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The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole^3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow., 50 pages, 18 figures, 3 tables, author's version of the paper published in Nature

As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.Statement of significancecGAS-STING signaling has long been recognized as playing a key role in triggering antitumor immunity. We reveal a new face of cGAS-STING signaling and an ability of cancer cells autonomously to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress.

Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V–PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.

Di Tang,1,* Duo Zhang,1,* Yu Heng,1 Xiao-Ke Zhu,1 Han-Qing Lin,1 Jian Zhou,1 Lei Tao,1 Li-Ming Lu2 1Department of Otorhinolaryngology and ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Ming Lu, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, People’s Republic of China, Tel +86-13916235624, Fax +86-021-63846383, Email lulunew2003@163.com Lei Tao, ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Tel +86-13916944810, Email doctortaolei@163.comPurpose: Chronic inflammation contributes to tumor initiation, progression, and immune escape. Neutrophils are the major component of inflammatory response and participate in the tumorigenesis process. However, compared to other immune cells in the tumor microenvironment of laryngeal squamous cell carcinoma (LSCC), neutrophils, especially the tumor-associated neutrophils (TANs), have not yet been comprehensively explored. The mechanism for regulating the crosstalk between TANs and tumor cells still remains unclear.Materials and Methods: The distribution profiles and phenotypic features of neutrophils and other inflammatory immune cell populations from a large LSCC patient cohort were systemically analyzed. Co-culturing of peripheral blood associated neutrophils (PANs) and TANs with PBMCs was performed, and the immunosuppression effect on T-cells was examined.Results: LSCC microenvironment is highly inflammatory with remarkable TANs infiltration, which is often associated with unfavorable prognosis and advanced clinical stage. We find that TANs in LSCC display morphologically immature and lower apoptosis, exhibit distinctively immunosuppressive phenotype of high PD-L1, and suppress CD8+ T lymphocytes proliferation and activation. We subsequently discover that PD-L1+TANs induced by LSCC-derived GM-CSF potently impair CD8+ T-cells proliferation and cytokines production function, which are partially blocked by a PD-L1-neutralizing antibody. Clinical data further support GM-CSF as an unfavorable prognostic biomarker and reveal a potential association with inflammatory immune cell infiltration, in particular neutrophils.Conclusion: Tumor-infiltrating PD-L1+ neutrophils induced by LSCC-derived GM-CSF suppress T cell proliferation and activation in the inflammatory microenvironment of LSCC and predict unfavorable prognosis. These TANs cripple antitumor T cell immunity and promote tumor progression. Our findings provide a basis for targeting PD-L1+TANs or GM-CSF as a new immunotherapeutic strategy for LSCC.Keywords: laryngeal squamous cell carcinoma, LSCC, tumor-associated neutrophils, TANs, PD-L1, inflammatory microenvironment, immune suppression, granulocyte-macrophage colony stimulating factor, GM-CSF

To observe the effect of acupotomy on the expression of Beclin-1, Bcl-2 and Caspase-3 in the cartilage tissue in rabbits with knee osteoarthritis (KOA), so as to explore its mechanism underling improvement of KOA.Twenty-four healthy male New Zealand rabbits were randomly and equally divided into blank control, model and acupotomy groups, with 8 rabbits in each group. By using the modified Videman's methods, the KOA model was established by left hind limb immobilization with a plaster cast for 6 weeks. The severity of KOA (knee pain, swelling and motor function) was assessed using Lequesne score, and the rabbits with a score below 4 were excluded. The acupotomy was applied to "Hedingci" (the attachment of the quadriceps tendon to the patella at the upper edge), "Binneixia" (the medial patellar supporting band attachment of medial inferior patellar margin), "Binwaixia" (the lateral patellar supporting band attachment of the lower lateral patellar margin), "Chengfeijian" (the lateral collateral ligament of the knee passes over the lateral joint space), "Weiyangci" (the medial margin of biceps femoris at the lateral end of popliteus), "Yinlingci" (the medial tibial attachment of anserinus tendon) on the left hind limb once a week for 4 weeks. One week after the last intervention, the left knee joint dysfunction severity(pain, maximum walking distance, and some activities of daily living) was evaluated by using modified Lequesne score. Histopathological changes of the cartilage were observed under light microscope after H.E. staining. The apoptosis of chondrocytes was observed after terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labeling (TUNEL) staining. The autophagolysosomes of chondrocytes were observed using transmission electron microscopy. The expression levels of Beclin-1, Bcl-2 and Caspase-3 (related factors of autophagy and apoptosis) were detected using Real-time PCR and Western blot separately.In comparison with the blank control group, the Lequesne score, apoptosis rate, expression levels of Caspase-3 mRNA and protein were significantly increased (Acupotomy can mitigate knee-joint pain and improve functional activity in KOA rabbits, which may be associated with its functions in promoting autophagy and suppressing apoptosis by up-regulating expressions of Beclin-1 and Bcl-2 mRNAs and proteins and down-regulation of Caspase-3 mRNA and protein.

Objectives: Systemic inflammatory response index (SIRI) values and tumor-infiltrating lymphocytes (TILs) are associated with the prognosis of various tumors. There is minimal evidence of those two as prognostic markers in laryngeal squamous cell carcinoma (LSCC). In this study, we aimed to examine the predictive value of SIRI and tumor-infiltrating CD3+/CD4+/CD8+T-cells in the prognosis of patients who underwent partial or total laryngectomy. Study Design: A total of 78 patients with LSCC who underwent total or partial laryngectomy at the Eye, Ear, Nose, and Throat Hospital of Fudan University between 2013 and 2015 were retrospectively analyzed. Methods: The tumor tissues of 78 LSCC patients were retrospectively evaluated using immunohistochemical staining for CD3+/CD4+/CD8+ -cells. The overall survival (OS) and disease-free survival (DFS) rates were recorded using the Kaplan-Meier method. Results: Patients with high immunoscore (IS) (3~4) had prolonged survival (PConclusions: The SIRI values and the density of TILs may help predict LSCC patients' outcomes after surgery. The combination of SIRI and IS may be a new component of the tumor, nodes, and metastases (TNM) classification of cancer and prognostic factor for T cell-target immunotherapy.

Acupuncture-moxibustion has affirmative curative effect in the prevention and treatment of senile dementia. Starting from the literature research, a visualization and application method of acupuncture-moxibustion knowledge of senile dementia in ancient books based on partial order structure is proposed. This method could extract and integrate the acupuncture-moxibustion knowledge of senile dementia contained in ancient books of traditional Chinese medicine, and establish a standardized, structured and visual knowledge graph. Applying this method to knowledge visual analysis and clinical auxiliary guidance could provide reference for combing the knowledge of ancient books of traditional Chinese medicine and transforming the knowledge of ancient books into clinical application.针灸在老年痴呆防治方面疗效肯定。本文从文献研究出发，提出一种基于偏序结构的老年痴呆古籍针灸知识可视化及应用方法。该方法可对中医古籍中蕴含的老年痴呆针灸诊治知识进行提取、整合，并建立规范化、结构化、可视化的知识图谱。将其运用于知识可视分析及临床辅助指导，可为中医古籍知识梳理及古籍知识向临床应用转化提供借鉴。.

Investigating the efficacy and safety of noninvasive cerebellar stimulation in improving the balance and walking function of patients with stroke.We searched 7 databases for randomized controlled trials (RCTs) related to noninvasive cerebellar stimulation in the treatment of stroke. The Berg Balance Scale (BBS), 6-minute walk test (6MWT), and Barthel Index (BI) were used as the outcome indexes to evaluate balance, walking and activities of daily living (ADL). The quality of the research was evaluated using the Cochrane Risk of Bias Tool. A meta-analysis was performed to evaluate the difference between the noninvasive cerebellar stimulation and control groups. Heterogeneity tests were performed to assess differences in treatment effects across noninvasive cerebellar stimulation modalities. A sensitivity analysis was performed to evaluate the robustness of the results.Seven studies were included, and 5 articles (71.43%) were rated as having a low risk of bias. Among the primary outcome indicators, 4 of the 7 articles were combined into the fixed effect model (I2 = 38%, P = .18). Compared with the control group, noninvasive cerebellar stimulation improved the BBS score, and the difference was statistically significant (mean difference [MD]: 3.00, 95% confidence interval [CI]: 1.10-5.40, P = .03); the sensitivity analysis showed that the statistical model was still stable after sequentially eliminating each article. Compared with the control group, noninvasive cerebellar stimulation improved the 6MWT results of patients with stroke (MD: 25.29, 95% CI: 4.86-45.73, P = .02). However, noninvasive cerebellar stimulation did not improve the BI (MD: 15.61, 95% CI: -7.91 to 39.13, P = .19). No safety problems or adverse reactions to noninvasive cerebellar stimulation were observed.Noninvasive cerebellar stimulation improves balance and walking function of patients with stroke, but its effect on ADL is uncertain. Due to the methodological weaknesses in the included trials, more RCTs are needed to confirm our conclusions.

