Biomedical Science Institute

Seoul, South Korea

Biomedical Science Institute

Seoul, South Korea
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Blocki A.,National University of Singapore | Blocki A.,Biomedical science Institute | Wang Y.,National University of Singapore | Koch M.,National University of Singapore | And 7 more authors.
Stem Cells and Development | Year: 2013

Pericytes play a crucial role in angiogenesis and vascular maintenance. They can be readily identified in vivo and isolated as CD146 +CD34- cells from various tissues. Whether these and other markers reliably identify pericytes in vitro is unclear. CD146 +CD34- selected cells exhibit multilineage potential. Thus, their perivascular location might represent a stem cell niche. This has spurred assumptions that not only all pericytes are mesenchymal stromal cells (MSCs), but also that all MSCs can act as pericytes. Considering this hypothesis, we developed functional assays by confronting test cells with endothelial cultures based on matrigel assay, spheroid sprouting, and cord formation. We calibrated these assays first with commercial cell lines [CD146+CD34- placenta-derived pericytes (Pl-Prc), bone marrow (bm)MSCs and fibroblasts]. We then functionally compared the angiogenic abilities of CD146+CD34-selected bmMSCs with CD146 - selected bmMSCs from fresh human bm aspirates. We show here that only CD146+CD34- selected Pl-Prc and CD146 +CD34- selected bmMSCs maintain endothelial tubular networks on matrigel and improve endothelial sprout morphology. CD146 - selected bmMSCs neither showed these abilities, nor did they attain pericyte function despite progressive CD146 expression once passaged. Thus, cell culture conditions appear to influence expression of this and other reported pericyte markers significantly without correlation to function. The newly developed assays, therefore, promise to close a gap in the in vitro identification of pericytes via function. Indeed, our functional data suggest that pericytes represent a subpopulation of MSCs in bm with a specialized role in vascular biology. However, these functions are not inherent to all MSCs. © Mary Ann Liebert, Inc.


News Article | February 15, 2017
Site: www.eurekalert.org

Researchers show, in an article in Cell, that the central nucleus of the amygdala is the brain region responsible for articulating the different skills involved in pursuing and killing prey For scientists who study the brain, predatory hunting, upon which many wild animals depend for survival, is a complex behavior involving different skills that must be exercised in an efficient and articulated manner if the predator is to succeed. Through experiments with mice, Brazilian and US researchers have demonstrated that a brain region called the central nucleus of the amygdala is responsible for organizing the actions involved in predatory hunting. They have also shown that this process occurs in two distinct neural networks: one that organizes prey pursuit and capture and another that controls the jaw and neck movements required for the predator to deliver a lethal bite. "The modular way in which control is exerted is relevant. The study provides novel details of the neural control of craniofacial muscles, potentially contributing to an understanding of the pathologies that affect this region. In addition, practical applications are being considered in the field of engineering, especially with regard to the development of robotics algorithms," said Ivan de Araujo, Associate Professor of Psychiatry at the Yale School of Medicine in the United States. Araujo's main focus in his laboratory work is research on the neural basis for the feeding behavior of mammals. He began partnering with Newton Canteras, a professor at the University of São Paulo's Biomedical Science Institute (ICB-USP) in Brazil, because of their shared interest in understanding how the hunt for food is controlled under conditions close to those prevailing in nature. Previous studies by Canteras's group at ICB-USP had shown that the central nucleus of the amygdala is strongly activated when an animal is hunting. "Canteras has ample experience in research on hunting behavior, and after members of his group visited my lab, we decided to apply the insect predation model to genetically modified mice," Araujo recalled. Several experiments and techniques were used with the aim of "interrogating" the neurons of the central amygdala and thereby discovering the pathways involved when an animal is hunting for prey. Motta explained that one of the most important techniques was optogenetics, which uses laser light to activate and deactivate neurons almost instantaneously. "Using a viral vector, we inserted into the neurons in the region of interest a protein that acts as a cellular receptor and makes the neurons respond to light. Depending on the receptor inserted, neurons can be activated or deactivated by the light stimulus," Motta said. "In addition, we inserted optical fibers to transmit the light to the site. The time between switching the laser on or off and the activation or deactivation of neurons is very short, allowing neural function to be correlated with the behavior observed." The same technique, in which neurons are modified by viral vectors, can be used to make activation and deactivation even more specific, distinguishing between glutamatergic neurons (which release the neurotransmitter glutamate) and GABAergic neurons (which secrete gamma aminobutyric acid), for example. "We performed experiments with animals that expressed the enzyme Cre recombinase only in glutamatergic neurons, for example. Next, we inserted a Cre-dependent virus that took the light-sensitive receptor only to neurons marked with the enzyme. In this way, we were able to activate or deactivate only the population of glutamatergic neurons. Our aim was to find out what happens in this case," Motta said. Another possibility is selectively killing a specific group of neurons by injecting a Cre-dependent virus capable of encoding caspases, a family of proteases that convey signals to cells that cause the cells to enter apoptosis (programmed cell death). This series of experiments enabled the researchers to map the two different neural pathways that together coordinate hunting behavior, both mediated by GABAergic neurons. One extends from the central nucleus of the amygdala to a region of the brainstem called the parvocellular reticular formation (PCRt). The neurons here project to the nucleus ambiguus of the accessory nerve (cranial nerve XI), which controls head movement, and the trigeminal motor nucleus, which is responsible for jaw movement. "The experiments showed, for example, that if we eliminate the neurons that project to the trigeminal motor nucleus, the animal engages in prey pursuit but is unable to deliver a lethal bite," Motta said. "On the other hand, it continues normally chewing the food offered in the lab, showing that feeding behavior is controlled by a different neural circuit." The second pathway runs from the central nucleus of the amygdala to the periaqueductal gray matter (PAG). Located in the midbrain, the PAG projects to the spinal cord and mediates motor responses consistent with fight-or-flight reactions. "When the neurons in this pathway were eliminated, the latency to begin pursuing prey increased significantly, but a killing bite was easily delivered once the prey had been captured, because the PCRt pathway was functioning normally," Motta said. Another experiment measured bite force, which did not change after elimination of PAG pathway neurons but decreased sharply after elimination of PCRt pathway neurons. For Canteras, the results of this research break a longstanding paradigm in neuroscience, which is the idea that the central amygdala is the region responsible for organizing fear-related behavior, such as freezing in the face of a larger predator or rolling over and demonstrating submission to a hierarchically superior member of the same community. The initial experiments showed that when the central nucleus of the amygdala was stimulated by light, instead of behaving defensively, which would indicate fear, the animals began masticating, even without having any food in their mouths. "We've now shown irrefutably that the central amygdala organizes hunting behavior and that in this system, there may be mechanisms that make the animal stop hunting in adverse environmental conditions," Canteras said. "So what was previously interpreted as fear might just be a signal to stop hunting, for lack of favorable conditions."


