scholarly journals Variability and compensation of cardiomycoyte ionic conductances at the population level

2018 ◽  
Author(s):  
Colin Rees ◽  
Jun-Hai Yang ◽  
Marc Santolini ◽  
Aldons J. Lusis ◽  
James N. Weiss ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Expression Patterns ◽  
Population Level ◽  
Quantitative Agreement ◽  
Feedback Mechanism ◽  
Computational Method ◽  
Mouse Strains ◽  
Ionic Conductances ◽  
Hybrid Mouse Diversity Panel ◽  
Cardiac Excitation

AbstractConductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new computational method to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances.

scholarly journals The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Colin M Rees ◽  
Jun-Hai Yang ◽  
Marc Santolini ◽  
Aldons J Lusis ◽  
James N Weiss ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Expression Patterns ◽  
Quantitative Agreement ◽  
Feedback Mechanism ◽  
Mouse Strains ◽  
Conceptual Approach ◽  
Ionic Conductances ◽  
Cardiac Gene ◽  
Hybrid Mouse Diversity Panel ◽  
Cardiac Excitation

Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances.

scholarly journals Transcriptomic analyses of gastrulation-stage C57BL/6J and C57BL/6NHsd mouse embryos with differential susceptibility to alcohol

2021 ◽  
Author(s):  
Karen E. Boschen ◽  
Travis S. Ptacek ◽  
Matthew E. Berginski ◽  
Jeremy M. Simon ◽  
Scott E. Parnell
Keyword(s):  
Gene Expression ◽  
Gene Networks ◽  
Fetal Alcohol Spectrum Disorders ◽  
Prenatal Alcohol Exposure ◽  
Expression Patterns ◽  
Differential Susceptibility ◽  
Alcohol Exposure ◽  
Health Concern ◽  
Mouse Strains ◽  
Alcohol Sensitivity

Fetal Alcohol Spectrum Disorders (FASD) are a serious public health concern, affecting approximately 5% of live births in the US. The more severe craniofacial and central nervous system malformations characteristic of FASD are caused by alcohol exposure during gastrulation (embryonic day 7 in mice; 3rd week of human pregnancy). Genetics are a known contributor to differences in alcohol sensitivity in humans and in animal models of FASD. Our study profiled gene expression in gastrulation-stage embryos from two commonly used, genetically similar mouse substrains, C57BL/6J and C57BL/6NHsd, that differ in alcohol sensitivity. First, we established normal gene expression patterns at three finely resolved timepoints during gastrulation and developed a web-based interactive tool. Baseline transcriptional differences across strains were associated with immune signaling, indicative of their molecular divergence. Second, we examined the gene networks impacted by alcohol in each strain. Alcohol was associated with a more pronounced transcriptional effect in the 6J's vs. 6N's, matching the 6J's increased susceptibility. The 6J strain exhibited down-regulation of cell proliferation and morphogenic signaling pathways and up-regulation of pathways related to cell death and craniofacial defects, while 6N's show enrichment of hypoxia (up) and cellular metabolism (down) pathways. Collectively, these datasets 1) provide insight into the changing transcriptional landscape across gastrulation in two commonly used mouse strains, 2) establish a valuable resource that enables the discovery of candidate genes that may modify susceptibility to prenatal alcohol exposure that can be validated in humans, and 3) identify novel pathogenic mechanisms potentially involved in alcohol's impact on development.

scholarly journals HiCRes: a computational method to estimate and predict the resolution of HiC libraries

2020 ◽  
Author(s):  
Claire Marchal ◽  
Nivedita Singh ◽  
Ximena Corso-Díaz ◽  
Anand Swaroop
Keyword(s):  
Expression Patterns ◽  
Three Dimensional ◽  
Computational Method ◽  
Mathematical Concepts ◽  
Regulate Gene Expression ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
A Cell ◽  
Cell Type Specific ◽  
Human And Mouse

