Biology subjects

Mathur, A.

Publications and source records attributed to Mathur, A..

3 recordsLinked to original sources

bioRxiv2018

Cytoskeleton mechanics determine resting size and activation dynamics of platelets.

Platelets are cell fragments of various size that help maintain hemostasis. The way platelets respond during a clotting process is known to depend on their size, with important physiological consequences. We characterized the cytoskeleton of platelets as a function of their size. In resting Human and Mice platelets, we find a quadradic law between the size of a platelet and the amount of microtubule polymer it contains. We further estimate the length and number of microtubules in the marginal band using Electron and Super-resolution microscopy. In platelets activated with ADP, the marginal band coils as a consequence of cortical contraction driven by actin. We observe that this elastic coiling response is accompanied by a reversible shortening of the marginal band. Moreover, larger platelets have a higher propensity to coil. These results establish the dynamic equilibrium that is responsible for platelet size and differential response on a more quantitative level.\n\nHighlightsO_LIPlatelet size scales consistently with amount of polymerized tubulin in both mouse and human.\nC_LIO_LIPolymerized actin is required for ADP-induced marginal band coiling.\nC_LIO_LIUpon activation, the marginal band exhibits a reversible visco-elastic response involving shortening.\nC_LIO_LILarger marginal bands have a higher propensity to coil than shorter ones.\nC_LI\n\nIn briefThe cytoskeleton is adapted to platelet size and its mechanical properties determine propensity of a platelet to undergo morphological changes in response to agonists.

cell biology↗

bioRxiv2018

First in-human PET study of 3 novel tau radiopharmaceuticals: RO6958948

Background[11C]RO-963, [11C]RO-643 and [18F]RO-948 (previously referred as [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data (1,2). Here we describe the first human evaluation of these novel radiotracers.\n\nMethodsAmyloid PET positive Alzheimers disease (AD) patients and young healthy subjects (YC) each received two different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO-963, [11C]RO-643 or [18F]RO-948. Arterial blood sampling was performed in 11 healthy controls (HC) and 11 AD. Regions were defined on MRI, and PET data were quantified by plasma reference graphical analysis (for VT) and target cerebellum ratio (SUVR60-90). SUVR images were also analyzed voxelwise. Five older healthy subjects (OC) each received two scans with [18F]RO-948 for evaluation of test-retest variability. Four AD subjects received a repeat [18F]RO-948 scan over about 1 year. Six additional HC (3M: 3F; 41-67y) each received one whole body dosimetry scan with [18F]RO-948.\n\nResultsIn YC, peak SUV values were observed in the temporal lobe with values of approximately 3.0 for [11C]RO-963, 1.5 for [11C]RO-643 and 3.5 for [18F]RO-948. Over all brain regions and subjects, the trend was that [18F]RO-948 had the highest peak SUV value, followed by [11C]RO-963, and then [11C]RO-643. Regional analysis of SUVR and VT for [11C]RO-643 and [18F]RO-948 clearly discriminated AD and HC groups. Compartmental modeling confirmed that [11C]RO-643 had lower brain entry than both [18F]RO-963 and [18F]RO-948, and [18F]RO-948 showed a better contrast between (predicted) areas of high vs low tau accumulation. Thus, our subsequent analysis focused on [18F]RO-948. Both voxelwise and region-based analysis of [18F]RO-948 binding in HC vs AD revealed multiple areas where AD and HC significantly differed. Of 22 high-binding regions, 13 showed significant group difference (following ANOVA, F=45, p<10-5). Voxelwise analysis also revealed a set of symmetrical clusters where AD>HC (threshold of p<0.001, cluster size k>50).\n\nConclusions[18F]RO-948 demonstrates superior characteristics to [11C]RO-643 and [18F]RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of RO-948 compare favorably with existing other tau PET tracers.

neuroscience↗

bioRxiv2016

Balance of microtubule stiffness and cortical tension determines the size of blood cells with marginal band across species

The fast blood stream of animals is associated with large shear stresses. Consequently, blood cells have evolved a special morphology and a specific internal architecture allowing them to maintain their integrity over several weeks. For instance, non-mammalian red blood cells, mammalian erythroblasts and platelets have a peripheral ring of microtubules, called the marginal band, that flattens the overall cell morphology by pushing on the cell cortex. In this article, we model how the shape of these cells stems from the balance between marginal band elasticity and cortical tension. We predict that the diameter of the cell scales with the total microtubule polymer, and verify the predicted law across a wide range of species. Our analysis also shows that the combination of the marginal band rigidity and cortical tension increases the ability of the cell to withstand forces without deformation. Finally, we model the marginal band coiling that occurs during the disc-to-sphere transition observed for instance at the onset of blood platelet activation. We show that when cortical tension increases faster than crosslinkers can unbind, the marginal band will coil, whereas if the tension increases slower, the marginal band may shorten as microtubules slide relative to each other.\n\nSignificance StatementMany blood cells have a discoidal shape, which is essential for them to function properly within the organism. For some cells, such as blood platelets, this shape is due to the interplay between the elasticity of the marginal band, which is a closed ring of stiff filaments called microtubules, and the tension of the cell cortex, a polymer scaffold associated with the plasma membrane. Dmitrieff et al. examined how cell size is determined by the mechanical balance between these two components. Remarkably, the theory is confirmed over nearly three orders of magnitudes, by data collected from 25 species. The theory also shows how the composite structure is adapted to resist transient mechanical challenges, as encountered in the blood stream.

biophysics↗