The genus Henipavirus in the family Paramyxoviridae contains two viruses, Hendra virus (HeV) and Nipah virus (NiV) for which pteropid bats act as the main natural reservoir. Each virus also causes ...serious and commonly lethal infection of people as well as various species of domestic animals, however little is known about the associated mechanisms of pathogenesis. Here, we report the isolation and characterization of a new paramyxovirus from pteropid bats, Cedar virus (CedPV), which shares significant features with the known henipaviruses. The genome size (18,162 nt) and organization of CedPV is very similar to that of HeV and NiV; its nucleocapsid protein displays antigenic cross-reactivity with henipaviruses; and it uses the same receptor molecule (ephrin-B2) for entry during infection. Preliminary challenge studies with CedPV in ferrets and guinea pigs, both susceptible to infection and disease with known henipaviruses, confirmed virus replication and production of neutralizing antibodies although clinical disease was not observed. In this context, it is interesting to note that the major genetic difference between CedPV and HeV or NiV lies within the coding strategy of the P gene, which is known to play an important role in evading the host innate immune system. Unlike HeV, NiV, and almost all known paramyxoviruses, the CedPV P gene lacks both RNA editing and also the coding capacity for the highly conserved V protein. Preliminary study indicated that CedPV infection of human cells induces a more robust IFN-β response than HeV.
Recognition of a need for patient-centred care is not new, however making patient-centred care a reality remains a challenge to organisations. We need empirical studies to extend current ...understandings, create new representations of the complexity of patient-centred care, and guide collective action toward patient-centred health care. To achieve these ends, the research aim was to empirically determine what organisational actions are required for patient-centred care to be achieved.
We used an established participatory concept mapping methodology. Cross-sector stakeholders contributed to the development of statements for patient-centred care requirements, sorting statements into groupings according to similarity, and rating each statement according to importance, feasibility, and achievement. The resultant data were analysed to produce a visual concept map representing participants' conceptualisation of patient-centred care requirements. Analysis included the development of a similarity matrix, multidimensional scaling, hierarchical cluster analysis, selection of the number of clusters and their labels, identifying overarching domains and quantitative representation of rating data.
The outcome was the development of a conceptual map for the Requirements of Patient-Centred Care Systems (ROPCCS). ROPCCS incorporates 123 statements sorted into 13 clusters. Cluster labels were: shared responsibility for personalised health literacy; patient provider dynamic for care partnership; collaboration; shared power and responsibility; resources for coordination of care; recognition of humanity - skills and attributes; knowing and valuing the patient; relationship building; system review evaluation and new models; commitment to supportive structures and processes; elements to facilitate change; professional identity and capability development; and explicit education and learning. The clusters were grouped into three overarching domains, representing a cross-sectoral approach: humanity and partnership; career spanning education and training; and health systems, policy and management. Rating of statements allowed the generation of go-zone maps for further interrogation of the relative importance, feasibility, and achievement of each patient-centred care requirement and cluster.
The study has empirically determined requirements for patient-centred care through the development of ROPCCS. The unique map emphasises collaborative responsibility of stakeholders to ensure that patient-centred care is comprehensively progressed. ROPCCS allows the complex requirements for patient-centred care to be understood, implemented, evaluated, measured, and shown to be occurring.