AbstractThree-dimensional (3D) conformation of the chromatin is crucial to stringently regulate gene expression patterns and DNA replication in a cell-type specific manner. HiC is a key technique for measuring 3D chromatin interactions genome wide. Estimating and predicting the resolution of a library is an essential step in any HiC experimental design. Here, we present the mathematical concepts to estimate the resolution of a library and predict whether deeper sequencing would enhance the resolution. We have developed HiCRes, a docker pipeline, by applying these concepts to human and mouse HiC libraries.

scholarly journals Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain

2018 ◽  
Vol 115 (3) ◽  
pp. 546-555 ◽  
Author(s):  
Zeynep Bastug-Özel ◽  
Peter T Wright ◽  
Axel E Kraft ◽  
Davor Pavlovic ◽  
Jacqueline Howie ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Myocytes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adult Rat ◽  
C Terminus ◽  
Complex Forms ◽  
Cardiac Excitation

Abstract Aims Cyclic adenosine monophosphate (cAMP) regulates cardiac excitation–contraction coupling by acting in microdomains associated with sarcolemmal ion channels. However, local real time cAMP dynamics in such microdomains has not been visualized before. We sought to directly monitor cAMP in a microdomain formed around sodium–potassium ATPase (NKA) in healthy and failing cardiomyocytes and to better understand alterations of cAMP compartmentation in heart failure. Methods and results A novel Förster resonance energy transfer (FRET)-based biosensor termed phospholemman (PLM)-Epac1 was developed by fusing a highly sensitive cAMP sensor Epac1-camps to the C-terminus of PLM. Live cell imaging in PLM-Epac1 and Epac1-camps expressing adult rat ventricular myocytes revealed extensive regulation of NKA/PLM microdomain-associated cAMP levels by β2-adrenoceptors (β2-ARs). Local cAMP pools stimulated by these receptors were tightly controlled by phosphodiesterase (PDE) type 3. In chronic heart failure following myocardial infarction, dramatic reduction of the microdomain-specific β2-AR/cAMP signals and β2-AR dependent PLM phosphorylation was accompanied by a pronounced loss of local PDE3 and an increase in PDE2 effects. Conclusions NKA/PLM complex forms a distinct cAMP microdomain which is directly regulated by β2-ARs and is under predominant control by PDE3. In heart failure, local changes in PDE repertoire result in blunted β2-AR signalling to cAMP in the vicinity of PLM.

Reproducing micro X-ray computed tomography (microXCT) observations of air–water distribution in porous media using revised pore-morphology method

2020 ◽  
Vol 57 (1) ◽  
pp. 149-156 ◽  
Author(s):  
Xin Liu ◽  
Annan Zhou ◽  
Jie Li ◽  
Shijin Feng
Keyword(s):  
Porous Media ◽  
Soil Moisture ◽  
Water Distribution ◽  
Lattice Gas ◽  
Quantitative Agreement ◽  
Computational Method ◽  
Moisture Distribution ◽  
Water Retention Curve ◽  
Equilibrium System ◽  
Air Liquid Interface

This study presents a novel and simple morphology approach to generate two-dimensional air–water distribution in porous media considering Or and Tuller’s cavitation mechanism (published in 2002). The connectedness condition for the nonwetting phase is replaced by the Laplace equation. An algorithm is developed to detect the ruptured water spaces that are incorrectly formed in the throat by the morphology approach, but cannot exist in a real thermodynamic equilibrium system. The distributions of soil moisture, water retention curve, and air–liquid interface area at different saturations predicted by this method are in a good quantitative agreement with the experimental observations on glass beads and Ottawa sand from micro X-raycomputed tomography (microXCT). Compared to Lu et al.’s Monte Carlo lattice-gas approach (published in 2010), another computational method to generate the soil moisture distribution, the proposed approach provides better results with significantly less computational power.

scholarly journals Models of cardiac excitation–contraction coupling in ventricular myocytes