Gamma-aminobutyric acid (GABA) is a nonproteinogenic amino acid that plays vital roles in plant growth and developmental processes. However, its role in regulating potato sprouting is unknown. Therefore, the physiological and molecular mechanisms underlying the sprouting process were assessed, and we found that GABA promoted sprouting after treatment for 50 d. In addition, the GABA and soluble sugar contents increased while the starch content decreased. To study the molecular mechanism by which exogenous GABA accelerates tuber sprouting, comparative proteomic analysis of tuber bud eyes was performed after GABA treatment for 48 h. Further analysis revealed 316 differentially abundant proteins (DAPs) that are mainly involved in fatty acid and sugar metabolism and cutin, suberin and wax biosyntheses. The qRT‒PCR results suggested that the GABA transaminase 2 (GABA-T2) and GABA-T3 expression levels showed the greatest decrease at 30 d of storage. Peroxidase 42 (StPOD42) expression showed the greatest increase at 30 d. Overexpression of StPOD42 in potato was found to promote tuber sprouting. Our results provide new insights into the role of GABA in regulating the sprouting process and indicate that StPOD42 is a target gene for molecular breeding to modulate potato sprouting.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Full list of authors: Akiyama, Kazunori; Alberdi, Antxon; Alef, Walter; Algaba, Juan Carlos; Anantua, Richard; Asada, Keiichi; Azulay, Rebecca; Bach, Uwe; Baczko, Anne-Kathrin; Ball, David; Balokovic, Mislav; Barrett, John; Baubock, Michi; Benson, Bradford A.; Bintley, Dan; Blackburn, Lindy; Blundell, Raymond; Bouman, Katherine L.; Bower, Geoffrey C.; Boyce, Hope; Bremer, Michael; Brinkerink, Christiaan D.; Brissenden, Roger; Britzen, Silke; Broderick, Avery E.; Broguiere, Dominique; Bronzwaer, Thomas; Bustamante, Sandra; Byun, Do-Young; Carlstrom, John E.; Ceccobello, Chiara; Chael, Andrew; Chan, Chi-kwan; Chatterjee, Koushik; Chatterjee, Shami; Chen, Ming-Tang; Chen, Yongjun; Cheng, Xiaopeng; Cho, Ilje; Christian, Pierre; Conroy, Nicholas S.; Conway, John E.; Cordes, James M.; Crawford, Thomas M.; Crew, Geoffrey B.; Cruz-Osorio, Alejandro; Cui, Yuzhu; Davelaar, Jordy; De Laurentis, Mariafelicia; Deane, Roger; Dempsey, Jessica; Desvignes, Gregory; Dexter, Jason; Dhruv, Vedant; Doeleman, Sheperd S.; Dougal, Sean; Dzib, Sergio A.; Eatough, Ralph P.; Emami, Razieh; Falcke, Heino; Farah, Joseph; Fish, Vincent L.; Fomalont, Ed; Ford, H. Alyson; Fraga-Encinas, Raquel; Freeman, William T.; Friberg, Per; Fromm, Christian M.; Fuentes, Antonio; Galison, Peter; Gammie, Charles F.; Garcia, Roberto; Gentaz, Olivier; Georgiev, Boris; Goddi, Ciriaco; Gold, Roman; Gomez-Ruiz, Arturo, I; Gomez, Jose L.; Gu, Minfeng; Gurwell, Mark; Hada, Kazuhiro; Haggard, Daryl; Haworth, Kari; Hecht, Michael H.; Hesper, Ronald; Heumann, Dirk; Ho, Luis C.; Ho, Paul; Honma, Mareki; Huang, Chih-Wei L.; Huang, Lei; Hughes, David H.; Ikeda, Shiro; Impellizzeri, C. M. Violette; Inoue, Makoto; Issaoun, Sara; James, David J.; Jannuzi, Buell T.; Janssen, Michael; Jeter, Britton; Jiang, Wu; Jimenez-Rosales, Alejandra; Johnson, Michael D.; Jorstad, Svetlana; Joshi, Abhishek, V; Jung, Taehyun; Karami, Mansour; Karuppusamy, Ramesh; Kawashima, Tomohisa; Keating, Garrett K.; Kettenis, Mark; Kim, Dong-Jin; Kim, Jae-Young; Kim, Jongsoo; Kim, Junhan; Kino, Motoki; Koay, Jun Yi; Kocherlakota, Prashant; Kofuji, Yutaro; Koch, Patrick M.; Koyama, Shoko; Kramer, Carsten; Kramer, Michael; Krichbaum, Thomas P.; Kuo, Cheng-Yu; La Bella, Noemi; Lauer, Tod R.; Lee, Daeyoung; Lee, Sang-Sung; Leung, Po Kin; Levis, Aviad; Li, Zhiyuan; Lico, Rocco; Lindahl, Greg; Lindqvist, Michael; Lisakov, Mikhail; Liu, Jun; Liu, Kuo; Liuzzo, Elisabetta; Lo, Wen-Ping; Lobanov, Andrei P.; Loinard, Laurent; Lonsdale, Colin J.; Lu, Ru-Sen; Mao, Jirong; Marchili, Nicola; Markoff, Sera; Marrone, Daniel P.; Marscher, Alan P.; Marti-Vidal, Ivan; Matsushita, Satoki; Matthews, Lynn D.; Medeiros, Lia; Menten, Karl M.; Michalik, Daniel; Mizuno, Izumi; Mizuno, Yosuke; Moran, James M.; Moriyama, Kotaro; Moscibrodzka, Monika; Muller, Cornelia; Mus, Alejandro; Musoke, Gibwa; Myserlis, Ioannis; Nadolski, Andrew; Nagai, Hiroshi; Nagar, Neil M.; Nakamura, Masanori; Narayan, Ramesh; Narayanan, Gopal; Natarajan, Iniyan; Nathanail, Antonios; Fuentes, Santiago Navarro; Neilsen, Joey; Neri, Roberto; Ni, Chunchong; Noutsos, Aristeidis; Nowak, Michael A.; Oh, Junghwan; Okino, Hiroki; Olivares, Hector; Ortiz-Leon, Gisela N.; Oyama, Tomoaki; Palumbo, Daniel C. M.; Paraschos, Georgios Filippos; Park, Jongho; Parsons, Harriet; Patel, Nimesh; Pen, Ue-Li; Pesce, Dominic W.; Pietu, Vincent; Plambeck, Richard; PopStefanija, Aleksandar; Porth, Oliver; Potzl, Felix M.; Prather, Ben; Preciado-Lopez, Jorge A.; Pu, Hung-Yi; Ramakrishnan, Venkatessh; Rao, Ramprasad; Rawlings, Mark G.; Raymond, Alexander W.; Rezzolla, Luciano; Ricarte, Angelo; Ripperda, Bart; Roelofs, Freek; Rogers, Alan; Ros, Eduardo; Romero-Canizales, Cristina; Roshanineshat, Arash; Rottmann, Helge; Roy, Alan L.; Ruiz, Ignacio; Ruszczyk, Chet; Rygl, Kazi L. J.; Sanchez, Salvador; Sanchez-Arguelles, David; Sanchez-Portal, Miguel; Sasada, Mahito; Satapathy, Kaushik; Savolainen, Tuomas; Schloerb, F. Peter; Schonfeld, Jonathan; Schuster, Karl-Friedrich; Shao, Lijing; Shen, Zhiqiang; Small, Des; Sohn, Bong Won; SooHoo, Jason; Souccar, Kamal; Sun, He; Tazaki, Fumie; Tetarenko, Alexandra J.; Tiede, Paul; Tilanus, Remo P. J.; Titus, Michael; Torne, Pablo; Traianou, Efthalia; Trent, Tyler; Trippe, Sascha; Turk, Matthew; van Bemmel, Ilse; van Langevelde, Huib Jan; van Rossum, Daniel R.; Vos, Jesse; Wagner, Jan; Ward-Thompson, Derek; Wardle, John; Weintroub, Jonathan; Wex, Norbert; Wharton, Robert; Wielgus, Maciek; Wiik, Kaj; Witzel, Gunther; Wondrak, Michael F.; Wong, George N.; Wu, Qingwen; Yamaguchi, Paul; Yoon, Doosoo; Young, Andre; Young, Ken; Younsi, Ziri; Yuan, Feng; Yuan, Ye-Fei; Zensus, J. Anton; Zhang, Shuo; Zhao, Guang-Yao; Zhao, Shan-Shan; Ozel, Feryal; Agurto, Claudio; Allardi, Alexander; Amestica, Rodrigo; Araneda, Juan Pablo; Arriagada, Oriel; Berghuis, Jennie L.; Bertarini, Alessandra; Berthold, Ryan; Blanchard, Jay; Brown, Ken; Cardenas, Mauricio; Cantzler, Michael; Caro, Patricio; Castillo-Dominguez, Edgar; Chan, Tin Lok; Chang, Chih-Cheng; Chang, Dominic O.; Chang, Shu-Hao; Chang, Song-Chu; Chen, Chung-Chen; Chilson, Ryan; Chuter, Tim C.; Ciechanowicz, Miroslaw; Colin-Beltran, Edgar; Coulson, Iain M.; Crowley, Joseph; Degenaar, Nathalie; Dornbusch, Sven; Duran, Carlos A.; Everett, Wendeline B.; Faber, Aaron; Forster, Karl; Fuchs, Miriam M.; Gale, David M.; Geertsema, Gertie; Gonzalez, Edouard; Graham, Dave; Gueth, Frederic; Halverson, Nils W.; Han, Chih-Chiang; Han, Kuo-Chang; Hasegawa, Yutaka; Hernandez-Rebollar, Jose Luis; Herrera, Cristian; Herrero-Illana, Ruben; Heyminck, Stefan; Hirota, Akihiko; Hoge, James; Schimpf, Shelbi R. Hostler; Howie, Ryan E.; Huang, Yau-De; Jiang, Homin; Jinchi, Hao; John, David; Kimura, Kimihiro; Klein, Thomas; Kubo, Derek; Kuroda, John; Kwon, Caleb; Lacasse, Richard; Laing, Robert; Leitch, Erik M.; Li, Chao-Te; Liu, Ching-Tang; Liu, Kuan-Yu; Lin, Lupin C-C; Lu, Li-Ming; Mac-Auliffe, Felipe; Martin-Cocher, Pierre; Matulonis, Callie; Maute, John K.; Messias, Hugo; Meyer-Zhao, Zheng; Montana, Alfredo; Montenegro-Montes, Francisco; Montgomerie, William; Nolasco, Marcos Emir Moreno; Muders, Dirk; Nishioka, Hiroaki; Norton, Timothy J.; Nystrom, George; Ogawa, Hideo; Olivares, Rodrigo; Oshiro, Peter; Perez-Beaupuits, Juan Pablo; Parra, Rodrigo; Phillips, Neil M.; Poirier, Michael; Pradel, Nicolas; Qiu, Richard; Raffin, Philippe A.; Rahlin, Alexandra S.; Ramirez, Jorge; Ressler, Sean; Reynolds, Mark; Rodriguez-Montoya, Ivan; Saez-Madain, Alejandro F.; Santana, Jorge; Shaw, Paul; Shirkey, Leslie E., Jr.; Silva, Kevin M.; Snow, William; Sousa, Don; Sridharan, T. K.; Stahm, William; Stark, Anthony A.; Test, John; Torstensson, Karl; Venegas, Paulina; Walther, Craig; Wei, Ta-Shun; White, Chris; Wieching, Gundolf; Wijnands, Rudy; Wouterloot, Jan G. A.; Yu, Chen-Yu; Yu, Wei; Zeballos, Milagros; Event Horizon Telescope Collaboration., We present the first Event Horizon Telescope (EHT) observations of Sagittarius A* (Sgr A*), the Galactic center source associated with a supermassive black hole. These observations were conducted in 2017 using a global interferometric array of eight telescopes operating at a wavelength of λ = 1.3 mm. The EHT data resolve a compact emission region with intrahour variability. A variety of imaging and modeling analyses all support an image that is dominated by a bright, thick ring with a diameter of 51.8 ± 2.3 μas (68% credible interval). The ring has modest azimuthal brightness asymmetry and a comparatively dim interior. Using a large suite of numerical simulations, we demonstrate that the EHT images of Sgr A* are consistent with the expected appearance of a Kerr black hole with mass ∼4 × 106 M⊙, which is inferred to exist at this location based on previous infrared observations of individual stellar orbits, as well as maser proper-motion studies. Our model comparisons disfavor scenarios where the black hole is viewed at high inclination (i > 50°), as well as nonspinning black holes and those with retrograde accretion disks. Our results provide direct evidence for the presence of a supermassive black hole at the center of the Milky Way, and for the first time we connect the predictions from dynamical measurements of stellar orbits on scales of 103–105 gravitational radii to event-horizon-scale images and variability. Furthermore, a comparison with the EHT results for the supermassive black hole M87* shows consistency with the predictions of general relativity spanning over three orders of magnitude in central mass. © 2022. The Author(s). Published by the American Astronomical Society., The Event Horizon Telescope Collaboration thanks the following organizations and programs: the Academia Sinica; the Academy of Finland (projects 274477, 284495, 312496, 315721); the Agencia Nacional de Investigación y Desarrollo (ANID), Chile via NCN19_058 (TITANs) and Fondecyt 1221421, the Alexander von Humboldt Stiftung; an Alfred P. Sloan Research Fellowship; Allegro, the European ALMA Regional Centre node in the Netherlands, the NL astronomy research network NOVA and the astronomy institutes of the University of Amsterdam, Leiden University and Radboud