Strong scientific writing skills are the foundation of a successful research career and require training and practice. Although these skills are critical for completing a PhD, most students receive ...little formal writing instruction prior to joining a graduate program. In 2015, the University of Iowa Medical Scientist Training Program (MSTP) addressed this issue by developing the scientific writing course Grant Writing Basics (GWB). Here we describe the structure of this course and its effectiveness. GWB is an interactive, workshop-based course that uses a National Institutes of Health (NIH) F30 predoctoral fellowship proposal as a platform for building writing expertise. GWB incorporates established pedagogical principles of adult learning, including flipped classrooms, peer teaching, and reiterative evaluation. Time spent in class centers on active student analysis of previously submitted fellowship applications, discussion of writing resources, active writing, facilitated small group discussion of critiques of student writing samples, revision, and a discussion with a panel of experienced study section members and a student who completed a fellowship submission. Outcomes of GWB include a substantial increase in the number of applications submitted and fellowships awarded. Rigorous evaluation provides evidence that learning objectives were met and that students gained confidence in both their scientific writing skills and their ability to give constructive feedback. Our findings show that investment in formal training in written scientific communication provides a foundation for good writing habits, and the knowledge and skills needed to succeed in this vital aspect of a scientific research career. Furthermore, they highlight that evaluation is valuable in guiding course evolution. Strategies embedded in GWB can be adapted for use in any graduate program to advance scientific writing skills among its trainees.
Sjögren syndrome is an autoimmune disease characterized by targeted destruction of the lacrimal and salivary glands resulting in symptoms of severe ocular and oral dryness. Despite its prevalence, ...the mechanisms driving autoimmune manifestations are unclear. In patients and in the nonobese diabetic (NOD) mouse model of Sjögren syndrome, lymphocytic infiltrates consist of CD4 and CD8 T cells, although the role of CD8 T cells in disease pathogenesis has been largely unexplored. Here, we evaluated the contribution of CD8 T cells to lacrimal and salivary gland autoimmunity. Within the lacrimal and salivary glands of NOD mice, CD8 T cells were proliferating, expressed an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes (LNs) of NOD mice into NOD-severe combined immunodeficiency recipients resulted in inflammation of the lacrimal glands, but was not sufficient to cause inflammation of the salivary glands. Lacrimal gland-infiltrating CD8 T cells displayed a cytotoxic phenotype, and epithelial cell damage in the lacrimal glands was observed in recipients of CD8 T cells regardless of the presence of CD4 T cells. Collectively, our results demonstrate that CD8 T cells have a pathogenic role in lacrimal gland autoimmunity. The gland-specific pathogenicity of CD8 T cells makes them a valuable resource to further understand the mechanisms that discriminate lacrimal versus salivary gland autoimmunity and for the development of new therapeutics that target the early stages of disease.
Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in ...T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27−/− and NOD.Il27ra−/− strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.
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•NOD mice deficient in IL-27 or IL-27Rα are completely resistant to type 1 diabetes•T cell-intrinsic IL-27 signaling is essential for type 1 diabetes development•IL-27 directly alters the balance of Treg and effector T cells to favor the latter•T cells require IL-27 signaling for Sjögren syndrome-like inflammation in NOD mice
Human genetic studies implicate IL-27 in the pathogenesis of type 1 diabetes (T1D). Ciecko et al. demonstrate that IL-27 signaling in T cells changes the balance of regulatory and effector subsets and is critical for T1D development as well as lacrimal and salivary gland inflammation in NOD mice.
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives ...T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (
,
) and other potentially disease-relevant genes (
,
) were upregulated in male lacrimal glands. Expression of
and
, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably,
-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.
Nipah virus (NiV) (Genus Henipavirus) is a recently emerged zoonotic virus that causes severe disease in humans and has been found in bats of the genus Pteropus. Whilst NiV has not been detected in ...Australia, evidence for NiV-infection has been found in pteropid bats in some of Australia's closest neighbours. The aim of this study was to determine the occurrence of henipaviruses in fruit bat (Family Pteropodidae) populations to the north of Australia. In particular we tested the hypothesis that Nipah virus is restricted to west of Wallace's Line. Fruit bats from Australia, Papua New Guinea, East Timor and Indonesia were tested for the presence of antibodies to Hendra virus (HeV) and Nipah virus, and tested for the presence of HeV, NiV or henipavirus RNA by PCR. Evidence was found for the presence of Nipah virus in both Pteropus vampyrus and Rousettus amplexicaudatus populations from East Timor. Serology and PCR also suggested the presence of a henipavirus that was neither HeV nor NiV in Pteropus alecto and Acerodon celebensis. The results demonstrate the presence of NiV in the fruit bat populations on the eastern side of Wallace's Line and within 500 km of Australia. They indicate the presence of non-NiV, non-HeV henipaviruses in fruit bat populations of Sulawesi and Sumba and possibly in Papua New Guinea. It appears that NiV is present where P. vampyrus occurs, such as in the fruit bat populations of Timor, but where this bat species is absent other henipaviruses may be present, as on Sulawesi and Sumba. Evidence was obtained for the presence henipaviruses in the non-Pteropid species R. amplexicaudatus and in A. celebensis. The findings of this work fill some gaps in knowledge in geographical and species distribution of henipaviruses in Australasia which will contribute to planning of risk management and surveillance activities.
