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Failure of integrin-mediated cell-matrix attachment is sufficient to initiate dermal fibrosis and autoimmunity in mouse models of scleroderma; integrin-modulating therapies prevent the recruitment and activation of plasmacytoid dendritic cells that appear central to immunological dysregulation and maintenance of the pro-fibrotic synthetic programme. Scleroderma pathogenesis and treatment Stiff skin syndrome, a form of scleroderma characterized by fibrosis of the skin, is caused by mutations in the integrin binding region of fibrillin-1. Harry Dietz and colleagues have developed a genetically engineered mouse model of stiff skin syndrome and show that mouse lines that harbour analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis, and that this can be prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). This work demonstrates that it is possible to reverse established dermal fibrosis, and suggests several therapeutic strategies including β 1 integrin activation and blockade of signalling by β 2 integrin, TGF-β or ERK. In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies 1 . Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown 2 . The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene ( FBN1 ) encoding fibrillin-1, the main constituent of extracellular microfibrils 3 . SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell–matrix interactions by binding to cell-surface integrins 3 . Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell–matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.

Most social challenges fall outside of the authority of any single individual and therefore require collective action—coordinated efforts by many stakeholders to implement solutions. Despite growing interest in teaching students to lead collective action, we lack models for how to teach these skills. Collective action ostensibly involves design: the act of planning to change existing situations into preferred ones. In other domains, instructors commonly scaffold design using an instructional model known as studio critique in which students strengthen their plans by exchanging arguments with peers and instructors. This study explores whether studio critique can serve as the basis for an effective instructional model in collective action. Using design-based research methods, we designed and implemented scoping deliberations, a new instructional model that augments studio critique with domain-specific templates for planning collective action and repeats weekly to enable iterations. We used process tracing to analyze data from field notes, video, and artifacts to evaluate causal explanations for events observed in this case study. By implementing scoping deliberations in a 10-week undergraduate course, we found that this model appeared effective at scaffolding engagement in planning collective action: students articulated and refined their plans by engaging in argumentation and iteration, as expected. However, students struggled to contact the community stakeholders with whom they planned to work. As a result, their plans rested on implausible, untested assertions. These findings advance instructional science by showing that collective action may require new instructional models that help students to test their assertions against feedback from community stakeholders. Practically, scoping deliberations appear most useful for scaffolding thoughtful planning in conditions when students are already collaborating with stakeholders.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-bgr; signaling. In this paper, the authors generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. The analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, the suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

Design educators have long used studio-based learning environments to create communities of learners to support authentic learning in design. Online social media platforms have enabled the creation of distributed studio networks (DSNs) that link studio-based learning environments into expanded communities of practice and potential networked improvement communities. As learning scientists, we do not adequately understand how to infrastructure learning and resource sharing across distributed studios. In this ethnography of the infrastructure of Design for America, a DSN, we analyzed data from interviews, online communication, and field observations as the organization grew its network of university design studios. We found that Design for America managers faced challenges of providing support and resources to address wide variation in needs across studios. Lacking an existing comprehensive network collaboration platform, managers created a proto-infrastructure to distribute support across studios. By studying their iterative adoption of communication and collaboration tools and organizational routines, we define a unique set of design principles to infrastructure DSNs: (a) surfacing local progress and problems, (b) affective crowding, (c) solution mapping, and (d) help routing. Assembling constellations of tools and designing platforms based on these principles could support learning in and the improvement of DSNs across domains.

Authentic project-based learning (APBL) is a highly effective way for instructors to help students learn disciplinary skills, modes of thinking, and collaborative practices by creating solutions to real-world problems for real users and clients. While educational technology innovations can bolster APBL by making a promising but challenging pedagogy more effective, as with many areas of education instructor adoption is slow. Diffusion of innovations theory predicts that instructors will adopt and maintain their use of innovations if innovations are perceived to, and then do, address their challenges. To guide design of future APBL technologies, we interviewed 47 university APBL instructors about their most significant challenges and inductively analyzed the resulting interview transcripts. APBL instructors reported interrelated challenges of: (a) scoping, sourcing challenges and balancing the needs of the program, students, and clients; (b) curriculum preparation, making the curriculum flexible enough for shifting project problems and codify standards to help students understand how to do quality work; (c) providing assistance to teams, including monitoring, and delivering assistance; and (d) coordinating a range of stakeholders involved in assisting teams, including co-instructors, clients, and students. To support instructor adoption in APBL, educational technology innovators might communicate existing technology, or create technological innovations, that provide: (a) scoping tools for sourcing projects, and forming teams; (b) authoring tools for sharing and remixing of curricular materials; (c) project management tools for team management and monitoring; and (d) coordination software to manage all APBL stakeholders.

