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BACKGROUND: The therapeutic relationship is often acknowledged as one of the most significant factors in clinical process that influences client outcomes. OBJECTIVE: While considerable research has been conducted on the therapeutic relationship in psychotherapy, there is a paucity of research on the impact of the therapeutic relationship in vocational rehabilitation counseling settings. METHODS: This study explored the relationship between areas of client functioning (individual, interpersonal, social, and overall) and the therapeutic alliance among clients who receive services from the State vocational rehabilitation agency. RESULTS: In this study, younger clients (ages between 16 to 29) reported stronger therapeutic alliance. CONCLUSION: The findings of this study suggested that clients’ perceived individual, interpersonal and overall functioning have a significant positive relationship with the task and bond components of therapeutic relationship.

Objective: The purpose of this paper is to describe an approach to dynamical systems (DS) using a set of differential equations, and how an application of these equations can be used to address a critical element of the therapeutic relationship. Using APA's Three Approaches to Psychotherapy with a Female Client: The Next Generation and Three Approaches to Psychotherapy with a Male Client: The Next Generation videos, DS models were created for each of the six sessions with expert clinicians (Judith Beck, Leslie Greenberg, and Nancy McWilliams) from the three theoretical approaches. Method: A second-by-second observational coding system of the emotional exchanges of the therapists and clients was used as the data for the equations. Results: DS modeling allowed for a side-by-side comparison between the three approaches as well as between the two clients. Examining the graphs created by plotting the results of the DS equations (in particular, phase-space portraits) revealed that there were similarities among the three theoretical approaches, and there were notable differences between the two clients. Conclusions: DS modelling can provide researchers and clinicians with a powerful tool to investigate the complex phenomenon that is psychotherapy.

Luminal esophageal temperature (LET) monitoring is not associated with reduced esophageal injury following pulmonary vein isolation (PVI).Detailed analysis of (the temporal and spatial gradients of) LET measurements may better predict the risk for esophageal injury.Between January 2020 and December 2021, LET maxima, duration of LET rise above baseline, and area under the LET curve (AUC) were calculated offline and correlated with (endoscopy and endoscopic ultrasound detected) esophageal injury (i.e., mucosal esophageal lesions [ELs], periesophageal edema, and gastric motility disorders) following PVI using moderate-power moderate-duration (MPMD [25-30 W/25-30s]) and high-power short-duration (HPSD [50 W/13s]) radiofrequency (RF) settings.63 patients (69 ± 9 years old, 32 male, 51 MPMD and 12 HPSD) were studied. The esophageal injury was frequent (40% in both groups), mucosal ELs were more common with MPMD, and edema was frequently observed following HPSD. RF-duration, total RF-energy at the left atrial (LA) posterior wall, and distance between LA and esophagus were not different between patients with/without esophageal injury. In contrast, to LET and LET duration above baseline, AUC was the best predictor and significantly increased in patients with esophageal injury (3422 vs. 2444 KFor both ablation strategies, AUC of the LET curves best predicted esophageal injury. HPSD is associated with similar rates of esophageal injury when (mostly subclinical) periesophageal alterations (that are of unclear clinical relevance) are included. Whether integration of these calculated LET parameters is useful to prevent esophageal injury remains to be seen.

Reflux-induced esophagitis might facilitate ablation-induced esophageal lesions (ELs) following pulmonary vein isolation (PVI), and these may progress to atrio-esophageal fistula (AEF). In contrast, preexisting ELs are not prone to progression but may affect procedure planning.To study the incidence of preexisting esophageal and upper gastrointestinal (UGI) pathology in patients undergoing PVI, and the relation to ablation-induced ELs.From 08/2018 to 09/2021, consecutive patients undergoing (radiofrequency [RF] or cryoballoon [CB]) PVI were examined by esophagogastroscopy (EGD) before and following ablation. Postprocedural endoscopic ultrasound (EUS) was added in 2021.412 patients (median age 67.5 [IQR 61.3-75.0] years, 56.1% male) were studied. Preprocedural EGD showed abnormalities in 226/399 patients, 15% in the lower third of the esophagus. Half (99/226) were relevant for PVI, 13 procedures were postponed, 6 due to pathological EGD results. A third of the patients with new esophageal injury following ablation had preexisting esophagitis which was associated with a trend for a higher incidence of ELs after RF ablation (12.5 vs. 6.9%, p = 0.232), and a six- and two-fold higher rate of food retention after CB-PVI (28.6 vs. 4.5%, p = 0.008) and RF ablation (8.3 vs. 4.4%, p = 0.279), respectively.(1) EGD before PVI showed UGI abnormalities in 50% of patients, one-fourth of these relevant for PVI. (2) Esophageal inflammation was associated with a higher incidence of post-ablation (peri)-esophageal injury. Whether having this information before ablation is able to reduce ELs or AEF remains to be shown.

