<i>Drosophila</i> Atlastin regulates the stability of muscle microtubules and is required for synapse development

Lee, Mihye,Paik, Sang Kyoo,Lee, Min-Jung,Kim, Yoon-Jung,Kim, Sungdae,Nahm, Minyeop,Oh, Soo-Jin,Kim, Hyun-Man,Yim, Jeongbin,Lee, C. Justin,Bae, Yong Chul,Lee, Seungbok Elsevier 2009 Developmental Biology Vol.330 No.2

<P><B>Abstract</B></P><P>Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterized by progressive spasticity and weakness of the lower extremities. The most common early-onset form of HSP is caused by mutations in the human gene that encodes the dynamin-family GTPase Atlastin-1 (Atl-1). Recently, loss of the <I>Drosophila</I> ortholog of Atl-1 (Atl) has been found to induce locomotor impairments from the earliest adult stages, suggesting the developmental role of atlastin-subfamily GTPases. Here, we provide evidence that Atl is required for normal growth of muscles and synapses at the neuromuscular junction (NMJ). Atl protein is highly expressed in larval body-wall muscles. Loss-of-function mutations in the <I>atl</I> gene reduce the size of muscles and increase the number of synaptic boutons. Rescue of these defects is accomplished by muscular, but not neuronal expression of Atl. Loss of Atl also disrupts ER and Golgi morphogenesis in muscles and reduces the synaptic levels of the scaffold proteins Dlg and α-spectrin. We also provide evidence that Atl functions with the microtubule-severing protein Spastin to disassemble microtubules in muscles. Finally, we demonstrate that the microtubule-destabilizing drug vinblastine alleviates synapse and muscle defects in <I>atl</I> mutants. Together, our results suggest that Atl controls synapse development and ER and Golgi morphogenesis by regulating microtubule stability.</P>

GluA1 phosphorylation at serine 831 in the lateral amygdala is required for fear renewal

Lee, Sukwon,Song, Beomjong,Kim, Jeongyeon,Park, Kyungjoon,Hong, Ingie,An, Bobae,Song, Sangho,Lee, Jiwon,Park, Sungmo,Kim, Jihye,Park, Dongeun,Lee, C Justin,Kim, Kyungjin,Shin, Ki Soon,Tsien, Richard W Nature Publishing Group, a division of Macmillan P 2013 NATURE NEUROSCIENCE Vol.16 No.10

Fear renewal, a widely pursued model of post-traumatic stress disorder and phobias, refers to the context-specific relapse of conditioned fear after extinction. However, its molecular mechanisms are largely unknown. We found that renewal-inducing stimuli, generally believed to be insufficient to induce synaptic plasticity, enhanced excitatory synaptic strength, activity of synaptic GluA2-lacking AMPA receptors and Ser831 phosphorylation of synaptic surface GluA1 in the lateral nucleus of the amygdala (LAn) of fear-extinguished rats. Consistently, the induction threshold for LAn synaptic potentiation was considerably lowered after extinction, and renewal occluded this low-threshold potentiation. The low-threshold potentiation (a potential cellular substrate for renewal), but not long-term potentiation, was attenuated by dialysis into LAn neurons of a GluA1-derived peptide that competes with Ser831-phosphorylated GluA1. Microinjections of the same peptide into the LAn attenuated fear renewal, but not fear learning. Our findings suggest that GluA1 phosphorylation constitutes a promising target for clinical treatment of aberrant fear-related disorders.

