Spatiotemporal dynamics of songbird breeding in arctic-boreal North America

The high northern latitudes of North America are undergoing rapid climatic change with acute impacts to the ecosystems in which millions of songbirds breed each year. The goal of this dissertation is to improve understanding of how concurrent and interacting changes in environmental and land surface conditions influence annual movements and habitat selections of long distance migratory birds who must navigate the mosaic of changing North American ecosystems. Chapter 1 presents novel automated bioacoustic methods for estimating arrival dates of the songbird community to their arctic breeding grounds. Automated acoustic networks could vastly expand the spatiotemporal coverage of wildlife observations. However, the enormous datasets that autonomous recorders typically generate demand automated analyses that remain largely undeveloped. Chapter 1 demonstrates novel machine learning and signal processing techniques for estimating songbird community arrival dates near Toolik Field Station which agreed well with traditional survey estimates and were strongly related to the landscape’s snow free dates. Daily variations in vocal activity were more strongly influenced by environmental conditions prior to egg-laying dates. The success of the approaches presented in Chapter 1 indicate that variation in songbird migratory arrival can be detected autonomously. Widespread deployment of this advance could provide avian monitoring on a scale large enough to enable global-scale understanding of how climate change influences migratory timing of avian species. Chapter 2 examines potential future changes in habitat suitability for for two songbirds breeding throughout North America’s high northern latitudes – a tundra-nesting species (Lapland Longspurs (Calcarius lapponicus)) and a shrub-nesting species (White-crowned Sparrows (Zonotrichia leucophyrs)). By the late 21st century, models based on both climate and vegetation projected habitat suitability for Lapland Longspurs decreased across nearly all of the study domain (54-96%), while that for White-crowned Sparrows decreased in 69% of North America’s high northern latitudes. For both species, currently unsuitable habitats in northern Canada and Alaska are projected to provide suitable breeding habitat in the future. In contrast, models based solely on climate showed more drastic declines in habitat suitability for both species (Lapland Longspur, ~100% and White-crowned Sparrow ~80%). This discrepancy between model projections demonstrates that the future availability of suitable songbird breeding habitat for both species will be strongly dependent on how both the vegetation and climate– as opposed to climate alone - of northern ecosystems respond to ongoing climate change. Chapter 3 investigates the environmental and ecological drivers of migratory movements of songbirds breeding at high northern latitudes. For North America alone, there is overwhelming evidence of major shifts in seasonality of meteorological conditions, snow cover, and vegetation phenology. Few studies have focused on how this suite of changes impacts long distance migratory species that annually navigate throughout the spatially and temporally dynamic mosaic of ecosystems because of technological constraints in animal tracking. However, recent advances in GPS technology have generated units small enough to be placed on songbird species. In 2016-2018 a total of 55 American robins (Turdus migratorius) were tracked during their spring migration through the Canadian boreal forest en route to their breeding grounds. We found a significant trend towards earlier arrival of robins to the Canadian boreal forest over the past quarter-century, consistent with advances in spring environmental conditions. Robin stopover timing at our tagging site was delayed in response to later seasonal snowmelt, but triggered by adverse environmental conditions. Individuals breeding in regions with shorter snow-free seasons moved faster than individuals breeding in areas with longer snow-free seasons and selected locations with less favorable environmental conditions. Overall, arrival timing to breeding grounds was negatively related to snow depth and positively related to snowmelt timing. Migratory movements and timing of American robins are highly tied to seasonal environmental dynamics en route to their breeding grounds. Our findings present a unique, mechanistic understanding of how migratory birds navigate highly dynamic ecosystems. In light of rapid global change, the use of multi-disciplinary, spatially explicit approaches similar to the ones used in this dissertation will be critical for understanding how avian taxa breeding at high northern latitudes may respond to ongoing and future change. This is important for investigating both regional and global impacts because species breeding in arctic-boreal zones perform key ecosystem services around the globe

Eavesdropping on the Arctic: Automated bioacoustics reveal dynamics in songbird breeding phenology

Bioacoustic networks could vastly expand the coverage of wildlife monitoring to complement satellite observations of climate and vegetation. This approach would enable global-scale understanding of how climate change influences phenomena such as migratory timing of avian species. The enormous data sets that autonomous recorders typically generate demand automated analyses that remain largely undeveloped. We devised automated signal processing and machine learning approaches to estimate dates on which songbird communities arrived at arctic breeding grounds. Acoustically estimated dates agreed well with those determined via traditional surveys and were strongly related to the landscape’s snow-free dates. We found that environmental conditions heavily influenced daily variation in songbird vocal activity, especially before egg laying. Our novel approaches demonstrate that variation in avian migratory arrival can be detected autonomously. Large-scale deployment of this innovation in wildlife monitoring would enable the coverage necessary to assess and forecast changes in bird migration in the face of climate change

Transmission of hepatitis C virus in HIV‐positive and PrEP‐using MSM in England

We sought to characterize risk factors and patterns of HCV transmission amongst men who have sex with men (MSM). MSM with recently acquired HCV (AHCV) were prospectively recruited ('clinic cohort') between January and September 2017. Clinical data and risk behaviours were identified and blood obtained for HCV whole genome sequencing. Phylogenetic analyses were performed, using sequences from this cohort and two other AHCV cohorts, to identify transmission clusters. Sixteen (40.0%) men in the clinic cohort were HIV‐negative MSM. HIV‐negative MSM were younger than HIV‐positive MSM; most (81.3%) had taken HIV PrEP in the preceding year. Eighteen men (45.0%) reported injection drug use; most (34, 85.0%) reported noninjection drug use in the last year. Most in both groups reported condomless anal sex, fisting and sex in a group environment. Few (7, 17.5%) men thought partners may have had HCV. There were 52 sequences in the HCV genotype 1a phylogeny, 18 from the clinic cohort and 34 from other AHCV cohorts; 47 (90.4%) clustered with ≥1 other sequence. There were 7 clusters of 2‐27 sequences; 6 clusters contained HIV‐negative and HIV‐positive MSM and 1 cluster only HIV‐positive MSM. Four of these clusters were part of larger clusters first described in 2007. PrEP‐using MSM are at risk of HCV, sharing similar risk factors to HIV‐positive MSM. Phylogenetics highlights that PrEP‐using and HIV‐positive MSM are involved in the same HCV transmission networks. Few men demonstrated HCV awareness and risk reduction strategies should be expanded

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

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

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707