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Loss of NF1 plays a major role as an oncogenic driver in many cancer types and can be found in up to 33% of all breast cancers (BC). Loss of NF1 is also a prognostic indicator for increased cancer risk at an earlier age, poorer outcomes, and therapeutic resistance. In addition, certain NF1 genotypes may increase cancer risks, while others do not. NF1 is largely perceived as a classic Ras-opathy syndrome due to inactivating mutations in neurofibromin affecting RAS-MAPK signaling. However, recently it has been shown that NF1 binds estrogen receptor alpha (ER) and acts as a transcriptional corepressor. This helps explain some BC findings specifically in ER+ BC. In this model, specific changes to NF1 that abrogate ER signaling lead to Ras driven tumor resistance to endocrine therapy as cells are able to grow in low levels of E2 (and tamoxifen). Hence, NF1-mutant tumors represent a distinct molecular class in need of new therapeutics. A preclinical mammalian model of NF1 loss and BC would be helpful in both evaluating the role of NF1/ER transcriptional signaling in BC, evaluating the role of immune cells in BC, and testing therapeutics. Novel Nf1 rat models have a very robust ER+ BC phenotype, therefore more closely recapitulating clinical tumors compared to other preclinical models. Our models include a pathogenic patient missense allele c.3827G>A, p.R1276Q (knockin or KI), associated in humans with familial spinal NF1 and malignancy, as well as a 14 base pair deletion c.3661_3674del, p.P1220fs*1223 (knockout or KO) model. Heterozygous (het) Nf1 females develop mammary gland adenocarcinoma spontaneously, but het KO rats develop multiple tumors with earlier onset while het KI rats tend to develop fewer tumors with later onset. Tumors are generally Grade 2 and do not differ by genotype. By 16 weeks, 70% of KO females have developed at least one tumor whereas only 20% of KI rats and 2% of WT rats have developed tumors. This impacts survival as by 1 year 76% of KI females survive yet only 58% of KO females survive. However, by 2 years, both alleles have 54% survival. The divergence in phenotype between patient and null alleles may be due to residual function of R1276Q missense NF1 protein. A more in-depth analysis indicates that mammary tumor formation likely begins relatively early, as we find evidence of aberrant morphology and hyperplasia prior to the formation of palpable tumors. Interestingly, we find histological evidence of lung metastases and expression of breast markers GCDFP15, MGA, and CEA in the lung. Again, we see allele-specific effects in that KO rats develop lung tumors earlier than KI rats. While het male rats also develop mammary tumors at low rates, they experience longer survival times (76% of KO males survive 1 year and 98% of KI males survive 1 year) and males also develop tumors in other locations. Using single nuclei RNASeq to characterize the transcriptional profile of the mammary tumors, we find allele-specific effects beyond repression of Ras activity that drive aggressive tumor development. We identified different tumor cell populations (2 epithelial cell populations, Myeloid cells, B cells, T cells, Basal mammary cells, and WT specific cells) and identified different pathways altered due to the loss of Nf1 including Ephrin B signaling, Cyclin and Cell Cycle signaling, and Glycolysis signaling. Our overall goal is to characterize the phenotype of these rat models in terms of histopathology, Ras signaling, hormone signaling, immune components, and targeted drug response and compare/contrast them with what is known regarding patients with somatic or germline inactivation of NF1 and breast cancer. Ultimately, this will provide better prognostic predictions for patients and better therapeutic options for treatment. Citation Format: Deeann Wallis, Christian Fay, Kelley Bradley, Erik Westin, William Bradley, Hui Liu, Laura Lambert, David Crossman, Jeremy Foote, Robert Kesterson. Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-01.