Attenuated Glial K ⁺ Clearance Contributes to Long-Term Synaptic Potentiation Via Depolarizing GABA in Dorsal Horn Neurons of Rat Spinal Cord

Lee, Jaekwang,Favorov, Oleg V,Tommerdahl, Mark,Lee, C. Justin,Whitsel, Barry L. The Korean Society for Brain and Neural Science 2014 Experimental Neurobiology Vol.23 No.1

<P>It has been reported that long-term enhancement of superficial dorsal horn (DH<SUB>s</SUB>) excitatory synaptic transmission underlies central sensitization, secondary hyperalgesia, and persistent pain. We tested whether impaired clearance of K<SUP>+</SUP> and glutamate by glia in DH<SUB>s</SUB> may contribute to initiation and maintenance of the CNS pain circuit and sensorimotor abnormalities. Transient exposure of the spinal cord slice to fluorocitrate (FC) is shown to be accompanied by a protracted <I>decrease</I> of the DH<SUB>s</SUB> optical response to repetitive electrical stimulation of the ipsilateral dorsal root, and by a similarly protracted <I>increase</I> in the postsynaptic response of the DH<SUB>s</SUB> like LTP. It also is shown that LTP<SUB>FC</SUB><I>does not</I> occur in the presence of APV, and becomes progressively <I>smaller</I> as [K<SUP>+</SUP>]<SUB>o</SUB> in the perfusion solution decreased from 3.0 mM to 0.0 mM. Interestingly LTP<SUB>FC</SUB> is <I>reduced</I> by bath application of Bic. Whole-cell patch recordings were carried out to evaluate the effects of FC on the response of DH<SUB>s</SUB> neurons to puffer-applied GABA. The observations reveal that transient exposure to FC is reliably accompanied by a prolonged (>1 hr) depolarizing shift of the equilibrium potential for the DH<SUB>s</SUB> neuron transmembrane ionic currents evoked by GABA. Considered collectively, the findings demonstrate that LTP<SUB>FC</SUB> involves (1) elevation of [K<SUP>+</SUP>]<SUB>o</SUB> in the DH<SUB>s</SUB>, (2) NMDAR activation, and (3) conversion of the effect of GABA on DH<SUB>s</SUB> neurons from inhibition to excitation. It is proposed that a transient impairment of astrocyte energy production can trigger the cascade of dorsal horn mechanisms that underlies hyperalgesia and persistent pain.</P>

The Effects of Diet Alone or in Combination with Exercise in Patients with Prehypertension and Hypertension: a Randomized Controlled Trial

Lee, Chan Joo,Kim, Ji Young,Shim, Eugene,Hong, Sung Hyun,Lee, MiKyung,Jeon, Justin Y.,Park, Sungha The Korean Society of Cardiology 2018 Korean Circulation Journal Vol.48 No.7

<P><B>Background and Objectives</B></P><P>Supervised lifestyle interventions, including dietary and exercise programs, may be infeasible to implement in real-world settings. Therefore, this study aimed to evaluate the effectiveness of a home-based lifestyle modification intervention on blood pressure (BP) management.</P><P><B>Methods</B></P><P>Eighty-five patients aged over 20 years and diagnosed with prehypertension or mild hypertension were randomly assigned to an advice-only comparison group (C group, n=28), a Dietary Approaches to Stop Hypertension (DASH) diet education group (D group, n=30), or a DASH and home-based exercise group (D+Ex group, n=27). The intervention lasted for 8 weeks. The primary outcome was the difference in office systolic blood pressure (SBP) before and after the study period (Trial registry at ClinicalTrials.gov, NCT01637909).</P><P><B>Results</B></P><P>Seventy-two participants (87.8%) completed the trial. The degree of change in office SBP did not significantly differ among the intervention groups; however, the D+Ex group demonstrated a tendency toward decreased SBP. Upon analysis of 24-hour ambulatory BP measurements, daytime ambulatory SBP was significantly lower in the D+Ex group (134 mmHg; 95% confidence interval [CI], 131 to 137; p=0.011) than in the C group (139.5 mmHg; 95% CI, 130.9 to 137), and daytime ambulatory SBP was significantly decreased in the D+Ex group (−5.2 mmHg; 95% CI, −8.3 to −2.1; p=0.011) compared to the C group (0.4 mmHg, 95% CI, −2.5 to 3.3).</P><P><B>Conclusions</B></P><P>In conclusion, lifestyle modification emphasizing both diet and exercise was effective for lowering BP and should be favored over diet-only modifications.</P>

