51 research outputs found
Mechanical and Systems Biology of Cancer
Mechanics and biochemical signaling are both often deregulated in cancer,
leading to cancer cell phenotypes that exhibit increased invasiveness,
proliferation, and survival. The dynamics and interactions of cytoskeletal
components control basic mechanical properties, such as cell tension,
stiffness, and engagement with the extracellular environment, which can lead to
extracellular matrix remodeling. Intracellular mechanics can alter signaling
and transcription factors, impacting cell decision making. Additionally,
signaling from soluble and mechanical factors in the extracellular environment,
such as substrate stiffness and ligand density, can modulate cytoskeletal
dynamics. Computational models closely integrated with experimental support,
incorporating cancer-specific parameters, can provide quantitative assessments
and serve as predictive tools toward dissecting the feedback between signaling
and mechanics and across multiple scales and domains in tumor progression.Comment: 18 pages, 3 figure
Effects of 3D Geometries on Cellular Gradient Sensing and Polarization
During cell migration, cells become polarized, change their shape, and move
in response to various internal and external cues. Cell polarization is defined
through the spatio-temporal organization of molecules such as PI3K or small
GTPases, and is determined by intracellular signaling networks. It results in
directional forces through actin polymerization and myosin contractions. Many
existing mathematical models of cell polarization are formulated in terms of
reaction-diffusion systems of interacting molecules, and are often defined in
one or two spatial dimensions. In this paper, we introduce a 3D
reaction-diffusion model of interacting molecules in a single cell, and find
that cell geometry has an important role affecting the capability of a cell to
polarize, or change polarization when an external signal changes direction. Our
results suggest a geometrical argument why more roundish cells can repolarize
more effectively than cells which are elongated along the direction of the
original stimulus, and thus enable roundish cells to turn faster, as has been
observed in experiments. On the other hand, elongated cells preferentially
polarize along their main axis even when a gradient stimulus appears from
another direction. Furthermore, our 3D model can accurately capture the effect
of binding and unbinding of important regulators of cell polarization to and
from the cell membrane. This spatial separation of membrane and cytosol, not
possible to capture in 1D or 2D models, leads to marked differences of our
model from comparable lower-dimensional models.Comment: 31 pages, 7 figure
InternalBlue - Bluetooth Binary Patching and Experimentation Framework
Bluetooth is one of the most established technologies for short range digital
wireless data transmission. With the advent of wearables and the Internet of
Things (IoT), Bluetooth has again gained importance, which makes security
research and protocol optimizations imperative. Surprisingly, there is a lack
of openly available tools and experimental platforms to scrutinize Bluetooth.
In particular, system aspects and close to hardware protocol layers are mostly
uncovered.
We reverse engineer multiple Broadcom Bluetooth chipsets that are widespread
in off-the-shelf devices. Thus, we offer deep insights into the internal
architecture of a popular commercial family of Bluetooth controllers used in
smartphones, wearables, and IoT platforms. Reverse engineered functions can
then be altered with our InternalBlue Python framework---outperforming
evaluation kits, which are limited to documented and vendor-defined functions.
The modified Bluetooth stack remains fully functional and high-performance.
Hence, it provides a portable low-cost research platform.
