scholarly journals Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations, and intrinsic excitability of entorhinal stellate cells

2018 ◽  
Vol 120 (2) ◽  
pp. 576-600 ◽  
Author(s):  
Divyansh Mittal ◽  
Rishikesh Narayanan
Keyword(s):  
Stellate Cells ◽  
Gamma Band ◽  
Heterogeneous Population ◽  
Coincidence Detection ◽  
Physiological Characteristics ◽  
Spectral Selectivity ◽  
Theta Frequency ◽  
Detection Capabilities ◽  
The Impact ◽  
Channel Properties

Biological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in channel properties, the impact of such heterogeneities on the robustness of their cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning nine voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 in vitro electrophysiological characteristics of LII stellate cells (SCs). We generated 150,000 models and found a heterogeneous subpopulation of 449 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma-band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale-efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function. NEW & NOTEWORTHY We assessed the impact of heterogeneities in channel properties on the robustness of cellular-scale physiology of medial entorhinal cortical stellate neurons. We demonstrate that neuronal models with disparate channel combinations were endowed with similar physiological characteristics, as a consequence of the many-to-many mapping between channel properties and the physiological characteristics that they modulate. We predict that the spike-triggered average of stellate cells should be endowed with theta-frequency spectral selectivity and fast gamma-band coincidence detection capabilities.

scholarly journals Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations and intrinsic excitability of entorhinal stellate cells

2017 ◽  
Author(s):  
Divyansh Mittal ◽  
Rishikesh Narayanan
Keyword(s):  
Stellate Cells ◽  
Heterogeneous Population ◽  
Coincidence Detection ◽  
Medial Entorhinal Cortex ◽  
Efficient Coding ◽  
Spectral Selectivity ◽  
Pairwise Correlations ◽  
Theta Frequency ◽  
Detection Capabilities ◽  
The Impact

ABSTRACTBiological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in their channel properties, the impact of such heterogeneities on the robustness of cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning 9 voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 electrophysiological characteristics of LII stellate cells (SCs). We generated 50,000 models and found a heterogeneous subpopulation of 155 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in LII SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of LII SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma-band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function.KEY POINTSStellate cells (SC) in layer II (LII) of the medial entorhinal cortex express cellular-scale degeneracy in the concomitant manifestation of several of their unique physiological signatures.Several disparate parametric combinations expressing weak pairwise correlations resulted in models with very similar physiological characteristics, including robust theta-frequency membrane potential oscillations spanning several levels of subthreshold depolarization.Electrophysiological measurements of LII SCs exhibited differential and variable dependencies on underlying channels, and the mapping between channels and measurements was many-to-many.Quantitative predictions point to theta-frequency spectral selectivity and fast gamma-range coincidence detection capabilities in class II/III spike-triggered average of LII SCs, with the postulate for this to be an instance of cellular-scale efficient coding.A heterogeneous cell population that accounts for both channel and intrinsic heterogeneities in LII SCs, which could be employed by network models of entorhinal function to probe the impact of several biological heterogeneities on spatial navigation circuits.

scholarly journals Theta-frequency selectivity in the somatic spike-triggered average of rat hippocampal pyramidal neurons is dependent on HCN channels

2017 ◽  
Vol 118 (4) ◽  
pp. 2251-2266 ◽  
Author(s):  
Anindita Das ◽  
Rishikesh Narayanan
Keyword(s):  
Pyramidal Neurons ◽  
Frequency Selectivity ◽  
Coincidence Detection ◽  
Hcn Channels ◽  
Hippocampal Pyramidal Neurons ◽  
Gamma Frequency ◽  
Spectral Selectivity ◽  
Electrophysiological Recordings ◽  
Theta Frequency ◽  
Spike Initiation

