scholarly journals Testing the state-dependent model of time perception against experimental evidence

2022 ◽  
Author(s):  
Pirathitha Ravichandran-Schmidt ◽  
Joachim Hass
Keyword(s):  
Time Perception ◽  
Computational Models ◽  
Linear Increase ◽  
The State ◽  
Mammalian Brain ◽  
Scalar Property ◽  
Stimulus Interval ◽  
State Dependent

Coordinated movements, speech and other actions are impossible without precise timing. Realistic computational models of interval timing in the mammalian brain are expected to provide key insights into the underlying mechanisms of timing. Existing computational models of time perception have only been partially replicating experimental observations, such as the linear increase of time, the dopaminergic modulation of this increase, and the scalar property, i.e., the linear increase of the standard deviation of temporal estimates. In this work, we incorporate the state-dependent computational model, which encodes time in the dynamic evolution of network states without the need for a specific network structure into a biologically plausible prefrontal cortex (PFC) model based on in vivo and in vitro recordings of rodents. Specifically, we stimulated 1000 neurons in the beginning and in the end of a range of different time intervals, extracted states of neurons and trained the readout layer based on these states using least squares to predict the respective inter stimulus interval. We show that the naturally occurring heterogeneity in cellular and synaptic parameters in the PFC is sufficient to encode time over several hundreds of milliseconds. The readout faithfully represents the duration between two stimuli applied to the superficial layers of the network, thus fulfilling the requirement of a linear encoding of time. A simulated activation of the D2 dopamine receptor leads to an overestimation and an inactivation to an underestimation of time, in line with experimental results. Furthermore, we show that the scalar property holds true for intervals of several hundred milliseconds, and provide a mechanistic explanation for the origin of the scalar property as well as its deviations. We conclude that this model can represent durations up to 750 ms in a biophysically plausible setting, compatible with experimental findings in this regime.

Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

2019 ◽  
Vol 14 (1) ◽  
pp. 5-18 ◽  
Author(s):  
Fabrizio Fontana ◽  
Michela Raimondi ◽  
Monica Marzagalli ◽  
Roberta M. Moretti ◽  
Marina Montagnani Marelli ◽  
...  
Keyword(s):  
Cancer Prevention ◽  
State Of The Art ◽  
Synergistic Effects ◽  
The State ◽  
Therapeutic Interventions ◽  
Multiple Tumor ◽  
Anti Cancer ◽  
Important Health

Background: Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.Objective:The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.Methods:Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.Results:TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.Conclusion:The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

Current trends in mathematical modeling of tumor–microenvironment interactions: a survey of tools and applications

2010 ◽  
Vol 235 (4) ◽  
pp. 411-423 ◽  
Author(s):  
Katarzyna A Rejniak ◽  
Lisa J McCawley
Keyword(s):  
Mathematical Modeling ◽  
Protein Interactions ◽  
Computational Models ◽  
Chemical Species ◽  
Tumor Stroma ◽  
Cellular Functions ◽  
Complex Interactions ◽  
Expanding Population

In its simplest description, a tumor is comprised of an expanding population of transformed cells supported by a surrounding microenvironment termed the tumor stroma. The tumor microcroenvironment has a very complex composition, including multiple types of stromal cells, a dense network of various extracellular matrix (ECM) fibers interpenetrated by the interstitial fluid and gradients of several chemical species that either are dissolved in the fluid or are bound to the ECM structure. In order to study experimentally such complex interactions between multiple players, cancer is dissected and considered at different scales of complexity, such as protein interactions, biochemical pathways, cellular functions or whole organism studies. However, the integration of information acquired from these studies into a common description is as difficult as the disease itself. Computational models of cancer can provide cancer researchers with invaluable tools that are capable of integrating the complexity into organizing principles as well as suggesting testable hypotheses. We will focus in this Minireview on mathematical models in which the whole cell is a main modeling unit. We will present a current stage of such cell-focused mathematical modeling incorporating different stromal components and their interactions with growing tumors, and discuss what modeling approaches can be undertaken to complement the in vivo and in vitro experimentation.