University; the ALMA North America Development Fund; the Black Hole Initiative, which is funded by grants from the John Templeton Foundation and the Gordon and Betty Moore Foundation (although the opinions expressed in this work are those of the author(s) and do not necessarily reflect the views of these Foundations); Chandra DD7-18089X and TM6-17006X; the China Scholarship Council; China Postdoctoral Science Foundation fellowship (2020M671266); Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico, projects U0004-246083, U0004-259839, F0003-272050, M0037-279006, F0003-281692, 104497, 275201, 263356); the Consejería de Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucía (grant P18-FR-1769), the Consejo Superior de Investigaciones Científicas (grant 2019AEP112); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Dirección General de Asuntos del Personal Académico-Universidad Nacional Autónoma de México (DGAPA-UNAM, projects IN112417 and IN112820); the Dutch Organization for Scientific Research (NWO) VICI award (grant 639.043.513) and grant OCENW.KLEIN.113; the Dutch National Supercomputers, Cartesius and Snellius (NWO Grant 2021.013); the EACOA Fellowship awarded by the East Asia Core Observatories Association, which consists of the Academia Sinica Institute of Astronomy and Astrophysics, the National Astronomical Observatory of Japan, Center for Astronomical Mega-Science, Chinese Academy of Sciences, and the Korea Astronomy and Space Science Institute; the European Research Council (ERC) Synergy Grant "BlackHoleCam: Imaging the Event Horizon of Black Holes" (grant 610058); the European Union Horizon 2020 research and innovation programme under grant agreements RadioNet (No 730562) and M2FINDERS (No 101018682); the Generalitat Valenciana postdoctoral grant APOSTD/2018/177 and GenT Program (project CIDEGENT/2018/021); MICINN Research Project PID2019-108995GB-C22; the European Research Council for advanced grant "JETSET: Launching, propagation and emission of relativistic jets from binary mergers and across mass scales" (Grant No. 884631); the Institute for Advanced Study; the Istituto Nazionale di Fisica Nucleare (INFN) sezione di Napoli, iniziative specifiche TEONGRAV; the International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne; DFG research grant "Jet physics on horizon scales and beyond" (Grant No. FR 4069/2-1); Joint Princeton/Flatiron and Joint Columbia/Flatiron Postdoctoral Fellowships, research at the Flatiron Institute is supported by the Simons Foundation; the Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT; grant JPMXP1020200109); the Japanese Government (Monbukagakusho: MEXT) Scholarship; the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for JSPS Research Fellowship (JP17J08829); the Joint Institute for Computational Fundamental Science, Japan; the Key Research Program of Frontier Sciences, Chinese Academy of Sciences (CAS, grants QYZDJ-SSW-SLH057, QYZDJSSW-SYS008, ZDBS-LY-SLH011); the Leverhulme Trust Early Career Research Fellowship; the Max-Planck-Gesellschaft (MPG); the Max Planck Partner Group of the MPG and the CAS; the MEXT/JSPS KAKENHI (grants 18KK0090, JP21H01137, JP18H03721, JP18K13594, 18K03709, JP19K14761, 18H01245, 25120007); the Malaysian Fundamental Research Grant Scheme (FRGS) FRGS/1/2019/STG02/UM/02/6; the MIT International Science and Technology Initiatives (MISTI) Funds; the Ministry of Science and Technology (MOST) of Taiwan (103-2119-M-001-010-MY2, 105-2112-M-001-025-MY3, 105-2119-M-001-042, 106-2112-M-001-011, 106-2119-M-001-013, 106-2119-M-001-027, 106-2923-M-001-005, 107-2119-M-001-017, 107-2119-M-001-020, 107-2119-M-001-041, 107-2119-M-110-005, 107-2923-M-001-009, 108-2112-M-001-048, 108-2112-M-001-051, 108-2923-M-001-002, 109-2112-M-001-025, 109-2124-M-001-005, 109-2923-M-001-001, 110-2112-M-003-007-MY2, 110-2112-M-001-033, 110-2124-M-001-007, and 110-2923-M-001-001); the Ministry of Education (MoE) of Taiwan Yushan Young Scholar Program; the Physics Division, National Center for Theoretical Sciences of Taiwan; the National Aeronautics and Space Administration (NASA, Fermi Guest Investigator grant 80NSSC20K1567, NASA Astrophysics Theory Program grant 80NSSC20K0527, NASA NuSTAR award 80NSSC20K0645); NASA Hubble Fellowship grant HST-HF2-51431.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555; the National Institute of Natural Sciences (NINS) of Japan; the National Key Research and Development Program of China (grant 2016YFA0400704, 2017YFA0402703, 2016YFA0400702); the National Science Foundation (NSF, grants AST-0096454, AST-0352953, AST-0521233, AST-0705062, AST-0905844, AST-0922984, AST-1126433, AST-1140030, DGE-1144085, AST-1207704, AST-1207730, AST-1207752, MRI-1228509, OPP-1248097, AST-1310896, AST-1440254, AST-1555365, AST-1614868, AST-1615796, AST-1715061, AST-1716327, AST-1716536, OISE-1743747, AST-1816420, AST-1935980, AST-2034306); NSF Astronomy and Astrophysics Postdoctoral Fellowship (AST-1903847); the Natural Science Foundation of China (grants 11650110427, 10625314, 11721303, 11725312, 11873028, 11933007, 11991052, 11991053, 12192220, 12192223); the Natural Sciences and Engineering Research Council of Canada (NSERC, including a Discovery Grant and the NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program); the National Youth Thousand Talents Program of China; the National Research Foundation of Korea (the Global PhD Fellowship Grant: grants NRF-2015H1A2A1033752, the Korea Research Fellowship Program: NRF-2015H1D3A1066561, Brain Pool Program: 2019H1D3A1A01102564, Basic Research Support Grant 2019R1F1A1059721, 2021R1A6A3A01086420, 2022R1C1C1005255); Netherlands Research School for Astronomy (NOVA) Virtual Institute of Accretion (VIA) postdoctoral fellowships; Onsala Space Observatory (OSO) national infrastructure, for the provisioning of its facilities/observational support (OSO receives funding through the Swedish Research Council under grant 2017-00648); the Perimeter Institute for Theoretical Physics (research at Perimeter Institute is supported by the Government of Canada through the Department of Innovation, Science and Economic Development and by the Province of Ontario through the Ministry of Research, Innovation and Science); the Spanish Ministerio de Ciencia e Innovación (grants PGC2018-098915-B-C21, AYA2016-80889-P, PID2019-108995GB-C21, PID2020-117404GB-C21); the University of Pretoria for financial aid in the provision of the new Cluster Server nodes and SuperMicro (USA) for a SEEDING GRANT approved towards these nodes in 2020; the Shanghai Pilot Program for Basic Research, Chinese Academy of Science, Shanghai Branch (JCYJ-SHFY-2021-013); the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofísica de Andalucía (SEV-2017- 0709); the Spinoza Prize SPI 78-409; the South African Research Chairs Initiative, through the South African Radio Astronomy Observatory (SARAO, grant ID 77948), which is a facility of the National Research Foundation (NRF), an agency of the Department of Science and Innovation (DSI) of South Africa; the Toray Science Foundation; Swedish Research Council (VR); the US Department of Energy (USDOE) through the Los Alamos National Laboratory (operated by Triad National Security, LLC, for the National Nuclear Security Administration of the USDOE (Contract 89233218CNA000001); and the YCAA Prize Postdoctoral Fellowship. APEX is a collaboration between the Max-Planck-Institut für Radioastronomie (Germany), ESO, and the Onsala Space Observatory (Sweden). The SMA is a joint project between the SAO and ASIAA and is funded by the Smithsonian Institution and the Academia Sinica. The JCMT is operated by the East Asian Observatory on behalf of the NAOJ, ASIAA, and KASI, as well as the Ministry of Finance of China, Chinese Academy of Sciences, and the National Key Research and Development Program (No. 2017YFA0402700) of China and Natural Science Foundation of China grant 11873028. Additional funding support for the JCMT is provided by the Science and Technologies Facility Council (UK) and participating universities in the UK and Canada. The LMT is a project operated by the Instituto Nacional de Astrófisica, Óptica, y Electrónica (Mexico) and the University of Massachusetts at Amherst (USA). The IRAM 30-m telescope on Pico Veleta, Spain is operated by IRAM and supported by CNRS (Centre National de la Recherche Scientifique, France), MPG (Max-Planck-Gesellschaft, Germany) and IGN (Instituto Geográfico Nacional, Spain). The SMT is operated by the Arizona Radio Observatory, a part of the Steward Observatory of the University of Arizona, with financial support of operations from the State of Arizona and financial support for instrumentation development from the NSF. Support for SPT participation in the EHT is provided by the National Science Foundation through award OPP-1852617 to the University of Chicago. Partial support is also provided by the Kavli Institute of Cosmological Physics at the University of Chicago. The SPT hydrogen maser was provided on loan from the GLT, courtesy of ASIAA. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant ACI-1548562, and CyVerse, supported by NSF grants DBI-0735191, DBI-1265383, and DBI-1743442. XSEDE Stampede2 resource at TACC was allocated through TG-AST170024 and TG-AST080026N. XSEDE JetStream resource at PTI and TACC was allocated through AST170028. This research is part of the Frontera computing project at the Texas Advanced Computing Center through the Frontera Large-Scale Community Partnerships allocation AST20023. Frontera is made possible by National Science Foundation award OAC-1818253. This research was carried out using resources provided by the Open Science Grid, which is supported by the National Science Foundation and the U.S. Department of Energy Office of Science. Additional work used ABACUS2.0, which is part of the eScience center at Southern Denmark University. Simulations were also performed on the SuperMUC cluster at the LRZ in Garching, on the LOEWE cluster in CSC in Frankfurt, on the HazelHen cluster at the HLRS in Stuttgart, and on the Pi2.0 and Siyuan Mark-I at Shanghai Jiao Tong University. The computer resources of the Finnish IT Center for Science (CSC) and the Finnish Computing Competence Infrastructure (FCCI) project are acknowledged. This research was enabled in part by support provided by Compute Ontario (http://computeontario.ca), Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca).