2010 ◽  
Vol 226 (1) ◽  
pp. 1-15 ◽  
Author(s):  
George S.B. Williams ◽  
Gregory D. Smith ◽  
Eric A. Sobie ◽  
M. Saleet Jafri
Keyword(s):  
Ventricular Myocytes ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Cardiac Excitation

scholarly journals Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

2020 ◽  
Vol 21 (18) ◽  
pp. 6715 ◽  
Author(s):  
Oxana Kapitansky ◽  
Shlomo Sragovich ◽  
Iman Jaljuli ◽  
Adva Hadar ◽  
Eliezer Giladi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Development ◽  
Motor Behavior ◽  
Expression Patterns ◽  
Feedback Mechanism ◽  
Bladder Function ◽  
Drug Candidate ◽  
Specific Gene ◽  
Muscle Gene Expression ◽  
Muscle Gene

The activity-dependent neuroprotective protein (ADNP), a double-edged sword, sex-dependently regulates multiple genes and was previously associated with the control of early muscle development and aging. Here we aimed to decipher the involvement of ADNP in versatile muscle gene expression patterns in correlation with motor function throughout life. Using quantitative RT-PCR we showed that Adnp+/− heterozygous deficiency in mice resulted in aberrant gastrocnemius (GC) muscle, tongue and bladder gene expression, which was corrected by the Adnp snippet, drug candidate, NAP (CP201). A significant sexual dichotomy was discovered, coupled to muscle and age-specific gene regulation. As such, Adnp was shown to regulate myosin light chain (Myl) in the gastrocnemius (GC) muscle, the language acquisition gene forkhead box protein P2 (Foxp2) in the tongue and the pituitary-adenylate cyclase activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP linked to bladder function. A tight age regulation was observed, coupled to an extensive correlation to muscle function (gait analysis), placing ADNP as a muscle-regulating gene/protein.

Evolution of gene expression patterns in a model of branching morphogenesis

1999 ◽  
Vol 277 (4) ◽  
pp. F650-F663 ◽  
Author(s):  
Anna Pavlova ◽  
Robert O. Stuart ◽  
Martin Pohl ◽  
Sanjay K. Nigam
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Expression Patterns ◽  
Branching Morphogenesis ◽  
Computational Method ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Cdna Arrays ◽  
Apoptotic Genes ◽  
Collecting System

Branching morphogenesis of the ureteric bud in response to unknown signals from the metanephric mesenchyme gives rise to the urinary collecting system and, via inductive signals from the ureteric bud, to recruitment of nephrons from undifferentiated mesenchyme. An established cell culture model for this process employs cells of ureteric bud origin (UB) cultured in extracellular matrix and stimulated with conditioned media (BSN-CM) from a metanephric mesenchymal cell line (H. Sakurai, E. J. Barros, T. Tsukamoto, J. Barasch, and S. K. Nigam. Proc. Natl. Acad. Sci. USA 94: 6279–6284, 1997.). In the presence of BSN-CM, the UB cells form branching tubular structures reminiscent of the branching ureteric bud. The pattern of gene regulation in this model of branching morphogenesis of the kidney collecting system was investigated using high-density cDNA arrays. Software and analytical methods were developed for the quantification and clustering of genes. With the use of a computational method termed “vector analysis,” genes were clustered according to the direction and magnitude of differential expression in n-dimensional log-space. Changes in gene expression in response to the BSN-CM consisted primarily of differential expression of transcription factors with previously described roles in morphogenesis, downregulation of pro-apoptotic genes accompanied by upregulation of anti-apoptotic genes, and upregulation of a small group of secreted products including growth factors, cytokines, and extracellular proteinases. Changes in expression are discussed in the context of a general model for epithelial branching morphogenesis. In addition, the cDNA arrays were used to survey expression of epithelial markers and secreted factors in UB and BSN cells, confirming the largely epithelial character of the former and largely mesenchymal character of the later. Specific morphologies (cellular processes, branching multicellular cords, etc.) were shown to correlate with the expression of different, but overlapping, genomic subsets, suggesting differences in morphogenetic mechanisms at these various steps in the evolution of branching tubules.

