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Ben-Ari M.,Sohnis Family Stem Cells Center | Ben-Ari M.,Rappaport Institute | Schick R.,Sohnis Family Stem Cells Center | Schick R.,Rappaport Institute | And 11 more authors.
Heart Rhythm | Year: 2014

Background We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells. Objective To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node. Methods We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell-derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual. Results Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincaré plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs (P <.05) and the in situ heart (the latter two were similar; P >.05). We also compared BRV magnitude among single cells, small EBs (∼5-10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P <.05). Disrupting intracellular Ca2+ handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. Conclusion The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca2+ handling determine HRV in humans and cardiomyocyte networks. © 2014 Heart Rhythm Society.


PubMed | Slovak Academy of Sciences, Rappaport Institute, Rimonyx Pharmaceuticals Ltd. and Institute of Materials and Environmental Chemistry
Type: Journal Article | Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] | Year: 2016

Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease.The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo.Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo.RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE.RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.


Ziv N.E.,Rappaport Institute | Ziv N.E.,Network Biology Research Laboratories
Neuromethods | Year: 2014

Activity-induced modification of synaptic connections ("synaptic plasticity") is widely believed to represent a major mechanism for modifying the functional properties of neuronal networks, possibly providing the basis for phenomena collectively referred to as "learning and memory." This belief has an important corollary: It implies that synapses, when not driven to change their characteristics by physiologically relevant stimuli, should retain these characteristics over time. Recent studies, however, have shown that synaptic molecules, organelles, and even patches of synaptic specializations continuously move in, out, and between synapses at significant rates. Given these intense dynamics, the ability of synapses to retain their individual characteristics over behaviorally relevant time scales is not at all obvious. This chapter focuses on techniques used to study the cellular and molecular dynamics of synaptic components and on quantitative measures of synaptic tenacity - the capacity of synapses to maintain their characteristics over time. These include fluorescence recovery after photobleaching (FRAP), fluorescence recovery after photoactivation (FRAPA), and several analytical tools used to quantify the (in)stability of individual synapses and of synaptic configurations. © 2014 Springer Science+Business Media New York.


Blumenfeld Z.,Rappaport Institute | Patel B.,Rappaport Institute | Leiba R.,Rappaport Institute | Zuckerman T.,Rappaport Institute
Fertility and Sterility | Year: 2012

Objective: To compare the rate of premature ovarian failure (POF) after stem cell transplantation (SCT) in young women receiving GnRH-agonist (GnRH-a) in conjunction with gonadotoxic chemotherapy. Design: Prospective, nonrandomized study. Setting: Tertiary university hospital. Patient(s): Ninety-five women received conditioning chemotherapy, with or without GnRH-a before SCT. Complete information was available for only 83 patients. Intervention(s): Conditioning chemotherapy, with or without GnRH-a before SCT. Main Outcome Measure(s): Cyclic ovarian function (COF) or POF after SCT. Result(s): There were no significant differences in age, chemotherapy treatment, or diagnoses between the study and control groups. In the GnRH-a group, 38.3% (18/47) patients resumed COF, compared with 11.1% (4/36) for patients who did not receive GnRH-a. Patients who resumed COF were on average 3.7 years (median, 3 years) younger at the time of transplantation than those who experienced POF. GnRH-a had a significant effect on long-term COF in patients with lymphomas (66.7% [14/21] for GnRH-a group vs. 18.2% [2/11] for control) but not for leukemia patients. Conclusion(s): GnRH-a cotreatment in conjunction with conditioning chemotherapy before SCT may significantly decrease the gonadotoxicity and POF from 82% to 33% in lymphoma but not in leukemia patients. Copyright © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.


Labin A.M.,Technion - Israel Institute of Technology | Labin A.M.,Rappaport Institute | Safuri S.K.,Rappaport Institute | Ribak E.N.,Technion - Israel Institute of Technology | Perlman I.,Rappaport Institute
Nature Communications | Year: 2014

Vision starts with the absorption of light by the retinal photoreceptors-cones and rods. However, due to the 'inverted' structure of the retina, the incident light must propagate through reflecting and scattering cellular layers before reaching the photoreceptors. It has been recently suggested that Müller cells function as optical fibres in the retina, transferring light illuminating the retinal surface onto the cone photoreceptors. Here we show that Müller cells are wavelength-dependent wave-guides, concentrating the green-red part of the visible spectrum onto cones and allowing the blue-purple part to leak onto nearby rods. This phenomenon is observed in the isolated retina and explained by a computational model, for the guinea pig and the human parafoveal retina. Therefore, light propagation by Müller cells through the retina can be considered as an integral part of the first step in the visual process, increasing photon absorption by cones while minimally affecting rod-mediated vision. © 2014 Macmillan Publishers Limited. All rights reserved.

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