Electrophysiological characterization and computational models of HVC neurons in the zebra finch

2013 ◽  
Vol 110 (5) ◽  
pp. 1227-1245 ◽  
Author(s):  
Arij Daou ◽  
Matthew T. Ross ◽  
Frank Johnson ◽  
Richard L. Hyson ◽  
Richard Bertram
Keyword(s):  
Computational Models ◽  
Premotor Cortex ◽  
Brain Slices ◽  
Ionic Currents ◽  
Proper Name ◽  
Using Data ◽  
Electrophysiological Characterization

The nucleus HVC (proper name) within the avian analog of mammal premotor cortex produces stereotyped instructions through the motor pathway leading to precise, learned vocalization by songbirds. Electrophysiological characterization of component HVC neurons is an important requirement in building a model to understand HVC function. The HVC contains three neural populations: neurons that project to the RA (robust nucleus of arcopallium), neurons that project to Area X (of the avian basal ganglia), and interneurons. These three populations are interconnected with specific patterns of excitatory and inhibitory connectivity, and they fire with characteristic patterns both in vivo and in vitro. We performed whole cell current-clamp recordings on HVC neurons within brain slices to examine their intrinsic firing properties and determine which ionic currents are responsible for their characteristic firing patterns. We also developed conductance-based models for the different neurons and calibrated the models using data from our brain slice work. These models were then used to generate predictions about the makeup of the ionic currents that are responsible for the different responses to stimuli. These predictions were then tested and verified in the slice using pharmacological manipulations. The model and the slice work highlight roles of a hyperpolarization-activated inward current ( Ih), a low-threshold T-type Ca2+ current ( ICa-T), an A-type K+ current ( IA), a Ca2+-activated K+ current ( ISK), and a Na+-dependent K+ current ( IKNa) in driving the characteristic neural patterns observed in the three HVC neuronal populations. The result is an improved characterization of the HVC neurons responsible for song production in the songbird.

Age-dependent changes in volume and haemoglobin content of erythrocytes in the carp (Cyprinus carpio L.)

1989 ◽  
Vol 141 (1) ◽  
pp. 133-149 ◽  
Author(s):  
W. Speckner ◽  
J. F. Schindler ◽  
C. Albers
Keyword(s):  
Gel Filtration ◽  
Linear Increase ◽  
Human Erythrocytes ◽  
Main Peak ◽  
Red Cell ◽  
Human Haemoglobin ◽  
Cell Fractions ◽  
Haemoglobin Content

Carp erythrocytes were fractionated by angle-head centrifugation which yielded fractions with a linear increase in density. Haematological examinations revealed that the heavier red blood cells of carp had greater volumes (MCV), more haemoglobin (MCH) and higher haemoglobin concentrations (MCHC) than light ones. The same experiments with human red cell fractions yielded a decrease in MCV, constant MCH and an increase in MCHC. Haemoglobin content in individual erythrocytes was also determined by scanning stage absorbance cytophotometry to establish the frequency distribution of the cellular haemoglobin contents. In carp, the distribution was symmetrical with the means increasing with density. No such change with cell density was found in human erythrocytes. Both carp and human erythrocytes incorporated [2-14C]glycine in vitro. After gel filtration, radioactivity was detected in carp, but not in human, haemoglobin fractions. 14C was found in all three haemoglobin fractions, obtained by isoelectric focusing, and was present in the haem and in the globin. [2-14C]glycine-labelled erythrocytes were reinjected into chronically cannulated carp and followed in vivo for several months. With time, the main peak of scintillation counts shifted from red cell fractions of low to high density. This is considered as evidence that density and age of red cells in carp are positively correlated and that erythrocytes can synthesize haemoglobin while circulating in the peripheral blood.

scholarly journals Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047522
Author(s):  
Abdul Jalil Rufaihah ◽  
Ching Kit Chen ◽  
Choon Hwai Yap ◽  
Citra N. Z. Mattar
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Computational Models ◽  
Developing Heart ◽  
Heterogenous Group ◽  
In Silico Models ◽  
Large Animals

