121 research outputs found
Running and tumbling with E. coli in polymeric solutions
Run-and-tumble motility is widely used by swimming microorganisms including
numerous prokaryotic eukaryotic organisms. Here, we experimentally investigate
the run-and-tumble dynamics of the bacterium E. coli in polymeric solutions. We
find that even small amounts of polymer in solution can drastically change E.
coli dynamics: cells tumble less and their velocity increases, leading to an
enhancement in cell translational diffusion and a sudden decline in rotational
diffusion. We show that suppression of tumbling is due to fluid viscosity while
the enhancement in swimming speed is mainly due to fluid elasticity.
Visualization of single fluorescently labeled DNA polymers reveals that the
flow generated by individual E. coli is sufficiently strong to stretch polymer
molecules and induce elastic stresses in the fluid, which in turn can act on
the cell in such a way to enhance its transport. Our results show that the
transport and spread of chemotactic cells can be independently modified and
controlled by the fluid material properties
Dynamic nuclear structure emerges from chromatin crosslinks and motors
The cell nucleus houses the chromosomes, which are linked to a soft shell of
lamin filaments. Experiments indicate that correlated chromosome dynamics and
nuclear shape fluctuations arise from motor activity. To identify the physical
mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a
polymeric shell. System-sized correlated motions occur but require both motor
activity {\it and} crosslinks. Contractile motors, in particular, enhance
chromosome dynamics by driving anomalous density fluctuations. Nuclear shape
fluctuations depend on motor strength, crosslinking, and chromosome-lamina
binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a
minimal, active chromosome-lamina system.Comment: 18 pages, 21 figure
How cells wrap around virus-like particles using extracellular filamentous protein structures
Nanoparticles, such as viruses, can enter cells via endocytosis. During
endocytosis, the cell surface wraps around the nanoparticle to effectively eat
it. Prior focus has been on how nanoparticle size and shape impacts
endocytosis. However, inspired by the noted presence of extracellular vimentin
affecting viral and bacteria uptake, as well as the structure of coronaviruses,
we construct a computational model in which both the cell-like construct and
the virus-like construct contain filamentous protein structures protruding from
their surfaces. We then study the impact of these additional degrees of freedom
on viral wrapping. We find that cells with an optimal density of filamentous
extracellular components (ECCs) are more likely to be infected as they uptake
the virus faster and use relatively less cell surface area per individual
virus. At the optimal density, the cell surface folds around the virus, and
folds are faster and more efficient at wrapping the virus than crumple-like
wrapping. We also find that cell surface bending rigidity helps generate folds,
as bending rigidity enhances force transmission across the surface. However,
changing other mechanical parameters, such as the stretching stiffness of
filamentous ECCs or virus spikes, can drive crumple-like formation of the cell
surface. We conclude with the implications of our study on the evolutionary
pressures of virus-like particles, with a particular focus on the cellular
microenvironment that may include filamentous ECCs.Comment: 15 pages, 8 figure
Cell nuclei as cytoplasmic rheometers
Some researchers probe the mechanics of cells by perturbing them from the outside, such as using an atomic force microscope probe to record the amount of deformation of the cell in response to applying a prescribed force at a defined speed. Other researchers probe the mechanics of cells by perturbing them from the inside, an example of which is particle-tracking microrheology, in which the spontaneous motion of submicron, passive fluorescent beads ballistically injected earlier into the cell decodes the cell moduli. Both types of probes are typically composed of nonliving material. In this issue of Biophysical Journal, Moradi and Nazockdas cleverly propose to use the cell nucleus itself as a rheological probe for the mechanics of the cytoplasm (1). The cell nucleus is typically the largest and the stiffest organelle in eukaryotic cells. The surrounding cytoplasm contains other organelles and the cytoskeleton, which is comprised different kinds of semiflexible polymers, including actin, microtubules, and intermediate filaments. For cells that are confined by geometries on the scale of the size of the cell, the nucleus is minimally deformed and can therefore be approximated as a rigid sphere. It is in this limit that the authors ask the following questions. As a cell moves inside a microchannel, what does the motion of the cell nucleus, in response to deformations in the cell cortex, reveal about the rheology of the cytoplasm? Is it viscoelastic? Is it porous? Is it a poroelastic network? Is it something else? Answers to such questions will help us better understand cell function, such as how the cytoplasm reorganizes in response to changes in a cell physical environment
Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in doberman pinschers with preclinical dilated cardiomyopathy (the PROTECT study)
<p>Background: The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported.</p>
<p>Hypothesis: That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival.</p>
