10 research outputs found
Variability of the innate immune response is globally constrained by transcriptional bursting
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability
Variability of the innate immune response is globally constrained by transcriptional bursting
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability
DataSheet1_Variability of the innate immune response is globally constrained by transcriptional bursting.pdf
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.</p
Table4_Variability of the innate immune response is globally constrained by transcriptional bursting.XLSX
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.</p
Table3_Variability of the innate immune response is globally constrained by transcriptional bursting.XLSX
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.</p
Table1_Variability of the innate immune response is globally constrained by transcriptional bursting.XLSX
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.</p
Table2_Variability of the innate immune response is globally constrained by transcriptional bursting.XLSX
No full textTranscription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.</p
Improving survival outcomes of people with ABC: a global expert review and call-to-action for 2025–2035 (Goal 1)
No full textAdvanced breast cancer (ABC) remains a significant public health challenge, accounting for the majority of the ∼670,000 breast cancer deaths globally in 2022. In the past decade, significant improvements in survival were seen across all ABC subtypes and patient populations, but disparities remain and ABC continues to be an incurable disease for most people.This manuscript provides an overview of the survival improvements reported for each ABC subtype in clinical trials and in real-world studies since 2015. It highlights where disparities remain and outlines recommendations for the ABC community over the next decade to further improve survival. It summarizes findings from reviews conducted for the ABC Global Alliance's Global Decade Report 2.0. The main findings are: a) Clinical trials showed significant survival gains for ABC in 2015–2025, particularly for hormone receptor-positive and human epidermal growth factor 2 receptor (HER2)-positive subtypes; b) Real-world data mirrors survival trends seen in ABC clinical trials; c) Biomarker-driven treatments offer benefits in ABC, but testing is inconsistent from healthcare professionals; d) Survival disparities remain between ABC subtypes; e) Survival in ABC remains poor compared to early breast cancer.The findings from the ABC Global Alliance's Global Decade Report 2.0 have informed the development of a new ABC Global Charter. The ABC Global Charter 2.0 defines ten new achievable and measurable goals for the decade 2025–2035, aiming at improving the lives of people living with ABC worldwide
Improving communication between healthcare professionals and patients living with advanced breast cancer: a global expert review and call-to-action for 2025–2035 (Goal 5)
No full textThe complexity of advanced breast cancer (ABC) and its treatment landscape makes communication between healthcare professionals (HCPs) and patients particularly challenging. It is essential that all HCPs receive comprehensive communication skills training starting at medical or nursing school and continuing throughout their careers. Effective communication can improve trust, treatment adherence, and ultimately, outcomes; it also facilitates shared and educated decision-making, all of which is crucial to ensure patients receive the most appropriate treatment and care.This manuscript explores the global landscape of communication skills training, highlights remaining communication gaps, and assesses the preference for, and implementation of, shared decision-making in clinical practice. It draws on research conducted for the ABC Global Alliance's Global Decade Report 2.0. The main findings are: a) Communication skills trainings now cover a broader range of topics; b) People with ABC report their broader communication needs are often not met; c) Doctors and patients differ in their preferences for shared decision-making in ABC; d) Improving ABC care requires patients to feel supported in expressing their needs.The findings from the ABC Global Alliance's Global Decade Report 2.0 have informed the development of a new ABC Global Charter. The ABC Global Charter 2.0 defines ten new achievable and measurable goals for the decade 2025–2035, aiming at improving the lives of people living with ABC worldwide
