550 research outputs found
Boccardia fleckera Hutchings and Turvey 1984
No full textBoccardia fleckera Hutchings and Turvey, 1984 Type locality: Cape du Couedic, Kangaroo Island; 36 ° 03’ S 136 ° 41 ’E; South Australia, 4.ii. 1979; exposed algal holdfasts. Type material: Holotype: AM W 194020, posteriorly incomplete, otherwise good. Location and author of most recently described material: Hutchings and Turvey (1984). Recorded distribution: Australia: South Australia (Cape du Couedic, Kangaroo Island).Published as part of Walker, Lexie M, 2011, A review of the current status of the Polydora - complex (Polychaeta: Spionidae) in Australia and a checklist of recorded species, pp. 40-62 in Zootaxa 2751 on page 48, DOI: 10.5281/zenodo.20356
Supplemental Material, Appendix_CJP_revised_final - Risk for Maternal Depressive Symptoms and Perceived Stress by Ethnicities in Canada: From Pregnancy Through the Preschool Years
No full textSupplemental Material, Appendix_CJP_revised_final for Risk for Maternal Depressive Symptoms and Perceived Stress by Ethnicities in Canada: From Pregnancy Through the Preschool Years by Christoffer Dharma, Diana L. Lefebvre, Zihang Lu, Wendy Y. W. Lou, Allan B. Becker, Piush J. Mandhane, Stuart E. Turvey, Theo J. Moraes, Meghan B. Azad, Edith Chen, Susan J. Elliott, Anita L. Kozyrskyj, Malcolm R. Sears, and Padmaja Subbarao in The Canadian Journal of Psychiatry</p
Functional and biochemical characterization of novel genetic variants in IRAK4 and IRF4 causing human inborn errors of immunity
No full textHuman inborn errors of immunity (IEIs) are a group of genetic disorders in which specific components of the human immune system are missing, dysfunctional, or poorly regulated. IEIs negatively impact the protective functions of the immune system, increasing susceptibility to infections, autoimmunity, inflammation, and malignancy. The investigation of monogenic IEIs enables the diagnosis and treatment of the affected individuals and provides unique opportunities to understand the role of the immune system and the functional roles of its constituents.
Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade which enables the production of protective inflammatory cytokines. Human IRAK4-deficiency is an autosomal recessive IEI which presents with a blunted inflammatory response to infection and susceptibility to certain bacteria. We demonstrate that the novel IRAK4 (c.1049delG, p.(Gly350Glufs*15)) variant abrogates IRAK4 protein expression and abolishes TLR signaling, expanding the knowledge of pathogenic variants causing human IRAK4-deficiency.
We have also identified 3 unrelated individuals with a phenotype of combined immunodeficiency (agammaglobulinemia and infectious susceptibility) who carry a novel heterozygous de novo missense variant in Interferon Regulatory Factor 4 (IRF4) gene (c.284C>G, p.T95R). IRF4 is a transcription factor expressed in immune cells which plays a critical role in the differentiation of various immune cells. We demonstrate adaptive immune cell differentiation defects in proband primary cells, as well as decreased effector cytokine production in T cells. We also demonstrate that the IRF4 T95R variant is able to bind the canonical GAAA binding site as well as a novel GATA binding site. Therefore, we propose that the IRF4 T95R variant is defined as a neomorphic variant, as it has gained novel DNA-binding functions. This increase in DNA-binding sequence promiscuity may result in a dominant negative redistribution of the wild-type IRF4 and the combined immunodeficiency phenotype in the proband. We have characterized a novel neomorphic variant in the IRF4 gene and defined a novel human IEI which highlights the potential of IRF4 as an immunomodulatory therapeutic target.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat
Defining the functional impact of three new human primary immune regulatory disorders caused by defects in genes NFATC2, STAT6 and OSMR
No full textThe full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty ofMedicine, Department ofGraduat
Characterizing the molecular and clinical impact of two novel human inborn errors of immunity caused by defects in IKZF2 and ZBTB7B
No full textInborn errors of immunity (IEIs) are a diverse group of genetic disorders that adversely affect the function and/or development of the immune system, resulting in increased susceptibility to infections, autoimmunity, allergy, and malignancies. Primary immune regulatory disorders and primary atopic disorders are two subcategories of IEIs. While IEIs are commonly associated with frequent, severe, and unconventional infections, primary immune regulatory disorders mainly present with immune dysregulation, and primary atopic disorders with severe, early-onset allergies. These manifestations can occur with or without the typical infectious symptoms expected with IEIs. Given the recently acknowledged diversity of symptoms associated with IEIs, there is a pressing need to sequence and investigate individuals presenting with unconventional and newly identified manifestations of IEIs. The overarching goal of this thesis was to use an established pipeline of studying single patients to discover and characterize novel monogenic causes of primary immune regulatory disorders and primary atopic disorders. The discovery of these novel classes of IEIs significantly enriches our understanding of fundamental human biology, presenting new pathways for therapeutic development and repurposing, which promise substantial enhancements in patient care. By employing a comprehensive approach that included the collection of phenotypic information from patients and the use of advanced genomic sequencing and bioinformatics analyses, we identified two novel diseases caused by germline variants in IKZF2 and ZBTB7B, which encode critical transcription factors – Helios and ThPOK – that regulate broad-ranging biological processes in the human body. The first study delineates the consequences of two dominant-negative variants in Helios, revealing an association with a complex syndrome in humans characterized by immune dysregulation and developmental anomalies, thus broadening our understanding of Helios’s role in human physiology and development. The second study describes the discovery of a multimorphic variant in ThPOK, outlining its critical involvement in CD4 T cell development and its unexpected association with tissue fibrosis in humans. These findings not only demonstrate the profound impact of transcriptional regulation on immune function and disease, but also expand the diagnostic and therapeutic approaches of IEIs, enriching the future landscape of IEI management.Medicine, Faculty ofMedicine, Department ofGraduat