Relationship between resting heart rate and metabolic risk factors in breast cancer patients

Lee, Mi Kyung,Lee, Dong Hoon,Park, Seho,Kim, Seung Il,Jeon, Justin Y. Elsevier 2018 Clinica chimica acta Vol.486 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Higher resting heart rate (RHR) was associated with poor prognosis in breast cancer survivors, but the mechanism underlying such association has not been fully studied. We investigated the association between RHR and metabolic risk factors in stage I-III breast cancer survivors.</P> <P><B>Methods</B></P> <P>Among 11,013 women diagnosed with breast cancer between 2005 and 2013 at the Severance hospital in Seoul, Korea, a total of 4980 patients met our inclusion criteria for the final analysis. Multivariable linear regressions were used to examine the association between RHR and metabolic risk factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, triglyceride (TG), total cholesterol, high density lipid cholesterol (HDLC), and low density lipid cholesterol.</P> <P><B>Results</B></P> <P>The results showed that RHR had significant linear associations with SBP (<I>p</I> = .02), DBP (<I>p</I> < .001), TG (<I>p</I> < .001), glucose (<I>p</I> < .001), and HDL-C (<I>p</I> < .001). Compared to participants in the lowest quintile of RHR (<68 beat per min (bpm)), participants in the highest quintile (≥85 bpm) had higher DBP by 4 mmHg, TG by 13 mg/dl, and glucose by 5 mg/dl after adjusting for potential confounders. Further subgroup analyses showed that the association of RHR may differ by age and menopausal status for fasting glucose and cancer stage, chemotherapy, estrogen and progesterone receptor status for TG.</P> <P><B>Conclusions</B></P> <P>We observed a strong positive association of RHR with fasting glucose, TG, and DBP in breast cancer survivors, which may potentially explain the association between RHR and breast cancer prognosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Underlying mechanism of resting heart rate (RHR) and cancer prognosis is unclear. </LI> <LI> Higher RHR was associated with higher glucose in breast cancer survivors. </LI> <LI> Higher RHR was associated with higher triglyceride in breast cancer survivors. </LI> <LI> Higher RHR was associated with higher diastolic blood pressure in breast cancer survivors. </LI> <LI> RHR may be a predictor of metabolic risk factors associated with cancer prognosis. </LI> </UL> </P>

Ca ²⁺ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

Lee, Jaekwang,Chun, Ye-Eun,Han, Kyung-Seok,Lee, Jungmoo,Woo, Dong Ho,Lee, C. Justin The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.1

<P>Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca<SUP>2+</SUP> oscillations. ATP is known to be released from astrocytes by Ca<SUP>2+</SUP>-dependent manner. However, the precise source of Ca<SUP>2+</SUP>, whether it is Ca<SUP>2+</SUP> entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca<SUP>2+</SUP> was released from intracellular stores by activation of Gα<SUB>q</SUB>-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca<SUP>2+</SUP> was omitted. Our results suggest that Ca<SUP>2+</SUP> entry, but not release from intracellular Ca<SUP>2+</SUP> store, is critical for MS-induced ATP release from astrocyte.</P>

Romo1 is a mitochondrial nonselective cation channel with viroporin-like characteristics

Lee, Gi Young,You, Deok-gyun,Lee, Hye-Ra,Hwang, Sun Wook,Lee, C. Justin,Yoo, Young Do Rockefeller University Press 2018 The Journal of cell biology Vol.217 No.6

<P>Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe<SUP>2+</SUP> ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data–guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes.</P>

A multichannel neural probe with embedded microfluidic channels for simultaneous in vivo neural recording and drug delivery.

