Biology subjects

Malingen, S. A.

Publications and source records attributed to Malingen, S. A..

3 recordsLinked to original sources

bioRxiv2024

Interplay between cortical adhesion and membrane bending regulates microparticle formation

The formation of blebs and microparticle formation requires the bending of the plasma membrane away from the cytosol. There are multiple factors that control the formation of the microparticles including the loss of lipid asymmetry, primarily the exposure of phosphatidylserine on the outer leaflet, detachment of the membrane from the cortical cytoskeleton, and bleb expansion due to pressure. In this work, we develop a biophysical model that accounts for the interaction between these different factors. Our findings reveal that linker attachment is a key determinant of outward budding and lays out the mechanical aspects of outward budding of the plasma membrane. Significance StatementCells release many types of membrane-enclosed vesicles in response to stress, inflammation, or other injuries. Formation of these membrane-enclosed structures is critical for proper function of the coagulation cascade and apoptosis. In many cases, these microparticles are also a part of the long distance intercellular communication and are implicated in chemoresistance. A particular class of vesicles called ectosomes or microparticles are released by the outward budding of the plasma membrane, a process which requires detachment of the membrane from the cortex, exposure of negatively charged, curvature-inducing lipids such as phosphatidylserine from the inner leaflet to the outer leaflet, and pressure-driven expansion of the bleb. Here, we used membrane mechanics coupled with the kinetics of adhesive linker binding-unbinding to investigate how these different factors interact together. Using our models, we predict how linker properties plays an important role in the outward budding of the plasma membrane and identify conditions that can promote or inhibit such curvature generation. These findings have implications not just for conditions that require successful microparticle formation such as the procoagulation cascade but also for inhibiting microparticle formation in cases of chemoresistant drug efflux by tumor cells.

biophysics↗

bioRxiv2022

Modeling membrane curvature generation using mechanics and machine learning

The deformation of cellular membranes regulates trafficking processes, such as exocytosis and endocytosis. Classically, the Helfrich continuum model is used to characterize the forces and mechanical parameters that cells tune to accomplish membrane shape changes. While this classical model effectively captures curvature generation, one of the core challenges in using it to approximate a biological process is selecting a set of mechanical parameters (including bending modulus and membrane tension) from a large set of reasonable values. We used the Helfrich model to generate a large synthetic dataset from a random sampling of realistic mechanical parameters and used this dataset to train machine learning models. These models produced promising results, accurately classifying model behavior and predicting membrane shape from mechanical parameters. We also note emerging methods in machine learning that can leverage the physical insight of the Helfrich model to improve performance and draw greater insight into how cells control membrane shape change.

biophysics↗

bioRxiv2020

In vivo x-ray diffraction and simultaneous EMG reveal the time course of myofilament lattice dilation and filament stretch

Muscles function within an organism depends on the feedback between molecular to meter-scale processes. While the motions of muscles contractile machinery are well described in isolated preparations, only a handful of experiments have documented the kinematics of the lattice occurring when multi-scale interactions are fully intact. We used time-resolved x-ray diffraction to record the kinematics of the myofilament lattice within a normal operating context: the tethered flight of Manduca sexta. Since the primary flight muscles of Manduca sexta are synchronous, we used these results to reveal the timing of in vivo cross-bridge recruitment, which occurred 24 (s.d. 26) ms following activation. In addition, the thick filaments stretched an average of 0.75 (s.d. 0.32)% and thin filaments stretched 1.11 (s.d. 0.65)%. In contrast to other in vivo preparations, lattice spacing changed an average of 2.72 (s.d. 1.47)%. Lattice dilation of this magnitude significantly impacts shortening velocity and force generation, and filament stretching tunes force generation. While kinematics were consistent within individual trials, there was extensive variation between trials. Using a mechanism-free machine learning model we searched for patterns within and across trials. While lattice kinematics were predictable within trials, the model could not create predictions across trials. This indicates that the variability we see across trials may be explained by latent variables occurring in this naturally functioning system. The diverse kinematic combinations we documented mirror muscles adaptability and may facilitate its robust function in unpredictable conditions.

biophysics↗