Background and purpose: Gadolinium enhancement on high-resolution vessel wall magnetic resonance imaging (HR-VWI) is a marker of instability in intracranial atherosclerotic plaques. This study aims to evaluate the role of hematological inflammatory indicators (the neutrophil-to-lymphocyte ratio [NLR], the lymphocyte-to-monocyte ratio [LMR], and systemic immune inflammation index [SII]) in predicting middle cerebral artery (MCA) atherosclerotic plaque enhancement.Methods: Adult patients diagnosed with MCA atherosclerotic stenosis from August 2018 to October 2021 were recruited retrospectively. Clinical and laboratory data, including neutrophil, lymphocyte, monocyte, and platelet counts, were collected, and then the NLR, LMR, and SII were calculated. The hematological inflammatory indicators were compared in MCA atherosclerotic stenosis patients with and without plaque enhancement. Multivariable logistic regression analyses were performed to explore the factors that can predict MCA atherosclerotic plaque enhancement. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory indicators in predicting plaque enhancement.Results: Forty-two patients (mean age 57.3 ± 9.5 and 66.7% male) were included. A higher NLR (P = 0.001) and SII (P = 0.017) and a lower LMR (P < 0.001) were significantly associated with MCA plaque enhancement. The cutoff value of the admission LMR that best-discriminated plaque enhancement was 4.0 (72.2% sensitivity and 87.5% specificity) on the receiver operating characteristic curve analysis. The NLR, LMR, and plaque enhancement were significantly associated with symptomatic MCA stenosis, and the multiple logistic regression analysis showed that only plaque enhancement was an independent risk factor for symptomatic MCA stenosis.Conclusion: There was a significant correlation between plaque enhancement and hematological inflammatory indicators. The LMR was an independent risk factor for MCA atherosclerotic plaque enhancement, and an LMR ≤ 4.0 may predict plaque enhancement.

