Publications by authors named "Ghanim Ullah"

42 Publications

All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission.

Cells 2021 05 14;10(5). Epub 2021 May 14.

Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.
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http://dx.doi.org/10.3390/cells10051202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156392PMC
May 2021

On the origin of ultraslow spontaneous Na fluctuations in neurons of the neonatal forebrain.

J Neurophysiol 2021 02 25;125(2):408-425. Epub 2020 Nov 25.

Department of Physics, University of South Florida, Tampa, Florida.

Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca concentration. Here, we use ratiometric Na imaging to demonstrate spontaneous fluctuations in the intracellular Na concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at (P2-4). These occur at very low frequency (∼2/h), can last minutes with amplitudes up to several millimolar, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Both our experiments and computational model show that blocking voltage-gated Na channels or GABAergic signaling significantly diminish the neuronal Na fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways does not have significant effects. Our model also shows that the amplitude and duration of Na fluctuations decrease as we increase the strength of glial K uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared with mature brain. Spontaneous activity in the neonate forebrain plays a key role in cell maturation and brain development. We report spontaneous, ultraslow, asynchronous fluctuations in the intracellular Na concentration of neurons and astrocytes. We show that this activity is not correlated with the previously reported synchronous neuronal population bursting or Ca oscillations, both of which occur at much faster timescales. Furthermore, extracellular K concentration remains nearly constant. The spontaneous Na fluctuations disappear after the first postnatal week.
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http://dx.doi.org/10.1152/jn.00373.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948148PMC
February 2021

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model.

J Neurosci 2021 01 24;41(3):524-537. Epub 2020 Nov 24.

Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.
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http://dx.doi.org/10.1523/JNEUROSCI.2132-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821857PMC
January 2021

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells.

Cells 2020 06 22;9(6). Epub 2020 Jun 22.

Department of Physics, University of South Florida, Tampa, FL 33647, USA.

Mitochondrial Ca ([Ca]) uptake through its Ca uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca ([Ca]), [Ca], and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca buffering proteins, the separation between mitochondrion and Ca-releasing stores, and the duration of opening of Ca-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU.
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http://dx.doi.org/10.3390/cells9061520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349584PMC
June 2020

PunctaSpecks: A tool for automated detection, tracking, and analysis of multiple types of fluorescently labeled biomolecules.

Cell Calcium 2020 07 25;89:102224. Epub 2020 May 25.

Department of Physics, University of South Florida, Tampa, FL 33647, USA. Electronic address:

Recent advances in imaging technology and fluorescent probes have made it possible to gain information about the dynamics of subcellular processes at unprecedented spatiotemporal scales. Unfortunately, a lack of automated tools to efficiently process the resulting imaging data encoding fine details of the biological processes remains a major bottleneck in utilizing the full potential of these powerful experimental techniques. Here we present a computational tool, called PunctaSpecks, that can characterize fluorescence signals arising from a wide range of biological molecules under normal and pathological conditions. Among other things, the program can calculate the number, areas, life-times, and amplitudes of fluorescence signals arising from multiple sources, track diffusing fluorescence sources like moving mitochondria, and determine the overlap probability of two processes or organelles imaged using indicator dyes of different colors. We have tested PunctaSpecks on synthetic time-lapse movies containing mobile fluorescence objects of various sizes, mimicking the activity of biomolecules. The robustness of the software is tested by varying the level of noise along with random but known pattern of appearing, disappearing, and movement of these objects. Next, we use PunctaSpecks to characterize protein-protein interaction involved in store-operated Ca entry through the formation and activation of plasma membrane-bound ORAI1 channel and endoplasmic reticulum membrane-bound stromal interaction molecule (STIM), the evolution of inositol 1,4,5-trisphosphate (IP)-induced Ca signals from sub-micrometer size local events into global waves in human cortical neurons, and the activity of Alzheimer's disease-associated β amyloid pores in the plasma membrane. The tool can also be used to study other dynamical processes imaged through fluorescence molecules. The open source algorithm allows for extending the program to analyze more than two types of biomolecules visualized using markers of different colors.
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http://dx.doi.org/10.1016/j.ceca.2020.102224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343294PMC
July 2020

Mitochondrial fragmentation and network architecture in degenerative diseases.

PLoS One 2019 26;14(9):e0223014. Epub 2019 Sep 26.

Department of Physics, University of South Florida, Tampa, FL, United States of America.

