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Understanding Epilepsy in Pediatric Tumors; New Therapeutic Target of Intractable Epilepsy Identified
Pediatric brain tumors are characterized by frequent complications due to intractable epilepsy compared to adult brain tumors. However, the genetic cause of refractory epilepsy in pediatric brain tumors has not been elucidated yet, and it is difficult to treat patients because the tumors do not respond to existing antiepileptic drugs and debilitate children’s development. A research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors. Their research results were published online in Nature Medicine on September 17. The research team studied patients’ tissue diagnosed with ganglioglioma (GG), one of the main causes of tumor-associated intractable epilepsy, and found that the BRAF V600E somatic mutation is involved in the development of neural stem cells by using deep DNA sequencing. This mutation was carried out in an animal model to reproduce the pathology of GG and to observe seizures to establish an animal model for the treatment of epileptic seizures caused by pediatric brain tumors. Using immunohistochemical and transcriptome analysis, they realized that the BRAF V600E mutation that arose in early progenitor cells during embryonic brain formation led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to a high proliferation of glial lineage cells exhibiting the mutation. Notably, researchers found that seizures in mice were significantly alleviated by intraventricular infusion of the BRAF V600E inhibitor, Vemurafenib, a clinical anticancer drug. The authors said, “Our study offers the first direct evidence that the BRAF somatic mutation arising from neural stem cells plays a key role in epileptogenesis in the brain tumor. This study also showed a new therapeutic target for tumor-associated epileptic disorders.” In collaboration with the KAIST startup company, SoVarGen, the research team is currently developing innovative therapeutics for epileptic seizures derived from pediatric brain tumors. This study was supported by the Suh Kyungbae Foundation (SUHF) and the Citizens United for Research in Epilepsy. (Figure: Preoperative and postoperative brain MRI (left panel), tumor H&E (right upper panel) and GFAP immunohistochemical (right lower panel) staining images from a patient with ganglioglioma (GG231) carrying the BRAFV600E mutation. The white arrow and the black arrowhead indicate the brain tumor and a dysplastic neuron, respectively.)
How to Trigger Innate Fear Response?
(Figure:This illustration describes how ACC-BLA circuit controls innate freezing response depending on its activity level.) When animals encounter danger, they usually respond to the situation in one of two ways: to freeze or to flee. How do they make this quick decision in a life or death moment? According to KAIST neuroscientists, there are two types of fear: learned versus innate. The latter is known to be induced without any prior experience and is thus naturally encoded in the brain. A research team under Professor Jin-Hee Han in the Department of Biological Sciences identified the brain circuit responsible for regulating the innate fear response. The study, which appeared in the July 24 issue of Nature Communications represents a significant step toward understanding how the neural circuits in the prefrontal cortex create behavioral responses to external threats. This also represents a new paradigm in therapeutic development for fear-related mental disorders. Responses of freezing or fleeing when facing external threats reflect behavioral and physiological changes in an instinctive move to adapt to the new environment for survival. These responses are controlled by the emotional circuit systems of the brain and the malfunction of this circuit leads to fear-related disorders. The anterior cingulate cortex (ACC) is a sub-region within the prefrontal cortex, comprising a part of the brain circuitry that regulates behavioral and physiological fear responses. This area is capable of high-order processing of the perceived sensory information and conveys ‘top-down’ information toward the amygdala and brainstem areas, known as the response outlet. Many studies have already demonstrated that the brain regions in the prefrontal cortex regulate the response against learned threats. However, it has been unknown how innate responses against fear are encoded in the neural circuits in the prefrontal cortex. Dr. Jinho Jhang, the lead author of the study explains how the team achieved their key idea. “Many overseas studies have already proved that the prefrontal cortex circuit works to regulate the fear response. However, researchers have paid little attention to the innate response against predators. Professor Han suggested we do research on the instinctive fear response instead of the learned response. We particularly focused on the anterior cingulate region, which has been connected with memory, pain, and sympathy, but not the fear response itself. Since we turned in this new direction, we have accumulated some significant data,” said Dr. Jhang. For this study, Professor Han’s team investigated how mice react when exposed to the olfactory stimuli of predators. Based on the results of optogenetic manipulation, neural circuit tracing, and ex vivo slice electrophysiology experiments, the team demonstrated that the anterior cingulate cortex and its projection input to the basolateral amygdala play a role in the inhibitory regulation of innate fear responses to predators’ odors in mice. Professor Han believes these results will extend the understanding of how instinctive fear responses can be encoded in our brain circuits. “Our findings will help to develop therapeutic treatments for mental disorders aroused from fear such as panic disorders and post-traumatic stress disorder,” said Professor Han.
