PUBLICATIONS

2020

앞으로 한빛사 (https://www.ibric.org/hanbitsa/)에 등록되시는 KOLIS 회원분들을 홍보해드릴려고 합니다. 

좋은 논문 내시는 분들을 회장단에게 제보해주시면 감사하겠습니다.

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​밑줄 친 부분을 클릭하시면 해당 논문의 원본을 다운로드 하실 수 있습니다.

Stanford University 김윤석 박사님 - 2020년 6월 한빛사 논문 Neuron

(Published: 22 June 2020) 

 

Comprehensive Dual- and Triple-Feature Intersectional Single-Vector Delivery of Diverse Functional Payloads to Cells of Behaving Mammals 

Lief E. Fenno, Charu Ramakrishnan, Yoon Seok Kim, Kathryn E. Evans, Maisie Lo, Sam Vesuna, Masatoshi Inoue, Kathy Y.M. Cheung, Elle Yuen, Nandini Pichamoorthy, Alice S.O. Hong, Karl Deisserot

Abstract

The resolution and dimensionality with which biologists can characterize cell types have expanded dramatically in recent years, and intersectional consideration of such features (e.g., multiple gene expression and anatomical parameters) is increasingly understood to be essential. At the same time, genetically targeted technology for writing in and reading out activity patterns for cells in living organisms has enabled causal investigation in physiology and behavior; however, cell-type-specific delivery of these tools (including microbial opsins for optogenetics and genetically encoded Ca2+ indicators) has thus far fallen short of versatile targeting to cells jointly defined by many individually selected features. Here, we develop a comprehensive intersectional targeting toolbox including 39 novel vectors for joint-feature-targeted delivery of 13 molecular payloads (including opsins, indicators, and fluorophores), systematic approaches for development and optimization of new intersectional tools, hardware for in vivo monitoring of expression dynamics, and the first versatile single-virus tools (Triplesect) that enable targeting of triply defined cell types.

Neuron, Available online 22 June 2020 | https://doi.org/10.1016/j.neuron.2020.06.003

Stanford University 정경오 박사님 - 2020년 6월 한빛사 논문 Nature Biomedical Engineering

(Published: 15 June 2020) 

 

Whole-body tracking of single cells via positron emission tomography

Kyung Oh Jung, Tae Jin Kim, Jung Ho Yu, Siyeon Rhee, Wei Zhao, Byunghang Ha, Kristy Red-Horse, Sanjiv Sam Gambhir, Guillem Pratx

Abstract

In vivo molecular imaging can measure the average kinetics and movement routes of injected cells through the body. However, owing to non-specific accumulation of the contrast agent and its efflux from the cells, most of these imaging methods inaccurately estimate the distribution of the cells. Here, we show that single human breast cancer cells loaded with mesoporous silica nanoparticles concentrating the 68Ga radioisotope and injected into immunodeficient mice can be tracked in real time from the pattern of annihilation photons detected using positron emission tomography, with respect to anatomical landmarks derived from X-ray computed tomography. The cells travelled at an average velocity of 50 mm s−1 and arrested in the lungs 2–3 s after tail-vein injection into the mice, which is consistent with the blood-flow rate. Single-cell tracking could be used to determine the kinetics of cell trafficking and arrest during the earliest phase of the metastatic cascade, the trafficking of immune cells during cancer immunotherapy and the distribution of cells after transplantation.

Nat. Biomed. Eng., Published: 15 June 2020 | https://doi.org/10.1038/s41551-020-0570-5

Stanford University School of Medicine 김동희 박사님 - 2020년 6월 한빛사 논문 The American Journal of Gastroenterology

(Published: 3 June 2020) 

 

Low Thyroid Function in Nonalcoholic Fatty Liver Disease Is an Independent Predictor of All-Cause and Cardiovascular Mortality

Kim, Donghee MD, PhD; Vazquez-Montesino, Luis Miguel MD; Escober, Jessica A. BA; Fernandes, Christopher T. BS; Cholankeril, George MD; Loomba, Rohit MD, MHSc; Harrison, Stephen A. MD; Younossi, Zobair M. MD; Ahmed, Aijaz MD

Abstract

In vivo molecular imaging can measure the average kinetics and movement routes of injected cells through the body. However, owing to non-specific accumulation of the contrast agent and its efflux from the cells, most of these imaging methods inaccurately estimate the distribution of the cells. Here, we show that single human breast cancer cells loaded with mesoporous silica nanoparticles concentrating the 68Ga radioisotope and injected into immunodeficient mice can be tracked in real time from the pattern of annihilation photons detected using positron emission tomography, with respect to anatomical landmarks derived from X-ray computed tomography. The cells travelled at an average velocity of 50 mm s−1 and arrested in the lungs 2–3 s after tail-vein injection into the mice, which is consistent with the blood-flow rate. Single-cell tracking could be used to determine the kinetics of cell trafficking and arrest during the earliest phase of the metastatic cascade, the trafficking of immune cells during cancer immunotherapy and the distribution of cells after transplantation. 

