IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection.

Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host's genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1ß-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.

Erratum: 17157 Racial/ethnic disparities in antibiotic-resistant infections: Knowledge gaps and opportunities for educational interventions - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2021.601.].

Persistence of cooperatively stabilized signaling clusters drives T-cell activation.

Antigen recognition triggers the recruitment of the critical adaptor protein SLP-76 to small macromolecular clusters nucleated by the T-cell receptor (TCR). These structures develop rapidly, in parallel with TCR-induced increases in tyrosine phosphorylation and cytosolic calcium, and are likely to contribute to TCR-proximal signaling. Previously, we demonstrated that these SLP-76-containing clusters segregate from the TCR and move towards the center of the contact interface. Neither the function of these clusters nor the structural requirements governing their persistence have been examined extensively. Here we demonstrate that defects in cluster assembly and persistence are associated with defects in T-cell activation in the absence of Lck, ZAP-70, or LAT. Clusters persist normally in the absence of phospholipase C-gamma1, indicating that in the absence of a critical effector, these structures are insufficient to drive T-cell activation. Furthermore, we show that the critical adaptors LAT and Gads localize with SLP-76 in persistent clusters. Mutational analyses of LAT, Gads, and SLP-76 indicated that multiple domains within each of these proteins contribute to cluster persistence. These data indicate that multivalent cooperative interactions stabilize these persistent signaling clusters, which may correspond to the functional complexes predicted by kinetic proofreading models of T-cell activation.

A High School Level Health and Disease-Focused Biology Curriculum Promotes Higher Level Skills in Nutrition Literacy.

OBJECTIVE: To determine the efficacy of a high school biology curriculum focused on promoting nutrition literacy skills. DESIGN: High school students participated in a six-week biology curriculum focused on the three subdomains of nutrition literacy: functional use of factual knowledge (FNL); interactive skills in seeking out information (INL); critical interpretation and analysis (CNL). We used a mixed-methods, change-over-time model that leverages longitudinal aspects of instructor practice and students' development. Pre- and posttest measures of FNL, INL and CNL were administered. Students were also given a retrospective pre-post online survey to measure interactive nutrition literacy and self-efficacy towards learning about nutrition topics. PARTICIPANTS: A total of 111 high school 11th and 12th grade students from four sections of a Biology II course participated. RESULTS: Students' overall NL scores improved (P<0.0001) and they also showed gains in each subdomain (FNL, INL and CNL, P<0.0001). Self-efficacy toward learning about nutrition also increased (P<0.0001). Students reported increased communication about the topics with family and peers who were neither classmates or friends (P<0.0001). CONCLUSIONS: Participation improved nutrition literacy in each of the subdomains, as well as self-efficacy. Self-efficacy was strongly related to increased communication.

Collaborative Curriculum Design as a Framework for Designing Teacher Professional Development that Produces the Content Knowledge for Teaching the Life Sciences.

Effective science teaching critically requires content focused professional development (PD), particularly in life sciences where content evolves rapidly. How subject matter knowledge related to teaching (SCK) is most effectively incorporated into PD has not been investigated. We studied how a professional learning community of high school teachers and scientists co-designing a bioscience curriculum produced the accompanying SCK-focused PD. SCK was level-specific but teachers could not generate it alone. Co-designing SCK with scientists was valuable to teachers, as evidenced by significant increases in their cognitive and attitudinal attributes toward the PD, in turn promoting change in practice and student learning gains, both within and outside the initial partnership. Surprisingly, social network analysis of how the collaborators interacted revealed that though the network was cognitively and effectively robust, it was behaviorally much sparser than anticipated for such a high functioning partnership, counter to commonly accepted PD best practices. We suggest that the scientist/educator facilitators who intentionally promoted collaboration in the context of distributed leadership were able to eliminate extraneous interactions, optimizing the process. The results are further evidence that developing content-focused PD relevant to 21st century life sciences requires dismantling the institutionalized segregation between practitioners of science and teaching.

Addressing Health Literacy Challenges With a Cutting-Edge Infectious Disease Curriculum for the High School Biology Classroom.

This study reports the secondary analysis of evaluation data from an innovative high school biology curriculum focused on infectious disease (ID) to examine the health literacy implications of teaching claims evaluation, data interpretation, and risk assessment skills in the context of 21st-Century health science. The curriculum was implemented between 2010 and 2013 in Biology II classes held in four public high schools (three in Massachusetts and one in Ohio), plus a private school in Virginia. A quasi-experimental design was used in which student participants (n = 273) were compared to an age-matched, nonparticipant, peer group (N = 125). Participants in each school setting demonstrated increases in conceptual content knowledge (Cohen's d > 1.89) as well as in understanding how to apply scientific principles to health claims evaluation and risk assessment (Cohen's d > 1.76) and in self-efficacy toward learning about ID (Cohen's d > 2.27). Participants also displayed enhanced communication about ID within their social networks relative to the comparison group (p < .05). The data show that integrating the claims evaluation, data interpretation, and risk assessment skills critical for 21st-century health literacy health into high school biology classrooms is effective at fostering both the skills and self-efficacy pertinent to health literacy learning in diverse populations.

