scholarly journals Strength–Duration Relationship for Extracellular Neural Stimulation: Numerical and Analytical Models

2010 ◽  
Vol 104 (4) ◽  
pp. 2236-2248 ◽  
Author(s):  
David Boinagrov ◽  
Jim Loudin ◽  
Daniel Palanker
Keyword(s):  
Channel Model ◽  
Single Pulse ◽  
Cell Polarization ◽  
Neural Stimulation ◽  
Analytical Models ◽  
Membrane Properties ◽  
Efficacy And Safety ◽  
Cell Shapes ◽  
Intracellular Stimulation ◽  
Duration Relationship

The strength–duration relationship for extracellular stimulation is often assumed to be similar to the classical intracellular stimulation model, with a slope asymptotically approaching 1/τ at pulse durations shorter than chronaxy. We modeled extracellular neural stimulation numerically and analytically for several cell shapes and types of active membrane properties. The strength–duration relationship was found to differ significantly from classical intracellular models. At pulse durations between 4 μs and 5 ms stimulation is dominated by sodium channels, with a slope of −0.72 in log-log coordinates for the Hodgkin–Huxley ion channel model. At shorter durations potassium channels dominate and slope decreases to −0.13. Therefore the charge per phase is decreasing with decreasing stimulus duration. With pulses shorter than cell polarization time (∼0.1–1 μs), stimulation is dominated by polarization dynamics with a classical −1 slope and the charge per phase becomes constant. It is demonstrated that extracellular stimulation can have not only lower but also upper thresholds and may be impossible below certain pulse durations. In some regimes the extracellular current can hyperpolarize cells, suppressing rather than stimulating spiking behavior. Thresholds for burst stimuli can be either higher or lower than that of a single pulse, depending on pulse duration. The modeled thresholds were found to be comparable to published experimental data. Electroporation thresholds, which limit the range of safe stimulation, were found to exceed stimulation thresholds by about two orders of magnitude. These results provide a biophysical basis for understanding stimulation dynamics and guidance for optimizing the neural stimulation efficacy and safety.

The Mechanical Properties of the Longitudinal Muscle in the Earthworm

1969 ◽  
Vol 50 (2) ◽  
pp. 431-443 ◽  
Author(s):  
T. HIDAKA ◽  
H. KURIYAMA ◽  
T. YAMAMOTO
Keyword(s):  
Mechanical Properties ◽  
Longitudinal Muscle ◽  
Sodium Concentration ◽  
Membrane Resistance ◽  
Membrane Properties ◽  
Active Tension ◽  
Spike Generation ◽  
Tension Development ◽  
Sustained Contraction ◽  
Intracellular Stimulation

1. A study of the mechanical properties of longitudinal muscle in relation to the membrane properties was carried out under isometric conditions. 2. When the stimulus duration exceeded 50 msec., active tension development was followed by sustained contraction. The sustained contractions were not related to spike generation. 3. The critical potassium concentration to produce the contracture depolarized the membrane from -36 to -20 mV. 4. Reduced sodium concentration and increased calcium and increased potassium (up to 27 mM) concentrations enhanced the amplitude of the active tension. 5. Reduced sodium concentration enhanced the amplitude and duration of the sustained tension, but increased potassium and calcium concentrations reduced them. 6. Caffeine (12 mM) induced contractures of the muscle, and reduced the membrane resistance and capacitance. 7. Spikes were not elicited by intracellular stimulation. 8. 5-Hydroxytryptamine (10-5 g./ml.) blocked the generation of the sustained contraction but no effect was observed on the phasic tension.

scholarly journals Single Cell Center of Mass for the Analysis of BMP Receptor Heterodimers Distributions

2021 ◽  
Author(s):  
Hendrik Boog ◽  
Rebecca Medda ◽  
Elisabetta Ada Cavalcanti-Adam
Keyword(s):  
Signaling Pathways ◽  
Single Cells ◽  
Center Of Mass ◽  
Control Cell ◽  
Culture Conditions ◽  
Cell Polarization ◽  
Receptor Complexes ◽  
Cell Shapes ◽  
Distribution Studies ◽  
Receptor Distribution