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.

PURPOSE To investigate the safety and efficacy of direct, intralesional doxycycline hyclate injection for improving the appearance of cosmetically significant lower eyelid festoons and malar edema. METHODS An Institutional Review Board approved, retrospective review was performed of 15 consecutive patients with malar edema and/or festoons injected with doxycycline hyclate at a concentration of 10 mg/ml. Pre- and postinjection photographs were reviewed and graded on a scale of 0 to 3 (0: no festoon; 1: small festoon; 2: medium festoon; 3: large festoon) by 2 masked physician observers. Patients were excluded from the final analysis if they received an alternate dose concentration, had incomplete photographic records, or did not follow up. Student t test was used for statistical analysis. RESULTS Twenty consecutive treatment areas of 11 patients were included in the analysis. Final follow up ranged from 3 to 104 weeks, with a mean follow up of 22.5 weeks. The average (standard deviation) initial festoon grade of 2.5 (0.58) decreased to 0.9 (0.82) with a p value of

When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 ± 3 μas, which is circular and encompasses a central depression in brightness with a flux ratio 10:1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M = (6.5 ± 0.7) × 109 Me. Our radiowave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.© 2019. The American Astronomical Society, The authors of this Letter 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; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT, Chile, via PIA ACT172033, Fondecyt 1171506, BASAL AFB170002, ALMA-conicyt 31140007); Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico, projects 104497, 275201, 279006, 281692); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Dirección General de Asuntos del Personal Académico-Universidad Nacional 9 The Astrophysical Journal Letters, 875:L1 (17pp), 2019 April 10 The EHT Collaboration et al. Autónoma de México (DGAPA-UNAM, project IN112417); the European Research Council (ERC) Synergy Grant “BlackHoleCam: Imaging the Event Horizon of Black Holes” (grant 610058); the Generalitat Valenciana postdoctoral grant APOSTD/2018/177; 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-in-Aid for JSPS Research Fellowship (JP17J08829); JSPS Overseas Research Fellowships; the Key Research Program of Frontier Sciences, Chinese, Academy of Sciences (CAS, grants QYZDJ-SSW-SLH057, QYZDJ-SSW-SYS008); 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, 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-M001-011, 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); 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, AST0705062, AST-0905844, AST-0922984, AST-1126433, AST1140030, DGE-1144085, AST-1207704, AST-1207730, AST1207752, MRI-1228509, OPP-1248097, AST-1310896, AST1312651, AST-1337663, AST-1440254, AST-1555365, AST1715061, AST-1615796, AST-1614868, AST-1716327, OISE1743747, AST-1816420); the Natural Science Foundation of China (grants 11573051, 11633006, 11650110427, 10625314, 11721303, 11725312, 11873028, 11873073, U1531245, 11473010); 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 (grant 2015-R1D1A1A01056807, the Global PhD Fellowship Grant: NRF-2015H1A2A1033752, and 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 Canada and by the Province of Ontario through the Ministry of Economic Development, Job Creation and Trade); the Russian Science Foundation (grant 17-12-01029); the Spanish Ministerio de Economía y Competitividad (grants AYA2015-63939-C2-1-P, AYA2016-80889-P); 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 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 Università e Ricerca through the grant Progetti Premiali 2012-iALMA (CUP C52I13000140001); the European Unionʼs Horizon 2020 research and innovation programme under grant agreement No 730562 RadioNet; ALMA North America Development Fund; Chandra TM6-17006X

Context Aging is a primary risk factor for most chronic diseases, including type 2 diabetes. Both exercise and hypoxia regulate pathways that ameliorate age-associated metabolic muscle dysfunction. Objective We hypothesized that the combination of hypoxia and exercise would be more effective in improving glucose metabolism than normoxia exercise. Design and Participants We randomized 29 older sedentary individuals (62 ± 6 years; 14 women, 15 men) to bicycle exercise under normobaric hypoxia (fraction of inspired oxygen = 15%) or normoxia (fraction of inspired oxygen = 21%). Intervention Participants trained thrice weekly for 30 to 40 minutes over 8 weeks at a heart rate corresponding to 60% to 70% of peak oxygen update. Main Outcome Measures Insulin sensitivity measured by hyperinsulinemic-euglycemic glucose clamp and muscle protein expression before and after hyperinsulinemic-euglycemic glucose clamp. Results Heart rate and perceived exertion during training were similar between groups, with lower oxygen saturation when exercising under hypoxia (88.7 ± 1.5 vs 96.2 ± 1.2%, P < 0.01). Glucose infusion rate after 8 weeks increased in both the hypoxia (5.7 ± 1.1 to 6.7 ± 1.3 mg/min/kg; P < 0.01) and the normoxia group (6.2 ± 2.1 to 6.8 ± 2.1 mg/min/kg; P = 0.04), with a mean difference between groups of –0.44 mg/min/kg; 95% CI, –1.22 to 0.34; (P = 0.25). Markers of mitochondrial content and oxidative capacity in skeletal muscle were similar after training in both groups. Changes in Akt phosphorylation and glucose transporter 4 under fasting and insulin-stimulated conditions were not different between groups over time. Conclusions Eight weeks of hypoxia endurance training led to similar changes in insulin sensitivity and markers of oxidative metabolism compared with normoxia training. Normobaric hypoxia exercise did not enhance metabolic effects in sedentary older women and men beyond exercise alone.

