Structural changes in troponin during activation of skeletal and heart muscle determined in situ by polarised fluorescence.

Calcium binding to troponin triggers the contraction of skeletal and heart muscle through structural changes in the thin filaments that allow myosin motors from the thick filaments to bind to actin and drive filament sliding. Here, we review studies in which those changes were determined in demembranated fibres of skeletal and heart muscle using fluorescence for in situ structure (FISS), which determines domain orientations using polarised fluorescence from bifunctional rhodamine attached to cysteine pairs in the target domain. We describe the changes in the orientations of the N-terminal lobe of troponin C (TnC) and the troponin IT arm in skeletal and cardiac muscle cells associated with contraction and compare the orientations with those determined in isolated cardiac thin filaments by cryo-electron microscopy.

The birth of the virtual clinic: welcome to the Mediverse.

The COVID-19 pandemic triggered a global pivot to virtual care (VC) technologies. While there has been considerable academic work exploring the "how" of VC, few studies have explored the impact of this pivot, its unintended consequences, and its governing rationales. This study addresses this gap in relation to care, professional identity and the evolving requirements for health professions education.

Preclinical model for evaluating human TCRs against chimeric syngeneic tumors.

Background: The adoptive cell transfer (ACT) of T cell receptor (TCR)-engineered T cells targeting the HLA-A2-restricted epitope NY-ESO-1 (A2/NY) has yielded important clinical responses against several cancers. A variety of approaches are being taken to augment tumor control by ACT including TCR affinity-optimization and T-cell coengineering strategies to address the suppressive tumor microenvironment (TME). Most TCRs of clinical interest are evaluated in immunocompromised mice to enable human T-cell engraftment and do not recapitulate the dynamic interplay that occurs with endogenous immunity in a treated patient.

CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation.

International consensus guidelines on the implementation and monitoring of vosoritide therapy in individuals with achondroplasia.

Achondroplasia is the most common genetic form of short-limbed skeletal dysplasia (dwarfism). Clinical manifestations and complications can affect individuals across the lifespan, including the need for adaptations for activities of daily living, which can affect quality of life. Current international guidelines focus on symptomatic management, with little discussion regarding potential medication, as therapeutic options were limited at the time of their publication.

Dental care and services of children and young people with cerebral palsy in Australia: A comprehensive survey of oral health-related quality of life.

Aims: To investigate caregiver-reported dental care experiences and oral health-related quality of life (OHRQoL) of children and young people with cerebral palsy (CP).

Methods: Between May and August 2023, caregivers of children and young people from three Australian states were invited to complete questionnaires, including the Child Oral Health Impact Profile (COHIP-SF 19).

Results: Sixty-eight caregivers participated in the survey.

Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study.

Background: Vosoritide is a C-type natriuretic peptide analog that addresses an underlying pathway causing reduced bone growth in achondroplasia. Understanding the vosoritide treatment effect requires evaluation over an extended duration and comparison with outcomes in untreated children.

Methods: After completing ≥6 months of a baseline observational growth study and 52 weeks in a double-blind, placebo-controlled study (ClinicalTrials.

Load-dependence of the activation of myosin filaments in heart muscle.

Contraction of heart muscle requires activation of both the actin and myosin filaments. The mechanism of myosin filament activation is unknown, but the leading candidate hypothesis is direct mechano-sensing by the filaments. Here, we tested this hypothesis by activating intact trabeculae from rat heart by electrical stimulation under different loads and measuring myosin filament activation by X-ray diffraction.

Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs.

The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor-antigen binding from T cell activation (i.e.

SmilesUp text message intervention for early childhood dental caries prevention: A protocol for a randomised controlled trial.

