Climate change is leading to shifts in species geographical distributions, but populations are also probably adapting to environmental change at different rates across their range. Owing to a lack of ...natural and empirical data on the influence of phenotypic adaptation on range shifts of marine species, we provide a general conceptual model for understanding population responses to climate change that incorporates plasticity and adaptation to environmental change in marine ecosystems. We use this conceptual model to help inform where within the geographical range each mechanism will probably operate most strongly and explore the supporting evidence in species. We then expand the discussion from a single-species perspective to community-level responses and use the conceptual model to visualize and guide research into the important yet poorly understood processes of plasticity and adaptation. This article is part of the theme issue 'The role of plasticity in phenotypic adaptation to rapid environmental change'.
We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis ...provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus; hippocampal dysgenesis; sterility; and chronic inflammation/infection of lung, middle ear, and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells and suggest that p73 marks these cells for MCC differentiation. In summary, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation, and, like p63, has an essential role in development of tissues.
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•p73 is required for murine MCC differentiation•MCC loss provides a unifying biological defect for phenotypes in p73−/− mice•p73 binds to the genome in proximity to 105 cilia-associated genes, including Foxj1•p73 directly regulates and is required for Foxj1 expression
Using a p73-deficient mouse model, Marshall et al. show that p73 is required for MCC differentiation. ChIP-seq of murine tracheal cells reveals many p73 target genes that regulate MCC differentiation. Lack of expression of key transcriptional regulators of ciliogenesis provides a mechanistic basis for the multiple defects in p73-deficient mice.
Vaccine-specific CD4
T cell, CD8
T cell, binding antibody, and neutralizing antibody responses to the 25-μg Moderna messenger RNA (mRNA)–1273 vaccine were examined over the course of 7 months after ...immunization, including in multiple age groups, with a particular interest in assessing whether preexisting cross-reactive T cell memory affects vaccine-generated immunity. Vaccine-generated spike-specific memory CD4
T cells 6 months after the second dose of the vaccine were comparable in quantity and quality to COVID-19 cases, including the presence of T follicular helper cells and interferon-γ–expressing cells. Spike-specific CD8
T cells were generated in 88% of subjects, with equivalent memory at 6 months post-boost compared with COVID-19 cases. Lastly, subjects with preexisting cross-reactive CD4
T cell memory exhibited stronger CD4
T cell and antibody responses to the vaccine, demonstrating the biological relevance of severe acute respiratory syndrome coronavirus 2–cross-reactive CD4
T cells.
Many unknowns exist about human immune responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. SARS-CoV-2-reactive CD4
T cells have been reported in unexposed ...individuals, suggesting preexisting cross-reactive T cell memory in 20 to 50% of people. However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4
T cell repertoire. We demonstrate a range of preexisting memory CD4
T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity observed in coronavirus disease 2019 (COVID-19) disease.
Simulation in clinical teaching and learning Weller, Jennifer M; Nestel, Debra; Marshall, Stuart D ...
Medical journal of Australia,
05/2012, Letnik:
196, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Simulation‐based education (SBE) is a rapidly developing method of supplementing and enhancing the clinical education of medical students.
Clinical situations are simulated for teaching and learning ...purposes, creating opportunities for deliberate practice of new skills without involving real patients.
Simulation takes many forms, from simple skills training models to computerised full‐body mannequins, so that the needs of learners at each stage of their education can be targeted.
Emerging evidence supports the value of simulation as an educational technique; to be effective it needs to be integrated into the curriculum in a way that promotes transfer of the skills learnt to clinical practice.
Currently, SBE initiatives in Australia are fragmented and depend on local enthusiasts; Health Workforce Australia is driving initiatives to develop a more coordinated national approach to optimise the benefits of simulation.
Health care inequities persist, and it is difficult to teach health professions students effectively about implicit bias, structural inequities, and caring for patients from underrepresented or ...minoritized backgrounds. Improvisational theater (improv), where performers create everything in a spontaneous and unplanned manner, may help teach health professions trainees about advancing health equity. Core improv skills, discussion, and self-reflection can help improve communication; build trustworthy relationships with patients; and address bias, racism, oppressive systems, and structural inequities.
Authors integrated a 90-minute virtual improv workshop using basic exercises into a required course for first-year medical students at University of Chicago in 2020. Sixty randomly chosen students took the workshop and 37 (62%) responded to Likert-scale and open-ended questions about strengths, impact, and areas for improvement. Eleven students participated in structured interviews about their experience.
Twenty-eight (76%) of 37 students rated the workshop as very good or excellent, and 31 (84%) would recommend it to others. Over 80% of students perceived their listening and observation skills improved, and that the workshop would help them take better care of patients with experiences different than their own. Six (16%) students experienced stress during the workshop but 36 (97%) felt safe. Eleven (30%) students agreed there were meaningful discussions about systemic inequities. Qualitative interview analysis showed that students thought the workshop helped develop interpersonal skills (communication, relationship building, empathy); helped personal growth (insights into perception of self and others, ability to adapt to unexpected situations); and felt safe. Students noted the workshop helped them to be in the moment with patients and respond to the unexpected in ways more traditional communication curricula have not. The authors developed a conceptual model relating improv skills and equity teaching methods to advancing health equity.
Improv theater exercises can complement traditional communication curricula to advance health equity.
Many promising vaccine candidates from pathogenic viruses, bacteria, and parasites are unstable and cannot be produced cheaply for clinical use. For instance, Plasmodium falciparum ...reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. However, functional RH5 is only expressible in eukaryotic systems and exhibits moderate temperature tolerance, limiting its usefulness in hot and low-income countries where malaria prevails. Current approaches to immunogen stabilization involve iterative application of rational or semirational design, random mutagenesis, and biochemical characterization. Typically, each round of optimization yields minor improvement in stability, and multiple rounds are required. In contrast, we developed a one-step design strategy using phylogenetic analysis and Rosetta atomistic calculations to design PfRH5 variants with improved packing and surface polarity. To demonstrate the robustness of this approach, we tested three PfRH5 designs, all of which showed improved stability relative to wild type. The best, bearing 18 mutations relative to PfRH5, expressed in a folded form in bacteria at >1 mg of protein per L of culture, and had 10–15 °C higher thermal tolerance than wild type, while also retaining ligand binding and immunogenic properties indistinguishable from wild type, proving its value as an immunogen for a future generation of vaccines against the malaria blood stage. We envision that this efficient computational stability design methodology will also be used to enhance the biophysical properties of other recalcitrant vaccine candidates from emerging pathogens.
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and ...merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.
The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We ...previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell-dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24(-/lo)CD44(+) phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse.
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