The Galactic Center black hole Sagittarius A* (Sgr A*) is a prime observing target for the Event Horizon Telescope (EHT), which can resolve the 1.3 mm emission from this source on angular scales comparable to that of the general relativistic shadow. Previous EHT observations have used visibility amplitudes to infer the morphology of the millimeter-wavelength emission. Potentially much richer source information is contained in the phases. We report on 1.3 mm phase information on Sgr A* obtained with the EHT on a total of 13 observing nights over 4 years. Closure phases, the sum of visibility phases along a closed triangle of interferometer baselines, are used because they are robust against phase corruptions introduced by instrumentation and the rapidly variable atmosphere. The median closure phase on a triangle including telescopes in California, Hawaii, and Arizona is nonzero. This result conclusively demonstrates that the millimeter emission is asymmetric on scales of a few Schwarzschild radii and can be used to break 180-degree rotational ambiguities inherent from amplitude data alone. The stability of the sign of the closure phase over most observing nights indicates persistent asymmetry in the image of Sgr A* that is not obscured by refraction due to interstellar electrons along the line of sight., Comment: 11 pages, accepted to ApJ

Neurodegenerative diseases affect millions of people worldwide, and as the global population ages, there is a critical need to improve our understanding of the molecular and cellular mechanisms that drive neurodegeneration. At the molecular level, neurodegeneration involves the activation of complex signaling pathways that drive the active destruction of neurons and their intracellular components. Here, we use an in vivo motor neuron injury assay to acutely induce neurodegeneration in order to follow the temporal order of events that occur following injury in Drosophila melanogaster. We find that sites of injury can be rapidly identified based on structural defects to the neuronal cytoskeleton that result in disrupted axonal transport. Additionally, the neuromuscular junction accumulates ubiquitinated proteins prior to the neurodegenerative events, occurring at 24 hours post injury. Our data provide insights into the early molecular events that occur during axonal and neuromuscular degeneration in a genetically tractable model organism. Importantly, the mechanisms that mediate neurodegeneration in flies are conserved in humans. Thus, these studies have implications for our understanding of the cellular and molecular events that occur in humans and will facilitate the identification of biomedically relevant targets for future treatments.

We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional {\it uv} coverage in the N-S direction, and leads to a spatial resolution of $\sim$30 $\mu$as ($\sim$3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of $\sim$4-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of $\sim$3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk- and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow a more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary., Comment: 11 pages, 5 figures, accepted to ApJ

