Improving science literacy is crucial amidst global challenges like climate change, emerging diseases, AI, and rampant disinformation. This is vital not only for future STEM generations but for all, ...to make informed decisions. Informal science communication efforts such as podcasts, popular science articles, and museum events are an essential part of the infrastructure for mobilizing knowledge and nurturing science literacy. However, in this Perspective , we emphasize the need to grow our capacity for STEM outreach in the formal K-12 classroom. While the majority of informal outreach mechanisms require audience members to seek out content, classrooms include those hard-to-reach target audiences that are not already STEM-engaged. We contrast the multitude of resources that have been developed to support informal outreach in recent decades with a relative paucity of such efforts in the K-12 formal classroom realm. We advocate for a more balanced deployment of resources and efforts between these two vital components of our knowledge mobilization and STEM engagement infrastructure. In particular, we highlight the key role of K-12 teachers as conduits for knowledge dissemination and the need for greater collaboration between scientists and teachers at individual and organizational levels. We also advocate for greater collaboration across programs in both the informal and formal outreach space, and dedicated effort to construct dissemination networks to share outreach materials at scale across disparate programs. The aim of our piece is to generate discussion about how we might refocus goals, funding mechanisms, and policies to grow the science-engaged society necessary to confront future challenges.
How should funding agencies enable researchers to explore high-risk but potentially high-reward science? One model that appears to work is the NSF-funded synthesis center, an incubator for ...community-led, innovative science.
Mutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome ...reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.
Defective Fas-mediated apoptosis in mice, caused by thegldmutation in thefas ligandgene, results in the development of lupus-like autoantibodies and severe lymphoproliferation. We previously ...demonstrated ectopic expression of the costimulatory molecule B7-1 (CD80) on T lymphocytes in B6/gldmice. This report extends these observations by demonstrating similar results in B6/lprmice, which possess a mutation in the gene encoding Fas. Additionally, we demonstrate that this phenomenon is age-dependent and occurs on multiple subsets of B6/gldT lymphocytes. B7-1 upregulation is observed on T cells from both conventionally housed and specific-pathogen-free B6/gldmice, suggesting that this is not a consequence of infection by pathogen. T cells fromlprandgldmice show increased binding of CTLA4-Ig fusion protein, suggesting that the upregulated B7-1 is functional. CD28, a receptor for B7-1 which activates T cells, is upregulated in B6/lprand B6/gldmice, while CTLA4, a negative regulator of T cells which binds B7-1, is not. Our results suggest that ectopic expression of B7-1 on T cells oflprandgldmice may be playing a role in exacerbation of lymphoproliferation and/or autoimmunity.
Defective Fas-mediated apoptosis in mice, caused by the gld mutation in the fas ligand gene, results in the development of lupus-like autoantibodies and severe lymphoproliferation. We previously ...demonstrated ectopic expression of the costimulatory molecule B7-1 (CD80) on T lymphocytes in B6/gld mice. This report extends these observations by demonstrating similar results in B6/lpr mice, which possess a mutation in the gene encoding Fas. Additionally, we demonstrate that this phenomenon is age-dependent and occurs on multiple subsets of B6/gld T lymphocytes. B7-1 upregulation is observed on T cells from both conventionally housed and specific-pathogen-free B6/gld mice, suggesting that this is not a consequence of infection by pathogen. T cells from lpr and gld mice show increased binding of CTLA4-Ig fusion protein, suggesting that the upregulated B7-1 is functional. CD28, a receptor for B7-1 which activates T cells, is upregulated in B6/lpr and B6/gld mice, while CTLA4, a negative regulator of T cells which binds B7-1, is not. Our results suggest that ectopic expression of B7-1 on T cells of lpr and gld mice may be playing a role in exacerbation of lymphoproliferation and/or autoimmunity.