News Article | February 16, 2017
Site: phys.org

Through experiments with mice, Brazilian and U.S. researchers have demonstrated that a brain region called the central nucleus of the amygdala is responsible for organizing the actions involved in predatory hunting. They have also shown that this process occurs in two distinct neural networks: one that organizes prey pursuit and capture; and another that controls the jaw and neck movements required for the predator to deliver a lethal bite. "The modular way in which control is exerted is relevant. The study provides novel details of the neural control of craniofacial muscles, potentially contributing to an understanding of the pathologies that affect this region. In addition, practical applications are being considered in the field of engineering, especially with regard to the development of robotics algorithms," said Ivan de Araujo, Associate Professor of Psychiatry at the Yale School of Medicine in the United States. Araujo's main focus in his laboratory work is research on the neural basis for the feeding behavior of mammals. He began partnering with Newton Canteras, a professor at the University of São Paulo's Biomedical Science Institute (ICB-USP) in Brazil, because of their shared interest in understanding how the hunt for food is controlled under conditions close to those prevailing in nature. Previous studies by Canteras's group at ICB-USP had shown that the central nucleus of the amygdala is strongly activated when an animal is hunting. "Canteras has ample experience in research on hunting behavior, and after members of his group visited my lab, we decided to apply the insect predation model to genetically modified mice," Araujo recalled. Several experiments and techniques were used with the aim of "interrogating" the neurons of the central amygdala and thereby discovering the pathways involved when an animal is hunting for prey. Motta explained that one of the most important techniques was optogenetics, which uses laser light to activate and deactivate neurons almost instantaneously. "Using a viral vector, we inserted into the neurons in the region of interest a protein that acts as a cellular receptor and makes the neurons respond to light. Depending on the receptor inserted, neurons can be activated or deactivated by the light stimulus," Motta said. "In addition, we inserted optical fibers to transmit the light to the site. The time between switching the laser on or off and the activation or deactivation of neurons is very short, allowing neural function to be correlated with the behavior observed." The same technique, in which neurons are modified by viral vectors, can be used to make activation and deactivation even more specific, distinguishing between glutamatergic neurons (which release the neurotransmitter glutamate) and GABAergic neurons (which secrete gamma aminobutyric acid), for example. "We performed experiments with animals that expressed the enzyme Cre recombinase only in glutamatergic neurons, for example. Next, we inserted a Cre-dependent virus that took the light-sensitive receptor only to neurons marked with the enzyme. In this way, we were able to activate or deactivate only the population of glutamatergic neurons. Our aim was to find out what happens in this case," Motta said. Another possibility is selectively killing a specific group of neurons by injecting a Cre-dependent virus capable of encoding caspases, a family of proteases that convey signals to cells that cause the cells to enter apoptosis (programmed cell death). This series of experiments enabled the researchers to map the two neural pathways that coordinate hunting behavior, both mediated by GABAergic neurons. One extends from the central nucleus of the amygdala to a region of the brainstem called the parvocellular reticular formation (PCRt). The neurons here project to the nucleus ambiguus of the accessory nerve (cranial nerve XI), which controls head movement, and the trigeminal motor nucleus, which is responsible for jaw movement. "The experiments showed, for example, that if we eliminate the neurons that project to the trigeminal motor nucleus, the animal engages in prey pursuit but is unable to deliver a lethal bite," Motta said. "On the other hand, it continues normally chewing the food offered in the lab, showing that feeding behavior is controlled by a different neural circuit." The second pathway runs from the central nucleus of the amygdala to the periaqueductal gray matter (PAG). Located in the midbrain, the PAG projects to the spinal cord and mediates motor responses consistent with fight-or-flight reactions. "When the neurons in this pathway were eliminated, the latency to begin pursuing prey increased significantly, but a killing bite was easily delivered once the prey had been captured, because the PCRt pathway was functioning normally," Motta said. Another experiment measured bite force, which did not change after elimination of PAG pathway neurons but decreased sharply after elimination of PCRt pathway neurons. For Canteras, the results of this research break a longstanding paradigm in neuroscience, which is the idea that the central amygdala is the region responsible for organizing fear-related behavior, such as freezing in the face of a larger predator or rolling over and demonstrating submission to a hierarchically superior member of the same community. The initial experiments showed that when the central nucleus of the amygdala was stimulated by light, instead of behaving defensively, which would indicate fear, the animals began masticating, even without having any food in their mouths. "We've now shown irrefutably that the central amygdala organizes hunting behavior and that in this system, there may be mechanisms that make the animal stop hunting in adverse environmental conditions," Canteras said. "So what was previously interpreted as fear might just be a signal to stop hunting, for lack of favorable conditions." Explore further: Scientists switch on predatory kill instinct in mice More information: Wenfei Han et al. Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala, Cell (2017). DOI: 10.1016/j.cell.2016.12.027