At the plasma membrane, transmembrane receptors are at the interface between cells and their environment. They allow sensing and transduction of chemical and mechanical extracellular signals. The spatial distribution of receptors and the specific recruitment of receptor subunits to the cell membrane is crucial for the regulation of signaling and cell behavior. However, it is challenging to define what regulates such spatial patterns for receptor localization, as cell shapes are extremely diverse when cells are maintained in standard culture conditions. Bone morphogenic protein receptors (BMPRs) are serine-threonine kinases, which build heteromeric complexes of BMPRI and II. These are especially interesting targets for receptor distribution studies, since the signaling pathways triggered by BMPR-complexes depends on their dimerization mode. They might exist as pre-formed complexes, or assemble upon binding of BMP, triggering cell signaling which leads to differentiation or migration. In this work we analyzed BMPR receptor distributions in single cells grown on micropatterns, which allows not only to control cell shape, but also the distribution of intracellular organelles and protein assemblies. We developed a script called ComRed (Center Of Mass Receptor Distribution), which uses center of mass calculations to analyze the shift and spread of receptor distributions according to the different cell shapes. ComRed was tested by simulating changes in experimental data, showing that shift and spread of distributions can be reliably detected. Our ComRed-based analysis of BMPR-complexes indicates that receptor distribution depends on cell polarization. The absence of a coordinated internalization after addition of BMP suggests that a rapid and continual recycling of BMPRs occurs. Receptor complexes formation and localization in cells induced by BMP might yield insights into the local regulation of different signaling pathways.

A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4141-TPS4141 ◽  
Author(s):  
Manish A. Shah ◽  
Jean-Philippe Metges ◽  
Patrick Youngwhan Chun ◽  
Victoria Smith ◽  
Julia D. Maltzman ◽  
...  
Keyword(s):  
T Cell ◽  
Performance Status ◽  
Randomized Study ◽  
Gastroesophageal Junction ◽  
Cell Polarization ◽  
Phase Iii ◽  
Matrix Remodeling ◽  
Cell Trafficking ◽  
Efficacy And Safety ◽  
Open Label

TPS4141 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. Results from the ATTRACTION-2 Phase III trial showed the PD-1 inhibitor nivolumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients with heavily pre-treated advanced gastric or gastroesophageal junction cancer. Preclinical studies indicate that selective inhibition of MMP9 can inhibit immune-suppressive myeloid cell polarization, regulatory T cell generation, desmoplasia, and the destruction of ligands for CXCR3 (a critical chemokine receptor that enables effector T cell trafficking). In combination with a checkpoint inhibitor, CD8+, CD4+ and CD44+ cytotoxic T cells are significantly increased in a checkpoint-refractory model, suggesting that MMP9 inhibition could relieve immune suppression. Methods: This phase 2, open-label, randomized study investigates the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in patients with unresectable or recurrent gastric or gastroesophageal adenocarcinoma. 120 patients will be randomized to either GS-5745 800mg IV + nivolumab 3mg/kg IV, or nivolumab alone. Treatment will be administered every 2 weeks and stratified by PD-L1 status. CT will be performed every 8 weeks to evaluate response. The primary endpoint of the study is ORR; secondary endpoints include PFS, OS, and occurrence of adverse events. Key inclusion criteria: metastatic or inoperable adenocarcinoma of the stomach or GEJ which has progressed after ≥1 prior systemic therapy, ECOG performance status ≤1, RECISTv1.1 measureable disease, archival tissue adequate for PD-L1 evaluation. Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016. Clinical trial information: NCT02864381.

scholarly journals Spots, stripes, and spiral waves in models for static and motile cells

2021 ◽  
Vol 82 (4) ◽  
Author(s):  
Yue Liu ◽  
Elisabeth G. Rens ◽  
Leah Edelstein-Keshet
Keyword(s):  
Cell Polarization ◽  
Spiral Waves ◽  
Eukaryotic Cells ◽  
Filamentous Actin ◽  
Cell Edge ◽  
Sources And Sinks ◽  
Spontaneous Formation ◽  
Motile Cells ◽  
Dynamic Cell ◽  
Cell Shapes

AbstractThe polarization and motility of eukaryotic cells depends on assembly and contraction of the actin cytoskeleton and its regulation by proteins called GTPases. The activity of GTPases causes assembly of filamentous actin (by GTPases Cdc42, Rac), resulting in protrusion of the cell edge. Mathematical models for GTPase dynamics address the spontaneous formation of patterns and nonuniform spatial distributions of such proteins in the cell. Here we revisit the wave-pinning model for GTPase-induced cell polarization, together with a number of extensions proposed in the literature. These include introduction of sources and sinks of active and inactive GTPase (by the group of A. Champneys), and negative feedback from F-actin to GTPase activity. We discuss these extensions singly and in combination, in 1D, and 2D static domains. We then show how the patterns that form (spots, waves, and spirals) interact with cell boundaries to create a variety of interesting and dynamic cell shapes and motion.

scholarly journals Membrane Properties of the Somatic Muscle (Obliquely Striated Muscle) of the Earthworm

1969 ◽  
Vol 50 (2) ◽  
pp. 387-403
Author(s):  
T. HIDAKA ◽  
Y. ITO ◽  
H. KURIYAMA
Keyword(s):  
Membrane Potential ◽  
Muscle Fibre ◽  
Striated Muscle ◽  
Longitudinal Muscle ◽  
Nervous Activity ◽  
Membrane Properties ◽  
Somatic Muscle ◽  
Intracellular Stimulation ◽  
Longitudinal Muscles ◽  
Spontaneous Discharges