C57BL/6-gld/gld (B6/gld) mice have a point mutation in the gene for Fas ligand (FasL) resulting in nonfunctional FasL protein. We hypothesized that the lack of normal Fas/FasL interactions in these ...mice might result in abnormalities of Fas expression. Thus, we compared spleen cells from B6/gld mice and normal B6 control mice. While B6 spleen cells consisted of two main populations, Fashigh (high Fas expression) and Faslow (low Fas expression), nearly all B6/gld spleen cells were Fashigh. Two-color immunofluorescence revealed that the Fashigh and Faslow populations in the B6 spleen were Thy-1.2+ (T cells) and IgM+ (B cells), respectively, whereas both T cells and B cells in the B6/gld spleen were Fashigh, indicating that Fas expression is increased on B cells in the B6/gld spleen. This phenomenon was age related and restricted to peripheral lymphocytes. In addition to Fas, B6/gld splenic B cells showed increased expression of the costimulatory molecule B7-2, while the related costimulatory molecule B7-1 was up-regulated on both B cells and T cells in the B6/gld spleen. In vitro, both B cells and T cells from the B6/gld spleen showed an increase in susceptibility to apoptosis mediated by soluble anti-Fas Ab. These results suggest that some lymphocytes in B6/gld mice are primed to undergo Fas-mediated apoptosis, but are unable to do so due to the absence of functional FasL. Further study of such abnormal lymphocytes in the B6/gld spleen may elucidate the nature of autoimmunity in these mice.
Thelprmutation in mice results in premature termination of transcription of the gene encoding the apoptosis-signaling receptor Fas. As a result,lprmice develop severe lymphoproliferation and ...lupus-like autoantibodies. Growing evidence suggests that thelprmutation is “leaky” and that low levels of Fas are expressed inlprmice. To determine if Fas expressed inlprmice is contributing to apoptosis we generated a novel strain of mice (B6/lprgld) which is homozygous for both thelprmutation and thegldmutation which encodes nonfunctional Fas ligand (FasL) protein. If low levels of Fas in B6/lprmice contribute to apoptosis and lessen the severity of disease, the B6/lprgldmice, which also lack functional FasL, would be expected to develop a more severe form of disease than B6/lprmice. Our results revealed no significant increase in either lymphoproliferation or autoimmunity in B6/lprgldmice compared to B6/lpror B6/gldmice. Additionally, no increase in surface expression of Fas was detected by flow cytometry on B6/lprgldlymphocytes compared to B6/lprlymphocytes. However, histological examination of B6/lprgldliver revealed a marked increase in lymphocytic infiltration, compared to livers of B6/lprand B6/gldmice. Our results suggest that, while low levels of Fas inlprmice may not be contributing to amelioration of lymphoproliferation or autoimmunity, they may be partially protecting the liver from abnormalities which arise in the absence of Fas-mediated apoptosis.
Interaction of the Fas receptor with Fas-ligand (Fas-L) results in apoptosis of the Fas-bearing cell. Mice with the Ipr mutation (a retrotransposon insertion in the fas gene) or the gld mutation (a ...point mutation in the fas ligand gene) develop severe lymphoproliferation and lupus-like autoantibodies due to defective lymphocyte apoptosis. The Ipr mutation is leaky and low levels of functional Fas are expressed in Ipr mice. To determine if this results in partial amelioration of disease, we generated a novel mouse strain, designated B6/Iprgld, which is homozygous for both the Ipr and gld mutations. Examination of B6/Iprgld mice revealed no significant increases in lymphoproliferation or autoimmunity as compared to the single-mutant parental strains (B6/Ipr and B6/gld). However, histological examination revealed significant increases in lymphocytic infiltration in B6/Iprgld livers. These results suggest that while low levels of Fas expressed in Ipr mice don't contribute to amelioration of lymphoproliferation or autoimmunity, they partially protect the liver from abnormalities which arise in the absence of Fas-mediated apoptosis. Defective apoptosis in Ipr and gld lymphocytes results in multiple phenotypic abnormalities, including constitutive expression of Fas-L, which is typically expressed primarily on mature, activated T lymphocytes. We examined gld lymphocytes for a similar upregulation of Fas and observed marked increases. Increased Fas expression in gld mice was age-dependent and restricted to peripheral B cells, however both B cells and T cells from gld mice were significantly more susceptible to in vitro anti-Fas-mediated apoptosis. These results suggest that some lymphocytes in gld mice are primed to undergo apoptosis, but are unable to do so due to a lack of functional Fas-L. We also observed upregulation of the costimulatory molecules B7-1 and B7-2 on Ipr and gld B cells. Surprisingly, B7-1 typically expressed only on activated APC's, was markedly increased on Ipr and gld T cells. Ectopic T cell expression of B7-1 was age-dependent and occurred on multiple T cell subsets in both conventionally-housed and SPF mice. The B7 receptor CD28 was also upregulated on Ipr and gld T cells, suggesting that hyperexpression of costimulatory molecules in Ipr and gld mice may contribute to lymphoproliferation and/or autoimmunity.