Fragmentation of mitochondrial network has been implicated in many neurodegenerative, renal, and metabolic diseases. However, a quantitative measure of the microscopic parameters resulting in the impaired balance between fission and fusion of mitochondria and consequently the fragmented networks in a wide range of pathological conditions does not exist. Here we present a comprehensive analysis of mitochondrial networks in cells with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), optic neuropathy (OPA), diabetes/cancer, acute kidney injury, Ca2+ overload, and Down Syndrome (DS) pathologies that indicates significant network fragmentation in all these conditions. Furthermore, we found key differences in the way the microscopic rates of fission and fusion are affected in different conditions. The observed fragmentation in cells with AD, HD, DS, kidney injury, Ca2+ overload, and diabetes/cancer pathologies results from the imbalance between the fission and fusion through lateral interactions, whereas that in OPA, PD, and ALS results from impaired balance between fission and fusion arising from longitudinal interactions of mitochondria. Such microscopic difference leads to major disparities in the fine structure and topology of the network that could have significant implications for the way fragmentation affects various cell functions in different diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223014PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762132PMC
March 2020

Mitochondrial dysfunction and role in spreading depolarization and seizure.

J Comput Neurosci 2019 12 11;47(2-3):91-108. Epub 2019 Sep 11.

Department of Physics, University of South Florida, 4202 E. Fowler Ave., Tampa, FL, 33620, USA.

The effect of pathological phenomena such as epileptic seizures and spreading depolarization (SD) on mitochondria and the potential feedback of mitochondrial dysfunction into the dynamics of those phenomena are complex and difficult to study experimentally due to the simultaneous changes in many variables governing neuronal behavior. By combining a model that accounts for a wide range of neuronal behaviors including seizures, normoxic SD, and hypoxic SD (HSD), together with a detailed model of mitochondrial function and intracellular Ca dynamics, we investigate mitochondrial dysfunction and its potential role in recovery of the neuron from seizures, HSD, and SD. Our results demonstrate that HSD leads to the collapse of mitochondrial membrane potential and cellular ATP levels that recover only when normal oxygen supply is restored. Mitochondrial organic phosphate and pH gradients determine the strength of the depolarization block during HSD and SD, how quickly the cell enters the depolarization block when the oxygen supply is disrupted or potassium in the bath solution is raised beyond the physiological value, and how fast the cell recovers from SD and HSD when normal potassium concentration and oxygen supply are restored. Although not as dramatic as phosphate and pH gradients, mitochondrial Ca uptake has a similar effect on neuronal behavior during these conditions.
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http://dx.doi.org/10.1007/s10827-019-00724-6DOI Listing
December 2019

Mechanism of Fibril and Soluble Oligomer Formation in Amyloid Beta and Hen Egg White Lysozyme Proteins.

J Phys Chem B 2019 07 27;123(27):5678-5689. Epub 2019 Jun 27.

Department of Physics , University of South Florida , Tampa , Florida 33620 , United States.

Assembly and deposition of insoluble amyloid fibrils with a distinctive cross-β-sheet structure is the molecular hallmark of amyloidogenic diseases affecting the central nervous system as well as non-neuropathic amyloidosis. Amyloidogenic proteins form aggregates via kinetic pathways dictated by initial solution conditions. Often, early stage, cytotoxic, small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs). Growing experimental evidence suggests that soluble gOs are off-pathway aggregates that do not directly convert into the final stage RFs. Yet, the kinetics of RFs aggregation under conditions that either promote or suppress the growth of gOs remain incompletely understood. Here we present a self-assembly model for amyloid fibril formation in the presence and absence of early stage off-pathway aggregates, driven by our experimental results on hen egg white lysozyme (HewL) and beta amyloid (Aβ) aggregation. The model reproduces a range of experimental observations including the sharp boundary in the protein concentration above which the self-assembly of gOs occurs. This is possible when both primary and secondary RFs nucleation rates are allowed to have a nonlinear dependence on initial protein concentration, hinting toward more complex prenucleation and RFs assembly scenarios. Moreover, analysis of RFs lag period in the presence and absence of gOs indicates that these off-pathway aggregates have an inhibitory effect on RFs nucleation. Finally, we incorporate the effect of an Aβ binding protein on the aggregation process in the model that allows us to identify the most suitable solution conditions for suppressing gOs and RFs formation.
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http://dx.doi.org/10.1021/acs.jpcb.9b02338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839771PMC
July 2019

CellSpecks: A Software for Automated Detection and Analysis of Calcium Channels in Live Cells.

Biophys J 2018 12 25;115(11):2141-2151. Epub 2018 Oct 25.