Modeling for Fidelity: virtual mentorship by scientists fosters teacher self-efficacy and promotes implementation of novel high school biomedical curricula.

This small-scale comparison case study evaluates the impact of an innovative approach to teacher professional development designed to promote implementation of a novel cutting edge high school neurological disorders curriculum. 'Modeling for Fidelity' (MFF) centers on an extended mentor relationship between teachers and biomedical scientists carried out in a virtual format in conjunction with extensive online educative materials. Four teachers from different diverse high schools in Massachusetts and Ohio who experienced MFF contextualized to a 6-week Neurological Disorders curriculum with the same science mentor were compared to a teacher who had experienced an intensive in-person professional development contextualized to the same curriculum with the same mentor. Fidelity of implementation was measured directly using an established metric and indirectly via student performance. The results show that teachers valued MFF, particularly the mentor relationship and were able to use it effectively to ensure critical components of the learning objectives were preserved. Moreover their students performed equivalently to those whose teacher had experienced intensive in-person professional development. Participants in all school settings demonstrated large (Cohen's d>2.0) and significant (p<0.0001 per-post) changes in conceptual knowledge as well as self-efficacy towards learning about neurological disorders (Cohen's d>1.5, p<0.0001 pre-post). The data demonstrates that the virtual mentorship format in conjunction with extensive online educative materials is an effective method of developing extended interactions between biomedical scientists and teachers that are scalable and not geographically constrained, facilitating teacher implementation of novel cutting-edge curricula.

The Great Diseases Project: a partnership between Tufts Medical School and the Boston public schools.

Medical schools, although the gatekeepers of much biomedical education and research, rarely engage formally with K-12 educators to influence curriculum content or professional development. This segregation of content experts from teachers creates a knowledge gap that limits inclusion of current biomedical science into high school curricula, affecting both public health literacy and the biomedical pipeline. The authors describe how, in 2009, scientists from Tufts Medical School and Boston public school teachers established a partnership of formal scholarly dialogue to create 11th- to 12th-grade high school curricula about critical health-related concepts, with the goal of increasing scientific literacy and influencing health-related decisions. The curricula are based on the great diseases (infectious diseases, neurological disorders, metabolic disease, and cancer). Unlike most health science curricular interventions that provide circumscribed activities, the curricula are comprehensive, each filling one full term of in-class learning and providing extensive real-time support for the teacher. In this article, the authors describe how they developed and implemented the infectious disease curriculum, and its impacts. The high school teachers and students showed robust gains in content knowledge and critical thinking skills, whereas the Tufts scientists increased their pedagogical knowledge and appreciation for health-related science communication. The results show how formal interactions between medical schools and K-12 educators can be mutually beneficial.

Genetic analysis of the innate immune responses in wild-derived inbred strains of mice.

The vertebrate immune system has evolved to recognize nucleic acids of bacterial and viral origin. Microbial DNA, as well as synthetic oligonucleotides based on these motifs, activates innate immune pathways mediated by the family of Toll-like receptors (TLR) initiating a cascade of signals in immune cells necessary for responses to pathogens. However, not all of the proteins that participate in TLR-mediated responses have been identified. In studies described herein, we observed significant variation in innate immune responses among selected wild-derived strains of mice. Specifically, we show that mice of MOLF/Ei, Czech/Ei, and MSM/Ms strains are hypo-responsive to polyinosinic-polycytidylic acid (poly(I:C)) because of a mutation in Tlr3. In addition, we discovered a hypo-response to cytosine guanine dinucleotide in MOLF/Ei mice and established that it is not linked to Tlr9, but to another locus. Further inquiry revealed that this hypo-response is transmitted as a monogenic dominant trait that can be mapped and cloned through positional cloning methods. These results suggest the existence of a novel molecule that can alter pro-inflammatory signals or activate additional signal transduction pathways. In addition, they support the wild-derived mouse strain as a forward genetic tool for the identification of novel immunological phenotypes.

Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS-induced lethality.

Despite significant progress in understanding the origin of soluble CD14 (sCD14), its physiological function remains largely unknown. Recent research has produced contradictory observations suggesting that sCD14 may have either beneficial or detrimental properties in protection against LPS-induced endotoxin shock. To resolve this controversy and to establish a mouse model suitable for elucidation of the functions of human CD14 (hCD14) in vivo, we generated several lines of transgenic mice bearing different copy numbers of the hCd14 transgene on a murine Cd14-/- background. The hCD14 was entirely capable of complementing loss of mouse CD14 to mediate cellular responses to LPS. Serum levels of sCD14 in a founder with multiple copies of the transgene were several times higher than in transgenic animals with a single copy of Cd14. Furthermore, mice with high levels of hCD14 were hypo-responsive to LPS and survived a lethal dose of LPS. Further inquiry into the mechanism of the hypo-response to LPS revealed that protection is associated with the higher amounts of circulating LPS. Most of this circulating LPS can be immunoprecipitated with anti-CD14 antibodies. These results suggest that sCD14 blocks circulating LPS by limiting the amount of monocyte-bound LPS and thus reduces inflammatory responses.