1. The membrane properties of the longitudinal muscle fibre of the earthworm Pheretima communissima were investigated by intra- and extracellular stimulating methods. 2. The membrane potential was -35.4 mV., and spontaneous discharges with overshoot (mean +18 mV.) and after-hyperpolarization (-60 mV.) were recorded. 3. Tetrodotoxin (10-7 g./ml.) blocked nervous activity but did not influence the spontaneous discharges or the spikes elicited in the muscle fibre by intracellular stimulation. 4. The critical membrane potential required to elicit a spike was not constant, and the falling phase of the spikes was markedly dependent on the level of the membrane potential. 5. The chronaxie, measured from the intensity-duration relation to elicit a spike by intracellular stimulation, was 55 msec. 6. When nervous activity was excluded the propagation of excitation in longitudinal muscles was decremental.

scholarly journals The Spatial Correlation of a Multiple-Input Multiple-Output and Channel Model using Huygens-Fresnel Principle for Underwater Acoustic

2019 ◽  
Vol 15 (4) ◽  
pp. 343-350
Author(s):  
Shahideh Kiehbadroudinezhad ◽  
Adib Shahabi ◽  
Mohammad Ali Kiehbadroudinezhad
Keyword(s):  
Spatial Correlation ◽  
Channel Model ◽  
Specular Reflection ◽  
Multiple Input Multiple Output ◽  
Acoustic Propagation ◽  
Sea Surface ◽  
Analytical Models ◽  
Underwater Acoustic ◽  
Multiple Input ◽  
Input Multiple Output

In this work, the spatial correlation of a multiple-input multiple-output (MIMO) for underwater acoustic (UWA) channel is modelled. To obtain the spatial correlation for such a channel, a mathematical method to model the effect of the surface on the acoustic propagation is studied. The sea surface has a significant impact on the underwater acoustic propagation (UWA) channel since the sound field is scattered, particularly in rough sea conditions. In a situation where the sea surface is calm, the reflection is specular. In contrast, a sea surface subject to high sea states generates scattered waves. In these conditions, more complex mathematical equations are required to model the propagation. Current analytical models have limitations in terms of complexity and are not practical. Therefore, this study aims to consider a specular reflection to model the time-varying sea surface on the UWA channel. It is a simple model with low computationally complexity and can be used to assess the performance of UWA communications. Specifically, the specular reflection and transmission of an acoustic wave at a calm sea surface is studied, using the Huygens-Fresnel principle and the superposition theorem. The analytical model is developed using physical oceanic parameters representing the sea conditions. The results show a good agreement with the experimental analysis.

scholarly journals Efficacy and safety of thrombolysis for acute ischemic stroke with atrial fibrillation: a meta-analysis

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yunzhen Hu ◽  
Chunmei Ji
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Meta Analysis ◽  
Intravenous Thrombolysis ◽  
Analytical Models ◽  
Efficacy And Safety ◽  
Fixed And Random Effects ◽  
Study Heterogeneity ◽  
Symptomatic Intracranial Hemorrhage

Abstract Background The efficacy and safety of intravenous thrombolysis (IVT) for acute ischemic stroke with atrial fibrillation (AF) is still controversial. Methods We conducted a meta-analysis of all relevant studies, retrieved through systematic search of PubMed, Embase, and Cochrane databases up to December 31, 2019. Modified Rankin Scale (mRS) scores of 0–1 at 90 days, mRS of 0–2 at 90 days, overall mortality, and incidence of symptomatic intracranial hemorrhage (sICH) were collected as outcome measures. Fixed- and random-effects meta-analytical models were applied, and between-study heterogeneity was assessed. Results A total of 8509 patients were enrolled in 18 studies. A comparison of IVT treatment in AF versus non-AF patients showed that AF was associated with a significantly lower proportion of patients with mRS of 0–1 (24.1% vs. 34.5%; OR 0.59; 95% CI 0.43–0.81; P < 0.001), mRS of 0–2 (33.6% vs. 47.8%; OR 0.55; 95% CI 0.43–0.70; P < 0.001), as well as significantly higher mortality (19.4% vs. 11.5%; OR 2.05; 95% CI 1.79–2.36; P < 0.001) and higher incidence of sICH (6.4% vs. 4.1%; OR 1.60; 95% CI 1.27–2.01; P < 0.001). A comparison of AF patients who were subjected or not to IVT showed that thrombolysis carried a higher risk of sICH (5.7% vs. 1.6%; OR 3.44; 95% CI 2.04–5.82; P < 0.001) and was not associated with a better prognosis. Subgroup analysis in prospective studies also suggested a poorer functional prognosis and higher mortality in AF patients treated with IVT compared with those who did not receive IVT. Some heterogeneity was present in this meta-analysis. Conclusions Acute IS patients with AF had worse outcomes than those without AF after thrombolytic therapy, and had a higher incidence of sICH after thrombolysis than those without thrombolysis. Thrombolysis in ischemic stroke patients with AF should be carefully considered based on clinical factors such as NIHSS score, age, and the type of AF.