Department of Neurobiology and Behavior,University of California Irvine, Irvine, California. Electronic address:

To couple the fidelity of patch-clamp recording with a more high-throughput screening capability, we pioneered a, to our knowledge, novel approach to single-channel recording that we named "optical patch clamp." By using highly sensitive fluorescent Ca indicator dyes in conjunction with total internal fluorescence microscopy techniques, we monitor Ca flux through individual Ca-permeable channels. This approach provides information about channel gating analogous to patch-clamp recording at a time resolution of ∼2 ms with the additional advantage of being massively parallel, providing simultaneous and independent recording from thousands of channels in the native environment. However, manual analysis of the data generated by this technique presents severe challenges because a video recording can include many thousands of frames. To overcome this bottleneck, we developed an image processing and analysis framework called CellSpecks capable of detecting and fully analyzing the kinetics of ion channels within a video sequence. By using randomly generated synthetic data, we tested the ability of CellSpecks to rapidly and efficiently detect and analyze the activity of thousands of ion channels, including openings for a few milliseconds. Here, we report the use of CellSpecks for the analysis of experimental data acquired by imaging muscle nicotinic acetylcholine receptors and the Alzheimer's disease-associated amyloid β pores with multiconductance levels in the plasma membrane of Xenopus laevis oocytes. We show that CellSpecks can accurately and efficiently generate location maps and create raw and processed fluorescence time traces; histograms of mean open times, mean close times, open probabilities, durations, and maximal amplitudes; and a "channel chip" showing the activity of all channels as a function of time. Although we specifically illustrate the application of CellSpecks for analyzing data from Ca channels, it can be easily customized to analyze other spatially and temporally localized signals.
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http://dx.doi.org/10.1016/j.bpj.2018.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289074PMC
December 2018

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease.

Cell Calcium 2018 12 12;76:23-35. Epub 2018 Sep 12.

Department of Physics, University of South Florida, Tampa, FL 33620, USA. Electronic address:

Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca rise on the many intracellular Ca-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP) receptor (IPR) and fluorescence imaging of whole-cell Ca response, induced by exogenously applied intracellular Aβ oligomers to show that Aβ inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IPR, which is then extended to build a model for the whole-cell Ca signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca release from the endoplasmic reticulum by intracellular Aβ oligomers through G-protein-mediated stimulation of IP production. The estimated IP concentration as a function of intracellular Aβ content together with the whole-cell model allows us to show that Aβ oligomers impair mitochondrial function through pathological Ca uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and HO. We further show that mitochondrial function can be restored by the addition of Ca buffer EGTA, in accordance with the observed abrogation of Aβ cytotoxicity by EGTA in our live cells experiments.
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http://dx.doi.org/10.1016/j.ceca.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289702PMC
December 2018

Origin of metastable oligomers and their effects on amyloid fibril self-assembly.

Chem Sci 2018 Jul 13;9(27):5937-5948. Epub 2018 Jun 13.

Department of Physics , University of South Florida , Tampa , FL 33620 , USA . Email:

Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a "critical oligomer concentration" (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.
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http://dx.doi.org/10.1039/c8sc01479eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050532PMC
July 2018

Voxel size and gray level normalization of CT radiomic features in lung cancer.

Sci Rep 2018 Jul 12;8(1):10545. Epub 2018 Jul 12.

Department of Physics, University of South Florida, Tampa, FL, 33620, USA.

Radiomic features are potential imaging biomarkers for therapy response assessment in oncology. However, the robustness of features with respect to imaging parameters is not well established. Previously identified potential imaging biomarkers were found to be intrinsically dependent on voxel size and number of gray levels (GLs) in a recent texture phantom investigation. Here, we validate the voxel size and GL in-phantom normalizations in lung tumors. Eighteen patients with non-small cell lung cancer of varying tumor volumes were analyzed. To compare with patient data, phantom scans were acquired on eight different scanners. Twenty four previously identified features were extracted from lung tumors. The Spearman rank (r) and interclass correlation coefficient (ICC) were used as metrics. Eight out of 10 features showed high (r > 0.9) and low (r < 0.5) correlations with number of voxels before and after normalizations, respectively. Likewise, texture features were unstable (ICC < 0.6) and highly stable (ICC > 0.8) before and after GL normalizations, respectively. We conclude that voxel size and GL normalizations derived from a texture phantom study also apply to lung tumors. This study highlights the importance and utility of investigating the robustness of radiomic features with respect to CT imaging parameters in radiomic phantoms.
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http://dx.doi.org/10.1038/s41598-018-28895-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043486PMC
July 2018

TraceSpecks: A Software for Automated Idealization of Noisy Patch-Clamp and Imaging Data.