To observe the effect of acupotomy on the morphology and ultrastructure of rectus femoris muscle in rabbits with knee osteoarthritis and to reveal the possible therapeutic mechanism involved in the effect of acupotomology on the treatment of knee osteoarthritis(KOA).Twenty-four male New Zealand rabbits aged 6 months and weighed (2.0±0.5) kg were randomly divided into blank group, model group and acupotomy group, 8 rabbits in each group. KOA model was established by modified Videman method with left hind limb extended plaster immobility for 6 weeks. In acupotomy group, the transfascial focal points of quadriceps femoris muscle were released by acupotomy under the guidance of Jingjin theory for 4 times and once a week, and the treatment points include Hedingci, Binwaixia, Binneixia. Blank group and model group were fed normally without intervention. One week after the end of the intervention, the pennation angle(PA), muscle thickness(MT), cross-sectional area(CSA) and strain ratio(SR) of rectus femoris were measured by ultrasound. HE staining was used to observe the changes of the tissue morphology, the number of muscle fibers and the average area of muscle fibers. The myofibril of rectus femoris, sarcomere and myofilament were observed by transmission electron microscope.The PA of rectus femoris muscle in the blank group was (9.05±0.21)°. The MT was(1.09±0.09) cm and the CSA was(1.30±0.01) cmBased on the jingjin theory, the release of quadriceps femoris by acupotomy can effectively improve the morphology and structure of rectus femoris, and promote the repair and reconstruction of chronic skeletal muscle injury in rabbits with KOA, which may be one of the mechanisms of acupotomy in the treatment of KOA.