Choi J.-S.,Biomedical Science Institute | Park C.,Biomedical Science Institute | Jeong J.-W.,Biomedical Science Institute
Biochemical and Biophysical Research Communications | Year: 2010

The selective loss of dopaminergic neurons in the substantia nigra pars compacta is a feature of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity is the most common experimental model used to investigate the pathogenesis of PD. Administration of MPTP in mice produces neuropathological defects as observed in PD and 1-methyl-4-pyridinium (MPP+) induces cell death when neuronal cell cultures are used. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. In the present study, we demonstrated that AMPK is activated by MPTP in mice and MPP+ in SH-SY5Y cells. The inhibition of AMPK by compound C resulted in an increase in MPP+-induced cell death. We further showed that overexpression of AMPK increased cell viability after exposure to MPP+ in SH-SY5Y cells. Based on these results, we suggest that activation of AMPK might prevent neuronal cell death and play a role as a survival factor in PD. © 2009 Elsevier Inc. All rights reserved.


Kim J.-H.,National Health Insurance Service Ilsan Hospital | Shim J.-K.,Yonsei University | Song J.-W.,Yonsei University | Song Y.,Yonsei University | And 2 more authors.
Critical Care | Year: 2013

Introduction: Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery. Methods: We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively. Results: Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period. Conclusions: Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery.Trial registration: Clinical Trial.gov, NCT01758861. © 2013 Kim et al.; licensee BioMed Central Ltd.


Russo L.C.,Biomedical science Institute | Castro L.M.,Biomedical science Institute | Gozzo F.C.,University of Campinas | Ferro E.S.,Biomedical science Institute
FEBS Letters | Year: 2012

Mammalian cells have a large number of intracellular peptides that are generated by extralysosomal proteases. In this study, the enzymatic activity of thimet oligopeptidase (EP24.15) was inhibited in human embryonic kidney (HEK) 293 cells using a specific siRNA sequence. The semi-quantitative intracellular peptidome analyses of siRNA-transfected HEK293 cells shows that the levels of specific intracellular peptides are either increased or decreased upon EP24.15 inhibition. Decreased expression of EP24.15 was sufficient to potentiate luciferase gene reporter activation by isoproterenol (1-10 μM). The protein kinase A inhibitor KT5720 (1 μM) reduced the positive effect of the EP24.15 siRNA on isoproterenol signaling. Thus, EP24.15 inhibition by siRNA modulates the levels of specific intracellular peptides and isoproterenol signal transduction. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Choi J.-S.,Biomedical Science Institute | Lee M.S.,Kyung Hee University | Jeong J.-W.,Biomedical Science Institute
Biochemical and Biophysical Research Communications | Year: 2010

