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Conveying the pathogenesis of type 1 diabetes to the blind, low‐vision and diverse needs communities through sensory stimulation
AbstractTo educate members of the blind, low‐vision and diverse needs communities on the pathogenesis of the chronic autoimmune disease, type 1 diabetes, members of our team with research expertise in immune‐mediated diseases, participated in the 2023 Monash Sensory Science (MSS) Exhibition. Using QR code linked audio commentary, participants were guided through tactile displays demonstrating normal insulin action in the regulation of blood glucose levels and its vital role in providing energy to tissues, followed by displays describing the various stages of the immune system's aberrant attack and the eventual complete destruction of the insulin producing beta‐cells of the pancreatic islets in type 1 diabetes. These models conveyed to the participants the huge effect that this autoimmune‐mediated disease has on the quality of life of affected individuals including the subsequent lifelong reliance on insulin injections to maintain glucose homeostasis. This MSS Exhibition provided a unique opportunity for our researchers to engage with under‐represented members of the community and to raise awareness about such a debilitating and common autoimmune disease.
Sulfated bile acid is a host-derived ligand for MAIT cells
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin–based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue–derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes ( Sult2a1-8 ) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.
CD4 + T cell–mediated HLA class II cross-restriction in HIV controllers
The structural basis of HIV-Gag recognition by class II–restricted T cell receptors in spontaneous controllers.
A molecular basis underpinning TRBV28+ T-cell receptor recognition of MR1–antigen
Mucosal-associated invariant T (MAIT) cells express a TRAV1-2+ T-cell receptor (TCR) that recognizes microbial vitamin B2 derivatives presented by the major histocompatibility complex class I–related molecule (MR1). Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilize other trbv genes, including TRBV28. A second conserved, albeit less frequent TRAV36+ TRBV28+ T-cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1–antigen (Ag) recognition compared with MAIT TCR–MR1 binding. Nevertheless, our understanding of how differing TCR gene usage results in altered MR1 binding modes remains incomplete. Here, binding studies demonstrated differential affinities and Ag specificities between TRBV6+ and TRBV28+ MR1-restricted TCRs. Alanine-scanning mutagenesis on the TRAV36–TRBV28 TCR revealed a strong dependence on germline-encoded residues within the highly selected complementarity-determining region 3α loop, similar to TRAV1-2–TRBV6 TCRs, and further alanine-scanning mutagenesis experiments demonstrate differential energetic footprints by these TCRs atop MR1. We determined the crystal structure of a MAIT TRAV1-2–TRBV28+ TCR–MR1–5-OP-RU ternary complex. This structure revealed a docking mode conserved amongst other TRAV1-2+ MAIT TCRs, with the trbv28-encoded TCR-β chain adopting highly distinct docking modes between the TRAV1-2+ and TRAV36+ TCRs. This indicates that the TCR-α chain dictates the positioning and role of the TCR-β chain. Taken together, these findings provide new molecular insights into MR1–Ag-driven selection of paired TCR-α and TCR-β chains.
Bridging science and accessibility: a tactile journey from gluten through to coeliac disease
AbstractAs part of the Monash Sensory Science Exhibition, our team guided participants through a multisensory journey unraveling coeliac disease development and pathology. Through tactile and sensory exhibits, we showed how benign dietary gluten can be transformed into a harmful entity for the 1 in 70 Australians with this illness. In contrast to the common misconception of coeliac disease as a food allergy, our exhibits revealed its closer association with autoimmune diseases such as type 1 diabetes, involving genetic susceptibility linked to specific human leukocyte antigens, crucial antigen‐specific T‐ and B‐cell responses and autoantibody production. Tactile models underscored the severe consequences of the proinflammatory immune response to gluten on patient health and quality of life. This educational event affirmed to us the value and importance of fostering inclusivity in science education.
Access all areas: multisensory science exhibitions tailored toward blind, low‐vision and diverse‐needs communities
AbstractMonash Sensory Science is a scientific outreach initiative specifically tailored to members of the community who are blind, have low vision and have diverse needs. The purpose of this initiative is to showcase Australian science and encourage greater participation in science from these often‐overlooked communities. This article presents our experience in establishing Monash Sensory Science at Monash University and inspiring other institutions to launch similar outreach events.
Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.
Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.
Holding space for spatial biology
Spatial biology is revolutionising our understanding of cellular organisation and disease by preserving the interactions between cells within tissues. Traditional methods often disrupted these delicate structures, making it challenging to study cells in their natural environments. This article explores key technologies, such as immunohistochemistry (IHC) and in situ hybridisation, which enable precise molecular analysis while maintaining spatial context. IHC remains essential for identifying protein markers in pathology, while multiplex imaging systems significantly enhance biomarker detection and high-throughput spatial profiling. Additionally, new computational tools like MuSpAn are advancing our understanding of spatial cell organisation. Despite challenges posed by data complexity, spatial biology opens exciting new possibilities for precision medicine, facilitating targeted therapies and advancing personalised treatment strategies. As the field rapidly evolves, it continues to drive groundbreaking breakthroughs in disease research and therapeutic development.