Early life stress (ELS) is an environmental trigger linked to increased risk of inflammatory bowel disease (IBD). Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to, and/or severity of, intestinal inflammation. We hypothesized that ELS alters the delicate balance of typical homeostatic mediators in the intestinal microenvironment, predisposing ELS-exposed individuals to IBD onset or worsened disease upon a pro-inflammatory triggering event within the gut. We utilized 2 published animal models of ELS. In the first model, newborn mice were separated from the dam daily for 4-8 hours beginning on postnatal day 2, then weaned early on postnatal day 17. Normally reared (NR) control mice were left undisturbed with the dams until standard weaning on postnatal day 21. In the second model, dams were fed the synthetic glucocorticoid – dexamethasone, or vehicle ad libitum in drinking water (3 μg/mL) on post-partum days 1-14. Colitis was induced in 4-week-old mice via intraperitoneal injection of IL-10 receptor blocking antibody (100 μg) every 5 days for 15 days. Five or 15 days later, histological colitis scores and colonic transcripts for Tnf, glucocorticoid receptors, and steroidogenic enzymes were measured. ELS-exposed mice displayed altered mucosa-associated immune cell balances, with an initial deficit in anti-inflammatory IL-10-producing CD4 T cells at 4-wks of age (n≥11, p Crohn's and Colitis Foundation Research Initiatives Award This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Recent research shows that “algorithmic radicalization” and “echo chambers”—the idea that recommendation algorithms on social media have a strong independent effect on radicalization and silo people into ideologically homogeneous communities—are not as prevalent nor influential as once feared. Yet, online political discourse is as toxic as ever while political misinformation continues to plague social media platforms. This begs the question: If algorithms aren’t encouraging radicalization, then what is producing it? Drawing from church-sect theory, this study interviews politically active Reddit users to better understand _how_ they arrived at their current media use, online engagement, and political beliefs. Results show that participants have a deep mistrust of mainstream media, leading them to seek alternative sources of political content. Reddit participation is also driven by a desire for “earnest” political discussions with like-minded individuals and cross-partisans, in part to “reject” partisan polarization. Despite engaging on more extreme subreddits, participants said their beliefs were unchanged, but that other Redditors had moved to more extreme beliefs over time. And, participants perceived their Reddit participation as necessary to _prevent_ radicalization and partisan polarization. Collectively, these results provide preliminary insight into the media and social/psychological pathways that could lead to online radicalization, providing an alternative explanation to algorithmic radicalization. This study also underscores the importance of interrogating the ecological pathways to radicalization for researchers and policy-makers; future interventions should account for attribution bias and the individual-level factors related to radicalization.

Many benefits of online communities---such as obtaining new information, opportunities, and social connections---increase with size. Thus, a "successful'' online community often evokes an image of hundreds of thousands of users, and practitioners and researchers alike have sought to devise methods to achieve growth and thereby, success. On the other hand, small online communities exist in droves and many persist in their smallness over time. Turning to the highly popular discussion website Reddit, which is made up of hundreds of thousands of communities, we conducted a qualitative interview study examining how and why people participate in these persistently small communities, in order to understand why these communities exist when popular approaches would assume them to be failures. Drawing from twenty interviews, this paper makes several contributions: we describe how small communities provide unique informational and interactional spaces for participants, who are drawn by the hyperspecific aspects of the community; we find that small communities do not promote strong dyadic interpersonal relationships but rather promote group-based identity; and we highlight how participation in small communities is part of a broader, ongoing strategy to curate participants' online experience. We argue that online communities can be seen as nested niches: parts of an embedded, complex, symbiotic socio-informational ecosystem. We suggest ways that social computing research could benefit from more deliberate considerations of interdependence between diverse scales of online community sizes.

We investigated the feasibility of utilizing an exon-skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which

We investigated the feasibility of utilizing an exon skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin function. Human neurofibromin is well-known as a GTPase activating protein (GAP), but outside of its GAP-related domain (GRD), it is unclear how critical other regions are for function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function. Utilizing a novel Nf1 cDNA system, we performed a functional screen to determine the effects of exon skipping on in vitro neurofibromin expression and GRD function. Loss of single exons 12, 17, 25, 41, 47, or 52 maintained significant GRD function in at least two Ras activity assays. Exons 18/19, 20 and 28 are critical for GRD function; deletion of exons 20, 41, or 47 led to significantly lower levels of neurofibromin. As suggested by in silico analysis, skipping of exons 17 or 52 resulted in both the highest neurofibromin levels and the greatest suppression of Ras activity. Assessment of NF1 patient databases indicates that pathogenic variants resulting in deletion or skipping of exons 17, 25, and 52 have not been reported; and truncating pathogenic variants in each exon account for ~0.91, 0.94, and 0.25% of unrelated NF1 cases, respectively. Hence, we designed antisense phosphodiamitate morpholino oligos (PMOs) to skip exon 17 and evaluated them in human cell lines that we generated via CRISPR/Cas9 with a patient-specific truncating pathogenic variant, c.1885G>A. We down-selected oligos that efficiently caused skipping of exon 17 and restored NF1 expression and function. Further, homozygous deletion of exon 17 in a novel mouse model is compatible with viable and grossly healthy animals with normal lifespan and no tumor development, providing proof-of-concept that exon 17 is not essential for murine neurofibromin function. Mild phenotypes observed include abnormal nesting behavior and lymphoid hyperplasia with increased numbers of both B- and T-cells. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with treatment of individuals with pathogenic variants in exon 17.