The Event Horizon Telescope (EHT) is a very long baseline interferometry (VLBI) array that comprises millimeter- and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth. At a nominal operating wavelength of ~1.3 mm, EHT angular resolution (λ/D) is ~25 μas, which is sufficient to resolve nearby supermassive black hole candidates on spatial and temporal scales that correspond to their event horizons. With this capability, the EHT scientific goals are to probe general relativistic effects in the strong-field regime and to study accretion and relativistic jet formation near the black hole boundary. In this Letter we describe the system design of the EHT, detail the technology and instrumentation that enable observations, and provide measures of its performance. Meeting the EHT science objectives has required several key developments that have facilitated the robust extension of the VLBI technique to EHT observing wavelengths and the production of instrumentation that can be deployed on a heterogeneous array of existing telescopes and facilities. To meet sensitivity requirements, high-bandwidth digital systems were developed that process data at rates of 64 gigabit s−1, exceeding those of currently operating cm-wavelength VLBI arrays by more than an order of magnitude. Associated improvements include the development of phasing systems at array facilities, new receiver installation at several sites, and the deployment of hydrogen maser frequency standards to ensure coherent data capture across the array. These efforts led to the coordination and execution of the first Global EHT observations in 2017 April, and to event-horizon-scale imaging of the supermassive black hole candidate in M87.© 2019. The American Astronomical Society, The authors of this Letter 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; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT, Chile, via PIA ACT172033, Fondecyt 1171506, BASAL AFB170002, ALMA-conicyt 31140007); Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico, projects 104497, 275201, 279006, 281692); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Dirección General de Asuntos del Personal Académico-Universidad Nacional 9 The Astrophysical Journal Letters, 875:L1 (17pp), 2019 April 10 The EHT Collaboration et al. Autónoma de México (DGAPA-UNAM, project IN112417); the European Research Council (ERC) Synergy Grant “BlackHoleCam: Imaging the Event Horizon of Black Holes” (grant 610058); the Generalitat Valenciana postdoctoral grant APOSTD/2018/177; 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-in-Aid for JSPS Research Fellowship (JP17J08829); JSPS Overseas Research Fellowships; the Key Research Program of Frontier Sciences, Chinese, Academy of Sciences (CAS, grants QYZDJ-SSW-SLH057, QYZDJ-SSW-SYS008); 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, 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-M001-011, 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); 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, AST0705062, AST-0905844, AST-0922984, AST-1126433, AST1140030, DGE-1144085, AST-1207704, AST-1207730, AST1207752, MRI-1228509, OPP-1248097, AST-1310896, AST1312651, AST-1337663, AST-1440254, AST-1555365, AST1715061, AST-1615796, AST-1614868, AST-1716327, OISE1743747, AST-1816420); the Natural Science Foundation of China (grants 11573051, 11633006, 11650110427, 10625314, 11721303, 11725312, 11873028, 11873073, U1531245, 11473010); 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 (grant 2015-R1D1A1A01056807, the Global PhD Fellowship Grant: NRF-2015H1A2A1033752, and 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 Canada and by the Province of Ontario through the Ministry of Economic Development, Job Creation and Trade); the Russian Science Foundation (grant 17-12-01029); the Spanish Ministerio de Economía y Competitividad (grants AYA2015-63939-C2-1-P, AYA2016-80889-P); 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 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 Università e Ricerca through the grant Progetti Premiali 2012-iALMA (CUP C52I13000140001); the European Unionʼs Horizon 2020 research and innovation programme under grant agreement No 730562 RadioNet; ALMA North America Development Fund; Chandra TM6-17006X

Melanoma, one of the most aggressive skin cancers, has steadily been on the rise over the last three decades. With limited treatment options, the recent impetus in immuno-oncology drugs, especially checkpoint inhibitors, has changed the treatment landscape. While anti-CTLA4 and anti-PD1 demonstrated success in clinic, the search for additional targets is needed to enable potent comprehensive curative combination therapies. Our laboratory has characterized and screened five primary patient-derived melanoma cell lines, MEL-2, MEL-V, 3MM, KFM, and GLM-2. While immunomodulatory molecules are canonically present on antigen presenting cells and T-cells, increasing evidence suggests that they are not expressed in isolation. In an effort to identify immunomodulatory molecules expressed on our primary melanoma cells, a comprehensive RT-PCR screen of 29 co-inhibitory and co-stimulatory molecules was carried out. Several molecules including CD160, CD226, TIM1, HVEM, and BTLA were seen to be differentially expressed in melanoma cells compared to normal melanocytes at the mRNA level. Western blots and immunocytochemistry validated the differential expression of these molecules at the protein level. 50-80% of melanoma cases are positive for the BRAFV600E mutation, and are treated with a small molecule inhibitor of the mutated BRAF, vemurafenib (PLX4032). Treatment of these cells with PLX4032 led to an upregulation of transcription factors MITF and AP-1, as well as immunomodulatory molecules, CD160, CD226, TIM1, HVEM, and BTLA, a phenomenon seen only in cells positive for the BRAFV600E lesion. MITF and AP-1, owing to the binding sites present in the promoter regions of these molecules, can drive their expression upon treatment with PLX4032. These additional immune-regulatory molecules of T-cell activation and/or immune tolerance mechanisms are potential targets for a combination therapy with PLX4032 in melanoma patients positive for the BRAFV600E genetic lesion. Our future directions aim to elucidate the role of these molecules on the tumor cells and devise an effective combination with small-molecule inhibitors and immunotherapies. Citation Format: Rachana Maniyar, Robert Freund, Aryan Malhotra, Sanjukta Chakraborty, Jan Geliebter, Marc Wallack, Raj K. Tiwari. Co-expression of stimulators and inhibitors of T-cell activation in melanoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B174.