Several recent studies have found that managers engage in redundant communication; that is, they send the same message to the same recipient sequentially through two or more unique media. Given how busy most managers are, and how much information their subordinates receive on a daily basis, this practice seems, initially, quite puzzling. We conducted an ethnographic investigation to examine the nature of events that compelled managers to engage in redundant communication. Our study of the communication patterns of project managers in six companies across three industries indicates that redundant communication is a response to unexpected endogenous or exogenous threats to meeting work goals. Managers used two distinct forms of redundant communication to mobilize team members toward mitigating potentially threatening discrepant events—unforeseen disruptive occurrences during the regular course of work. Managers with positional power over team members reactively followed up on a single communication when their attempt to communicate the existence of a threatening discrepant event failed, and they determined that a second communication was needed to enable its joint interpretation and to gain buy-in. In contrast, managers without positional power over team members proactively used redundant communication to enroll team members in the interpretation process—leading team members to believe that they had come up with the idea that completion of their project was under threat—and then to solidify those interpretations. Moreover, findings indicate that managers used different types of technologies for these sequential pairings based on whether their motivation was simply to transmit a communication of threat or to persuade people that a threat existed. We discuss the implications of these findings for theory about, and the practice of, technologically mediated communication, power, and interpretation in organizations.

We may be able to educate social designers who can design for human needs through social innovation networks (SINs). SINs engage in three interrelated activities of: supporting design teams' project-based learning, supporting the leadership in studio-based learning communities, and continuous network improvement. SINs face challenges in diffusing social design that might be overcome through networked coaching platforms that support teams' socially-regulated learning and leaders' studio orchestration. SINs offer way to spread design education across disciplines in any organization where design teams need to both innovate and learn.

Intelligent tutors based on expert systems often struggle to provide formative feedback on complex, ill-defined problems where answers are unknown. Hybrid crowdsourcing systems that combine the intelligence of multiple novices in face-to-face settings might provide an alternate approach for providing intelligent formative feedback. The purpose of this study was to develop empirically grounded design principles for crowdcritique systems that provide intelligent formative feedback on complex, ill-defined problems. In this design research project, we iteratively developed and tested a crowdcritique system through 3 studies of 43 novice problem solvers in 3 formal and informal learning environments. We collected observations, interviews, and surveys and used a grounded theory approach to develop and test socio-technical design principles for crowdcritique systems. The project found that to provide formative feedback on ill-defined problems, crowdcritique systems should provide a combination of technical features including: quick invite tools; formative framing; a public, near-synchronous social media interface; critique scaffolds; “like” system; community hashtags; analysis tools and “to do” lists; along with social practices including: prep/write-first/write-last script and critique training. Such a system creates a dual-channel conversation that increases the volume of quality critique by grounding comments, scaffolding and recording critique, and reducing production blocking. Such a design provides the benefits of both face-to-face critique and computer-support in both formal and informal learning environments while reducing the orchestration burden on instructors.

Learning communities (LCs) can provide authentic, social learning experiences but require an extensive amount of time and effort to orchestrate, often more than instructors can provide in typical university courses. Extracurricular, undergraduate, student-led learning communities (SLLCs) overcome this cost through volunteer peer-instructors. Unfortunately, LCs theory is based exclusively on teacher-led LCs. Here we ask what instructional processes emerge in SLLCs? We conducted a qualitative case study of SLLC student leaders' attempts to teach a project management practice (StandUp) to student innovation teams. We found that instruction in SLLCs takes the form of a bidirectional diffusion process, in which peer-instructors influence students' decisions about what practices to participate in, and students influence peer-instructors' decisions about advocating for practices. Three major findings support the bi-directional diffusion model. First, students' participation in StandUp hinged on whether they saw the practice as valuable with respect to their social, learning, and/or performance goals. Second, peer-instructors struggled to persuade and scaffold students to participate in StandUp. Third, students influenced peer-instructors to stop advocating for StandUp. The bi-directional diffusion model highlights the practical importance of persuading students to participate in the community's practices. The model suggests that we might support peer-instruction by promoting peer-instructors' content knowledge about practices, their persuasion skills, and their motivation to advocate for practices.