ABSTRACTBirth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.

scholarly journals Imaging Subthreshold Voltage Oscillation With Cellular Resolution in the Inferior Olive in vitro

2020 ◽  
Vol 14 ◽  
Author(s):  
Kevin Dorgans ◽  
Bernd Kuhn ◽  
Marylka Yoe Uusisaari
Keyword(s):  
Inferior Olive ◽  
Brain Slices ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Wide Field ◽  
Voltage Imaging ◽  
Subthreshold Oscillations ◽  
Cellular Resolution

Voltage imaging with cellular resolution in mammalian brain slices is still a challenging task. Here, we describe and validate a method for delivery of the voltage-sensitive dye ANNINE-6plus (A6+) into tissue for voltage imaging that results in higher signal-to-noise ratio (SNR) than conventional bath application methods. The not fully dissolved dye was injected into the inferior olive (IO) 0, 1, or 7 days prior to acute slice preparation using stereotactic surgery. We find that the voltage imaging improves after an extended incubation period in vivo in terms of labeled volume, homogeneous neuropil labeling with saliently labeled somata, and SNR. Preparing acute slices 7 days after the dye injection, the SNR is high enough to allow single-trial recording of IO subthreshold oscillations using wide-field (network-level) as well as high-magnification (single-cell level) voltage imaging with a CMOS camera. This method is easily adaptable to other brain regions where genetically-encoded voltage sensors are prohibitively difficult to use and where an ultrafast, pure electrochromic sensor, like A6+, is required. Due to the long-lasting staining demonstrated here, the method can be combined, for example, with deep-brain imaging using implantable GRIN lenses.

scholarly journals THE SPECIFICITY OF ALLERGIC REACTIONS

1963 ◽  
Vol 117 (3) ◽  
pp. 401-423 ◽  
Author(s):  
John E. Coe ◽  
S. B. Salvin
Keyword(s):  
Immune Response ◽  
Guinea Pig ◽  
The State ◽  
Delayed Hypersensitivity ◽  
Protein Carrier ◽  
Specific Contact ◽  
Tolerant Animal ◽  
Gastric Feeding

"Gastric feeding" of adult guinea pigs with dinitrochlorobenzene (DCB) resulted in a specific unresponsiveness to sensitization with the specific contact hapten. The more DCB gastric-fed to a guinea pig, the more complete the unresponsiveness to the hapten. When mycobacteria were incorporated into the sensitizing emulsion, the state of unresponsiveness to the dinitrophenyl (DNP) group was less apparent. When animals gastric-fed with DCB were later sensitized with an in vitro conjugate of the hapten combined with a heterologous protein such as dinitrophenyl-hen egg albumin (DNP·HEA), an immune response similar to that in the controls occurred both to the hapten and to the protein carrier. However, when the tolerant animals were sensitized with a conjugate containing a homologous protein carrier such as dinitrophenyl guinea pig serum (DNP·GPS), they showed diminished immune responses in comparison with those in the non-tolerant controls. The presence of circulating anti-DNP antibodies from sensitization with DNP-HEA did not affect the unresponsiveness to the specific contact hapten, regardless of whether these antibodies are present before or after induction of tolerance. Sensitization with picryl chloride (PiCl) (a cross-reacting hapten), either before or after gastric feeding of DCB, did not affect the state of unresponsiveness to DNP. Similarly when the DNP-tolerant animal was sensitized with PiCl, the subsequent immune response was similar to that in the controls; cross-reactions with the DNP group both in the contact and circulating antibody phase occurred at a rate similar to that in the controls. The foregoing relationships can be explained by presuming that, upon the gastric feeding of DCB, an in vivo conjugate is formed with a somatic protein, which determines the basic specificity of the tolerance. Acquired tolerance seems to manifest an immunologic specificity similar to that of delayed hypersensitivity, a relationship not unexpected if delayed hypersensitivity is an early phase of the immune response.

scholarly journals Prediction of Aerosol Deposition in the Human Respiratory Tract via Computational Models: A Review with Recent Updates