InternalBlue is a versatile framework and we demonstrate its abilities by
implementing tests and demos for known Bluetooth vulnerabilities. Moreover, we
discover a novel critical security issue affecting a large selection of
Broadcom chipsets that allows executing code within the attacked Bluetooth
firmware. We further show how to use our framework to fix bugs in chipsets out
of vendor support and how to add new security features to Bluetooth firmware
Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics
Cells are highly dynamic and mechanical automata powered by molecular motors that respond to external cues. Intracellular signaling pathways, either chemical or mechanical, can be activated and spatially coordinated to induce polarized cell states and directional migration. Physiologically, cells navigate through complex microenvironments, typically in three-dimensional (3D) fibrillar networks. In diseases, such as metastatic cancer, they invade across physiological barriers and remodel their local environments through force, matrix degradation, synthesis, and reorganization. Important external factors such as dimensionality, confinement, topographical cues, stiffness, and flow impact the behavior of migrating cells and can each regulate motility. Here, we review recent progress in our understanding of single-cell migration in complex microenvironments.National Cancer Institute (U.S.) (Grant No. 5U01CA177799)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award
Serum neurofilament light chains in progressive multiple sclerosis patients treated with repeated cycles of high-dose intravenous steroids
Background and objectives: In progressive multiple sclerosis (MS) patients, CNS inflammation trapped behind a closed blood brain barrier drives continuous neuroaxonal degeneration, thus leading to deterioration of neurological function. Therapeutics in progressive MS are limited. High-dose intravenous glucocorticosteroids (HDCS) can cross the blood-brain barrier and may reduce inflammation within the CNS. However, the treatment efficacy of HDCS in progressive MS remains controversial. Serum neurofilament light chains (sNfL) are an established biomarker of neuroaxonal degeneration and are used to monitor treatment responses. We aimed to investigate whether repeated cycles of intravenous HDCS reduce the level of sNfL in progressive MS patients.
Methods: We performed a monocentric observational study of 25 patients recruited during ongoing clinical routine care who were treated with repeated cycles of intravenous HDCS as long-term therapy for their progressive MS. sNfL were measured in 103 repeated blood samples (median time interval from baseline 28 weeks, range 2-55 weeks) with the Single Molecular Array (SiMoA) technology. The Expanded Disability Status Score (EDSS) was documented at baseline and follow-up.
Results: The median age of patients was 55 years (range 46-77 years) with a median disease duration of 26 years (range 11-42 years). sNfL baseline levels at study inclusion were significantly higher in progressive MS patients compared to age-matched healthy controls (median 16.7 pg/ml vs 11.5 pg/ml, p=0.002). sNfL levels showed a positive correlation with patient age (r=0.2, p=0.003). The majority of patients (72%, 16/23) showed reduced sNfL levels ≥20 weeks after HDCS compared to baseline (median 13.3 pg/ml, p=0.03). sNfL levels correlated negatively with the time interval from baseline HDCS therapy (r=-0.2, p=0.03). This association was also evident after correction for treatment with disease-modifying drugs (adjusted R2=0.10, p=0.001). The EDSS remained stable (median 6.5) within a median treatment duration of 26 weeks (range 13-51 weeks).
Conclusion: Although larger studies are needed to confirm our findings, we were able to demonstrate that HDCS treatment reduces sNfL levels and therefore may slow down neuroaxonal damage in a subgroup of patients with progressive MS. Moreover, a stable EDSS was observed during therapy. Findings suggest that HDCS may be beneficial for the treatment of progressive MS
Peanut Allergen Reaction Thresholds during Controlled Food Challenges in 2 Canadian Randomized Studies (Canada-ARM1 and PISCES)
In 2 randomized studies addressing peanut allergy (Canada-Food Allergy Risk Management 1 [NCT01812798] and Peanut Immunotherapy Starting in Canada, Evaluation and DiScovery [NCT0 1601522]), we quantified peanut allergen thresholds to food challenge using Bayesian stacked model averaging to inform policy and clinical practice. About 50% of patients tolerated more than 70 mg (~ ¼ peanut)
SAS profile correlations reveal SAS hierarchical nature and information content.
In structural biology, Small-Angle Scattering experiments (SAS) are unique, because although they provide low resolution data, they can be performed in closer-to-native conditions than those arising in X-Ray crystallography. A number of questions on SAS, however, remain unsolved, particularly in the light of modelling ensembles of conformers in solution. In this article, we study the ensemble average and covariance of SAS profiles analytically. Using this ensemble covariance, we demonstrate the hierarchical nature of SAS profiles. Furthermore, we show that the information content is not uniform and reaches its maximum in the intermediate q range. The arguments are generalized using microsecond-scale molecular dynamics trajectories of the lysozyme and on an ensemble of the intrinsically disordered protein p15PAF. We show that for highly flexible systems, the SAS profile is a representation of the ensemble of conformers in solution, and not that of one conformer in particular
SAS Profile Correlations Reveal the Hierarchical Nature of SAS Data and Suggest New Scoring Strategies
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