A method of coculturing adult rat hepatic parenchymal cells (PC) and stromal cells in a three-dimensional framework of nylon filtration screens or biodegradable polymer meshes was developed in our ...laboratory. Rat liver stroma, which includes vascular and bile duct endothelial cells, fat-storing cells, fibroblasts, and Kupffer cells, were isolated by gradient centrifugation after in situ liver perfusion and expanded in monolayer culture prior to seeding onto nylon screens or bioresorbable polyglycolic acid (PGA) polymers oriented into a felt-like construct. A second inoculum of freshly isolated PC was applied after the stromal cells became established. Histological analyses revealed that PC proliferation occurred until all available space for expansion within the template was exhausted. These cells retained their rounded morphology, and after 4-5 wk 7-9 "layers" of PC filled the 140-microns deep template. Dioxin-inducible cytochrome P450 activity was detected for up to 58 d in culture, and albumin, fibrinogen, transferrin, and soluble fibronectin were detected in the medium by enzyme-linked immunosorbent assay (ELISA) for 48 d in vitro. Immunohistochemical analysis of sections through the cultures confirmed the presence of these proteins as well as cytokeratin at the cellular level; the extracellular matrix stained for both collagen type III and laminin. Long-term PC proliferation and function were enhanced by the presence of stromal cells as well as by a meshwork template whose geometry allows the interaction of PC with stroma and matrix on several different planes. To permit transplantation, cocultures of hepatic PC and stromal cells were established on PGA felt constructs instead of nylon screens. After approximately 24 d in vitro, these constructs were grafted into sites in the mesentery, omentum, and subcutaneous tissues of adult Long-Evans rats. The growth of hepatocytes after 30 d in situ was evident by histological analysis; grafts of cocultures regenerated a liver-like architecture consisting of sinusoids and putative biliary structures. In addition, PC at these extrahepatic graft sites were positive for albumin, transferrin, and fibrinogen synthesis by immunohistochemistry. Graft survival was enhanced when recipients were subjected to approximately 40% hepatectomy. Hepatic PC:stromal cell cocultures may prove useful in the restoration of liver function either by direct transplantation using PGA or similar templates, or as extracorporeal devices, using nylon screens.
Department of Molecular Biology, 10666 North Torrey Pines Road, Research Institute Scripps Clinic, La Jolla, California 92037, U.S.A.
A peptide from the carboxyl-terminal region of the Mengo virus ...capsid protein VP1, representing residues 259 to 277, can induce serum neutralizing (SN) antibodies in both the mouse and guinea-pig. This peptide, termed F164, also induces high levels of protective neutralizing antibodies in mice subsequent to immunization; 87 to 100% of mice are refractory to the effects of an intraperitoneal challenge of 100 LD 50 of Mengo virus. The mouse model discussed herein will prove useful for studying the immune response to Mengo virus and evaluating the immunogenicity of individual viral components.
Present address: Institut Pasteur, UPMTG/Biotechnologies, 25 rue du Dr Roux, 75015 Paris, France.
Received 26 July 1990;
accepted 25 January 1991.
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