Biophys J 2018 07;115(1):9-21

Department of Physics, University of South Florida, Tampa, Florida. Electronic address:

Experimental records of single molecules or ion channels from fluorescence microscopy and patch-clamp electrophysiology often include high-frequency noise and baseline fluctuations that are not generated by the system under investigation and have to be removed. Moreover, multiple channels or conductance levels can be present at a time in the data that need to be quantified to accurately understand the behavior of the system. Manual procedures for removing these fluctuations and extracting conducting states or multiple channels are laborious, prone to subjective bias, and likely to hinder the processing of often very large data sets. We introduce a maximal likelihood formalism for separating signal from a noisy and drifting background such as fluorescence traces from imaging of elementary Ca release events called puffs arising from clusters of channels, and patch-clamp recordings of ion channels. Parameters such as the number of open channels or conducting states, noise level, and background signal can all be optimized using the expectation-maximization algorithm. We implement our algorithm following the Baum-Welch approach to expectation-maximization in the portable Java language with a user-friendly graphical interface and test the algorithm on both synthetic and experimental data from the patch-clamp electrophysiology of Ca channels and fluorescence microscopy of a cluster of Ca channels and Ca channels with multiple conductance levels. The resulting software is accurate, fast, and provides detailed information usually not available through manual analysis. Options for visual inspection of the raw and processed data with key parameters are provided, in addition to a range of statistics such as the mean open probabilities, mean open times, mean close times, dwell-time distributions for different number of channels open or conductance levels, amplitude distribution of all opening events, and number of transitions between different number of open channels or conducting levels in asci format with a single click.
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http://dx.doi.org/10.1016/j.bpj.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035303PMC
July 2018

Reduced cooperativity of voltage-gated sodium channels in the hippocampal interneurons of an aged mouse model of Alzheimer's disease.

Eur Biophys J 2018 Jul 9;47(5):539-547. Epub 2018 Feb 9.

Department of Physics, ISA 2019, University of South Florida, 4202 East Fowler Ave, Tampa, 33620, FL, USA.

Beta amyloid (A[Formula: see text] ) associated with Alzheimer's disease (AD) leads to abnormal behavior in inhibitory neurons, resulting in hyperactive neuronal networks, epileptiform behavior, disrupted gamma rhythms, and aberrant synaptic plasticity. Previously, we used a dual modeling-experimental approach to explain several observations, including failure to reliably produce action potentials (APs), smaller AP amplitudes, higher resting membrane potential, and higher membrane depolarization in response to a range of stimuli in hippocampal inhibitory neurons from 12- to 16-month-old female AP Pswe/PSEN1DeltaE9 (APdE9) AD mice as compared to age-matched non-transgenic (NTG) mice. Our experimental results also showed that AP initiation in interneurons from APdE9 mice are significantly different from that of NTG mice. APs in interneurons from NTG mice are characterized by abrupt onset and an upstroke that is much steeper and occurs with larger variability as compared to cells from APdE9 mice. The phase plot (the rate of change of membrane potential versus the instantaneous membrane potential) of APs produced by interneurons from APdE9 mice shows a biphasic behavior, whereas that from NTG mice shows a monophasic behavior. Here we show that using the classic Hodgkin-Huxley (HH) formalism for the gating of voltage-gated sodium channels (VGSCs) in a single-compartment neuron, we cannot reproduce these features, and a model that takes into account a cooperative activation of VGSCs is needed. We also argue that considering a realistic multi-compartment neuron where the kinetics of VGSC is modeled by HH formalism, as done in the past, would not explain our observations when APs from both NTG and APdE9 mice are considered simultaneously. We further show that VGSCs in interneurons from APdE9 mice exhibit significantly lower cooperativity in their activation as compared to those from NTG mice.
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http://dx.doi.org/10.1007/s00249-017-1274-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008176PMC
July 2018

Accounting for reconstruction kernel-induced variability in CT radiomic features using noise power spectra.

J Med Imaging (Bellingham) 2018 Jan 14;5(1):011013. Epub 2017 Dec 14.

University of South Florida, Department of Physics, Tampa, Florida, United States.

Large variability in computed tomography (CT) radiomics feature values due to CT imaging parameters can have subsequent implications on the prognostic or predictive significance of these features. Here, we investigated the impact of pitch, dose, and reconstruction kernel on CT radiomic features. Moreover, we introduced correction factors to reduce feature variability introduced by reconstruction kernels. The credence cartridge radiomics and American College of Radiology (ACR) phantoms were scanned on five different scanners. ACR phantom was used for 3-D noise power spectrum (NPS) measurements to quantify correlated noise. The coefficient of variation (COV) was used as the variability assessment metric. The variability in texture features due to different kernels was reduced by applying the NPS peak frequency and region of interest (ROI) maximum intensity as correction factors. Most texture features were dose independent but were strongly kernel dependent, which is demonstrated by a significant shift in NPS peak frequency among kernels. Percentage improvement in robustness was calculated for each feature from original and corrected %COV values. Percentage improvements in robustness of 19 features were in the range of 30% to 78% after corrections. We show that NPS peak frequency and ROI maximum intensity can be used as correction factors to reduce variability in CT texture feature values due to reconstruction kernels.
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http://dx.doi.org/10.1117/1.JMI.5.1.011013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729963PMC
January 2018

Analyzing optical imaging of Ca signals via TIRF microscopy: The limits on resolution due to chemical rates and depth of the channels.

