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Sclerotic GVHD and scleroderma share dysregulated gene expression that is ameliorated by EREG therapeutic antibody
Abstract Immune-driven fibrotic skin diseases, including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host disease (GVHD), cause skin stiffening that has a major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that epiregulin (EREG), a dendritic cell type 3–derived epidermal growth factor receptor (EGFR) ligand, is elevated in the skin and lungs of patients with SSc and required for the maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knockin mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma), and sclerotic GVHD (SclGVHD) with disease biomarkers. EREG expression in the skin was elevated in all 3 fibrotic diseases and is a driver of tenascin C (TNC) production by myofibroblasts. TNC is a proinflammatory extracellular glycoprotein that functions as an endogenous Toll-like receptor 4 (TLR4) ligand, which induces expression of TLR4 target genes CCL2 and interleukin-6. Examination of skin explants from patients with active SclGVHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients and type I collagen and FN1 in three-fourths of patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.
Gestational physical exercise prevents early-life behavioral impairments in the offspring of a rat model of attention deficit hyperactivity disorder
Beyond Arg39: new insights into antiphospholipid antibodies
Multi-scale spatial-temporal transformer for traffic flow prediction
Acalabrutinib to assail CLL in the frail
Awareness, usage, and perspectives on ChatGPT in dental education among graduate and undergraduate students
New approach targets key traffickers in the fibrosis network
Impacts of cold stress and temperature fluctuations on bud abortion and malformed flower development on Hayward kiwifruit
Matchmaking gene therapy with mimetic antibodies
JAK-1 inhibitors in the management of atopic dermatitis in patients over 65 years old: a descriptive cohort study
A genome-wide screen identifies <i>Runx2</i> as a novel regulator of hematopoietic stem cell expansion and T-cell commitment
Abstract Self-renewing multipotent hematopoietic stem cells (HSCs) are a rare but important cell population that can reconstitute the entire blood and immune system after transplantation. Due to their rarity, it has been difficult to comprehensively study the mechanisms regulating HSC activity. However, recent improvements in hematopoietic stem and progenitor cell (HSPC) culture methods using polyvinyl alcohol–based media now facilitate large-scale ex vivo HSC expansion. Here, we performed a genome-wide CRISPR knockout (KO) screen in primary mouse HSPCs to discover novel regulators of ex vivo expansion. The screen identified Runx2 as a strong negative regulator of HSC expansion, which we validated using ex vivo and in vivo assays. Loss of Runx2 increased the frequency of immunophenotypic HSCs in HSPC cultures by approximately threefold. After expansion, these Runx2-KO HSCs engrafted at approximately fivefold higher levels in transplantation assays. Noncultured Runx2-KO HSCs also displayed enhanced reconstitution potential, but loss of Runx2 did not alter blood parameters. Notably, however, T-cell reconstitution was diminished from Runx2-KO HSCs, and we further validated an additional role for Runx2 in T-cell commitment using ex vivo and in vivo assays. In summary, we have identified a multifaceted role for Runx2 in HSCs, as a negative regulator of HSC self-renewal and as a facilitator of T-cell commitment. These results contribute to our understanding of the transcriptional regulation of hematopoiesis and HSC therapies.
Immersive experience in virtual reality gamification teaching: analysis of the mediating effect on educational learning outcomes
Cognitive fitness and mental health outcomes following COVID-19 lockdowns in Australia
Abstract The uncertainty, stress and prolonged social isolation caused by pandemics significantly affect mental health. This paper presents two cross-sectional studies examining key psychological variables associated with mental well-being, distress, and anxiety following COVID-19 lockdowns in Australia, utilizing the Cognitive Fitness Framework (CF2). We also report the development and validation of the COVID-19 Character Growth Awareness (CGA) scale. In Study 1 (N = 417), impulsivity/lack of self-control, resilience/adaptability and COVID-19 CGA predicted 6% of variance in post-lockdown mental well-being beyond all other variables. From the same block of variables, only CGA predicted a significant amount of variance (3%) in mental well-being recovery. In Study 2 (N = 1898), intolerance of uncertainty correlated positively with psychological distress and anxiety, while CGA correlated negatively while controlling for other covariates. These results highlight the importance of psychological strengths and vulnerabilities in enabling adaptation and recovery following public health crises. The COVID-19 CGA emerged as one of those strengths. The results also help unify the theory of resilience as a trait, process, and outcome. Understanding what assists the maintenance and recovery of mental health amid the challenges and isolation of pandemics can help develop strategies to mitigate the impacts of future crises that present similar challenges.
Assessment of the biomechanical performance of digitally manufactured space maintainers: a finite element analysis
Identification of dysregulated gene clusters and pathways driving ocular surface squamous neoplasia progression
Structural optimization and performance analysis of the cable-driven fine adjustment mechanism for the new FAST feed cabin
Biohybrid microvascular interponates with integrated elastin-like recombinamers – validation of stability and biomimetic elasticity in human vessels
Abstract Autologous vein grafts remain the gold standard for microvascular interpositions in reconstructive maxillofacial surgery, despite their high failure rates and the additional operation site. Against this background, this ex vivo study investigates a novel biohybrid microvascular graft based on elastin-like recombinamers (ELRs). The biohybrid graft design consists of ELRs combined with the mechanical support of textile components. The compliance and pressure resistance of the developed grafts were evaluated and compared with human fresh cadaver vessels (radial artery). The ELRs biohybrid grafts were microsurgically anastomosed with human radial arteries, and were compared with human vein interposition grafts from the saphena vein. The ELRs grafts exhibited comparable and favorable compliance to real human vessels. The burst pressure values of 543 ± 71 mmHg of the ELRs grafts were above the physiological blood pressure load. The tensile strength of the interponated ELRs grafts were significantly higher at 4.2 ± 1.15 N ( p = 0.025) compared to interponated venous grafts with tensile strength of 3.20 ± 0.65 N. The ex vivo investigations of the novel ELRs biohybrid microvascular grafts revealed promising properties for the application as microvascular interposition graft in terms of compliance, pressure resistance, and tensile strength compared to the current gold standard.