Ethyl pyruvate (EP), a simple derivative of endogenous pyruvate, has an anti-inflammatory function. Recently, the protective neurological effects of EP have been reported in cell culture and animal models of neurological diseases. The present study investigates the protective effects of EP on dopaminergic cell death in Parkinson's disease models. The selective death of dopaminergic neurons in substantia nigra was prevented by EP in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. EP also suppressed the 1-methyl-4-pyridinium-induced cell death of SH-SY5Y cells and restored the phosphorylation of extracellular signal-regulated kinase. Thus, EP has neuroprotective effects of EP in Parkinson's disease and its related signaling pathways. © 2010 Elsevier Inc. All rights reserved.


Hur J.,Biomedical Science Institute | Lee P.,Semyung University | Kim M.J.,Biomedical Science Institute | Kim Y.,Biomedical Science Institute | Cho Y.-W.,Biomedical Science Institute
Biochemical and Biophysical Research Communications | Year: 2010

Although glial cells play a major role in the pathogenesis of many neurological diseases by exacerbating neuronal and non-neuronal cell death, the mechanisms involved are unclear. We examined the effects of microglia-(MCM) or astrocyte-(ACM) conditioned media obtained by chemical ischemia on the neuronal injury in SH-SY5Y cells. Chemical ischemia was induced by the treatment with NaN3 and 2-deoxy-d-glucose for 2 h. MCM-treated SH-SY5Y cells showed reduced the viability, increased caspase-3 activity, decreased Bcl-2/Bax ratio, and increased cytochrome c release, increased inflammatory cytokines, and increased reactive oxygen species (ROS) generation. MCM also increased gp91phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which was inhibited by NADPH oxidase inhibitor, apocynin, and gp91phox siRNA. However, ACM did not show any significant changes. The results suggest that microglia activated by ischemic insult may increase reactive oxygen species generation via activation of gp91phox NADPH oxidase, resulting in neuronal injury. © 2009 Elsevier Inc. All rights reserved.


Karok S.,Biomedical science Institute | Witney A.G.,Biomedical science Institute
PLoS ONE | Year: 2013

Objective: Transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has beneficial effects on motor performance and motor learning in healthy subjects and is emerging as a promising tool for motor neurorehabilitation. Applying tDCS concurrently with a motor task has recently been found to be more effective than applying stimulation before the motor task. This study extends this finding to examine whether such task-concurrent stimulation further enhances motor learning on a dual M1 montage. Method: Twenty healthy, right-handed subjects received anodal tDCS to the right M1, dual tDCS (anodal current over right M1 and cathodal over left M1) and sham tDCS in a repeated-measures design. Stimulation was applied for 10 mins at 1.5 mA during an explicit motor learning task. Response times (RT) and accuracy were measured at baseline, during, directly after and 15 mins after stimulation. Motor cortical excitability was recorded from both hemispheres before and after stimulation using single-pulse transcranial magnetic stimulation. Results: Task-concurrent stimulation with a dual M1 montage significantly reduced RTs by 23% as early as with the onset of stimulation (p<0.01) with this effect increasing to 30% at the final measurement. Polarity-specific changes in cortical excitability were observed with MEPs significantly reduced by 12% in the left M1 and increased by 69% in the right M1. Conclusion: Performance improvement occurred earliest in the dual M1 condition with a stable and lasting effect. Unilateral anodal stimulation resulted only in trendwise improvement when compared to sham. Therefore, task-concurrent dual M1 stimulation is most suited for obtaining the desired neuromodulatory effects of tDCS in explicit motor learning. © 2013 Karok, Witney.


Chan P.M.,Biomedical science Institute
Protein and Cell | Year: 2011

Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses. The class III subfamily comprises the platelet-derived growth factor receptor, c-Kit, Flt3 and c-Fms, all of which relay cell proliferation signals upon ligand binding. Accordingly, mutations in these proteins that confer ligand-independent activation are found in a subset of cancers. These mutations cluster in the juxtamembrane (JM) and catalytic tyrosine kinase domain (TKD) regions. In the case of acute myeloid leukemia (AML), the juxtamembrane (named ITD for internal tandem duplication) and TKD Flt3 mutants differ in their spectra of clinical outcomes. Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases, the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain. This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation, to account for the disease variation. This will have bearing on therapeutic approaches in a complex disease such as AML, for which no efficacious drug yet exists. © 2011 Higher Education Press and Springer-Verlag Berlin Heidelberg.

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