Lee, Hyunjoo J,Son, Yoojin,Kim, Jeongyeon,Lee, C Justin,Yoon, Eui-Sung,Cho, Il-Joo Royal Society of Chemistry 2015 Lab on a chip Vol.15 No.6

<P>Multi-functional neural probes integrated with various stimulation modalities are becoming essential tools in neuroscience to study the brain more effectively. In this paper, we present a new multi-functional neural probe that allows chemical stimulation through drug delivery and simultaneous recording of individual neuron signals through a microelectrode array. By embedding microchannels in silicon using a proposed glass reflow process, we successfully fabricated 40 μm thick silicon neural probes suitable for small animal experiments. The electrochemical impedance spectroscopy confirms that impedance of iridium microelectrodes is low enough (<1 Mω at 1 kHz) to measure neural signals. Flow rate characterization in a 0.9% w/v agarose gel shows the capability to deliver a small volume of drugs (<1 μl) at a controlled flow rate. We demonstrate the viability and potential of this new probe by conducting in vivo experiments on mice. Because of the proposed compact structure, both action potentials of individual neurons and local field potentials (LFP) at the thalamus region of a mouse brain were successfully detected with a noise level of ~30 μVpp. Furthermore, we successfully induced absence seizure by injecting seizure-inducing drugs (baclofen) at a local target region and observed distinctive changes in neural signal patterns. Specifically, spike-wave discharge (SWD), which is an indicative signal pattern of absence seizure, was successfully recorded. These signals were also directly compared to SWD detected after inducing absence seizure through direct injection of baclofen through the abdomen. This work demonstrates the potential of our multi-functional neural probes for use in effective investigation of brain functions and disorders by using widely available mouse models.</P>

Improved stability of silver nanowire (AgNW) electrode for high temperature applications using selective photoresist passivation

Lee, Jong Chan,Min, Jeongho,Justin Jesuraj, P.,Hafeez, Hassan,Kim, Dong Hyun,Lee, Won Ho,Choi, Dae Keun,Cha, Jun Hwan,Lee, Chang Min,Song, Myungkwan,Kim, Chang Su,Ryu, Seung Yoon Elsevier 2019 MICROELECTRONIC ENGINEERING Vol.206 No.-

<P><B>Abstract</B></P> <P>Metal nanostructure arrays have been progressed as an alternative to the conventional oxides-based transparent conductive electrodes. Herein, we demonstrate the improved reliability of silver nanowire (AgNW) electrodes by photoresist encapsulation. The incorporation of photoresist followed by photolithography is beneficial to selectively pattern the AgNWs on poly[ether sulfone]. By varying the development or removal time of the ultraviolet (UV)-exposed photoresist, the properties of the AgNWs in the electrode are significantly varied. The optical parameters such as transmittance, haziness, and the yellow index of the electrodes have been extensively studied to reveal the advantage of the selective photoresist patterning. The AgNW electrodes patterned under 120 s of development time explored superior optical and electrical properties with high durability. The electrical properties of the AgNW electrodes at high temperatures (250 °C) demonstrate the photoresist-induced stability as compared to bare samples. Further, the morphological examination after the high temperature treatment reveals the reduced Rayleigh instability effects in 120 s developed AgNWs that facilitate the reliability under harsh conditions.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Selective passivation of AgNWs electrode achieved with a photoresist. </LI> <LI> Haze/yellow index variation of AgNW electrode with various developing time revealed. </LI> <LI> AgNW passivated with 120 s developing time show high reliability until 250 °C. </LI> <LI> Selective passivation of AgNWs suppressed thermally induced Rayleigh instability. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Dynamic Changes in the Bridging Collaterals of the Basal Ganglia Circuitry Control Stress-Related Behaviors in Mice

Lee, Young,Han, Na-Eun,Kim, Wonju,Kim, Jae Gon,Lee, In Bum,Choi, Su Jeong,Chun, Heejung,Seo, Misun,Lee, C. Justin,Koh, Hae-Young,Kim, Joung-Hun,Baik, Ja-Hyun,Bear, Mark F.,Choi, Se-Young,Yoon, Bong-Ju Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.4

The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) ('bridging collaterals') was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and controls appropriate coping responses in which the bridging collateral connections in the GPe play a critical regulatory role.