The ability to distill specific frequencies from complex spatiotemporal patterns of afferent inputs is a pivotal functional requirement for neurons residing in networks receiving frequency-multiplexed inputs. Although the expression of theta-frequency subthreshold resonance is established in hippocampal pyramidal neurons, it is not known if their spike initiation dynamics manifest spectral selectivity, or if their intrinsic properties are tuned to process gamma-frequency inputs. Here, we measured the spike-triggered average (STA) of rat hippocampal pyramidal neurons through electrophysiological recordings and quantified spectral selectivity in their spike initiation dynamics and their coincidence detection window (CDW). Our results revealed strong theta-frequency selectivity in the STA, which was also endowed with gamma-range CDW, with prominent neuron-to-neuron variability that manifested distinct pairwise dissociations and correlations with different intrinsic measurements. Furthermore, we demonstrate that the STA and its measurements substantially adapted to the state of the neuron defined by its membrane potential and to the statistics of its afferent inputs. Finally, we tested the effect of pharmacologically blocking the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels on the STA and found that the STA characteristic frequency reduced significantly to the delta-frequency band after HCN channel blockade. This delta-frequency selectivity in the STA emerged in the absence of subthreshold resonance, which was abolished by HCN channel blockade, thereby confirming computational predictions on the dissociation between these two forms of spectral selectivity. Our results expand the roles of HCN channels to theta-frequency selectivity in the spike initiation dynamics, apart from underscoring the critical role of interactions among different ion channels in regulating neuronal physiology. NEW & NOTEWORTHY We had previously predicted, using computational analyses, that the spike-triggered average (STA) of hippocampal neurons would exhibit theta-frequency (4–10 Hz) spectral selectivity and would manifest coincidence detection capabilities for inputs in the gamma-frequency band (25–150 Hz). Here, we confirmed these predictions through direct electrophysiological recordings of STA from rat CA1 pyramidal neurons and demonstrate that blocking HCN channels reduces the frequency of STA spectral selectivity to the delta-frequency range (0.5–4 Hz).

scholarly journals Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3628
Author(s):  
Manoj Amrutkar ◽  
Nils Tore Vethe ◽  
Caroline S. Verbeke ◽  
Monica Aasrum ◽  
Anette Vefferstad Finstadsveen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Stellate Cells ◽  
Drug Uptake ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
The Impact

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.

SEARCHING FOR AXIONS AND OTHER EXOTICS WITH DARK MATTER DETECTORS

2010 ◽  
Vol 25 (02n03) ◽  
pp. 564-572
Author(s):  
MAXIM POSPELOV
Keyword(s):  
Dark Matter ◽  
Standard Model ◽  
Cold Dark Matter ◽  
Direct Detection ◽  
Annual Modulation ◽  
The Standard Model ◽  
Detection Capabilities ◽  
The Impact ◽  
Particle Decays ◽  
O 10

I consider models of light super-weakly interacting cold dark matter, with [Formula: see text] mass, focusing on bosonic candidates such as pseudoscalars and vectors. I analyze the cosmological abundance, the γ-background created by particle decays, the impact on stellar processes due to cooling, and the direct detection capabilities in order to identify classes of models that pass all the constraints. In certain models, variants of photoelectric (or axioelectric) absorption of dark matter in direct-detection experiments can provide a sensitivity to the superweak couplings to the Standard Model which is superior to all existing indirect constraints. In all models studied, the annual modulation of the direct-detection signal is at the currently unobservable level of O(10-5).

scholarly journals Pharmacotherapy: Its impact on morphofunctional characteristics of the epidermal barrier

2019 ◽  
Vol 95 (1) ◽  
pp. 59-76 ◽  
Author(s):  
D. D. Petrunin
Keyword(s):  
Literature Review ◽  
Systemic Therapy ◽  
Skin Disease ◽  
Barrier Properties ◽  
Physiological Characteristics ◽  
Human Epidermis ◽  
Disease Treatment ◽  
Epidermal Barrier ◽  
The Impact

Various pharmaceuticals used for topical and systemic therapy are capable of exerting significant impact on morphological and physiological characteristics of human epidermis, as well as its barrier properties. This may affect the course of dermatologic diseases and the efficacy of their treatment. In this literature review, the author analyzes the impact of various pharmaceutical classes on the morphofunctional characteristics of the epidermal barrier and formulates recommendations for skin disease treatment.

scholarly journals Vaccine escape in a heterogeneous population: insights for SARS-CoV-2 from a simple model

2021 ◽  
Vol 8 (7) ◽  
pp. 210530
Author(s):  
Julia R. Gog ◽  
Edward M. Hill ◽  
Leon Danon ◽  
Robin N. Thompson
Keyword(s):  
Mathematical Model ◽  
Clinical Trial ◽  
Immune Response ◽  
Simple Model ◽  
Selection Pressure ◽  
Heterogeneous Population ◽  
Reproduction Ratio ◽  
Contact Rates ◽  
Vaccination Campaigns ◽  
The Impact