Cell Calcium 2017 11 31;67:65-73. Epub 2017 Aug 31.

T-6 Theoretical Biology and Biophysics Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.

High resolution total internal reflection (TIRF) microscopy (TIRFM) together with detailed computational modeling provides a powerful approach towards the understanding of a wide range of Ca signals mediated by the ubiquitous inositol 1,4,5-trisphosphate (IP) receptor (IPR) channel. Exploiting this fruitful collaboration further requires close agreement between the models and observations. However, elementary Ca release events, puffs, imaged through TIRFM do not show the rapid single-channel openings and closings during and between puffs as are present in simulated puffs using data-driven single channel models. TIRFM also shows a rapid equilibration of 10ms after a channel opens or closes which is not achievable in simulation using standard Ca diffusion coefficients and reaction rates between indicator dye and Ca. Furthermore, TIRFM imaging cannot decipher the depth of the channel with respect to the microscope, which will affect the change in fluorescence that the microscope detects, thereby affecting its sensitivity to fast single-channel activity. Using the widely used Ca diffusion coefficients and reaction rates, our simulations show equilibration rates that are eight times slower than TIRFM imaging. We show that to get equilibrium rates consistent with observed values, the diffusion coefficients and reaction rates have to be significantly higher than the values reported in the literature, and predict the channel depth to be 200-250nm. Finally, we show that with the addition of noise, short events due to 1-2ms opening and closing of channels that are observed in computational models can be missed in TIRFM.
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http://dx.doi.org/10.1016/j.ceca.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679457PMC
November 2017

The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization.

PLoS Comput Biol 2017 Oct 12;13(10):e1005804. Epub 2017 Oct 12.

Department of Physics, University of South Florida, Tampa, Florida, United States of America.

Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)-the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K+ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function.
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http://dx.doi.org/10.1371/journal.pcbi.1005804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655358PMC
October 2017

Intrinsic dependencies of CT radiomic features on voxel size and number of gray levels.

Med Phys 2017 Mar;44(3):1050-1062

Department of Physics, University of South Florida, Tampa, FL, 33620, USA.

Purpose: Many radiomics features were originally developed for non-medical imaging applications and therefore original assumptions may need to be reexamined. In this study, we investigated the impact of slice thickness and pixel spacing (or pixel size) on radiomics features extracted from Computed Tomography (CT) phantom images acquired with different scanners as well as different acquisition and reconstruction parameters. The dependence of CT texture features on gray-level discretization was also evaluated.

Methods And Materials: A texture phantom composed of 10 different cartridges of different materials was scanned on eight different CT scanners from three different manufacturers. The images were reconstructed for various slice thicknesses. For each slice thickness, the reconstruction Field Of View (FOV) was varied to render pixel sizes ranging from 0.39 to 0.98 mm. A fixed spherical region of interest (ROI) was contoured on the images of the shredded rubber cartridge and the 3D printed, 20% fill, acrylonitrile butadiene styrene plastic cartridge (ABS20) for all phantom imaging sets. Radiomic features were extracted from the ROIs using an in-house program. Features categories were: shape (10), intensity (16), GLCM (24), GLZSM (11), GLRLM (11), and NGTDM (5), fractal dimensions (8) and first-order wavelets (128), for a total of 213 features. Voxel-size resampling was performed to investigate the usefulness of extracting features using a suitably chosen voxel size. Acquired phantom image sets were resampled to a voxel size of 1 × 1 × 2 mm using linear interpolation. Image features were therefore extracted from resampled and original datasets and the absolute value of the percent coefficient of variation (%COV) for each feature was calculated. Based on the %COV values, features were classified in 3 groups: (1) features with large variations before and after resampling (%COV >50); (2) features with diminished variation (%COV <30) after resampling; and (3) features that had originally moderate variation (%COV <50%) and were negligibly affected by resampling. Group 2 features were further studied by modifying feature definitions to include voxel size. Original and voxel-size normalized features were used for interscanner comparisons. A subsequent analysis investigated feature dependency on gray-level discretization by extracting 51 texture features from ROIs from each of the 10 different phantom cartridges using 16, 32, 64, 128, and 256 gray levels.

Results: Out of the 213 features extracted, 150 were reproducible across voxel sizes, 42 improved significantly (%COV <30, Group 2) after resampling, and 21 had large variations before and after resampling (Group 1). Ten features improved significantly after definition modification effectively removed their voxel-size dependency. Interscanner comparison indicated that feature variability among scanners nearly vanished for 8 of these 10 features. Furthermore, 17 out of 51 texture features were found to be dependent on the number of gray levels. These features were redefined to include the number of gray levels which greatly reduced this dependency.