Two ore blends containing substantial channel iron deposit (CID) and Marra Mamba (MM) ores were assessed. The blends granulated well with addition of hydrated lime, which was found to improve the morphology and strength, and consequently the bed permeability of the resultant green granules. Compared with Blend 2 (a simulated industry blend), Blend 1, containing more MM and less CID ores was slightly less permeable but required similar moisture to achieve its optimum permeability. Both blends showed similar sintering characteristics as evidenced by sintering productivity and sinter quality, suggesting that Blend 1 was comparable to Blend 2. This was further supported by observations of sinter macro- and microstructure. Addition of hydrated lime improves the bed permeability and the formation and fluidity of sinter melt, consequently leading to improved sinter yield and strength along with sintering productivity. To achieve sinter return balance, the sinter return ratio had to decrease as the coke addition increased.

Objective Interleukin (IL)-33 is a mediator in the pathogenesis of several inflammatory diseases. Its receptor, ST2, is overexpressed in nonrheumatic aortic valve stenosis (NR-AS). This study compared smooth muscle α-actin (α-SMA), osteopontin (OPN), and suppression of tumorigenicity 2 (ST2) expression between specimens from fibrotic and calcific stages of NR-AS and observed the effects and mechanisms of phenotypic transition of porcine valvular interstitial cells (VICs) in the presence of IL-33. Methods Peripheral blood IL-1 family mRNA and protein levels in NR-AS patients and healthy adults were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence were used to detect the expression and coexpression of α-SMA, OPN, and ST2 in NR-AS specimens. Porcine VICs were stimulated with IL-33, IL-33+SB203580, or IL-33+SC75741. mRNA and protein expression levels of porcine VICs were detected by RT-qPCR and western blot. Results The mRNA and protein levels of IL-33 and sST2 in peripheral blood of NR-AS patients were higher than those in healthy adults. Immunohistochemistry and immunofluorescence showed higher expression of α-SMA, OPN, and ST2 in the calcific stage of NR-AS than in the fibrotic stage. Coexpression of ST2/α-SMA or ST2/OPN was found only in the calcific stage. Nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels were associated with IL-33-induced porcine VIC differentiation into myofibroblasts and osteoblasts, respectively. IL-33 stimulation also promoted the coexpression of ST2/OPN or α-SMA/OPN/ST2. Conclusion IL-33 might be a potential biomarker for NR-AS. IL-33-induced porcine VIC differential phenotypic transition and differentiation into myofibroblasts and osteoblasts were dependent on the NF-κB and p38 MAPK signaling pathways, respectively.

Background Serine threonine kinase 10 (STK10) is an ERM kinase involved in the activation of ERM proteins and plays an essential role in the aggregation and adhesion of lymphocytes. STK10 is expressed in about 17 cancer types, including cervical cancer. Cervical cancer is the fourth most common cancer that seriously threatens women’s health worldwide. Previous studies have shown that STK10 may affect LFA-1-mediated cell adhesion. Other studies reported a mutation (R634H) of STK10 detected in peripheral T-cell lymphoma. This study aimed to evaluate the functional roles of STK10 in the pathogenesis of cervical cancer. Methods We generated STK10 knockout cervical cancer cell lines using the CRISPR-Cas9 gene-editing system, and further analyzed the effects of STK10 deficiency on tumor biological behaviors. The proliferation, apoptosis, migration and invasive activity of these cells were respectively detected by BrdU incorporation, AnnexinV/propidium iodide (PI) staining, wound healing assay and Transwell assays without and with Matrigel. The phosphorylation and expression level of indicated proteins were analyzed by Western blot. The differential expression genes between STK10 knockout and control cells were identified by RNA-seq analysis and further confirmed using qRT-PCR. Results Our data revealed that target deletion of STK10 does not affect cell proliferation and apoptosis, but promotes the adhesion, migration, and invasion of cervical cancer cells. Most strikingly, the phosphorylation and expression level of ezrin and other ERM proteins in STK10 knockout cells was comparable with that in the control cells. Further, RNA-seq analysis indicated that the knockout of STK10 resulted in a profound alteration of gene expression in cervical cancer cells. Conclusions This is the first study to provide evidence that STK10 executes various physiological functions in addition to phosphorylation of ERM proteins, and plays a vital role in the migration and invasion of cervical cancer cells.

Many human activities require high cognitive performance over long periods, while impairments induced by sleep deprivation influence various aspects of cognitive abilities, including working memory (WM), attention, and processing speed. Based on previous research, vagal nerve stimulation can modulate cognitive abilities, attention, and arousal. Two experiments were conducted to assess the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) to relieve the deleterious effects of sleep deprivation. In the first experiment, 35 participants completed N-back tasks at 8:00 a.m. for two consecutive days in a within-subject study. Then, the participants received either taVNS or earlobe stimulation (active control) intervention in two sessions at random orders after 24 h of sustained wakefulness. Then, they completed the N-back tasks again. In the second experiment, 30 participants completed the psychomotor vigilance task (PVT), and 32 completed the N-back tasks at 8:00 a.m. on the first and second days. Then, they received either taVNS or earlobe stimulation at random orders and finished the N-back and PVT tasks immediately after one hour. In Experiment 1, taVNS could significantly improve the accuracy rate of participants in spatial 3-back tasks compared to active control, which was consistent with experiment 2. However, taVNS did not specifically enhance PVT performance. Therefore, taVNS could be a powerful intervention for acute sleep deprivation as it can improve performance on high cognitive load tasks and is easy to administer.

Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice. We demonstrated that aldo-keto reductase family 1 member B1 (AKR1B1) interacts with and activates signal transducer and activator of transcription 3 (STAT3) to up-regulate the cystine transporter solute carrier family 7 member 11 (SLC7A11). This leads to enhanced cystine uptake and flux to glutathione de novo synthesis, reactive oxygen species (ROS) scavenging, protection from cell death, and EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Suppression of AKR1B1 with selective inhibitors, including the clinically approved antidiabetic drug epalrestat, restored the sensitivity of resistant cell lines to EGFR TKIs and delayed resistance in lung cancer patient-derived xenograft mice. Our findings suggest a metabolic mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the third-generation inhibitor osimertinib.

To explore the ultrasonic anatomical characteristics and needle-knife insertion approach of common tendon lesions in knee osteoarthritis (KOA), so as to provide the references for accurate release of KOA by needle- knife along tendon lesions based on meridian sinew theory.Sixty patients with one-knee KOA were selected. High-frequency musculoskeletal ultrasound was used to collect sonograms at the anatomical positions of "Hedingci" "Binwaixia" "Binneixia" and "Yinlingshang". The anatomic levels were marked on the sonograms. The anatomic levels and sonographic features of lesions were compared and analyzed, and the relevant data of needle-knife simulation approach was measured.The "Hedingci" lesions were mainly located at the attachment of quadriceps tendon to patella and suprapatellar bursa. The "Binwaixia" and "Binneixia" lesions were mainly located at the attachment of retinaculum patellae laterale and retinaculum patellae mediale to patella and infrapatellar fat pad. The "Yinlingshang" lesions were mainly located at the attachment of goose foot tendon to medial tibial condyle and bursa of goose foot. With "Hedingci" as an example, when the needle-knife entry point was 1 cm above the patella, the attachment of quadriceps tendon to patella was released, and the average depth of needle-knife was (3.60±0.10) cm, and the needle body was perpendicular to the skin. The average depth of needle-knife for releasing suprapatellar bursa was (2.35±0.17) cm, and the needle body was 45° towards head.The musculoskeletal ultrasound could clearly show the local detailed anatomical level, ultrasonic characteristics and anatomical level of common tendon lesions of KOA, and could improve the accuracy of needle-knife along tendon lesions with non-direct vision, which has important reference value for needle-knife medical standardization and standardized operation.

Background Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. The aim of this study was to investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma. Methods We conducted RIG-I knockout and RIG-I overexpressing B16-F10 melanoma cell line, and further analyzed the RIG-I mediated change of tumor biology behaviors in spontaneous and poly I:C induced RIG-I activation status. Cell proliferation, cell cycle, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation, Annexin V-PI staining assay and transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently Ki67 staining and TUNEL assay. Furthermore, Western blot was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Results Our data showed that RIG-I promotes the apoptosis and inhibits the proliferation by G1 phase cell-cycle arrest in B16-F10 melanoma cell line. Mechanically, RIG-I could induce the phosphorylation level of p38 MAPK and MAPK kinase MKK3/MKK4. Conclusion The current study demonstrated that RIG-I suppressed the development of melanoma via regulating the activity of MKK/p38 MAPK signaling pathway, which will be useful in the research of novel therapeutic targets for this malignant disease.