Cellular redox state protects acetaldehyde-induced alteration in cardiomyocyte function by modifying Ca2+ release from sarcoplasmic reticulum

2008 ◽  
Vol 294 (1) ◽  
pp. H121-H133 ◽  
Author(s):  
Toshiharu Oba ◽  
Yoshitaka Maeno ◽  
Masataka Nagao ◽  
Nagahiko Sakuma ◽  
Takashi Murayama
Keyword(s):  
Redox Potential ◽  
Redox State ◽  
Ventricular Myocytes ◽  
Imaging System ◽  
Reduced Glutathione ◽  
Confocal Imaging ◽  
Minor Effect ◽  
Channel Activity ◽  
Ryr2 Channel ◽  
Cardiac Excitation

Recent studies indicate that low concentrations of acetaldehyde may function as the primary factor in alcoholic cardiomyopathy by disrupting Ca2+ handling or disturbing cardiac excitation-contraction coupling. By producing reactive oxygen species, acetaldehyde shifts the intracellular redox potential from a reduced state to an oxidized state. We examined whether the redox state modulates acetaldehyde-induced Ca2+ handling by measuring Ca2+ transient using a confocal imaging system and single ryanodine receptor type 2 (RyR2) channel activity using the planar lipid bilayer method. Ca2+ transient was recorded in isolated rat ventricular myocytes with incorporated fluo 3. Intracellular reduced glutathione level was estimated using the monochlorobimane fluorometric method. Acetaldehyde at 1 and 10 μM increased Ca2+ transient amplitude and its relative area in intact myocytes, but acetaldehyde at 100 μM decreased Ca2+ transient area significantly. Acetaldehyde showed a minor effect on Ca2+ transient in myocytes in which intracellular reduced glutathione content had been decreased against challenge of diethylmaleate to a level comparable to that induced by exposure to ∼50 μM acetaldehyde. Channel activity of the RyR2 with slightly reduced cytoplasmic redox potential from near resting state (−213 mV) or without redox fixation was augmented by all concentrations of acetaldehyde (1–100 μM) used here. However, acetaldehyde failed to activate the RyR2 channel, when the cytoplasmic redox potential was kept with a reduced (−230 mV) or markedly oxidized (−180 mV) state. This result was similar to effects of acetaldehyde on Ca2+ transient in diethylmaleate-treated myocytes, probably being in oxidized redox potential. The present results suggest that acetaldehyde acts as an RyR2 activator to disturb cardiac muscle function, and redox potential protects the heart from acetaldehyde-induced alterations in myocytes.

scholarly journals HIPSTR and thousands of lncRNAs are heterogeneously expressed in human embryos, primordial germ cells and stable cell lines

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Dinar Yunusov ◽  
Leticia Anderson ◽  
Lucas Ferreira DaSilva ◽  
Joanna Wysocka ◽  
Toshihiko Ezashi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Germ Cells ◽  
Expression Patterns ◽  
Primordial Germ Cells ◽  
Population Level ◽  
Human Embryos ◽  
Cell Stage ◽  
Lncrna Gene ◽  
Stable Cell Lines ◽  
The Individual

Abstract Eukaryotic genomes are transcribed into numerous regulatory long non-coding RNAs (lncRNAs). Compared to mRNAs, lncRNAs display higher developmental stage-, tissue-, and cell-subtype-specificity of expression, and are generally less abundant in a population of cells. Despite the progress in single-cell-focused research, the origins of low population-level expression of lncRNAs in homogeneous populations of cells are poorly understood. Here, we identify HIPSTR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), a novel lncRNA gene in the developmentally regulated TFAP2A locus. HIPSTR has evolutionarily conserved expression patterns, its promoter is most active in undifferentiated cells, and depletion of HIPSTR in HEK293 and in pluripotent H1BP cells predominantly affects the genes involved in early organismal development and cell differentiation. Most importantly, we find that HIPSTR is specifically induced and heterogeneously expressed in the 8-cell-stage human embryos during the major wave of embryonic genome activation. We systematically explore the phenomenon of cell-to-cell variation of gene expression and link it to low population-level expression of lncRNAs, showing that, similar to HIPSTR, the expression of thousands of lncRNAs is more highly heterogeneous than the expression of mRNAs in the individual, otherwise indistinguishable cells of totipotent human embryos, primordial germ cells, and stable cell lines.

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