Conclusion: Voxel-size resampling is an appropriate pre-processing step for image datasets acquired with variable voxel sizes to obtain more reproducible CT features. We found that some of the radiomics features were voxel size and gray-level discretization-dependent. The introduction of normalizing factors in their definitions greatly reduced or removed these dependencies.
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http://dx.doi.org/10.1002/mp.12123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462462PMC
March 2017

Analyzing and Modeling the Dysfunction of Inhibitory Neurons in Alzheimer's Disease.

PLoS One 2016 30;11(12):e0168800. Epub 2016 Dec 30.

Department of Physics, University of South Florida, Tampa, FL 33620, United States of America.

Alzheimer's disease (AD) is characterized by the abnormal proteolytic processing of amyloid precursor protein, resulting in increased production of a self-aggregating form of beta amyloid (Aβ). Several lines of work on AD patients and transgenic mice with high Aβ levels exhibit altered rhythmicity, aberrant neuronal network activity and hyperexcitability reflected in clusters of hyperactive neurons, and spontaneous epileptic activity. Recent studies highlight that abnormal accumulation of Aβ changes intrinsic properties of inhibitory neurons, which is one of the main reasons underlying the impaired network activity. However, specific cellular mechanisms leading to interneuronal dysfunction are not completely understood. Using extended Hodgkin-Huxley (HH) formalism in conjunction with patch-clamp experiments, we investigate the mechanisms leading to the impaired activity of interneurons. Our detailed analysis indicates that increased Na+ leak explains several observations in inhibitory neurons, including their failure to reliably produce action potentials, smaller action potential amplitude, increased resting membrane potential, and higher membrane depolarization in response to a range of stimuli in a model of APPSWE/PSEN1DeltaE9 (APdE9) AD mice as compared to age-matched control mice. While increasing the conductance of hyperpolarization activated cyclic nucleotide-gated (HCN) ion channel could account for most of the observations, the extent of increase required to reproduce these observations render such changes unrealistic. Furthermore, increasing the conductance of HCN does not account for the observed changes in depolarizability of interneurons from APdE9 mice as compared to those from NTG mice. None of the other pathways tested could lead to all observations about interneuronal dysfunction. Thus we conclude that upregulated sodium leak is the most likely source of impaired interneuronal function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201300PMC
June 2017

The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore.

Cell Calcium 2016 07 7;60(1):13-24. Epub 2016 May 7.

Department of Physics, University of South Florida, Tampa, FL 33620, USA. Electronic address:

Mutants in presenilins (PS1 or PS2) are the major cause of familial Alzheimer's disease (FAD). They affect intracellular Ca(2+) homeostasis by increasing the open probability (Po) of inositol 1,4,5-trisposphate (IP3) receptor (IP3R) Ca(2+) release channel located on the endoplasmic reticulum (ER) leading to exaggerated Ca(2+) release into a cytoplasmic microdomain formed by neighboring cluster of a few IP3R channels and mitochondrial Ca(2+) uniporter (MCU). Ca(2+) concentration in the microdomain ( [Formula: see text] ) depends on the distance between the cluster and MCU (r); the number of IP3R in the cluster releasing Ca(2+) to the cytoplasm ( [Formula: see text] ), and Po of IP3R. Using experimental whole-cell IP3R-mediated cytosolic Ca(2+) data, in conjunction with a computational model of cell bioenergetics, a data-driven Markov chain model for IP3R gating, and a model for the dynamics of the mitochondrial permeability transition pore (PTP), we explore differences in mitochondrial Ca(2+) uptake in cells expressing wild type (PS1-WT) and FAD-causing mutant (PS1-M146L) PS. We find that increased mitochondrial [Formula: see text] due to the gain-of-function enhancement of IP3R channels in the cells expressing PS1-M146L leads to the opening of PTP in high conductance state (PTPh), where the latency of opening is inversely correlated with r and proportional to [Formula: see text] . Furthermore, we observe diminished inner mitochondrial membrane potential (ΔΨm), [NADH], [Formula: see text] , and [ATP] when PTP opens. Additionally, we explore how parameters such as the pH gradient, inorganic phosphate concentration, and the rate of the Na(+)/Ca(2+)-exchanger affect the latency of PTP to open in PTPh.
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http://dx.doi.org/10.1016/j.ceca.2016.05.002DOI Listing
July 2016

Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca signals.

J Biol Phys 2016 10 6;42(4):507-524. Epub 2016 May 6.

Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, 22030, USA.

