Abstract
We recently discovered a role for Nod2 within T cells in controlling Th17-immunity, such that deletion of Nod2 exacerbated experimental autoimmune arthritis and uveitis. Protection against ...opportunistic Candida albicans infection relies on intact Th17-responses. Thus, we considered whether the T cell intrinsic Nod2 might control antifungal Th17 responses at the cost of increasing host susceptibility to autoimmunity. Nod2−/− mice infected with 105 (LD50) Candida albicans had increased survival and reduced fungal burden in the kidney within 24–72 h post-infection, suggesting a critical role for Nod2 in C. albicans immunity. Rag−/− mice reconstituted with Nod2fl/fl/CD4-cre CD4+ T cells and infected with C. albicans had decreased fungal burden compared to control CD4-Cre T cell recipients, and IL-17 depletion reverted the phenotype. After 48h infection, Nod2fl/fl/CD4-cre CD4+ T cells in the kidney had increased activation (CD69), increased proportion of T effector cells, and decreased Tregs compared to controls, suggesting endogenous Nod2 negatively regulates fungal-triggered Teff/Th17 cell responses. We next asked how Nod2 might function in SKG mice that are genetically susceptible to arthritis. Whereas Nod2−/− SKG mice developed an exacerbated form of arthritis compared to Nod2+/+ SKG controls, these same mice cleared C. albicans infection better than Nod2+/+ SKG mice. Cumulatively our data indicate a critical role for T cell intrinsic Nod2 in antifungal Th17 immunity. Given these studies we posit that human NOD2 genetic variants may offer enhanced ability to fight fungal infection via a T cell intrinsic mechanism, at the cost of triggering autoimmunity.
Supported by grants from VA (CDA-2 IK2BX004523 and Merit I01BX002180) and NIH (R01 EY025250).
Abstract
Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) is a pattern recognition receptor known to promote anti-bacterial immunity yet its function in fungal disease is less ...understood. Here we sought to investigate the role of Nod2 in regulating fungal infection. Our results demonstrate that Nod2−/− mice infected with 105 (LD50) Candida albicans had increased survival and reduced kidney pathology compared to WT mice, indicating an important role for Nod2-deficiency in protection against infection. In corroboration, Nod2−/− mice had increased fungal clearance in the kidney within 24–72 h post-infection. T cell-deficient Rag−/− or Nod2−/− Rag−/− mice infected with C. albicans had similar fungal burdens, indicating a cellular role for Nod2 outside of innate and non-hematopoietic cells. In support, Nod2−/− mouse kidneys had increased frequencies of CD4+ T cells 48h post-infection, indicating a potential protective function for Nod2−/− T cells. To evaluate a putative T cell-intrinsic function of Nod2 we infected Rag1−/− mice reconstituted with CD4+ T cells from conditional knockout mice deficient in Nod2 in CD4+ T cells (Nod2fl/fl/CD4-cre) or control mice (CD4-cre). Mice harboring CD4+ T cells from Nod2fl/fl/CD4-cre mice had decreased fungal burden within 48 h and increased Th17 cells in the kidneys akin to the global Nod2−/− mice. Protection conferred by Nod2-deficient CD4+ T cells was abrogated by neutralization of IL-17, indicating the functional importance of the Nod2/IL-17 response in CD4+ T cells in C. albicans pathogenesis. Cumulatively, our data suggest that in opposition to the known protective role of Nod2 in bacterial infections, T cell-intrinsic Nod2 promotes fungal infection.
Despite previous recommendations from the American Academy of Pediatrics discouraging home use of trampolines, recreational use of trampolines in the home setting continues to be a popular activity ...among children and adolescents. This policy statement is an update to previous statements, reflecting the current literature on prevalence, patterns, and mechanisms of trampoline-related injuries. Most trampoline injuries occur with multiple simultaneous users on the mat. Cervical spine injuries often occur with falls off the trampoline or with attempts at somersaults or flips. Studies on the efficacy of trampoline safety measures are reviewed, and although there is a paucity of data, current implementation of safety measures have not appeared to mitigate risk substantially. Therefore, the home use of trampolines is strongly discouraged. The role of trampoline as a competitive sport and in structured training settings is reviewed, and recommendations for enhancing safety in these environments are made.
Thousands of boys and girls younger than 19 years participate in boxing in North America. Although boxing provides benefits for participants, including exercise, self-discipline, and self-confidence, ...the sport of boxing encourages and rewards deliberate blows to the head and face. Participants in boxing are at risk of head, face, and neck injuries, including chronic and even fatal neurologic injuries. Concussions are one of the most common injuries that occur with boxing. Because of the risk of head and facial injuries, the American Academy of Pediatrics and the Canadian Paediatric Society oppose boxing as a sport for children and adolescents. These organizations recommend that physicians vigorously oppose boxing in youth and encourage patients to participate in alternative sports in which intentional head blows are not central to the sport.
Many of his works explore aspects of Tasmania's landscape and history, especially its Indigenous life before and since invasion, and of his three hundred works, approximately ten percent are designed ...specifically for children to perform.1 Through these latter works, Kay has made a substantial contribution to educating children about locally relevant topics, a practice often overlooked within the context of art music and education, yet one that warrants greater consideration.2 Fellow composer Larry Sitsky observed that 'Don Kay is an individual voice in Australian music. Since he has lived and worked in Tasmania almost all his life, the so-called "mainland" has yet to recognise his worth. A subsequent immersion in the Victorian town of Colac as a high school music teacher, and as the founder of the Colac Town Choir, afforded Kay an introduction to Australian expatriate composer Malcolm Williamson by way of Williamson's cousin.6 At the time a self-professed anglophile, Kay left eagerly for England in 1959 to train in composition with Williamson, who encouraged him to engage rigorously with the European technique of serialism. ...he stated in 2018 that it had been an 'excellent means of establishing basic techniques i.e., gaining understanding of the idiosyncrasies of voice types and instruments,' and had enabled the 'testing of his capacity to communicate through music, through rehearsal processes including comments made.'12 Further, he noted that writing music for children's performance had taught him valuable lessons about 'the need to be flexible in certain practical matters, without compromising personal integrity,' and acknowledged the importance of being 'respectful of performer colleagues and trustful of their capacity to help realise your intentions or even exceed your anticipations by adding a new dimension,' all of which had led him to realise that 'each new work involves new learnings for the composer as well as the performer.'13 Ultimately, his primary aim 'always has been to contribute musically to the welfare of children-to enrich and extend their experience through music performance and listening.'14 Importantly, for Kay, the goal of extending children's experience relates not only to their musical encounters, but also to their learning about the world around them. Examples of such works include several of his songs (or collections of songs) for youth choir, such as Four Australian Folk Songs (1971) for unaccompanied S.S.A. choir, which was commissioned by the Rosny Children's Choir; The Wild Mountain Thyme (1971) for S.S.A. choir with flute, composed for the Tasmanian Girls' Choir; Song of Welcome (1990) for massed youth choir and symphonic wind band, commissioned by the Mersey Valley Tasmania Music Festival for performance at the opening ceremony of the World Rowing Championships at Lake Barrington in the north of the state; and Song of'Greeting'and 'Farewell' (1996) for unaccompanied S.S.A.A. choir, written for the Ogilvie High School's 'Overseas Choir' and performed on the group's 1996 tour.
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