Atmosphere ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 137 ◽  
Author(s):  
Vu Khac Hoang Bui ◽  
Ju-Young Moon ◽  
Minhe Chae ◽  
Duckshin Park ◽  
Young-Chul Lee
Keyword(s):  
Respiratory Tract ◽  
Particle Deposition ◽  
Computational Models ◽  
Aerosol Particles ◽  
Three Dimensional ◽  
Aerosol Deposition ◽  
Research Area ◽  
Human Respiratory Tract

The measurement of deposited aerosol particles in the respiratory tract via in vivo and in vitro approaches is difficult due to those approaches’ many limitations. In order to overcome these obstacles, different computational models have been developed to predict the deposition of aerosol particles inside the lung. Recently, some remarkable models have been developed based on conventional semi-empirical models, one-dimensional whole-lung models, three-dimensional computational fluid dynamics models, and artificial neural networks for the prediction of aerosol-particle deposition with a high accuracy relative to experimental data. However, these models still have some disadvantages that should be overcome shortly. In this paper, we take a closer look at the current research trends as well as the future directions of this research area.

scholarly journals Models of tendon development and injury

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Sophia K. Theodossiou ◽  
Nathan R. Schiele
Keyword(s):  
Computational Models ◽  
Ex Vivo ◽  
Current Model ◽  
Stem Cell Differentiation ◽  
Tendon Injury ◽  
Model Systems ◽  
Tendon Development ◽  
Key Aspects

AbstractTendons link muscle to bone and transfer forces necessary for normal movement. Tendon injuries can be debilitating and their intrinsic healing potential is limited. These challenges have motivated the development of model systems to study the factors that regulate tendon formation and tendon injury. Recent advances in understanding of embryonic and postnatal tendon formation have inspired approaches that aimed to mimic key aspects of tendon development. Model systems have also been developed to explore factors that regulate tendon injury and healing. We highlight current model systems that explore developmentally inspired cellular, mechanical, and biochemical factors in tendon formation and tenogenic stem cell differentiation. Next, we discuss in vivo, in vitro, ex vivo, and computational models of tendon injury that examine how mechanical loading and biochemical factors contribute to tendon pathologies and healing. These tendon development and injury models show promise for identifying the factors guiding tendon formation and tendon pathologies, and will ultimately improve regenerative tissue engineering strategies and clinical outcomes.

scholarly journals A Method to Estimate Synaptic Conductances From Membrane Potential Fluctuations

2004 ◽  
Vol 91 (6) ◽  
pp. 2884-2896 ◽  
Author(s):  
Michael Rudolph ◽  
Zuzanna Piwkowska ◽  
Mathilde Badoual ◽  
Thierry Bal ◽  
Alain Destexhe
Keyword(s):  
Membrane Potential ◽  
Computational Models ◽  
Network Activity ◽  
Intracellular Recordings ◽  
Neocortical Neurons ◽  
Underlying Network ◽  
Analytic Expression ◽  
Synaptic Conductances

In neocortical neurons, network activity can activate a large number of synaptic inputs, resulting in highly irregular subthreshold membrane potential ( Vm) fluctuations, commonly called “synaptic noise.” This activity contains information about the underlying network dynamics, but it is not easy to extract network properties from such complex and irregular activity. Here, we propose a method to estimate properties of network activity from intracellular recordings and test this method using theoretical and experimental approaches. The method is based on the analytic expression of the subthreshold Vm distribution at steady state in conductance-based models. Fitting this analytic expression to Vm distributions obtained from intracellular recordings provides estimates of the mean and variance of excitatory and inhibitory conductances. We test the accuracy of these estimates against computational models of increasing complexity. We also test the method using dynamic-clamp recordings of neocortical neurons in vitro. By using an on-line analysis procedure, we show that the measured conductances from spontaneous network activity can be used to re-create artificial states equivalent to real network activity. This approach should be applicable to intracellular recordings during different network states in vivo, providing a characterization of the global properties of synaptic conductances and possible insight into the underlying network mechanisms.

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