The inositol 1,4,5-trisphosphate (InsP) receptor (InsPR) channel is crucial for the generation and modulation of highly specific intracellular Ca signals performing numerous functions in animal cells. However, the single channel behavior during Ca signals of different spatiotemporal scales is not well understood. To elucidate the correlation between the gating dynamics of single InsPRs and spatiotemporal Ca patterns, we simulate a cluster of InsPRs under varying ligand concentrations and extract comprehensive gating statistics of all channels during events of different sizes and durations. Our results show that channels gating predominantly in the low activity mode with negligible occupancy of intermediate and high modes leads to single channel Ca release event blips. Increasing occupancies of intermediate and high modes results in events with increasing size. When the channel has more than 50% probability of gating in the intermediate and high modes, the cluster generates very large puffs that would most likely result in global Ca signals. The size, duration and frequency of Ca signals all increase linearly with the total probability of channel gating in the intermediate and high modes. To our knowledge, this is the first study that quantitatively relates the modal characteristics of InsPR to the shaping of different spatiotemporal scales of Ca signals.
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http://dx.doi.org/10.1007/s10867-016-9419-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059592PMC
October 2016

Anions Govern Cell Volume: A Case Study of Relative Astrocytic and Neuronal Swelling in Spreading Depolarization.

PLoS One 2016 14;11(3):e0147060. Epub 2016 Mar 14.

Department of Physics, University of South Florida, Tampa, FL 33620, United States of America.

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little about the dynamics of cell and tissue swelling, and the differential changes in the volumes of neurons and glia during pathological states such as spreading depolarizations (SD) under ischemic and non-ischemic conditions, and epileptic seizures. By combining the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations, and simultaneous neuronal and astroglial volume changes into a comprehensive model, we elucidate why glial cells swell more than neurons in SD and the special case of anoxic depolarization (AD), and explore the relative contributions of the two cell types to tissue swelling. Our results demonstrate that anion channels, particularly Cl-, are intrinsically connected to cell swelling and blocking these currents prevents changes in cell volume. The model is based on a simple and physiologically realistic description. We introduce model extensions that are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles, or by a phenomenological combination of these principles and known physiological facts. This work provides insights into numerous studies related to neuronal and glial volume changes in SD that otherwise seem contradictory, and is broadly applicable to swelling in other cell types and conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147060PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790933PMC
August 2016

Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions.

Cell Calcium 2016 05 5;59(5):240-50. Epub 2016 Mar 5.

Department of Physics, University of South Florida, Tampa, FL 33620, United States. Electronic address:

Mutants in presenilins (PS1 or PS2) is the major cause of familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca(2+) homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca(2+) release channel on the endoplasmic reticulum, leading to exaggerated Ca(2+) release into the cytoplasm. Using experimental IP3R-mediated Ca(2+) release data, in conjunction with a computational model of cell bioenergetics, we explore how the differences in mitochondrial Ca(2+) uptake in control cells and cells expressing FAD-causing PS mutants affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial Ca(2+). We find that as a result of exaggerated cytosolic Ca(2+) in FAD-causing mutant PS-expressing cells, the rate of oxygen consumption increases dramatically and overcomes the Ca(2+) dependent enzymes that stimulate NADH production. This leads to decreased rates in proton pumping due to diminished membrane potential along with less ATP and enhanced ROS production. These results show that through Ca(2+) signaling disruption, mutant PS leads to mitochondrial dysfunction and potentially to cell death.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088788PMC
http://dx.doi.org/10.1016/j.ceca.2016.02.013DOI Listing
May 2016

Large extracellular space leads to neuronal susceptibility to ischemic injury in a Na+/K+ pumps-dependent manner.

J Comput Neurosci 2016 Apr 6;40(2):177-92. Epub 2016 Feb 6.

Department of Physics, University of South Florida, Tampa, FL, 33620, USA.

The extent of anoxic depolarization (AD), the initial electrophysiological event during ischemia, determines the degree of brain region-specific neuronal damage. Neurons in higher brain regions exhibiting nonreversible, strong AD are more susceptible to ischemic injury as compared to cells in lower brain regions that exhibit reversible, weak AD. While the contrasting ADs in different brain regions in response to oxygen-glucose deprivation (OGD) is well established, the mechanism leading to such differences is not clear. Here we use computational modeling to elucidate the mechanism behind the brain region-specific recovery from AD. Our extended Hodgkin-Huxley (HH) framework consisting of neural spiking dynamics, processes of ion accumulation, and ion homeostatic mechanisms unveils that glial-vascular K(+) clearance and Na(+)/K(+)-exchange pumps are key to the cell's recovery from AD. Our phase space analysis reveals that the large extracellular space in the upper brain regions leads to impaired Na(+)/K(+)-exchange pumps so that they function at lower than normal capacity and are unable to bring the cell out of AD after oxygen and glucose is restored.
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http://dx.doi.org/10.1007/s10827-016-0591-yDOI Listing
April 2016

Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer's Disease-Causing Mutants in Presenilins.

PLoS Comput Biol 2015 Oct 6;11(10):e1004529. Epub 2015 Oct 6.

Department of Physics, University of South Florida, Tampa, Florida, United States of America.