Introduction: Despite improvements in health outcomes for children, early childhood dental caries (ECC) remains a chronic lifestyle-mediated disease that affects an estimated 600 million children worldwide. Parental influence on oral health-promoting behaviours is pivotal in preventing ECC. The latest WHO publications Ending Early Childhood Dental Caries and Mobile Technologies for Oral Health highlights the opportunity for mobile Health programs (including text message programs) to improve oral health behaviours and oral health self-efficacy.

Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.

CD8 + T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8 + T cells expressing low-affinity TCR. We further find decreased mTORC1 signaling activity and c-Myc levels at low pH.

Validation of the C-X-C chemokine receptor 3 (CXCR3) as a target for PET imaging of T cell activation.

Purpose: CXCR3 is expressed on activated T cells and plays a crucial role in T-cell recruitment to the tumor microenvironment (TME) during cell-based and immune checkpoint inhibitor (ICI) immunotherapy. This study utilized a Cu-labeled NOTA-α-CXCR3 antibody to assess CXCR3 expression in the TME and validate it as a potential T cell activation biomarker in vivo.

Procedures: CXCR3 cells infiltrating MC38 tumors (B57BL/6 mice, untreated and treated with αPD-1/αCTLA-4 ICI) were quantified using fluorescence microscopy and flow cytometry.

Functional control of myosin motors in the cardiac cycle.

Contraction of the heart is driven by cyclical interactions between myosin and actin filaments powered by ATP hydrolysis. The modular structure of heart muscle and the organ-level synchrony of the heartbeat ensure tight reciprocal coupling between this myosin ATPase cycle and the macroscopic cardiac cycle. The myosin motors respond to the cyclical activation of the actin and myosin filaments to drive the pressure changes that control the inflow and outflow valves of the heart chambers.

Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.

The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT.

European Achondroplasia Forum Practical Considerations for Following Adults with Achondroplasia.

Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines.

How do phytophagous insects affect phyllosphere fungi? Tracking fungi from milkweed to monarch caterpillar frass reveals communities dominated by fungal yeast.

Since a significant proportion of plant matter is consumed by herbivores, a necessary adaptation for many phyllosphere microbes could be to survive through the guts of herbivores. While many studies explore the gut microbiome of herbivores by surveying the microbiome in their frass, few studies compare the phyllosphere microbiome to the gut microbiome of herbivores. High-throughput metabarcode sequencing was used to track the fungal community from milkweed (Asclepias spp.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

Background And Objective: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

Methods: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.

Interviews with policymakers in Australian health policy: Understanding the process of policy development.

Objective: To determine the barriers and enablers oral health and chronic disease policymakers identify during policy development.

Methods: Semi-structured interview questions were developed utilizing an interview guide and applying a knowledge mobilization framework. Reflective thematic analysis of the data was completed based on the research of Braun and Clarke encompassing a critical realist approach.

Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years.

Methods: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA.

Dependence of myosin filament structure on intracellular calcium concentration in skeletal muscle.

Contraction of skeletal muscle is triggered by an increase in intracellular calcium concentration that relieves the structural block on actin-binding sites in resting muscle, potentially allowing myosin motors to bind and generate force. However, most myosin motors are not available for actin binding because they are stabilized in folded helical tracks on the surface of myosin-containing thick filaments. High-force contraction depends on the release of the folded motors, which can be triggered by stress in the thick filament backbone, but additional mechanisms may link the activation of the thick filaments to that of the thin filaments or to intracellular calcium concentration.

Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8 T cell exhaustion.

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8 T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8 T cell exhaustion.

Temperature alters the toxicological impacts of plant terpenoids on the polyphagous model herbivore Vanessa cardui.

Terpenes are a major class of secondary metabolites present in all plants, and long hypothesized to have diversified in response to specific plant-herbivore interactions. Herbivory is a major biotic interaction that plays out across broad temporal and spatial scales that vary dramatically in temperature regimes, both due to climatic variation across geographic locations as well as the effect of seasonality. In addition, there is an emerging understanding that global climate change will continue to alter the temperature regimes of nearly every habitat on Earth over the coming centuries.