The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis.
BackgroundThe development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools.MethodsIn this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST.Results and conclusionThe use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.
Design of a novel electrospun PVA platform for gene therapy applications using the CHAT peptide.
The electrospinning of polymers has previously shown excellent potential for localised gene therapy. Thus, it was proposed that for the first time, the cell-penetrating CHAT peptide could be utilised to deliver DNA via electrospun nanofibres for localised gene therapy treatment. CHAT is an effective delivery system that encapsulates pDNA to form nanoparticles with the physicochemical characteristics for cellular uptake and protein generation. In this study, the production of smooth, bead-free PVA nanofibres by electrospinning was optimised through a Design of Experiments approach. Bead-free PVA nanofibres were consistently produced using the optimised parameters as follows: applied voltage (8 kV); collector-emitter distance (8 cm); polymer flow rate (4 µL/min); polymer concentration (9 wt% polymer); PVA MW (146-180 kDa). PVA nanofibres were subsequently crosslinked in 1 vol% glutaraldehyde in methanol to confer stability under aqueous conditions with minimal change to morphology, and no compromise to biocompatibility. Nanoparticles of CHAT/pDNA were synthesised and incorporated into the crosslinked nanofibres via soak-loading. Evaluation studies indicated that 100% of the loaded cargo was released within 48 h from the nanofibres. Furthermore, the released pDNA retained structural integrity and functionality as confirmed by gel electrophoresis and transfection studies in NCTC-929 fibroblast cells. Taken together, this data demonstrates that delivery of CHAT/pDNA nanoparticles from electrospun PVA nanofibres represents a solution for localised gene therapy.
Rational design and characterisation of a linear cell penetrating peptide for non-viral gene delivery.
The design of a non-viral gene delivery system that can release a functional nucleic acid at the intracellular destination site is an exciting but also challenging proposition. The ideal gene delivery vector must be non-toxic, non-immunogenic, overcome extra- and intra-cellular barriers, protect the nucleic acid cargo from degradation with stability over a range of temperatures. A new 15 amino acid linear peptide termed CHAT was designed in this study with the goal of delivering DNA with high efficiency into cells in vitro and tissues in vivo. Rational design involved incorporation of key amino acids including arginine for nucleic acid complexation and cellular uptake, tryptophan to enhance hydrophobic interaction with cell membranes, histidine to facilitate endosomal escape and cysteine for stability and controlled cargo release. Six linear peptides were synthesised with strategic sequences and amino acid substitutions. Data demonstrated that all six peptides complexed pDNA to produce cationic nanoparticles less than 200 nm in diameter, but not all peptides resulted in successful transfection; indicating the influence of peptide design for endosomal escape. Peptide 4, now termed CHAT, was non-cytotoxic, traversed the plasma membrane of breast and prostate cancer cell lines, and elicited reporter-gene expression following intra-tumoural and intravenous delivery in vivo. CHAT presents an exciting new peptide for the delivery of nucleic acid therapeutics.
Improving the Intercellular Uptake and Osteogenic Potency of Calcium Phosphate via Nanocomplexation with the RALA Peptide.
Calcium phosphate-base materials (e.g., alpha tri-calcium phosphate (α-TCP)) have been shown to promote osteogenic differentiation of stem/progenitor cells, enhance osteoblast osteogenic activity and mediate in vivo bone tissue formation. However, variable particle size and hydrophilicity of the calcium phosphate result in an extremely low bioavailability. Therefore, an effective delivery system is required that can encapsulate the calcium phosphate, improve cellular entry and, consequently, elicit a potent osteogenic response in osteoblasts. In this study, collagenous matrix deposition and extracellular matrix mineralization of osteoblast lineage cells were assessed to investigate osteogenesis following intracellular delivery of α-TCP nanoparticles. The nanoparticles were formed via condensation with a novel, cationic 30 mer amphipathic peptide (RALA). Nanoparticles prepared at a mass ratio of 5:1 demonstrated an average particle size of 43 nm with a zeta potential of +26 mV. The average particle size and zeta potential remained stable for up to 28 days at room temperature and across a range of temperatures (4-37 °C). Cell viability decreased 24 h post-transfection following RALA/α-TCP nanoparticle treatment; however, recovery ensued by Day 7. Immunocytochemistry staining for Type I collagen up to Day 21 post-transfection with RALA/α-TCP nanoparticles (NPs) in MG-63 cells exhibited a significant enhancement in collagen expression and deposition compared to an untreated control. Furthermore, in porcine mesenchymal stem cells (pMSCs), there was enhanced mineralization compared to α-TCP alone. Taken together these data demonstrate that internalization of RALA/α-TCP NPs elicits a potent osteogenic response in both MG-63 and pMSCs.