New Quantum Mechanical States Observed
(Professor Han (far right) and his research team) A KAIST research team observed a new quantum mechanical magnetic state ‘Jeff = 3/2.’ This first observation of ‘Jeff=3/2’ could be the foundation for future research on superconductivity and quantum magnetism. In quantum mechanics, total angular momentum is defined as the sum of spin and orbital angular momenta and is denoted with the ‘J.’ The newly identified magnetic moment can be described as a kind of angular momentum that occurs when specific conditions are met and has been denoted ‘Jeff’ with the meaning ‘effective angular momentum’ in the field. Jeff=3/2 has been a topic of discussion but was yet to be observed. The research was co-led by Professor Myung Joon Han of the Department of Physics at Chung-Ang University in Korea, RIKEN in Japan, and the Argonne National Laboratory in the US. This research was published in Nature Communications on October 14, 2017. In academia, spin-orbital coupling was known to lead to a unique quantum state and has been an active area of recent research. In contrast to magnetic moment by electron spin and orbital, the effective magnetic moment Jeff, formed from the coupling of the two, shows a unique ground state and interaction patterns, which could lead to new phenomena and properties. Most studies in the last decade focused on ‘Jeff=1/2’, but there has not been any observation of ‘Jeff=3/2’, which led to slow progress. In 2014, the research team led by Prof. Han theoretically predicted the possibility of the ‘Jeff=3/2’ state in a certain type of materials based on molecular orbital, instead of atomic orbital. In the current study, the team applied the Selection Rule of quantum mechanics for the ‘Jeff=3/2’ state, which differs to the general spin moment, in order to experimentally detect this moment. When electrons near the atomic nucleus are excited by X-rays, the excited electrons can be absorbed or re-emitted through interactions with other electrons. Here, the Selection Rule is applied to electrons. According to quantum mechanics, this rule is very unique in the ‘Jeff=3/2’ state and ‘Jeff=3/2’ is predicted to be distinguishable from general spin states. The prediction that was made using this idea was verified through the experiment using electrons extracted from tantalum at two different energy levels. In this material, the unique quantum mechanical interference by the ‘Jeff=3/2’ moment can be taken as direct evidence for its existence. The new quantum state is very unique from any of the previously known magnetic states and this study could be the starting point for future research on the ‘Jeff=3/2’ moment. Further, this finding could contribute to future research on various properties of the magnetic states and its interactions. (Figure 1: Crystal structure, MO levels, and RIXS process in GaTa4Se8.) (Figure 2: Cluster model calculations of the L3 and L2 RIXS spectra)
KAIST-Taiwanese Team: Zinc Supplements May Help Treat Autism
A KAIST and Taiwanese research team has recently discovered strong evidence that Zinc is associated with autism spectrum disorders (ASD) and improves social interaction in mouse models with ASD. The research findings, titled “Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation,” were published in Nature Communications on May 18, 2015. For details, please see an article below: The China Post, June 4, 2015 “Zinc supplements may help treat autism: study” http://www.chinapost.com.tw/health/mental-health/2015/06/04/437612/Zinc-suppliments.htm
The Real Time Observation of the Birth of a Molecule
