodiversity conservation and food production—are increasingly in conflict. Efforts to evaluate trade-offs between agriculture and conservation have shaped scholarly discourse around two broad strategies to agricultural production that seek to either “share” land with biodiversity or “spare” land from agriculture. However, efforts to negotiate these trade-offs are challenged by rising concern for the welfare of individual animals, both wild and domestic. We use recent efforts to “coexist” with large carnivores to illustrate how sharing and sparing strategies both create tragic, and often unacknowledged trade-offs between livestock production and carnivore conservation. We conclude the best means of conserving carnivores while feeding the world\u27s growing population requires explicitly confronting and adjudicating ethical trade-offs associated with sharing and sparing approaches. To accomplish this, we recommend engaging scholars trained in ethics and social justice and use of deliberative processes to synthesize disparate facts and competing values when evaluating trade-offs

An applied ecology of fear framework: linking theory to conservation practice

Research on the ecology of fear has highlighted the importance of perceived risk from predators and humans in shaping animal behavior and physiology, with potential demographic and ecosystem-wide consequences. Despite recent conceptual advances and potential management implications of the ecology of fear, theory and conservation practices have rarely been linked. Many challenges in animal conservation may be alleviated by actively harnessing or compensating for risk perception and risk avoidance behavior in wild animal populations. Integration of the ecology of fear into conservation and management practice can contribute to the recovery of threatened populations, human–wildlife conflict mitigation, invasive species management, maintenance of sustainable harvest and species reintroduction plans. Here, we present an applied framework that links conservation interventions to desired outcomes by manipulating ecology of fear dynamics. We discuss how to reduce or amplify fear in wild animals by manipulating habitat structure, sensory stimuli, animal experience (previous exposure to risk) and food safety trade-offs to achieve management objectives. Changing the optimal decision-making of individuals in managed populations can then further conservation goals by shaping the spatiotemporal distribution of animals, changing predation rates and altering risk effects that scale up to demographic consequences. We also outline future directions for applied research on fear ecology that will better inform conservation practices. Our framework can help scientists and practitioners anticipate and mitigate unintended consequences of management decisions, and highlight new levers for multi-species conservation strategies that promote human–wildlife coexistence

Opportunities and Challenges in Functional Genomics Research in Osteoporosis:Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis

Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020.

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD