Modeling Reaching Impairment After Stroke Using a Population Vector Model of Movement Control That Incorporates Neural Firing-Rate Variability

2003 ◽  
Vol 15 (11) ◽  
pp. 2619-2642 ◽  
Author(s):  
David J. Reinkensmeyer ◽  
Mario G. Iobbi ◽  
Leonard E. Kahn ◽  
Derek G. Kamper ◽  
Craig D. Takahashi
Keyword(s):  
Cell Death ◽  
Standard Deviation ◽  
Firing Rate ◽  
Movement Control ◽  
Vector Model ◽  
Neural Firing ◽  
Population Vector ◽  
Directional Error ◽  
Wide Range ◽  
Impairment Severity

The directional control of reaching after stroke was simulated by including cell death and firing-rate noise in a population vector model of movement control. In this model, cortical activity was assumed to cause the hand to move in the direction of a population vector, defined by a summation of responses from neurons with cosine directional tuning. Two types of directional error were analyzed: the between-target variability, defined as the standard deviation of the directional error across a wide range of target directions, and the within-target variability, defined as the standard deviation of the directional error for many reaches to a single target. Both between and within-target variability increased with increasing cell death. The increase in between-target variability arose because cell death caused a nonuniform distribution of preferred directions. The increase in within-target variability arose because the magnitude of the population vector decreased more quickly than its standard deviation for increasing cell death, provided appropriate levels of firing-rate noise were present. Comparisons to reaching data from 29 stroke subjects revealed similar increases in between and within-target variability as clinical impairment severity increased. Relationships between simulated cell death and impairment severity were derived using the between and within-target variability results. For both relationships, impairment severity increased similarly with decreasing percentage of surviving cells, consistent with results from previous imaging studies. These results demonstrate that a population vector model of movement control that incorporates cosine tuning, linear summation of unitary responses, firing-rate noise, and random cell death can account for some features of impaired arm movement after stroke.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

2019 ◽  
Vol 19 (5) ◽  
pp. 599-609 ◽  
Author(s):  
Sumathi Sundaravadivelu ◽  
Sonia K. Raj ◽  
Banupriya S. Kumar ◽  
Poornima Arumugamand ◽  
Padma P. Ragunathan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Black Cumin ◽  
In Silico Docking ◽  
Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

scholarly journals Individual Expression of Hepatitis A Virus 3C Protease Induces Ferroptosis in Human Cells In Vitro

2021 ◽  
Vol 22 (15) ◽  
pp. 7906
Author(s):  
Alexey A. Komissarov ◽  
Maria A. Karaseva ◽  
Marina P. Roschina ◽  
Andrey V. Shubin ◽  
Nataliya A. Lunina ◽  
...  
Keyword(s):  
Cell Death ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Proteolytic Enzymes ◽  
Morphological Changes ◽  
Human Cells ◽  
Mitochondrial Potential ◽  
3C Protease ◽  
Wide Range

Regulated cell death (RCD) is a fundamental process common to nearly all living beings and essential for the development and tissue homeostasis in animals and humans. A wide range of molecules can induce RCD, including a number of viral proteolytic enzymes. To date, numerous data indicate that picornaviral 3C proteases can induce RCD. In most reported cases, these proteases induce classical caspase-dependent apoptosis. In contrast, the human hepatitis A virus 3C protease (3Cpro) has recently been shown to cause caspase-independent cell death accompanied by previously undescribed features. Here, we expressed 3Cpro in HEK293, HeLa, and A549 human cell lines to characterize 3Cpro-induced cell death morphologically and biochemically using flow cytometry and fluorescence microscopy. We found that dead cells demonstrated necrosis-like morphological changes including permeabilization of the plasma membrane, loss of mitochondrial potential, as well as mitochondria and nuclei swelling. Additionally, we showed that 3Cpro-induced cell death was efficiently blocked by ferroptosis inhibitors and was accompanied by intense lipid peroxidation. Taken together, these results indicate that 3Cpro induces ferroptosis upon its individual expression in human cells. This is the first demonstration that a proteolytic enzyme can induce ferroptosis, the recently discovered and actively studied type of RCD.

scholarly journals Variance prior specification for a basket trial design using Bayesian hierarchical modeling

2018 ◽  
Vol 16 (2) ◽  
pp. 142-153 ◽  
Author(s):  
Kristen M Cunanan ◽  
Alexia Iasonos ◽  
Ronglai Shen ◽  
Mithat Gönen
Keyword(s):  
Standard Deviation ◽  
Prior Distribution ◽  
Hierarchical Modeling ◽  
Bayesian Hierarchical Modeling ◽  
Bayesian Hierarchical ◽  
Inverse Gamma ◽  
Wide Range ◽  
Basket Trial ◽  
Basket Trials ◽  
Variance Parameter

Background: In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared across baskets. Methods: A common approach used to capture the correlated binary endpoints across baskets is Bayesian hierarchical modeling. We evaluate a Bayesian adaptive design in the context of a non-randomized basket trial and investigate three popular prior specifications: an inverse-gamma prior on the basket-level variance, a uniform prior and half-t prior on the basket-level standard deviation. Results: From our simulation study, we can see that the inverse-gamma prior is highly sensitive to the input hyperparameters. When the prior mean value of the variance parameter is set to be near zero [Formula: see text], this can lead to unacceptably high false-positive rates [Formula: see text] in some scenarios. Thus, use of this prior requires a fully comprehensive sensitivity analysis before implementation. Alternatively, we see that a prior that places sufficient mass in the tail, such as the uniform or half-t prior, displays desirable and robust operating characteristics over a wide range of prior specifications, with the caveat that the upper bound of the uniform prior and the scale parameter of the half-t prior must be larger than 1. Conclusion: Based on the simulation results, we recommend that those involved in designing basket trials that implement hierarchical modeling avoid using a prior distribution that places a majority of the density mass near zero for the variance parameter. Priors with this property force the model to share information regardless of the true efficacy configuration of the baskets. Many commonly used inverse-gamma prior specifications have this undesirable property. We recommend to instead consider the more robust uniform prior or half-t prior on the standard deviation.

scholarly journals Cell Death and Survival Pathways Involving ATM Protein Kinase

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1581
Author(s):  
Toshihiko Aki ◽  
Koichi Uemura
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genotoxic Stress ◽  
Short Review ◽  
Research Progress ◽  
Cellular Protection ◽  
Cellular Survival ◽  
Cell Death Pathways ◽  
Wide Range ◽  
Atm Protein

Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.

scholarly journals The “ARTS” of Cell Death in Service of Life: How Do We Force Cancer Cells to Commit Suicide?

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarit Larisch
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Novel Therapy ◽  
The Arts ◽  
Wide Range ◽  
Cell Death Program ◽  
Cancerous Cells ◽  
Critical Process ◽  
Cells Death ◽  
Commit Suicide

Every cell in our body contains a “self-destruction” program. This cell death is a critical process allowing replacement of damaged cells with healthy ones to prevent wide range of diseases. When the cell’s death mechanism gets “stuck” and is not activated, cancer can result. In healthy cells there is a balanced system of proteins, some of which activate the normal death mechanism, and some of which inhibit this process. This is like the system of gas and brakes in a car. Researchers have found that cancer cells lack a protein, called ARTS, which is crucial for activating the cells’ death mechanism. The lack of ARTS causes cancer cells to escape death and become “immortal.” Small ARTS-like molecules have been discovered that can penetrate cancerous cells and reactivate the cell death program, effectively making the cancer cells “commit suicide.” We envision that these ARTS-like molecules will provide novel therapy for cancer.

Vision-based target point tracking and aiming method

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Xiao Bo Liang ◽  
Xinghua Qu ◽  
YuanJun Zhang ◽  
Lianyin Xu ◽  
Fumin Zhang
Keyword(s):  
Standard Deviation ◽  
Target Tracking ◽  
High Precision ◽  
Visual Tracking ◽  
Laser Ranging ◽  
Content Type ◽  
Mean Error ◽  
Wide Range ◽  
The Mean ◽  
Correlation Filtering

Purpose Laser absolute distance measurement has the characteristics of high precision, wide range and non-contact. In laser ranging system, tracking and aiming measurement point is the precondition of automatic measurement. To solve this problem, this paper aims to propose a novel method. Design/methodology/approach For the central point of the hollow angle coupled mirror, this paper proposes a method based on correlation filtering and ellipse fitting. For non-cooperative target points, this paper proposes an extraction method based on correlation filtering and feature matching. Finally, a visual tracking and aiming system was constructed by combining the two-axis turntable, and experiments were carried out. Findings The target tracking algorithm has an accuracy of 91.15% and a speed of 19.5 frames per second. The algorithm can adapt to the change of target scale and short-term occlusion. The mean error and standard deviation of the center point extraction of the hollow Angle coupling mirror are 0.20 and 0.09 mm. The mean error and standard deviation of feature points matching for non-cooperative target were 0.06 mm and 0.16 mm. The visual tracking and aiming system can track a target running at a speed of 0.7 m/s, aiming error mean is 1.74 pixels and standard deviation is 0.67 pixel. Originality/value The results show that this method can achieve fast and high precision target tracking and aiming and has great application value in laser ranging.