As a countermeasure to the SARS-CoV-2 pandemic, there has been swift development and clinical trial assessment of candidate vaccines, with subsequent deployment as part of mass vaccination campaigns. However, the SARS-CoV-2 virus has demonstrated the ability to mutate and develop variants, which can modify epidemiological properties and potentially also the effectiveness of vaccines. The widespread deployment of highly effective vaccines may rapidly exert selection pressure on the SARS-CoV-2 virus directed towards mutations that escape the vaccine-induced immune response. This is particularly concerning while infection is widespread. By developing and analysing a mathematical model of two population groupings with differing vulnerability and contact rates, we explore the impact of the deployment of vaccines among the population on the reproduction ratio, cases, disease abundance and vaccine escape pressure. The results from this model illustrate two insights: (i) vaccination aimed at reducing prevalence could be more effective at reducing disease than directly vaccinating the vulnerable; (ii) the highest risk for vaccine escape can occur at intermediate levels of vaccination. This work demonstrates a key principle: the careful targeting of vaccines towards particular population groups could reduce disease as much as possible while limiting the risk of vaccine escape.

scholarly journals Epigenetic mechanisms driving tumor supportive microenvironment differentiation and function: a role in cancer therapy?

Epigenomics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 157-169 ◽  
Author(s):  
Marvin Sylvestre ◽  
Karin Tarte ◽  
David Roulois
Keyword(s):  
Stromal Cell ◽  
Somatic Mutations ◽  
Tumor Development ◽  
Cell Subset ◽  
Heterogeneous Population ◽  
Cancer Associated Fibroblasts ◽  
Epigenetic Mechanisms ◽  
Immunosuppressive Microenvironment ◽  
And Function ◽  
The Impact

The tumor microenvironment (TME) plays a central role in tumor development and drug resistance. Within TME, the stromal cell subset, called cancer-associated fibroblasts, is a heterogeneous population originating from poorly characterized precursors. Since cancer-associated fibroblasts do not acquire somatic mutations, other mechanisms like epigenetic regulation, could be involved in the development of these cells and in the acquisition of tumor supportive phenotypes. Moreover, such epigenetic modulations have been correlated to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. These findings underline the need to deepen our knowledge on epigenetic mechanisms driving TME development and function, and to understand the impact of epigenetic drugs that could be used in future to target both tumor cells and their TME.

scholarly journals Physiological state of reused brewing yeast

2013 ◽  
Vol 31 (No. 3) ◽  
pp. 264-269 ◽  
Author(s):  
E. Kordialik-Bogacka ◽  
A. Diowksz
Keyword(s):  
Yeast Strain ◽  
Significant Variation ◽  
Physiological Condition ◽  
Physiological State ◽  
Physiological Characteristics ◽  
Yeast Culture ◽  
Brewing Yeast ◽  
Flavour Compounds ◽  
The Impact ◽  
Is Strain

In brewing, yeast may be reused many times. A number of yeast repitchings differs significantly among the breweries. Adjusting the number of times a strain may be serially repitched is of great importance for quality and consistency of final products. The fermentative and physiological characteristics of the yeast culture used in successive laboratory scale fermentations were determined. Yeast physiological state was assessed by the measurement of the levels of intracellular carbohydrates. In our investigation there were not any detectable changes in yeast capacity to ferment. No significant variation in the production of flavour compounds was found either. However, intracellular glycogen and trehalose contents were dependant on the yeast strain, generation number and wort gravity. Nevertheless, an alteration in the yeast physiological condition during serial repitchings occurred in a different mode than in previous studies confirming that the impact of serial repitchings is strain and medium dependent to a large extent.  

Physiologic Basis of Symptoms in Pleural Disease

2019 ◽  
Vol 40 (03) ◽  
pp. 305-313
Author(s):  
Erin M. DeBiasi ◽  
David Feller-Kopman
Keyword(s):  
Pleural Effusion ◽  
Respiratory Mechanics ◽  
Respiratory Muscles ◽  
Heterogeneous Population ◽  
Pleural Pressure ◽  
Routine Monitoring ◽  
Physiologic Parameters ◽  
Relationship Of ◽  
The Impact ◽  
Ventilation And Perfusion

AbstractPleural effusions are commonly encountered and have a significant impact on the respiratory system. The reported effect of thoracentesis on physiologic parameters including oxygenation, lung volumes, and respiratory mechanics is variable likely owing to studies with a small, heterogeneous population of patients.Most patients who are short of breath from pleural effusion experience relief following drainage due to improvement in the length–tension relationship of the respiratory muscles. An observed increase in oxygenation following thoracentesis is likely due to improved ventilation and perfusion matching. Recent advances in methods of measuring pleural pressure provide a greater understanding of the impact of pleural effusion on pleural pressure and changes in pleural pressure with thoracentesis; however, there has been no demonstrated benefit of routine monitoring of pleural pressure to reduce complications from thoracentesis. Manometry does allow for the identification of patients with unexpandable lung which is useful when determining options for pleural palliation. The following article will review the pathophysiological effects of pleural effusion and thoracentesis.

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