We report about a 230 GHz very long baseline interferometry (VLBI) fringe finder observation of blazar 3C 279 with the APEX telescope in Chile, the phased submillimeter array (SMA), and the SMT of the Arizona Radio Observatory (ARO). We installed VLBI equipment and measured the APEX station position to 1 cm accuracy (1 sigma). We then observed 3C 279 on 2012 May 7 in a 5 hour 230 GHz VLBI track with baseline lengths of 2800 M$\lambda$ to 7200 M$\lambda$ and a finest fringe spacing of 28.6 micro-arcseconds. Fringes were detected on all baselines with SNRs of 12 to 55 in 420 s. The correlated flux density on the longest baseline was ~0.3 Jy/beam, out of a total flux density of 19.8 Jy. Visibility data suggest an emission region, Comment: accepted for publication in A&A

Near a black hole, differential rotation of a magnetized accretion disk is thought to produce an instability that amplifies weak magnetic fields, driving accretion and outflow. These magnetic fields would naturally give rise to the observed synchrotron emission in galaxy cores and to the formation of relativistic jets, but no observations to date have been able to resolve the expected horizon-scale magnetic-field structure. We report interferometric observations at 1.3-millimeter wavelength that spatially resolve the linearly polarized emission from the Galactic Center supermassive black hole, Sagittarius A*. We have found evidence for partially ordered fields near the event horizon, on scales of ~6 Schwarzschild radii, and we have detected and localized the intra-hour variability associated with these fields., Comment: Accepted for publication in Science; includes Supplementary material

The Arizona Radio Observatory (ARO) operates two radio telescopes in the millimeter and sub-millimeter wavelength region. Recently, one of these instruemnts, the aging, former NRAO 12 meter telescope on Kitt Peak, was replaced with one of the 12 m ALMA prototype antennas. The high performance design of this new instrument, including its 20 microns surface and sub-arcsecond pointing, will expand observational capabilites at the ARO. New receivers and backends are also in development at ARO. A dual polarization sideband separating SIS mixer covering the 0.7 mm atmospheric windw, ranging from 385 GHz to 500 GHz, has been installed as a facility instrument on the Sub-Millimeter Telescope (SMT) on Mount Graham. A prototype Band 2 receiever, based on HEMT amplifier technology, has been built and tested on the sky. These new additions and other developments will be presented.

At radio wavelengths, images of the compact radio source Sagittarius A* (Sgr A*) in the Galactic Center are scatter broadened with a lambda^2 dependence due to an intervening ionized medium. We present VLBI observations of Sgr A* at 86 GHz using a six station array including the VLBA antennas at Pie Town, Fort Davis and Los Alamos, the 12m antenna at Kitt Peak and the millimeter arrays at Hat Creek and Owens Valley. To avoid systematic errors due to imperfect antenna calibration, the data were modeled using interferometric closure information. The data are best modeled by a circular Gaussian brightness distribution of FWHM 0.18 +- 0.02 mas. The data are also shown to be consistent with an elliptical model corresponding to the scattering of a point source. The source structure in the N-S direction, which is less well determined than in the E-W direction due to the limited N-S (u,v) coverage of the array, is constrained to be less than 0.27 mas by these measurements. These results are consistent with extrapolations of intrinsic structure estimates obtained with VLBI at 7mm wavelength assuming the intrinsic size of Sgr A* has a greater dependence than lambda^0.9 with wavelength.

The role of apoptosis in affinity maturation was investigated by determining the affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific antibody-forming cells (AFCs) and serum antibody in transgenic mice that overexpress a suppressor of apoptosis, Bcl-xL, in the B cell compartment. Although transgenic animals briefly expressed higher numbers of splenic AFCs after immunization, the bcl-xL transgene did not increase the number or size of germinal centers (GCs), alter the levels of serum antibody, or change the frequency of NP-specific, long-lived AFCs. Nonetheless, the bcl-xL transgene product, in addition to endogenous Bcl-xL, reduced apoptosis in GC B cells and resulted in the expansion of B lymphocytes bearing VDJ rearrangements that are usually rare in primary anti-NP responses. Long-lived AFCs bearing these noncanonical rearrangements were frequent in the bone marrow and secreted immunoglobulin G1 antibodies with low affinity for NP. The abundance of noncanonical cells lowered the average affinity of long-lived AFCs and serum antibody, demonstrating that Bcl-xL and apoptosis influence clonal selection/maintenance for affinity maturation.

Retinoic acid inhibits transformation of cells by polyoma virus middle T oncoprotein. Inhibition of transformation results from a retinoic acid-dependent failure of cells to fully express the c-fos proto-oncogene. Retinoic acid prevents transactivation of the c-fos promoter by disrupting signaling between tyrosine kinases at the plasma membrane and trans-acting factors at the c-fos promoter. We used complementary genetic, biochemical and molecular approaches to demonstrate that: (1) phosphatidylinositol 3-kinase signaling is the principle mechanism of polyoma virus middle T oncoprotein activation of c-fos expression; (2) middle T/phosphatidylinositol 3-kinase transactivation of the c-fos promoter and transformation of cells requires activation of both the small GTP-binding protein Rac and Jun N-terminal kinase; (3) retinoic acid inhibits activation of Jun N-terminal kinase, thereby preventing c-fos transactivation and transformation; and (4) middle T activation of c-fos transcription requires both the serum response element and the promoter proximal cyclic AMP response element. These studies identify a novel target through which retinoids prevent oncogenic transformation.