Am. J. Gastroenterol., June 3, 2020 - Volume Publish Ahead of Print - Issue | 10.14309/ajg.0000000000000654

University of California, San Francisco 조경아 박사님 - 2020년 5월 한빛사 논문 Nature Neuroscience 

(Published: 25 May 2020) 

Cross-hemispheric gamma synchrony between prefrontal parvalbumin interneurons supports behavioral adaptation during rule shift learning

Kathleen K. A. Cho, Thomas J. Davidson, Guy Bouvier, Jesse D. Marshall, Mark J. Schnitzer, and Vikaas S. Sohal

Abstract

Organisms must learn new strategies to adapt to changing environments. Activity in different neurons often exhibits synchronization that can dynamically enhance their communication and might create flexible brain states that facilitate changes in behavior. We studied the role of gamma-frequency (~40 Hz) synchrony between prefrontal parvalbumin (PV) interneurons in mice learning multiple new cue–reward associations. Voltage indicators revealed cell-type-specific increases of cross-hemispheric gamma synchrony between PV interneurons when mice received feedback that previously learned associations were no longer valid. Disrupting this synchronization by delivering out-of-phase optogenetic stimulation caused mice to perseverate on outdated associations, an effect not reproduced by in-phase stimulation or out-of-phase stimulation at other frequencies. Gamma synchrony was specifically required when new associations used familiar cues that were previously irrelevant to behavioral outcomes, not when associations involved new cues or for reversing previously learned associations. Thus, gamma synchrony is indispensable for reappraising the behavioral salience of external cues.

https://doi.org/10.1038/s41593-020-0647-1

Stanford University School of Medicine 김주용 박사님 - 2020년 5월 한빛사 논문 Circulation (Published: 22 May 2020) 

The Environment-Sensing Aryl-Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions

Juyong Brian Kim, Quanyi Zhao, Trieu Nguyen, Milos Pjanic, Paul Cheng, Robert Wirka, Stanislao Travisano, Manabu Nagao, Ramendra Kundu, and Thomas Quertermous

Abstract

Background: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.

Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease.

Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes" (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses.

Conclusions: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.

https://doi.org/10.1161/CIRCULATIONAHA.120.045981

Stanford University, University of California, Davis 서재웅 박사님 - 2020년 4월 한빛사 논문 Nature Communications (Published: 30 April 2020) 

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

Jai Woong Seo, Elizabeth S. Ingham, Lisa Mahakian, Spencer Tumbale, Bo Wu, Sadaf Aghevlian, Shahin Shams, Mo Baikoghli, Poorva Jain, Xiaozhe Ding, Nick Goeden, Tatyana Dobreva, Nicholas C. Flytzanis, Michael Chavez, Kratika Singhal, Ryan Leib, Michelle L. James, David J. Segal, R. Holland Cheng, Eduardo A. Silva, Viviana Gradinaru & Katherine W. Ferrara

Nat. Commun., Published: 30 April 2020, 11, Article number: 2102| https://doi.org/10.1038/s41467-020-15818-4

 

Abstract

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

https://doi.org/10.1038/s41467-020-15818-4

Stanford Medical School 김동희 박사님 - 2020년 5월 한빛사 논문 Gastroenterology (Published: 7 May 2020)

Decline in Annual Mortality of Hepatitis C Virus-related Hepatocellular Carcinoma in the United States, From 2009 to 2018

Donghee Kim, Peter Konyn, George Cholankeril, Robert J. Wong, Zobair M.  Younossi, Aijaz Ahmed

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths in the world, accounting for 810,000 fatalities in 2015.1 With the introduction of direct-acting antiviral (DAA) agents in late 2013, the overall sustained virological response (SVR) for HCV infection increased significantly and it allowed treatment of patients over a wide spectrum of clinical disease severity including those with end-stage liver disease who were in the past deemed poor candidates for antiviral therapy. Therefore, it is plausible to hypothesize that a highly potent DAA-based antiviral regimen may reduce the risk of HCC by eradicating the HCV infection followed by regression in hepatic fibrosis and an improvement in survival partly due to reduction in the incidence of HCC.2 Furthermore, smaller studies have proposed an association between the use of DAA agents and HCC.3 In patients with history of successful response HCC treatment in the setting of HCV-related cirrhosis, hepatic decompensation may have a higher contribution to mortality than HCC recurrence.4 We studied the temporal trends in etiologybased HCC- and cirrhosis-related mortality in the United States (US) from 2009 to 2018.

https://doi.org/10.1053/j.gastro.2020.05.007

UC Davis - 김보경 박사님 - 2020년 4월 한빛사 논문 Nature Communications (Published: 24 April 2020)

 

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

Sheng Zhang, Bokyung Kim, Xiaoqing Zhu, Xuehong Gui, Yan Wang, Zhaohui Lan, Preeti Prabhu, Kenneth Fond, Aijun Wang, & Fuzheng Guo
 

