Modeling membrane nanotube morphology: the role of heterogeneity in composition and material properties.

Membrane nanotubes are dynamic structures that may connect cells over long distances. Nanotubes are typically thin cylindrical tubes, but they may occasionally have a beaded architecture along the tube. In this paper, we study the role of membrane mechanics in governing the architecture of these tubes and show that the formation of bead-like structures along the nanotubes can result from local heterogeneities in the membrane either due to protein aggregation or due to membrane composition. We present numerical results that predict how membrane properties, protein density, and local tension compete to create a phase space that governs the morphology of a nanotube. We also find that there exists a discontinuity in the energy that impedes two beads from fusing. These results suggest that the membrane-protein interaction, membrane composition, and membrane tension closely govern the tube radius, number of beads, and the bead morphology

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Application of continuum mechanics for a variety of curvature generation phenomena in cell biophysics

To dynamically reshape the membrane, cells rely on a variety of intracellular mechanisms, ranging from forces exerted by the cytoskeleton to the spontaneous curvature induced by membrane–protein interactions. In this thesis, we present mathematical models in a continuum framework to understand the physics underlying membrane deformation by two different modes of curvature-generating mechanisms (1) protein-induced spontaneous curvature and (2) forces due to membrane-cytoskeleton interactions. In the first part of the thesis, we model the effects of curvature-generating proteins by extending the classical Helfrich-Canham bending energy and demonstrate how the local shape of the membrane can be used to infer the traction acting locally on the membrane. Particularly, we first propose a technique to extract effective line tension at the protein interface using the morphology and the composition of the membrane. We then analyze the beading morphology of membrane nanotubes due to heterogeneity in the membrane properties and protein distribution. We find that there exists a discontinuity in the energy that impedes two beads from fusing. Finally, we show the application of our continuum framework for studying curvature generation due to protein phase separation on membranes. In the second part of the thesis, we model the forces due to membrane-cytoskeleton interactions by adding an extra degree of freedom to the energy equation to account for heterogeneous forces representing the effects of actin polymerization and activity of molecular motors such as myosin on the plasma membrane. Using this framework, we show that a non-uniform force distribution coupled with membrane tension characterized the biconcave shape of Red Blood Cells (RBCs). We also explore the application of our mathematical framework to identify the possible force regimes that give rise to the classic shapes of dendritic spines which are bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. We identify different mechanical pathways that are likely associated with different dendritic spine shapes, and find that some mechanisms may be energetically more favorable than others. We believe our models identify mechanisms of cell shape adaption by two modes of curvature generation, enabling future work to establish the contribution of cell membrane mechanics in many human diseases and designing better systems for drug and gene delivery

Application of continuum mechanics for a variety of curvature generation phenomena in cell biophysics

To dynamically reshape the membrane, cells rely on a variety of intracellular mechanisms, ranging from forces exerted by the cytoskeleton to the spontaneous curvature induced by membrane–protein interactions. In this thesis, we present mathematical models in a continuum framework to understand the physics underlying membrane deformation by two different modes of curvature-generating mechanisms (1) protein-induced spontaneous curvature and (2) forces due to membrane-cytoskeleton interactions. In the first part of the thesis, we model the effects of curvature-generating proteins by extending the classical Helfrich-Canham bending energy and demonstrate how the local shape of the membrane can be used to infer the traction acting locally on the membrane. Particularly, we first propose a technique to extract effective line tension at the protein interface using the morphology and the composition of the membrane. We then analyze the beading morphology of membrane nanotubes due to heterogeneity in the membrane properties and protein distribution. We find that there exists a discontinuity in the energy that impedes two beads from fusing. Finally, we show the application of our continuum framework for studying curvature generation due to protein phase separation on membranes. In the second part of the thesis, we model the forces due to membrane-cytoskeleton interactions by adding an extra degree of freedom to the energy equation to account for heterogeneous forces representing the effects of actin polymerization and activity of molecular motors such as myosin on the plasma membrane. Using this framework, we show that a non-uniform force distribution coupled with membrane tension characterized the biconcave shape of Red Blood Cells (RBCs). We also explore the application of our mathematical framework to identify the possible force regimes that give rise to the classic shapes of dendritic spines which are bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. We identify different mechanical pathways that are likely associated with different dendritic spine shapes, and find that some mechanisms may be energetically more favorable than others. We believe our models identify mechanisms of cell shape adaption by two modes of curvature generation, enabling future work to establish the contribution of cell membrane mechanics in many human diseases and designing better systems for drug and gene delivery

Effective cell membrane tension protects red blood cells against malaria invasion.

A critical step in how malaria parasites invade red blood cells (RBCs) is the wrapping of the membrane around the egg-shaped merozoites. Recent experiments have revealed that RBCs can be protected from malaria invasion by high membrane tension. While cellular and biochemical aspects of parasite actomyosin motor forces during the malaria invasion have been well studied, the important role of the biophysical forces induced by the RBC membrane-cytoskeleton composite has not yet been fully understood. In this study, we use a theoretical model for lipid bilayer mechanics, cytoskeleton deformation, and membrane-merozoite interactions to systematically investigate the influence of effective RBC membrane tension, which includes contributions from the lipid bilayer tension, spontaneous tension, interfacial tension, and the resistance of cytoskeleton against shear deformation on the progression of membrane wrapping during the process of malaria invasion. Our model reveals that this effective membrane tension creates a wrapping energy barrier for a complete merozoite entry. We calculate the tension threshold required to impede the malaria invasion. We find that the tension threshold is a nonmonotonic function of spontaneous tension and undergoes a sharp transition from large to small values as the magnitude of interfacial tension increases. We also predict that the physical properties of the RBC cytoskeleton layer-particularly the resting length of the cytoskeleton-play key roles in specifying the degree of the membrane wrapping. We also found that the shear energy of cytoskeleton deformation diverges at the full wrapping state, suggesting the local disassembly of the cytoskeleton is required to complete the merozoite entry. Additionally, using our theoretical framework, we predict the landscape of myosin-mediated forces and the physical properties of the RBC membrane in regulating successful malaria invasion. Our findings on the crucial role of RBC membrane tension in inhibiting malaria invasion can have implications for developing novel antimalarial therapeutic or vaccine-based strategies