Polyomavirus productively infects mouse cells, transforms rat fibroblasts in culture, and induces a broad spectrum of tumors when inoculated into newborn mice. The expression of large, middle, and small T antigen are necessary for virus growth and oncogenic transformation. We have generated a small deletion in a region common to both large and middle T antigen that encodes three consecutive prolines. In this report we characterize this mutant virus in terms of its ability to replicate in mouse cells, transform rat fibroblasts, and induce tumors in the mouse. We find that the virus immortalizes primary cells and that viral DNA replication is not impaired, indicating that these functions of large T antigen are not altered. However, the ability of the virus to transform rat fibroblasts is defective. The mutant virus makes fewer foci and the foci are weaker in appearance. The mutant middle T still associates with PI 3-kinase and shc, suggesting that the overall structure of the protein has not been disrupted. When inoculated into newborn C3H mice, the mutant virus induces fewer overall tumors with a longer latency than wild-type virus. These results indicate that this proline-rich domain in middle T antigen is important for oncogenesis in a wide variety of tissues and cell types.

The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3(-/-)) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3(-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3(-/-) soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3(-/-) mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.

Infection of mouse fibroblasts by wild-type polyomavirus results in increased phosphorylation of ribosomal protein S6 (D.A. Talmage, J. Blenis, and T.L. Benjamin, Mol. Cell. Biol. 8:2309-2315, 1988). Here we identify pp70 S6 kinase (pp70S6K) as a target for signal transduction events leading from polyomavirus middle tumor antigen (mT). Two partially transforming virus mutants altered in different mT signalling pathways have been studied to elucidate the pathway leading to S6 phosphorylation. An upstream role for mT-phosphatidylinositol 3-kinase (PI3K) complexes in pp70S6K activation is implicated by the failure of 315YF, a mutant unable to promote PI3K binding, to elicit a response. This conclusion is supported by studies using wortmannin, a known inhibitor of PI3K. In contrast, stable interaction of mT with Shc, a protein thought to be involved upstream of Ras, is dispensable for pp70S6K activation. 250YS, a mutant mT which retains a binding site for PI3K but lacks one for Shc, stimulates pp70S6K to wild-type levels. Mutants 315YF and 250YS induce partial transformation of rats fibroblasts with distinct phenotypes, as judged from morphological and growth criteria. Neither mutant induces growth in soft agar, indicating that an increase in S6 phosphorylation, while necessary for cell cycle progression in normal mitogenesis, is not sufficient for anchorage-independent cell growth. In the polyomavirus systems, the latter requires integration of signals from mT involving both Shc and PI3K.

We present the first 1.3 mm (230 GHz) very long baseline interferometry model image of an AGN jet using closure phase techniques with a four-element array. The model image of the quasar 1924-292 was obtained with four telescopes at three observatories: the James Clerk Maxwell Telescope (JCMT) on Mauna Kea in Hawaii, the Arizona Radio Observatory's Submillimeter Telescope (SMT) in Arizona, and two telescopes of the Combined Array for Research in Millimeterwave Astronomy (CARMA) in California in April 2009. With the greatly improved resolution compared with previous observations and robust closure phase measurement, the inner jet structure of 1924-292 was spatially resolved. The inner jet extends to the northwest along a position angle of $-53^\circ$ at a distance of 0.38\,mas from the tentatively identified core, in agreement with the inner jet structure inferred from lower frequencies, and making a position angle difference of $\sim 80^{\circ}$ with respect to the cm-jet. The size of the compact core is 0.15\,pc with a brightness temperature of $1.2\times10^{11}$\,K. Compared with those measured at lower frequencies, the low brightness temperature may argue in favor of the decelerating jet model or particle-cascade models. The successful measurement of closure phase paves the way for imaging and time resolving Sgr A* and nearby AGN with the Event Horizon Telescope., Comment: 6 pages, 4 figures, accepted for publication in ApJL

Approximately 10% of active galactic nuclei exhibit relativistic jets, which are powered by accretion of matter onto super massive black holes. While the measured width profiles of such jets on large scales agree with theories of magnetic collimation, predicted structure on accretion disk scales at the jet launch point has not been detected. We report radio interferometry observations at 1.3mm wavelength of the elliptical galaxy M87 that spatially resolve the base of the jet in this source. The derived size of 5.5 +/- 0.4 Schwarzschild radii is significantly smaller than the innermost edge of a retrograde accretion disk, suggesting that the M87 jet is powered by an accretion disk in a prograde orbit around a spinning black hole., Comment: 12 pages, 3 figures, accepted version