<p>Animals: Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America.</p>
<p>Methods: The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo.</p>
<p>The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint.</p>
<p>Results: The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034).</p>
<p>Conclusion and Clinical Importance: The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.</p>
Loops versus lines and the compression stiffening of cells
Both animal and plant tissue exhibit a nonlinear rheological phenomenon known
as compression stiffening, or an increase in moduli with increasing uniaxial
compressive strain. Does such a phenomenon exist in single cells, which are the
building blocks of tissues? One expects an individual cell to compression
soften since the semiflexible biopolymer-based cytoskeletal network maintains
the mechanical integrity of the cell and in vitro semiflexible biopolymer
networks typically compression soften. To the contrary, we find that mouse
embryonic fibroblasts (mEFs) compression stiffen under uniaxial compression via
atomic force microscopy (AFM) studies. To understand this finding, we uncover
several potential mechanisms for compression stiffening. First, we study a
single semiflexible polymer loop modeling the actomyosin cortex enclosing a
viscous medium modeled as an incompressible fluid. Second, we study a
two-dimensional semiflexible polymer/fiber network interspersed with
area-conserving loops, which are a proxy for vesicles and fluid-based
organelles. Third, we study two-dimensional fiber networks with
angular-constraining crosslinks, i.e. semiflexible loops on the mesh scale. In
the latter two cases, the loops act as geometric constraints on the fiber
network to help stiffen it via increased angular interactions. We find that the
single semiflexible polymer loop model agrees well with our AFM experiments
until approximately 35% compressive strain. We also find for the fiber network
with area-conserving loops model that the stress-strain curves are sensitive to
the packing fraction and size distribution of the area-conserving loops,
thereby creating a mechanical fingerprint across different cell types. Finally,
we make comparisons between this model and experiments on fibrin networks
interlaced with beads as well as discuss the tissue-scale implications of
cellular compression stiffening.Comment: 19 pages, 17 figure
Phevamine A, a small molecule that suppresses plant immune responses
Bacterial plant pathogens cause significant crop damage worldwide. They invade plant cells by producing a variety of virulence factors, including small-molecule toxins and phytohormone mimics. Virulence of the model pathogen Pseudomonas syringae pv. tomato DC3000 (Pto) is regulated in part by the sigma factor HrpL. Our study of the HrpL regulon identified an uncharacterized, three-gene operon in Pto that is controlled by HrpL and related to the Erwinia hrp-associated systemic virulence (hsv) operon. Here, we demonstrate that the hsv operon contributes to the virulence of Pto on Arabidopsis thaliana and suppresses bacteria-induced immune responses. We show that the hsv-encoded enzymes in Pto synthesize a small molecule, phevamine A. This molecule consists of L-phenylalanine, L-valine, and a modified spermidine, and is different from known small molecules produced by phytopathogens. We show that phevamine A suppresses a potentiation effect of spermidine and L-arginine on the reactive oxygen species burst generated upon recognition of bacterial flagellin. The hsv operon is found in the genomes of divergent bacterial genera, including ∼37% of P. syringae genomes, suggesting that phevamine A is a widely distributed virulence factor in phytopathogens. Our work identifies a small-molecule virulence factor and reveals a mechanism by which bacterial pathogens overcome plant defense. This work highlights the power of omics approaches in identifying important small molecules in bacteria–host interactions
Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Myxomatous Mitral Valve Disease Receiving Pimobendan or Benazepril The QUEST Study
Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study
Background: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described.
Objectives: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF.
Animals: Three hundred and fifty-four dogs with MMVD and cardiomegaly.
Materials and Methods: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored.
Results: At day 35, heart size had reduced in the pimobendan group:median change in (Delta) LVIDDN -0.06 (IQR:-0.15 to + 0.02), P < 0.0001, and LA:Ao -0.08 (IQR:-0.23 to + 0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in Delta LVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in Delta LA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar.
Conclusions and Clinical Importance: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo
Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study - A Randomized Clinical Trial
Background: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. Animals: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio >= 1.6, normalized left ventricular internal diameter in diastole >= 1.7, and vertebral heart sum >10.5. Methods: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. Results: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). Conclusions and Clinical Importance: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit
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