Introduction: Infiltrating pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of 10%. The PDAC tumor microenvironment (TME) is characterized by a fibroinflammatory response mediated by a complex mix of cancer-associated fibroblast (CAF) subsets resulting significant deposition of extracellular matrix (ECM), poor vascularization, T cell exclusion, and recruitment of immune-suppressive myeloid cells. Collectively, these factors contribute to a resistance to aggressive chemotherapeutics and failure of checkpoint inhibitors. Preclinical studies as well as clinical efforts designed to deplete the dense tumor stroma or ECM have been successful, but unexpectedly accelerated tumor progression underscoring critical gaps in our understanding of the dynamics between tumor, stromal elements, and infiltrating immune cell subsets. Rationale: In some cancer subtypes, B cells have been shown to suppress cancer progression through secretion of antibodies targeted to aberrantly expressed self-, stress-associated-, or tumor-specific antigens on neoplastic cells. A considerable body of literature also indicates that B cells may play a role in promotion of pancreatic tumor progression, however, the role of antibodies in PDAC progression is unclear. The major objective of our studies is to understand the significance of anti-tumor antibody responses in pancreatic tumorigenesis. Methods: To address this question, we crossed the spontaneous mouse model of pancreatic cancer where Pdx1 drives Cre-mediated activation of a mutant KrasG12D allele on a heterozygous Tp53+/FL mutant background (KPC-WT mice) with animals that retain B cells that lack the ability to secrete antibody of any immunoglobulin (Ig) isotype (KPC-μS-AID mice). Results: Kaplan-Meier survival studies demonstrate that loss of all circulating antibody accelerates progression to lethal PDAC in KPC-μS-AID versus KPC-WT mice (median survival of 3- versus 5-months, respectively), with increased incidence of lung and liver metastases. Further, loss of circulating antibodies increased the density of intratumoral neutrophils, reduced numbers of podoplanin+ CAFs and reduced ECM density. IgG subclass antibodies were localized at higher densities within stroma/ECM in pancreata from both mice and surgically resected tumor specimens from human PDAC patients. Loss of AID-dependent class switched antibodies similarly accelerated lethal PDAC in KPC-AID versus KPC-WT mice. Conclusions: These findings implicate class-switched antibodies in delaying pancreatic tumor progression through potential regulation of intratumoral neutrophil density and ECM production within the PDAC TME. Citation Format: Jeremy Foote. Evaluating the role of antibody in pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1342.

Adolescents' social cognitive understanding of their social world is often inaccurate and biased. Focusing on peer groups, this study examines how adolescents' psychological, behavioral, and relational characteristics influence the extent to which they accurately identify their own and others' peer groups. Analyses were conducted with a sample of 1481 seventh- and tenth-grade Chinese students who are embedded with 346 peer groups. Overall, females and older students had more accurate perceptions. In addition, lower self-esteem, higher indegree centrality, and lower betweenness centrality in the friendship network predicted more accurate perception of one's own groups, whereas higher academic performance and lower betweenness centrality in the friendship network predicted more accurate perception of others' groups. Implications for understanding the connection between adolescents' psychological and behavioral traits, social relationships, and social cognition are discussed.

Kate Chopin's “The Story of an Hour” has been taught and analyzed almost exclusively from a feminist perspective. As Lawrence Berkove writes, “There has been …virtual critical agreement on what the...

The sparse nature of Wikipedia’s main content interface, dominated by clearly laid out content, neatly organized into information boxes, and structured into headings and subheadings projects an image of a simple and flexible content management system. Even though the process of social production that undergirds Wikipedia is rife with conflict, power struggles, revert wars, content transactions, and coordination efforts, not to mention vandalism, the article pages on Wikipedia shun information gauges that highlight the social nature of the contributions. Rather, they are characterized by a “less is more” ideology of design, which aims to maximize readability and to encourage future contributions. The tools for discerning the social dynamics that lead to the creation of any given page are buried deep into the structure of the interface. Often they are created and maintained by voluntary contributors, who host the information on their own servers. The reason for which the design choices made for the Wikipedia interface hide rather than highlight the true nature of these social dynamics remains a continuous motive for puzzlement.

To this point, no collaborative research environment has been remotely effective at allowing scholars interested in researching trust, authority, authorship, and roles on social media knowledge markets to seamlessly transition between engaging other researchers, uploading and analyzing data, and reporting findings for the world to observe. Theories that continue, rather than ignore, social and mass media theory, are yet to be developed. In our increasingly global society, with its growing emphasis on collaborative work, this is a critical gap in the research process. This chapter proposes a carefully designed approach and framework that would more actively listen to the needs of the research community in order to offer the perspective, resources, and tools that would best allow them to address the most important research problems of today and of tomorrow in the fields of authorship, roles, and credibility. Based upon present and future research needs expressed by a panel of leading researchers attending the KredibleNet workshop at Purdue University in April 2014, the authors propose the development of a new approach that problematizes the lack of theoretical coherence of current work, that advocates for strong multidisciplinary collaboration, for funding of nonintuitive research agendas and for the development of collaborative platforms that would support scholars at all stages of the scholarly process.

The paper examines the role played by the most productive members of social media systems on leading the project and influencing the degree of project structuration. The paper focuses on findings of a large computational social science project that examines Wikipedia. 1