Astronomical observations in the millimeter and sub-millimeter regions are performed at the two facilities of the Arizona Radio Observatory (ARO). The Sub-Millimeter Telescope (SMT) located on Mount Graham utilizes 3 heterodyne SIS receivers to cover 3 of the 4 atmospheric windows from 210 to 720 GHz and soon a new receiver will cover the remaining window. The 12-Meter telescope located on Kitt Peak use 3 heterodyne SIS receivers to the cover the 2 windows from 68 to 180 GHz. All receivers now employ orthogonal polarization optics and soon 4 will utilize wideband dual channel sideband separating mixer technology. Presented here are new instrumentation developments and recent scientific results from the ARO.

The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca(2+)-dependent upregulation of myosin heavy chain (MyHC) I/β expression during skeletal muscle fiber type transformation. Here, we report activation of extracellular signal-regulated kinase (ERK) 1/2 in Ca(2+)-ionophore-treated C2C12 myotubes and electrostimulated soleus muscle. Activated ERK1/2 enhanced NFATc1-dependent upregulation of a -2.4 kb MyHCI/β promoter construct without affecting subcellular localization of endogenous NFATc1. Instead, ERK1/2-augmented phosphorylation of transcriptional coactivator p300, promoted its recruitment to NFATc1 and increased NFATc1-DNA binding to a NFAT site of the MyHCI/β promoter. In line, inhibition of ERK1/2 signaling abolished the effects of p300. Comparison between wild-type p300 and an acetyltransferase-deficient mutant (p300DY) indicated increased NFATc1-DNA binding as a consequence of p300-mediated acetylation of NFATc1. Activation of the MyHCI/β promoter by p300 depends on two conserved acetylation sites in NFATc1, which affect DNA binding and transcriptional stimulation. NFATc1 acetylation occurred in Ca(2+)-ionophore treated C2C12 myotubes or electrostimulated soleus. Finally, endogenous MyHCI/β gene expression in C2C12 myotubes was strongly inhibited by p300DY and a mutant deficient in ERK phosphorylation sites. In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca(2+)-induced MyHCI/β expression.

Results in a previous report established the presence of dominant genetic factor(s) in C3H/BiDa mice which contributed to the unusually high susceptibility of this strain to polyoma virus-induced tumors (Freund et al. (1992) Virology 191, 724-731). Here we show that C57BR/cdJ mice, while identical to C3H/BiDa at the H-2 locus, are almost completely lacking in susceptibility. Analysis of crosses between these two H-2 k strains has shown that susceptibility is due to a single dominant autosomal gene, designated Pyv S . On an H-2 k background, Pyv S acts in a highly penetrant manner to confer susceptibility to induction of a broad range of tumors by the virus. Analysis of F1 mice between C3H/BiDa and the highly resistant C57BL/6 (H-2 b ) strain shows that Pyv S can partially overcome the immunologically mediated resistance associated with an H-2 b haplotype. Pyv S does not encode cell receptors for the virus, nor does it affect levels of virus replication or anti-viral humoral responses in the host. Studies with early passage embryo fibroblasts in culture show that Pyv S does not affect intracellular events essential for either productive infection or cell transformation by the virus. Pyv S thus determines a generalized susceptibility of the host to polyoma-induced tumors but apparently does not act at the level of target cells for tumor induction.

Sagittarius A*, the ~4 x 10^6 solar mass black hole candidate at the Galactic Center, can be studied on Schwarzschild radius scales with (sub)millimeter wavelength Very Long Baseline Interferometry (VLBI). We report on 1.3 mm wavelength observations of Sgr A* using a VLBI array consisting of the JCMT on Mauna Kea, the ARO/SMT on Mt. Graham in Arizona, and two telescopes of the CARMA array at Cedar Flat in California. Both Sgr A* and the quasar calibrator 1924-292 were observed over three consecutive nights, and both sources were clearly detected on all baselines. For the first time, we are able to extract 1.3 mm VLBI interferometer phase information on Sgr A* through measurement of closure phase on the triangle of baselines. On the third night of observing, the correlated flux density of Sgr A* on all VLBI baselines increased relative to the first two nights, providing strong evidence for time-variable change on scales of a few Schwarzschild radii. These results suggest that future VLBI observations with greater sensitivity and additional baselines will play a valuable role in determining the structure of emission near the event horizon of Sgr A*., 8 pages, submitted to ApJL

In the twenty-first century, a company has to organize around the customer in order to be a successful and viable firm. Today, the marketplace is customer driven. Customers expect to get what they would like, with a side order of customization. This alteration of traditional organization of a company through the involvement of the customer into the configuration of the final product faces some obvious problems. The fundamental challenge is to avoid the abortion of the configuration process by the customer. The problem of adapting the process of co-creation to different customers can be solved by identification of different customer profiles that suit each individual customer's needs and limitations. The paper presents one approach in solving the presented problem, by the introduction of a methodology for adaptive involvement of customers as co-creators in mass customization of products and services.