scholarly journals Efficacy and safety of thrombolysis for acute ischemic stroke with atrial fibrillation: a meta-analysis

2020 ◽  
Author(s):  
Yunzhen Hu ◽  
Chunmei Ji
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Intravenous Thrombolysis ◽  
Analytical Models ◽  
Efficacy And Safety ◽  
Study Heterogeneity ◽  
Symptomatic Intracranial Hemorrhage

Abstract Background The efficacy and safety of intravenous thrombolysis (IVT) in acute ischemic stroke with atrial fibrillation (AF) were controversial. Methods We performed a meta-analysis of all relevant studies retrieved by systematic searches of the, Embase, and Cochrane databases up to December 31, 2019. Modified Rankin Scale (mRS) scores 0–1 at 90 days, mRS 0–2 at 90 days, overall mortality, and symptomatic intracranial hemorrhage (sICH) incidence were collected as outcome measures. Fixed effects meta-analytical models were used, and between-study heterogeneity was assessed. Results A total of 8,509 patients were enrolled in eighteen studies. In AF IVT versus non-AF IVT studies, AF was associated with a significant decrease in the proportion of patients with mRS of 0–1 (24.1% vs. 34.5%; OR 0.57; 95% CI 0.50–0.65; P = 0.000), mRS of 0–2 (33.6% vs. 47.8%; OR 0.50; 95% CI 0.44–0.57; P = 0.000) and significant higher in mortality (19.4% vs. 11.5%; OR 2.05; 95% CI 1.79–2.36; P = 0.000) and sICH incidence (6.4% vs. 4.1%; OR 1.60; 95% CI 1.27–2.01; P = 0.000). In AF IVT versus AF non-IVT studies, thrombolysis carried a higher risk of sICH (5.7% vs. 1.6%; OR 3.44; 95% CI 2.04–5.82; P = 0.000) instead of a better prognosis. Subgroup analysis in prospective studies also suggested a poorer functional prognosis and higher mortality in AF patients treated IVT compared with non-IVT. Conclusion Patients with AF had worse outcomes than those without AF after thrombolytic therapy. Patients with AF had a higher incidence of sICH after thrombolysis than those without thrombolysis.

scholarly journals Single Cell Center of Mass for the Analysis of BMP Receptor Heterodimers Distributions

2021 ◽  
Vol 7 (11) ◽  
pp. 219
Author(s):  
Hendrik Boog ◽  
Rebecca Medda ◽  
Elisabetta Ada Cavalcanti-Adam
Keyword(s):  
Signaling Pathways ◽  
Single Cells ◽  
Center Of Mass ◽  
Control Cell ◽  
Culture Conditions ◽  
Cell Polarization ◽  
Receptor Complexes ◽  
Cell Shapes ◽  
Distribution Studies ◽  
Receptor Distribution

At the plasma membrane, transmembrane receptors are at the interface between cells and their environment. They allow sensing and transduction of chemical and mechanical extracellular signals. The spatial distribution of receptors and the specific recruitment of receptor subunits to the cell membrane is crucial for the regulation of signaling and cell behavior. However, it is challenging to define what regulates such spatial patterns for receptor localization, as cell shapes are extremely diverse when cells are maintained in standard culture conditions. Bone morphogenetic protein receptors (BMPRs) are serine-threonine kinases, which build heteromeric complexes of BMPRI and II. These are especially interesting targets for receptor distribution studies, since the signaling pathways triggered by BMPR-complexes depends on their dimerization mode. They might exist as preformed complexes, or assemble upon binding of BMP, triggering cell signaling which leads to differentiation or migration. In this work we analyzed BMPR receptor distributions in single cells grown on micropatterns, which allow not only to control cell shape, but also the distribution of intracellular organelles and protein assemblies. We developed a script called ComRed (Center Of Mass Receptor Distribution), which uses center of mass calculations to analyze the shift and spread of receptor distributions according to the different cell shapes. ComRed was tested by simulating changes in experimental data showing that shift and spread of distributions can be reliably detected. Our ComRed-based analysis of BMPR-complexes indicates that receptor distribution depends on cell polarization. The absence of a coordinated internalization after addition of BMP suggests that a rapid and continual recycling of BMPRs might occur. Receptor complexes formation and localization in cells induced by BMP might yield insights into the local regulation of different signaling pathways.

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