Cell death and the development of limb form and skeletal pattern in normal and wingless (ws) chick embryos

Development ◽  
1973 ◽  
Vol 30 (3) ◽  
pp. 753-772
Author(s):  
J. R. Hinchliffe ◽  
D. A. Ede
Keyword(s):  
Cell Death ◽  
Phenotypic Expression ◽  
Mesenchymal Cell ◽  
Limb Bud ◽  
Death Process ◽  
Electron Microscopic ◽  
Wide Range ◽  
Skeletal Pattern ◽  
Autoradiographic Analysis ◽  
Mutant Phenotypes

The wingless condition resulting from the action of the sex-linked wingless (ws) gene arises from the precocious appearance of cell death in the anterior necrotic zone (ANZ) of the forelimb-bud at stage 19 (3 days) and its progressive extension beyond its normal area during stages 20–23. A similar though less pronounced effect occurs in the hindlimb-bud. Although some wingless hindlimb-buds are normal, others are affected by the precocious appearance of cell death in the ANZ. The ws wingless mutant resembles the different wingless mutant investigated by Zwilling (1956) in that the apical ectodermal ridge (AER) is absent in most ws wing-buds. AER absence could be due to ws mesenchymal cell death interfering with the production of apical ectodermal maintenance factor (AEMF), which Zwilling claims is necessary to maintain the AER which plays an essential role in inducing limb outgrowth. Wingless mutant phenotypes range from birds with rudimentary wings and normal legs through a modal type with forelimbs absent and hindlimbs normal to wingless and legless forms showing a high degree of expressivity. Individual wingless embryos vary in the degree to which the precocious ANZ appearing at 3 days is extended into the limb-bud and the wide range of wingless phenotypic expression is attributed to this variation. Electron microscopic and histochemical analysis of the cell death process in wingless wing-buds revealed the presence of both isolated dead cells and macrophages, which contained intense acid phosphatase activity. These findings are interpreted as showing that isolated dead cells are ingested by neighbouring mesenchymal cells which thus become transformed into macrophages, first ingesting and then digesting further dead cells. A study was made of the origin of the anomalous hindlimb condition, including absence or reduction of the tibia and digits, characteristic of severely affected wingless embryos. Autoradiographic analysis of the pattern of 35SO4 uptake revealed that at stage 24/5 (4½ days) wingless hindlimb-buds which were smaller than normal had a normal prospective fibula region, but that the prospective tibia region was small or absent. Thus the effect of a precocious hindlimb ANZ at stages 19–22 is to reduce or delete the pre-axial prospective tibia at stage 24/5.

Possible Effects of Depolarizing GABAA Conductance on the Neuronal Input–Output Relationship: A Modeling Study

2005 ◽  
Vol 93 (6) ◽  
pp. 3504-3523 ◽  
Author(s):  
Kenji Morita ◽  
Kunichika Tsumoto ◽  
Kazuyuki Aihara
Keyword(s):  
Firing Rate ◽  
Cortical Neurons ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Input Output ◽  
Wide Range ◽  
The Relationship

Recent in vitro experiments revealed that the GABAA reversal potential is about 10 mV higher than the resting potential in mature mammalian neocortical pyramidal cells; thus GABAergic inputs could have facilitatory, rather than inhibitory, effects on action potential generation under certain conditions. However, how the relationship between excitatory input conductances and the output firing rate is modulated by such depolarizing GABAergic inputs under in vivo circumstances has not yet been understood. We examine herewith the input–output relationship in a simple conductance-based model of cortical neurons with the depolarized GABAA reversal potential, and show that a tonic depolarizing GABAergic conductance up to a certain amount does not change the relationship between a tonic glutamatergic driving conductance and the output firing rate, whereas a higher GABAergic conductance prevents spike generation. When the tonic glutamatergic and GABAergic conductances are replaced by in vivo–like highly fluctuating inputs, on the other hand, the effect of depolarizing GABAergic inputs on the input–output relationship critically depends on the degree of coincidence between glutamatergic input events and GABAergic ones. Although a wide range of depolarizing GABAergic inputs hardly changes the firing rate of a neuron driven by noncoincident glutamatergic inputs, a certain range of these inputs considerably decreases the firing rate if a large number of driving glutamatergic inputs are coincident with them. These results raise the possibility that the depolarized GABAA reversal potential is not a paradoxical mystery, but is instead a sophisticated device for discriminative firing rate modulation.

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