A mutant strain of polyoma virus encoding a truncated middle T protein has been studied for its ability to replicate and induce tumors following inoculation into newborn mice. Virus replication in the acute period prior to expected onset of tumors as well as persistence of virus in older animals were followed. The mutant virus proved to be defective in replication and persistence and failed to induce tumors. These results demonstrate that middle T plays an essential role in productive viral infection in the animal. Since the mutant virus encodes normal large and small T proteins, the results also indicate that functions associated with these T antigens, including large T binding of the retinoblastoma tumor suppressor gene product and the ability to immortalize, are insufficient to cause development of tumors in this system.

The functional importance of the two clusters of positively charged amino acids which flank the hydrophobic membrane-anchoring sequence of polyomavirus middle T (mT) protein has been investigated by using site-directed mutagenesis. A clear asymmetry was apparent. No effect on transformation was seen following multiple alterations or complete removal of the cluster at the carboxyl end of the protein. In contrast, a single substitution replacing the first arginine amino terminal to the hydrophobic stretch with glutamic acid, but not with lysine, histidine, or methionine, produced a partially transformation-defective mutant with a novel phenotype. This mutant failed to confer anchorage-independent growth on F111 established rat embryo fibroblasts but induced foci with altered morphology compared with wild-type mT. Biochemical studies on this mutant revealed that F111 clones expressing levels of mutant mT equivalent to those of wild-type controls showed a 65% reduction in pp60c-src activation and an 87% reduction in mT-associated phosphatidylinositol 3-kinase activity. However, F111 clones expressing seven times more mutant mT than did wild-type controls showed equal or greater levels of kinase activities yet remained incompletely transformed. Possible mechanisms involving this transformation-sensitive region of mT are discussed.

This paper presents the web based intelligent product configurator for thermal insulation and decoration of buildings. Configurator is a three-tier client server application which was developed with modern internet technologie/techniques: xhtml, css, php, mysql, javascript, xml and flash. The functionality and architecture of the configurator are described. Web forms are secured with CAPTCHA (Completely Automated Public Turing test to tell Computers and Humans Apart) method.

Patterns of polyomavirus replication and spread have been studied following inoculation of virus into newborn mice. Levels of virus replication in different tissues were followed in situ by using whole mouse section blots and immunoperoxidase staining for the major capsid protein VP1, as well as by tissue extraction and direct quantitation of viral DNA and infectious virus. Patterns of replication and spread were compared between the "high tumor" strain (inducing a high incidence of tumors) PTA and and the "low tumor" strain (inducing a low incidence of tumors) RA, following different routes of inoculation. The ability to induce a high tumor profile correlated with the ability to establish disseminated productive infection, with the kidney as a major site of amplification. Furthermore, results with PTA-RA recombinant viruses and site-directed mutants showed that the VP1 specificity of PTA, demonstrated earlier to be a critical determinant for induction of a high tumor profile (R. Freund, A. Calderone, C. J. Dawe, and T. L. Benjamin, J. Virol. 65:335-341, 1991), is also critical for amplification in the kidney and for establishment of disseminated infections.

By testing recombinants between "high tumor" (inducing a high incidence of tumors) and "low tumor" (inducing a low incidence of tumors) strains of polyomavirus, we have previously shown that the key determinant(s) for induction of a high tumor profile resides in coding regions of the high tumor strain (R. Freund, G. Mandel, G. G. Carmichael, J. P. Barncastle, C. J. Dawe, and T. L. Benjamin, J. Virol. 61:2232-2239, 1987). Three single-amino-acid differences between the PTA (high tumor) and RA (low tumor) virus strains have now been identified by DNA sequencing, one each in the large T antigen, in the region common to the middle and small T antigens, and in the major capsid protein VP1. Further tests of appropriate recombinants and oligonucleotide-induced mutants show that VP1 of PTA is the major determinant for induction of a high tumor profile, including all tumors of epithelial origin. The differential effect of the VP1s of PTA and RA on the tumor profile is discussed in terms of a likely contribution of the polymorphic region of VP1 to binding of receptors and infection of different cell types in the animal. The polymorphism in the large T antigen has a more restricted action, which is seen only when tested in virus carrying the VP1 type of PTA; the PTA large T antigen then promotes more rapid growth of tumors of salivary gland and thymus than the RA large T antigen.