Sexual dimorphism of song and life history trade-offs in the New Zealand bellbird : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Ecology at Massey University, Albany, New Zealand

Appendix B: Reprint of Published Paper was removed for copyright reasons.Birdsong and its function is well studied in terms of male-male competition and female-mate choice. This has generated a male bias in the song literature and the dilemma that little is known about female song. However, recent research posits that female song is not only common but is also the ancestral state of songbirds. Therefore, it is timely that I investigate the ontogeny, structure and production of female song within the context of the life history of female songbirds in order to increase our current understanding of the function and evolution of birdsong. In this thesis, I use a wild population of New Zealand bellbirds (Anthornis melanura) as a model species. The New Zealand bellbird is ideal for this research as they produce complex but sexually dimorphic song. With a cross-sectional approach, I found the songs of each sex diverged and became more consistent as the song developed from juveniles to adults, and that their sexually dimorphic songs developed over similar timeframes, suggesting potentially related functions. I also compared how the adult song repertoire of each sex varied over time, and found that males had larger repertoires at both the population and individual levels. The syllable repertoire of each sex changed at a similar rate due to shifts in relative abundance over time, suggesting both sexes may have analogous song functions and are potentially under similar selection pressures. Sexual variation in song could theoretically be explained by differences in the syrinx structure but there is a lack of comparative research in this field. I found that bellbirds had greater sexual dimorphism in the size of their bronchial half rings compared to species both with and without female song. This suggests syrinx size alone cannot explain sexual dimorphism in repertoire size, but may have a stronger influence on sex- and species-specific song frequencies. Long term studies provide insights to life history and my study population on Tiritiri Matangi Island has breeding data available as far back as 1977. The island’s history of ecological restoration has resulted in exponential growth of the bellbird population, and I found correlated reproductive trade-offs with a reduction in clutch size over time, likely owing to increasing competition for resources. My research demonstrates how female songbirds develop and change their song over time and that they have flexible life-history traits that enable them to cope with changing breeding conditions. My research is significant in that it is one of the first to study female song in a wild population and provides important insights into male and female song development, structure and role

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.</p

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Female song rate and structure predict reproductive success in a socially monogamous bird.

Bird song is commonly regarded as a male trait that has evolved through sexual selection. However, recent research has prompted a re-evaluation of this view by demonstrating that female song is an ancestral and phylogenetically widespread trait. Species with female song provide opportunities to study selective pressures and mechanisms specific to females within the wider context of social competition. We investigated the relationship between reproductive success and female song performance in the New Zealand bellbird (Anthornis melanura), a passerine resident year round in New Zealand temperate forests. We monitored breeding behavior and song over three years on Tiritiri Matangi Island. Female bellbirds contributed significantly more towards parental care than males (solely incubating young and provisioning chicks at more than twice the rate of males). Female song rate in the vicinity of the nest was higher than that of males during incubation and chick-rearing stages but similar during early-nesting and post-breeding stages. Using GLMs, we found that female song rates during both incubation and chick-rearing stages strongly predicted the number of fledged chicks. However, male song rate and male and female chick provisioning rates had no effect on fledging success. Two measures of female song complexity (number of syllable types and the number of transitions between different syllable types) were also good predictors of breeding success (GLM on PC scores). In contrast, song duration, the total number of syllables, and the number of ‘stutter’ syllables per song were not correlated with fledging success. It is unclear why male song rate was not associated with reproductive success and we speculate that extra-pair paternity might play a role. While we have previously demonstrated that female bellbird song is important in intrasexual interactions, we clearly demonstrate here that female song predicts reproductive success. These results, with others, highlight the need for a change in how we view the significance of female secondary sexual traits; traits long underestimated due to a focus on male song

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration ClinicalTrials.gov Identifier: NCT01603407