Familial Alzheimer's disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca(2+) release channels resulting in enhanced IP3R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca(2+) signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca(2+) signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca(2+) and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP3 and Ca(2+) and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS.
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http://dx.doi.org/10.1371/journal.pcbi.1004529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595473PMC
October 2015

Analyzing and Modeling the Kinetics of Amyloid Beta Pores Associated with Alzheimer's Disease Pathology.

PLoS One 2015 8;10(9):e0137357. Epub 2015 Sep 8.

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, United States of America.

Amyloid beta (Aβ) oligomers associated with Alzheimer's disease (AD) form Ca2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca2+) homeostasis. The resultant up-regulation of intracellular Ca2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. The fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. Towards the end, we demonstrate the up-regulation of gating of various Ca2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca2+ permeability transition into those with high open probability and Ca2+ permeability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137357PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562663PMC
May 2016

The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

PLoS Comput Biol 2015 Aug 14;11(8):e1004414. Epub 2015 Aug 14.

Center for Neural Engineering, Departments of Engineering Science and Mechanics, Neurosurgery, and Physics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States of America.

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.
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http://dx.doi.org/10.1371/journal.pcbi.1004414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537206PMC
August 2015

Unification of neuronal spikes, seizures, and spreading depression.

J Neurosci 2014 Aug;34(35):11733-43

Center for Neural Engineering, Department of Engineering Science and Mechanics, and Departments of Neurosurgery and Physics, The Pennsylvania State University, University Park, Pennsylvania 16802, Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio 43210

The pathological phenomena of seizures and spreading depression have long been considered separate physiological events in the brain. By incorporating conservation of particles and charge, and accounting for the energy required to restore ionic gradients, we extend the classic Hodgkin-Huxley formalism to uncover a unification of neuronal membrane dynamics. By examining the dynamics as a function of potassium and oxygen, we now account for a wide range of neuronal activities, from spikes to seizures, spreading depression (whether high potassium or hypoxia induced), mixed seizure and spreading depression states, and the terminal anoxic "wave of death." Such a unified framework demonstrates that all of these dynamics lie along a continuum of the repertoire of the neuron membrane. Our results demonstrate that unified frameworks for neuronal dynamics are feasible, can be achieved using existing biological structures and universal physical conservation principles, and may be of substantial importance in enabling our understanding of brain activity and in the control of pathological states.
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http://dx.doi.org/10.1523/JNEUROSCI.0516-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145176PMC
August 2014

Oxygen and seizure dynamics: II. Computational modeling.

J Neurophysiol 2014 Jul 26;112(2):213-23. Epub 2014 Mar 26.

Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania; Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio; and Departments of Neurosurgery and Physics, The Pennsylvania State University, University Park, Pennsylvania

Electrophysiological recordings show intense neuronal firing during epileptic seizures leading to enhanced energy consumption. However, the relationship between oxygen metabolism and seizure patterns has not been well studied. Recent studies have developed fast and quantitative techniques to measure oxygen microdomain concentration during seizure events. In this article, we develop a biophysical model that accounts for these experimental observations. The model is an extension of the Hodgkin-Huxley formalism and includes the neuronal microenvironment dynamics of sodium, potassium, and oxygen concentrations. Our model accounts for metabolic energy consumption during and following seizure events. We can further account for the experimental observation that hypoxia can induce seizures, with seizures occurring only within a narrow range of tissue oxygen pressure. We also reproduce the interplay between excitatory and inhibitory neurons seen in experiments, accounting for the different oxygen levels observed during seizures in excitatory vs. inhibitory cell layers. Our findings offer a more comprehensive understanding of the complex interrelationship among seizures, ion dynamics, and energy metabolism.
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http://dx.doi.org/10.1152/jn.00541.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064403PMC
July 2014

The role of IP3 receptor channel clustering in Ca2+ wave propagation during oocyte maturation.

Prog Mol Biol Transl Sci 2014 ;123:83-101

Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.

During oocyte maturation, the calcium-signaling machinery undergoes a dramatic remodeling resulting in distinctly different calcium-release patterns on all organizational scales from puffs to waves. The dynamics of the Ca(2+) release wave in mature as compared to immature oocytes are defined by a slower propagation speed and longer duration of the high Ca(2+) plateau. In this chapter, we use computational modeling to identify the changes in the signaling machinery, which contribute most significantly to the alterations observed in Ca(2+) wave propagation during Xenopus oocyte maturation. In addition to loss of store-operated calcium entry and internalization of plasma membrane pumps, we propose that spatial reorganization of the IP3 receptors in the plane of the ER membrane is a key factor for the observed signaling changes in Ca(2+) wave propagation.
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http://dx.doi.org/10.1016/B978-0-12-397897-4.00006-1DOI Listing
April 2015
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