Summary
Immune cell‐mediated destruction of salivary glands is a hallmark feature of Sjögren syndrome. Similar to the female predominance in humans, female non‐obese diabetic (NOD) mice develop ...spontaneous salivary gland autoimmunity. However, in both humans and mice it is unclear what factors contribute to the initial immune infiltration of the salivary glands. Here, we used an adoptive transfer model of Sjögren syndrome to determine if female mice harbor a sex‐specific defect in salivary‐gland‐protective regulatory T (Treg) cells. Transfer of cervical lymph node (LN) cells from female NOD mice into sex‐matched NOD‐severe combined immunodeficient (SCID) recipients resulted in sialadenitis, regardless of the presence or absence of Treg cells. In contrast, transfer of cervical LN cells from male NOD mice into sex‐matched NOD‐SCID recipients only resulted in sialadenitis when Treg cells were depleted before transfer, suggesting that male NOD mice have functional salivary‐gland‐protective Treg cells. Notably, the host environment affected the ability of Treg cells to prevent sialadenitis with testosterone promoting salivary gland protection. Treg cells from male mice did not protect against sialadenitis in female recipients. Testosterone treatment of female recipients of bulk cervical LN cells decreased sialadenitis, and Treg cells from female mice were capable of protecting against development of sialadenitis in male recipients. Hence, our data demonstrate that female NOD mice develop sialadenitis through a defect in salivary‐gland‐protective Treg cells that can be reversed in the presence of testosterone.
In the non‐obese diabetic mouse model of Sjögren syndrome, salivary gland inflammation occurs spontaneously in females but not males. Here we show that testosterone is protective, and, in an adoptive transfer model, we show that regulatory T cells are capable of preventing salivary gland inflammation in male but not female recipients. Thus, female‐specific salivary gland autoimmunity is associated with a defect in salivary‐gland‐protective regulatory T cells.
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the ...spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
•Both CD4 effector T cells and CD8 T cells require IL-27Rα to mediate focal lacrimal gland inflammation.•IL-27 promotes PD-1+ ICOS+ T follicular helper-like CD4 T cells in lacrimal gland autoimmunity.•IL-27 promotes T follicular cytotoxic-like and exhausted-like CD8 T cells in lacrimal glands.•IL-27 confers competitive disadvantage to T regulatory cells in lacrimal gland autoimmunity.
Brain death during the second trimester of pregnancy creates a unique situation in which the mother is deceased, but life of the developing fetus still depends on somatic functions in the mother’s ...body. In this article, I show that when a pregnant woman becomes brain dead during the second trimester, it is morally licit, though not morally obligatory, to continue somatic support while the fetus develops. The interventions on the mother’s body are justified for the life of the fetus, especially in light of the unique mother–child dyad and the responsibilities the mother has for her child. However, this therapy is not frequently employed, and its success is unpredictable. In many cases, the expense and uncertain nature of the therapy may make it disproportionate. In such cases, somatic support of the mother’s body may be discontinued.
Summary:
When brain death is diagnosed during pregnancy, it is a challenging decision whether to use artificial ventilation and other heroic measures to support the developing fetus. This paper demonstrates that while these interventions are acceptable, they are not obligatory.
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