From right to left: Dr. Kyung-Hwan Kim, Professor Hyotcherl Lhee, and Jong-Gu Kim, a Ph.D. candidate Professor Hyotcherl Lhee of the Department of Chemistry at KAIST and Japanese research teams jointly published their research results showing that they have succeeded in the direct observation of how atoms form a molecule in the online issue of Nature on February 19, 2015. The researchers used water in which gold atoms ([Au(CN) 2- ]) are dissolved and fired X-ray pulses over the specimen in femtosecond timescales to study chemical reactions taking place among the gold atoms. They were able to examine in real time the instant process of how gold atoms bond together to become a molecule, to a trimer or tetramer state. This direct viewing of the formation of a gold trimer complex ([Au(CN) 2- ] 3 ) will provide an opportunity to understand complex chemical and biological systems. For details, please see the following press release that was distributed by the High Energy Accelerator Research Organization, KEK, in Japan: Direct Observation of Bond Formations February 18, 2015 A collaboration between researchers from KEK, the Institute for Basic Science (IBS), the Korea Advanced Institute of Science and Technology (KAIST), RIKEN, and the Japan Synchrotron Radiation Research Institute (JASRI) used the SACLA X-ray free electron laser (XFEL) facility for a real time visualization of the birth of a molecular that occurs via photoinduced formation of a chemical bonds. This achievement was published in the online version of the scientific journal “Nature” (published on 19 February 2015). Direct “observation” of the bond making, through a chemical reaction, has been longstanding dream for chemists. However, the distance between atoms is very small, at about 100 picometer, and the bonding is completed very quickly, taking less than one picosecond (ps). Hence, previously, one could only imagine the bond formation between atoms while looking at the chemical reaction progressing in the test-tube. In this study, the research group focused on the process of photoinduced bond formation between gold (Au) ions dissolved in water. In the ground state (S 0 state in Fig. 1) Au ions that are weakly bound to each other by an electron affinity and aligned in a bent geometry. Upon a photoexcitation, the S 0 state rapidly converts into an excited (S 1 state in Fig. 1) state where Au-Au covalent bonds are formed among Au ions aligned in a linear geometry. Subsequently, the S 1 state transforms to a triplet state (T 1 state in Fig. 1) in 1.6 ps while accompanying further contraction of Au-Au bonds by 0.1 Å. Later, the T 1 state of the trimer converts to a tetramer (tetramer state in Fig. 1) on nanosecond time scale. Finally, the Au ions returned to their original loosely interacting bent structure. In this research, the direct observation of a very fast chemical reaction, induced by the photo-excitation, was succeeded (Fig. 2, 3). Therefore, this method is expected to be a fundamental technology for understanding the light energy conversion reaction. The research group is actively working to apply this method to the development of viable renewable energy resources, such as a photocatalysts for artificial photosynthesis using sunlight. This research was supported by the X-ray Free Electron Laser Priority Strategy Program of the MEXT, PRESTO of the JST, and the the Innovative Areas "Artificial Photosynthesis (AnApple)" grant from the Japan Society for the Promotion of Science (JSPS). Publication: Nature , 518 (19 February 2015) Title: Direct observation of bond formation in solution with femtosecond X-ray scattering Authors: K. H. Kim 1 , J. G. Kim 1 , S. Nozawa 1 , T. Sato 1 , K. Y. Oang, T. W. Kim, H. Ki, J. Jo, S. Park, C. Song, T. Sato, K. Ogawa, T. Togashi, K. Tono, M. Yabashi, T. Ishikawa, J. Kim, R. Ryoo, J. Kim, H. Ihee, S. Adachi. ※ 1: These authors contributed equally to the work. DOI: 10.1038/nature14163 Figure 1. Structure of a gold cyano trimer complex (Au(CN) 2 - ) 3 . Figure 2. Observed changes in the molecular structure of the gold complex Figure 3. Schematic view of the research of photo-chemical reactions by the molecular movie
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