Background: Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as erlotinib is a major challenge to achieve an overall clinical benefit of the targeted therapy. Recently, aldehyde dehydrogenase 1 (ALDH1) induction has been found to render lung adenocarcinomas resistant to EGFR-TKIs, and targeting ALDH1A1 becomes a novel strategy to overcome resistance. However, the molecular mechanism underlying such effect remains poorly understood. Methods: Comprehensive assays were performed in a panel of lung adenocarcinoma cell lines and xenografts that acquired resistance to erlotinib. Cancer phenotype was evaluated by cell viability, apoptosis, migration, and epithelial-mesenchymal transition analysis in vitro, tumorsphere formation analysis ex vivo, and tumor growth and dissemination analysis in vivo. Reactive oxygen species (ROS) and reactive carbonyl species (RCS) were detected based on fluorescent oxidation indicator and liquid chromatography coupled to mass spectrometry, respectively. Protein target was suppressed by RNA interference and pharmacological inhibition or ecto-overexpressed by lentivirus-based cloning. Gene promoter activity was measured by dual-luciferase reporting assay. Results: Knockdown or pharmacological inhibition of ALDH1A1 overcame erlotinib resistance in vitro and in vivo. ALDH1A1 overexpression was sufficient to induce erlotinib resistance. Metabolomic analysis demonstrated lower ROS-RCS levels in ALDH1A1-addicted, erlotinib-resistant cells; in line with this, key enzymes for metabolizing ROS and RCS, SOD2 and GPX4, respectively, were upregulated in these cells. Knockdown of SOD2 or GPX4 re-sensitized the resistant cells to erlotinib and the effect was abrogated by ROS-RCS scavenging and mimicked by ROS-RCS induction. The ALDH1A1 overexpressed cells, though resisted erlotinib, were more sensitive to SOD2 or GPX4 knockdown. The ALDH1A1 effect on erlotinib resistance was abrogated by ROS-RCS induction and mimicked by ROS-RCS scavenging. Detection of GPX4 and SOD2 expression and analysis of promoter activities of GPX4 and SOD2 under the condition of suppression or overexpression of ALDH1A1 demonstrated that the RCS-ROS-metabolic pathway was controlled by the ALDH1A1-GPX4-SOD2 axis. The ROS-RCS metabolic dependence mechanism in ALDH1A1-induced resistance was confirmed in vivo. Analysis of public databases showed that in patients undergoing chemotherapy, those with high co-expression of ALDH1A1, GPX4, and SOD2 had a lower probability of survival. Conclusions: ALDH1A1 confers erlotinib resistance by facilitating the ROS-RCS metabolic pathway. ALDH1A1-induced upregulation of SOD2 and GPX4, as well as ALDH1A1 itself, mitigated erlotinib-induced oxidative and carbonyl stress, and imparted the TKI resistance. The elucidation of previously unrecognized metabolic mechanism underlying erlotinib resistance provides new insight into the biology of molecular targeted therapies and help to design improved pharmacological strategies to overcome the drug resistance.

To observe the effect of "knot-loosing method" of acupotomy on morphological changes in knee osteoarthritis (KOA) rabbits, so as to provide experimental basis for clinical acupotomy treatment of KOA.Male New Zealand rabbits were randomly divided into blank control, model and acupotomy groups, with 8 rabbits in each group. By using the modified Videman method, the left hindlimb was immobilized for 6 weeks with a plaster cast to replicate the KOA model. The knot-loosing manipulation of acupotomy was applied to "Hedingci" (located at the attachment of the positive upper margin of the quadriceps tendon and the patella),"Binneixia"（at "Neixiyan" ［EX-LE4］, the medial side of ligamentum patella）, "Binwaixia" （at "Waixiyan" ［ST35］, the lateral side of patellar ligament）, "Chengfeijian" (at the lateral collateral ligament of the knee in the la-teral joint space), "Weiyangci"(at the medial margin of the biceps femoris and the lateral side of the transverse striation), and "Yinlingci"(at the end-point of the medial tibia of the goose foot tendon), respectively, once a week for 4 times. One week after the last intervention, the left knee joint dysfunction severity (pain, maximum walking distance, and some activities of daily living) was evaluated by using modified Lequesne Index score. X-ray and magnetic resonance imaging(MRI)examinations were conducted to assess the articular space size, effusion and cartilage smoothness of the left knee for which the MRI Osteoarthritis Knee Score (MOAKS) was given according to their severity. The histopathologic changes of the cartilage of the left knee were observed by Hematoxylin-eosin (H.E.) staining and light microscope, which Mankin score was given. In addition, the surface of the cartilage was also examined by macroscopic observation.①Following modeling, the Lequesne Index score, MOAKS, macroscopic observation score and Mankin score were significantly increased in the model group (P0.05). X-ray and MRI imaging showed a narrower joint space, more effusion, rough cartilage surface; and H.E. staining displayed rough cartilage surface, and disordered arrangement and occasional clusters of the chondrocytes in the left knee joint. ②In comparison with the blank control group, the Lequesne Index, MOAKS, macroscopic observation and Mankin scores were significantly down-regulated in the acupo-tomy group (P0.05). The abovementioned injury changes shown by X-ray, MRI, macroscopic and microscopic observations were relatively milder in the acupotomy group.Acupotomy loosing based on the "Jingjin theory" of traditional Chinese medicine can effectively improve the motor ability of knee joint and repair pathological changes of the cartilage in KOA rabbits.

Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Open Access funding provided by Max Planck Society.--All authors: Kim, Jae-Young; Krichbaum, Thomas P.; Broderick, Avery E.; Wielgus, Maciek; Blackburn, Lindy; Gómez, José L.; Johnson, Michael D.; Bouman, Katherine L.; Chael, Andrew; Akiyama, Kazunori; Jorstad, Svetlana; Marscher, Alan P.; Issaoun, Sara; Janssen, Michael; Chan, Chi-kwan; Savolainen, Tuomas; Pesce, Dominic W.; Özel, Feryal; Alberdi, Antxon; Alef, Walter Asada, Keiichi; Azulay, Rebecca; Baczko, Anne-Kathrin; Ball, David; Baloković, Mislav; Barrett, John; Bintley, Dan; Boland, Wilfred; Bower, Geoffrey C.; Bremer, Michael; Brinkerink, Christiaan D.; Brissenden, Roger; Britzen, Silke; Broguiere, Dominique; Bronzwaer, Thomas; Byun, Do-Young; Carlstrom, John E.; Chatterjee, Shami; Chatterjee, Koushik; Chen, Ming-Tang; Chen, Yongjun; Cho, Ilje; Christian, Pierre; Conway, John E.; Cordes, James M.; Crew, Geoffrey B.; Cui, Yuzhu; Davelaar, Jordy; De Laurentis, Mariafelicia; Deane, Roger; Dempsey, Jessica; Desvignes, Gregory; Dexter, Jason; Doeleman, Sheperd S.; Eatough, Ralph P.; Falcke, Heino; Fish, Vincent L.; Fomalont, Ed; Fraga-Encinas, Raquel; Friberg, Per; Fromm, Christian M.; Galison, Peter; Gammie, Charles F.; García, Roberto; Gentaz, Olivier; Georgiev, Boris; Goddi, Ciriaco; Gold, Roman; Gómez-Ruiz, Arturo I.; Gu, Minfeng; Gurwell, Mark; Hada, Kazuhiro; Hecht, Michael H.; Hesper, Ronald; Ho, Luis C.; Ho, Paul; Honma, Mareki; Huang, Chih-Wei L.; Huang, Lei; Hughes, David H.; Ikeda, Shiro; Inoue, Makoto; James, David J.; Jannuzi, Buell T.; Jeter, Britton; Jiang, Wu; Jimenez-Rosales, Alejandra; Jung, Taehyun; Karami, Mansour; Karuppusamy, Ramesh; Kawashima, Tomohisa; Keating, Garrett K.; Kettenis, Mark; Kim, Junhan; Kim, Jongsoo; Kino, Motoki; Koay, Jun Yi; Koch, Patrick M.; Koyama, Shoko; Kramer, Michael; Kramer, Carsten; Kuo, Cheng-Yu; Lauer, Tod R.; Lee, Sang-Sung; Li, Yan-Rong; Li, Zhiyuan; Lindqvist, Michael; Lico, Rocco; Liu, Kuo; Liuzzo, Elisabetta; Lo, Wen-Ping; Lobanov, Andrei P.; Loinard, Laurent; Lonsdale, Colin; Lu, Ru-Sen; MacDonald, Nicholas R.; Mao, Jirong; Markoff, Sera; Marrone, Daniel P.; Martí-Vidal, Iván; Matsushita, Satoki; Matthews, Lynn D.; Medeiros, Lia; Menten, Karl M.; Mizuno, Yosuke; Mizuno, Izumi; Moran, James M.; Moriyama, Kotaro; Moscibrodzka, Monika; Musoke, Gibwa; Müller, Cornelia; Nagai, Hiroshi; Nagar, Neil M.; Nakamura, Masanori; Narayan, Ramesh; Narayanan, Gopal; Natarajan, Iniyan; Neri, Roberto; Ni, Chunchong; Noutsos, Aristeidis; Okino, Hiroki; Olivares, Héctor; Ortiz-León, Gisela N.; Oyama, Tomoaki; Palumbo, Daniel C. M.; Park, Jongho; Patel, Nimesh; Pen, Ue-Li; Piétu, Vincent; Plambeck, Richard; PopStefanija, Aleksandar; Porth, Oliver; Prather, Ben; Preciado-López, Jorge A.; Psaltis, Dimitrios; Pu, Hung-Yi; Ramakrishnan, Venkatessh; Rao, Ramprasad; Rawlings, Mark G.; Raymond, Alexander W.; Rezzolla, Luciano; Ripperda, Bart; Roelofs, Freek; Rogers, Alan; Ros, Eduardo; Rose, Mel; Roshanineshat, Arash; Rottmann, Helge; Roy, Alan L.; Ruszczyk, Chet; Ryan, Benjamin R.; Rygl, Kazi L. J.; Sánchez, Salvador; Sánchez-Arguelles, David; Sasada, Mahito; Schloerb, F. Peter; Schuster, Karl-Friedrich; Shao, Lijing; Shen, Zhiqiang; Small, Des; Sohn, Bong Won; SooHoo, Jason; Tazaki, Fumie; Tiede, Paul; Tilanus, Remo P. J.; Titus, Michael; Toma, Kenji; Torne, Pablo; Trent, Tyler; Traianou, Efthalia; Trippe, Sascha; Tsuda, Shuichiro; van Bemmel, Ilse; van Langevelde, Huib Jan; van Rossum, Daniel R.; Wagner, Jan; Wardle, John; Ward-Thompson, Derek; Weintroub, Jonathan; Wex, Norbert; Wharton, Robert; Wong, George N.; Wu, Qingwen; Yoon, Doosoo; Young, André; Young, Ken; Younsi, Ziri; Yuan, Feng; Yuan, Ye-Fei; Zensus, J. Anton; Zhao, Guangyao; Zhao, Shan-Shan; Zhu, Ziyan; Algaba, Juan-Carlos; Allardi, Alexander; Amestica, Rodrigo; Anczarski, Jadyn; Bach, Uwe; Baganoff, Frederick K.; Beaudoin, Christopher; Benson, Bradford A.; Berthold, Ryan; Blanchard, Jay M.; Blundell, Ray; Bustamente, Sandra; Cappallo, Roger; Castillo-Domínguez, Edgar; Chang, Chih-Cheng; Chang, Shu-Hao; Chang, Song-Chu; Chen, Chung-Chen; Chilson, Ryan; Chuter, Tim C.; Rosado, Rodrigo Córdova; Coulson, Iain M.; Crowley, Joseph; Derome, Mark; Dexter, Matthew; Dornbusch, Sven; Dudevoir, Kevin A.; Dzib, Sergio A.; Eckart, Andreas; Eckert, Chris; Erickson, Neal R.; Everett, Wendeline B.; Faber, Aaron; Farah, Joseph R.; Fath, Vernon; Folkers, Thomas W.; Forbes, David C.; Freund, Robert; Gale, David M.; Gao, Feng; Geertsema, Gertie; Graham, David A.; Greer, Christopher H.; Grosslein, Ronald; Gueth, Frédéric; Haggard, Daryl; Halverson, Nils W.; Han, Chih-Chiang; Han, Kuo-Chang; Hao, Jinchi; Hasegawa, Yutaka; Henning, Jason W.; Hernández-Gómez, Antonio; Herrero-Illana, Rubén; Heyminck, Stefan; Hirota, Akihiko; Hoge, James; Huang, Yau-De; Violette Impellizzeri, C. M.; Jiang, Homin; John, David; Kamble, Atish; Keisler, Ryan; Kimura, Kimihiro; Kono, Yusuke; Kubo, Derek; Kuroda, John; Lacasse, Richard; Laing, Robert A.; Leitch, Erik M.; Li, Chao-Te; Lin, Lupin C. -C.; Liu, Ching-Tang; Liu, Kuan-Yu; Lu, Li-Ming; Marson, Ralph G.; Martin-Cocher, Pierre L.; Massingill, Kyle D.; Matulonis, Callie; McColl, Martin P.; McWhirter, Stephen R.; Messias, Hugo; Meyer-Zhao, Zheng; Michalik, Daniel; Montaña, Alfredo; Montgomerie, William; Mora-Klein, Matias; Muders, Dirk; Nadolski, Andrew; Navarro, Santiago; Neilsen, Joseph; Nguyen, Chi H.; Nishioka, Hiroaki; Norton, Timothy; Nowak, Michael A.; Nystrom, George; Ogawa, Hideo; Oshiro, Peter; Oyama, Tomoaki; Parsons, Harriet; Peñalver, Juan; Phillips, Neil M.; Poirier, Michael; Pradel, Nicolas; Primiani, Rurik A.; Raffin, Philippe A.; Rahlin, Alexandra S.; Reiland, George; Risacher, Christopher; Ruiz, Ignacio; Sáez-Madaín, Alejandro F.; Sassella, Remi; Schellart, Pim; Shaw, Paul; Silva, Kevin M.; Shiokawa, Hotaka; Smith, David R.; Snow, William; Souccar, Kamal; Sousa, Don; Sridharan, Tirupati K.; Srinivasan, Ranjani; Stahm, William; Stark, Antony A.; Story, Kyle; Timmer, Sjoerd T.; Vertatschitsch, Laura; Walther, Craig; Wei, Ta-Shun; Whitehorn, Nathan; Whitney, Alan R.; Woody, David P.; Wouterloot, Jan G. A.; Wright, Melvin; Yamaguchi, Paul; Yu, Chen-Yu; Zeballos, Milagros; Zhang, Shuo; Ziurys, Lucy; Event Horizon Telescope Collaboration, 3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable-ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array, at an angular resolution of ∼20 μas (at a redshift of z = 0:536 this corresponds to ∼0:13 pc ∼ 1700 Schwarzschild radii with a black hole mass MBH = 8 × 108 M⊙). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation.We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across diffierent imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI "core". This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet.We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of ∼15 c and ∼20 c (∼1:3 and ∼1:7 μas day-1, respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3mm core and the outer jet. The intrinsic brightness temperature of the jet components are ≤1010 K, a magnitude or more lower than typical values seen at ≥7mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths. © J.-Y. Kim et al. 2020., The authors of the present paper thank the following organizations and programs: the Academy of Finland (projects 274477, 284495, 312496); the Advanced European Network of E-infrastructures for Astronomy with the SKA (AENEAS) project, supported by the European Commission Framework Programme Horizon 2020 Research and Innovation action under grant agreement 731016; the Alexander von Humboldt Stiftung; the Black Hole Initiative at Harvard University, through a grant (60477) from the John Templeton Foundation; the China Scholarship Council; Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT, Chile, via PIA ACT172033, Fondecyt projects 1171506 and 3190878, BASAL AFB-170002, ALMA-conicyt 31140007); Consejo Nacional de Ciencia y Tecnologia (CONACYT, Mexico, projects 104497, 275201, 279006, 281692); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Direccion General de Asuntos del Personal Academico -Universidad Nacional Autonoma de Mexico (DGAPA -UNAM, project IN112417); the European Research Council Synergy Grant "BlackHoleCam: Imaging the Event Horizon of Black Holes" (grant 610058); the Generalitat Valenciana postdoctoral grant APOSTD/2018/177 and GenT Program (project CIDEGENT/2018/021); the Gordon and Betty Moore Foundation (grants GBMF-3561, GBMF-5278); the Istituto Nazionale di Fisica Nucleare (INFN) sezione di Napoli, iniziative specifiche TEONGRAV; the International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne; the Jansky Fellowship program of the National Radio Astronomy Observatory (NRAO); the Japanese Government (Monbukagakusho: MEXT) Scholarship; the Japan Society for the Promotion of Science (JSPS) Grant-inAid for JSPS Research Fellowship (JP17J08829); the Key Research Program of Frontier Sciences, Chinese Academy of Sciences (CAS, grants QYZDJSSW-SLH057, QYZDJ-SSW-SYS008, ZDBS-LY-SLH011); the Leverhulme Trust Early Career Research Fellowship; the Malaysian Fundamental Research Grant Scheme (FRGS, grant FRGS/1/2019/STG02/UM/02/6); the Max-PlanckGesellschaft (MPG); the Max Planck Partner Group of the MPG and the CAS; the MEXT/JSPS KAKENHI (grants 18KK0090, JP18K13594, JP18K03656, JP18H03721, 18K03709, 18H01245, 25120007); the MIT International Science and Technology Initiatives (MISTI) Funds; the Ministry of Science and Technology (MOST) of Taiwan (105-2112-M-001-025-MY3, 106-2112-M-001-011, 106-2119-M-001-027, 107-2119-M-001-017, 107-2119-M-001-020, and 107-2119-M-110-005); the National Aeronautics and Space Administration (NASA, Fermi Guest Investigator grant 80NSSC17K0649 and Hubble Fellowship grant HST-HF2-51431.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc. r , for NASA, under contract NAS5-26555); the National Institute of Natural Sciences (NINS) of Japan; the National Key Research and Development Program of China (grant 2016YFA0400704, 2016YFA0400702); the National Science Foundation (NSF, grants AST-0096454, AST-0352953, AST-0521233, AST-0705062, AST-0905844, AST-0922984, AST-1126433, AST-1140030, DGE-1144085, AST-1207704, AST-1207730, AST-1207752, MRI-1228509, OPP-1248097, AST-1310896, AST-1312651, AST-1337663, AST-1440254, AST-1555365, AST-1715061, AST-1615796, AST-1716327, OISE-1743747, AST-1816420); the Natural Science Foundation of China (grants 11573051, 11633006, 11650110427, 10625314, 11721303, 11725312, 11933007); the Natural Sciences and Engineering Research Council of Canada (NSERC, including a Discovery Grant and the NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program); the National Youth Thousand Talents Program of China; the National Research Foundation of Korea (the Global PhD Fellowship Grant: grants NRF-2015H1A2A1033752, 2015-R1D1A1A01056807, the Korea Research Fellowship Program: NRF-2015H1D3A1066561); the Netherlands Organization for Scientific Research (NWO) VICI award (grant 639.043.513) and Spinoza Prize SPI 78-409; the New Scientific Frontiers with Precision Radio Interferometry Fellowship awarded by the South African Radio Astronomy Observatory (SARAO), which is a facility of the National Research Foundation (NRF), an agency of the Department of Science and Technology (DST) of South Africa; the Onsala Space Observatory (OSO) national infrastructure, for the provisioning of its facilities/observational support (OSO receives funding through the Swedish Research Council under grant 2017-00648) the Perimeter Institute for Theoretical Physics (research at Perimeter Institute is supported by the Government of Canada through the Department of Innovation, Science and Economic Development and by the Province of Ontario through the Ministry of Research, Innovation and Science); the Russian Science Foundation (grant 17-12-01029); the Spanish Ministerio de Economia y Competitividad (grants PGC2018-098915-B-C21, AYA201680889-P); the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofisica de Andalucia (SEV-2017-0709); the Toray Science Foundation; the US Department of Energy (USDOE) through the Los Alamos National Laboratory (operated by Triad National Security, LLC, for the National Nuclear Security Administration of the USDOE (Contract 89233218CNA000001)); the Italian Ministero dell'Istruzione Universita e Ricerca through the grant Progetti Premiali 2012-iALMA (CUP C52I13000140001); the European Union's Horizon 2020 research and innovation programme under grant agreement No 730562 RadioNet; ALMA North America Development Fund; the Academia Sinica; Chandra TM6-17006X; the GenT Program (Generalitat Valenciana) Project CIDEGENT/2018/021. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant ACI-1548562, and CyVerse, supported by NSF grants DBI-0735191, DBI-1265383, and DBI1743442. XSEDE Stampede2 resource at TACC was allocated through TGAST170024 and TG-AST080026N. XSEDE JetStream resource at PTI and TACC was allocated through AST170028. The simulations were performed in part on the SuperMUC cluster at the LRZ in Garching, on the LOEWE cluster in CSC in Frankfurt, and on the HazelHen cluster at the HLRS in Stuttgart. This research was enabled in part by support provided by Compute Ontario (http://computeontario. r ca), Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca).We thank the sta ff at the participating observatories, correlation centers, and institutions for their enthusiastic support. This paper makes use of the following ALMA data: ADS/JAO.ALMA#2016.1.01154.V, ADS/JAO.ALMA#2016.1.01176.V. ALMA is a partnership of the European Southern Observatory (ESO; Europe, representing its member states), NSF, and National Institutes of Natural Sciences of Japan, together with National Research Council (Canada), Ministry of Science and Technology (MOST; Taiwan), Academia Sinica Institute of Astronomy and Astrophysics (ASIAA; Taiwan), and Korea Astronomy and Space Science Institute (KASI; Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, Associated Universities, Inc. (AUI)/NRAO, and the National Astronomical Observatory of Japan (NAOJ). The NRAO is a facility of the NSF operated under cooperative agreement by AUI. APEX is a collaboration between the Max-Planck-Institut fur Radioastronomie (Germany), ESO, and the Onsala Space Observatory (Sweden). The SMA is a joint project between the SAO and ASIAA and is funded by the Smithsonian Institution and the Academia Sinica. The JCMT is operated by the East Asian Observatory on behalf of the NAOJ, ASIAA, and KASI, as well as the Ministry of Finance of China, Chinese Academy of Sciences, and the National Key R&D Program (No. 2017YFA0402700) of China. Additional funding support for the JCMT is provided by the Science and Technologies Facility Council (UK) and participating universities in the UK and Canada. The LMT is a project operated by the Instituto Nacional de Astrofisica, Optica, y Electronica (Mexico) and the University of Massachusetts at Amherst (USA). The IRAM 30-m telescope on Pico Veleta, Spain is operated by IRAM and supported by CNRS (Centre National de la Recherche Scientifique, France), MPG (Max-Planck-Gesellschaft, Germany) and IGN (Instituto Geografico Nacional, Spain). The SMT is operated by the Arizona Radio Observatory, a part of the Steward Observatory of the University of Arizona, with financial support of operations from the State of Arizona and financial support for instrumentation development from the NSF. The SPT is supported by the National Science Foundation through grant PLR1248097. Partial support is also provided by the NSF Physics Frontier Center grant PHY-1125897 to the Kavli Institute of Cosmological Physics at the University of Chicago, the Kavli Foundation and the Gordon and Betty Moore Foundation grant GBMF 947. The SPT hydrogen maser was provided on loan from the GLT, courtesy of ASIAA. The EHTC has received generous donations of FPGA chips from Xilinx Inc., under the Xilinx University Program. The EHTC has benefited from technology shared under open-source license by the Collaboration for Astronomy Signal Processing and Electronics Research (CASPER). The EHT project is grateful to T4Science and Microsemi for their assistance with Hydrogen Masers. This research has made use of NASA's Astrophysics Data System. We gratefully acknowledge the support provided by the extended sta ff of the ALMA, both from the inception of the ALMA Phasing Project through the observational campaigns of 2017 and 2018. We would like to thank A. Deller and W. Brisken for EHT-specific support with the use of DiFX. We acknowledge the significance that Maunakea, where the SMA and JCMT EHT stations are located, has for the indigenous Hawaiian people. r This research has made use of data obtained with the Global Millimeter VLBI Array (GMVA), which consists of telescopes operated by the MPIfR, IRAM, Onsala, Metsahovi, Yebes, the Korean VLBI Network, the Green Bank Observatory and the Very Long Baseline Array (VLBA). The VLBA is an instrument of the National Radio Astronomy Observatory. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated by Associated Universities, Inc. The data were correlated at the correlator of the MPIfR in Bonn, Germany. This study makes use of 43 GHz VLBA data from the VLBA-BU Blazar Monitoring Program (VLBABU-BLAZAR; http://www.bu.edu/blazars/VLBAproject.html), funded by NASA through the Fermi Guest Investigator Program.

According to clinical practice, the characteristics and issues of pragmatic randomized controlled trial(PRCT) and expertise-based randomized controlled trial (EBRCT) in acupuncture-moxibustion clinical research were summarized. The characteristics of expertise-based pragmatic randomized controlled trial (EB-PRCT), which is the combination of above two, and its application in acupuncture-moxibustion clinical trial were explored. PRCT emphasizes the clinical practice, the positive control of standard therapy and the the blind performance on data collection and statistics. PRCT has the advantage of flexible grouping, nevertheless, it also has shortcomings such as higher cost and lack of typical subjects. EBRCT emphasizes the participation of professional acupuncturists, so that the therapeutic effect is ensured, the compliance of subjects and the bias of manipulation are improved. Thus, the replacement scheme of acupuncturists is essential in EBRCT. Having the complementary advantages, EB-PRCT provides a superior research method for acupuncture-moxibustion clinical trial, and leads to convincing results.