Abstract

The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but rather activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. These findings suggest an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.

https://doi.org/10.1038/s41467-020-15656-4

Stanford Medical School 이보미 박사님 - 2020년 4월 한빛사 논문 Journal of Clinical Investigation (Published: 20 April 2020)
 

Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitis

Bomi Lee, Julia Z. Adamska, Hong Namkoong, Melena D. Bellin, Josh Wilhelm, Gregory L. Szot, David M. Louis, Mark M. Davis, Stephen J. Pandol, and Aida Habtezion
 

Abstract

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.

https://doi.org/10.1172/JCI134066

UCSF Gladstone 류재규 박사님 - 2020년 4월 한빛사 논문 Nature Immunology (Published: 13 April 2020)

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Andrew S. Mendiola, Jae Kyu Ryu, Sophia Bardehle, Anke Meyer-Franke, Kenny Kean-Hooi Ang, Chris Wilson, Kim M. Baeten, Kristina Hanspers, Mario Merlini, Sean Thomas, Mark A. Petersen, Alexander Williams, Reuben Thomas, Victoria A. Rafalski, Rosa Meza-Acevedo, Reshmi Tognatta, Zhaoqi Yan, Samuel J. Pfaff, Michael R. Machado, Catherine Bedard, Pamela E. Rios Coronado, Xiqian Jiang, Jin Wang, Michael A. Pleiss, Ari J. Green, Scott S. Zamvil, Alexander R. Pico, Benoit G. Bruneau, Michelle R. Arkin & Katerina Akassoglou

Abstract

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress–producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.

Stanford 박승민, 원대연, 이준 박사님  - 2020년 4월 한빛사 논문 Nature Biomedical Engineering (Published: 06 April 2020)

A mountable toilet system for personalized health monitoring via the analysis of excreta

Seung-min Park, Daeyoun D. Won, Brian J. Lee, Diego Escobedo, Andre Esteva, Amin Aalipour, T. Jessie Ge, Jung Ha Kim, Susie Suh, Elliot H. Choi, Alexander X. Lozano, Chengyang Yao, Sunil Bodapati, Friso B. Achterberg, Jeesu Kim, Hwan Park, Youngjae Choi, Woo Jin Kim, Jung Ho Yu, Alexander M. Bhatt, Jong Kyun Lee, Ryan Spitler, Shan X. Wang & Sanjiv S. Gambhir

Abstract

Technologies for the longitudinal monitoring of a person’s health are poorly integrated with clinical workflows, and have rarely produced actionable biometric data for healthcare providers. Here, we describe easily deployable hardware and software for the long-term analysis of a user’s excreta through data collection and models of human health. The ‘smart’ toilet, which is self-contained and operates autonomously by leveraging pressure and motion sensors, analyses the user’s urine using a standard-of-care colorimetric assay that traces red–green–blue values from images of urinalysis strips, calculates the flow rate and volume of urine using computer vision as a uroflowmeter, and classifies stool according to the Bristol stool form scale using deep learning, with performance that is comparable to the performance of trained medical personnel. Each user of the toilet is identified through their fingerprint and the distinctive features of their anoderm, and the data are securely stored and analysed in an encrypted cloud server. The toilet may find uses in the screening, diagnosis and longitudinal monitoring of specific patient populations.

Stanford 김윤석 Ph.D. candidate - 2020년 3월 한빛사 논문 Science (Published: 20 March 2020)

Genetically targeted chemical assembly of functional materials in living cells, tissues, and animals

Jia Liu, Yoon Seok Kim, Claire E. Richardson, Ariane Tom, Charu Ramakrishnan, Fikri Birey, Toru Katsumata, Shucheng Chen, Cheng Wang, Xiao Wang, Lydia-Marie Joubert, Yuanwen Jiang, Huiliang Wang, Lief E. Fenno, Jeffrey B.-H. Tok, Sergiu P. Pașca, Kang Shen, Zhenan Bao, Karl Deisseroth

 

Abstract

The structural and functional complexity of multicellular biological systems, such as the brain, are beyond the reach of human design or assembly capabilities. Cells in living organisms may be recruited to construct synthetic materials or structures if treated as anatomically defined compartments for specific chemistry, harnessing biology for the assembly of complex functional structures. By integrating engineered-enzyme targeting and polymer chemistry, we genetically instructed specific living neurons to guide chemical synthesis of electrically functional (conductive or insulating) polymers at the plasma membrane. Electrophysiological and behavioral analyses confirmed that rationally designed, genetically targeted assembly of functional polymers not only preserved neuronal viability but also achieved remodeling of membrane properties and modulated cell type–specific behaviors in freely moving animals. This approach may enable the creation of diverse, complex, and functional structures and materials within living systems.

 

Science, 20 Mar 2020: Vol. 367, Issue 6484, pp. 1372-1376 | DOI: 10.1126/science.aay4866 

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