Defining the role of infant gut microbiota in child health
No full textThe full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty ofMedicine, Department ofGraduat
The hygiene hypothesis: current perspectives and future therapies
No full textLeah T Stiemsma,1,2 Lisa A Reynolds,3 Stuart E Turvey,1,2,4 B Brett Finlay1,3,5 1Department of Microbiology & Immunology, University of British Columbia, 2The Child and Family Research Institute, 3Michael Smith Laboratories, University of British Columbia, 4Department of Pediatrics, University of British Columbia, 5Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada Abstract: Developed countries have experienced a steady increase in atopic disease and disorders of immune dysregulation since the 1980s. This increase parallels a decrease in infectious diseases within the same time period, while developing countries seem to exhibit the opposite effect, with less immune dysregulation and a higher prevalence of infectious disease. The “hygiene hypothesis”, proposed by Strachan in 1989, aimed to explain this peculiar generational rise in immune dysregulation. However, research over the past 10 years provides evidence connecting the commensal and symbiotic microbes (intestinal microbiota) and parasitic helminths with immune development, expanding the hygiene hypothesis into the “microflora” and “old friends” hypotheses, respectively. There is evidence that parasitic helminths and commensal microbial organisms co-evolved with the human immune system and that these organisms are vital in promoting normal immune development. Current research supports the potential for manipulation of the bacterial intestinal microbiota to treat and even prevent immune dysregulation in the form of atopic disease and other immune-mediated disorders (namely inflammatory bowel disease and type 1 diabetes). Both human and animal model research are crucial in understanding the mechanistic links between these intestinal microbes and helminth parasites, and the human immune system. Pro-, pre-, and synbiotic, as well as treatment with live helminth and excretory/secretory helminth product therapies, are all potential therapeutic options for the treatment and prevention of these diseases. In the future, therapeutics aimed at decreasing the prevalence of inflammatory bowel disease, type 1 diabetes, and atopic disorders will likely involve personalized microbiota and/or helminth treatments used early in life. Keywords: inflammatory bowel disease, microbiota, helminths, atopic disease, type 1 diabete
Current concepts: host–pathogen interactions in cystic fibrosis airways disease
No full textChronic infection and inflammation are defining characteristics of cystic fibrosis (CF) airway disease. Conditions within the airways of patients living with CF are conducive to colonisation by a variety of opportunistic bacterial, viral and fungal pathogens. Improved molecular identification of microorganisms has begun to emphasise the polymicrobial nature of infections in the CF airway microenvironment. Changes to CF airway physiology through loss of cystic fibrosis transmembrane conductance regulator functionality result in a wide range of immune dysfunctions, which permit pathogen colonisation and persistence. This review will summarise the current understanding of how CF pathogens infect, interact with and evade the CF host
Asthma and the microbiome: defining the critical window in early life
No full textAbstract
Asthma is a chronic inflammatory immune disorder of the airways affecting one in ten children in westernized countries. The geographical disparity combined with a generational rise in prevalence, emphasizes that changing environmental exposures play a significant role in the etiology of this disease. The microflora hypothesis suggests that early life exposures are disrupting the composition of the microbiota and consequently, promoting immune dysregulation in the form of hypersensitivity disorders. Animal model research supports a role of the microbiota in asthma and atopic disease development. Further, these model systems have identified an early life critical window, during which gut microbial dysbiosis is most influential in promoting hypersensitivity disorders. Until recently this critical window had not been characterized in humans, but now studies suggest that the ideal time to use microbes as preventative treatments or diagnostics for asthma in humans is within the first 100\ua0days of life. This review outlines the major mouse-model and human studies leading to characterization of the early life critical window, emphasizing studies analyzing the intestinal and airway microbiotas in asthma and atopic disease. This research has promising future implications regarding childhood immune health, as ultimately it may be possible to therapeutically administer specific microbes in early life to prevent the development of asthma in children
Book Review: Toxic Exposures: Contested Illnesses and the Environmental Health Movement, by Phil Brown
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