Do Quiescent and Active Galaxies Have Different M_(BH)-σ* Relations?

To investigate the validity of the assumption that quiescent galaxies and active galaxies follow the same black hole mass (M_BH)-stellar velocity dispersion (σ*) relation, as required for the calibration of M_BH estimators for broad line active galactic nuclei (AGNs), we determine and compare the M_BH-σ* relations, respectively, for quiescent and active galaxies. For the quiescent galaxy sample, composed of 72 dynamical M_BH measurements, we update σ* for 28 galaxies using homogeneous H-band measurements that are corrected for galaxy rotation. For active galaxies, we collect 25 reverberation-mapped AGNs and improve σ* measurement for two objects. Combining the two samples, we determine the virial factor f, first by scaling the active galaxy sample to the M_BH-σ* relation of quiescent galaxies, and second by simultaneously fitting the quiescent and active galaxy samples, as f=5.1^(+1.5)_(-1.1) and f=5.9^(+2.1)_(-1.5), respectively. The M_BH-σ* relation of active galaxies appears to be shallower than that of quiescent galaxies. However, the discrepancy is caused by a difference in the accessible M_BH distribution at given σ*, primarily due to the difficulty of measuring reliable stellar velocity dispersion for the host galaxies of luminous AGNs. Accounting for the selection effects, we find that active and quiescent galaxies are consistent with following intrinsically the same M_BH-σ* relation

Calibrating Stellar Velocity Dispersions Based on Spatially Resolved H-band Spectra for Improving the M_(BH)-σ_* Relation

To calibrate stellar velocity dispersion measurements from optical and near-IR stellar lines, and to improve the black hole mass (M_(BH))-stellar velocity dispersion (σ_*) relation, we measure σ_* based on high-quality H-band spectra for a sample of 31 nearby galaxies, for which dynamical M_(BH) is available in the literature. By comparing velocity dispersions measured from stellar lines in the H-band with those measured from optical stellar lines, we find no significant difference, suggesting that optical and near-IR stellar lines represent the same kinematics and that dust effect is negligible for early-type galaxies. Based on the spatially resolved rotation and velocity dispersion measurements along the major axis of each galaxy, we find that a rotating stellar disk is present for 80% of galaxies in the sample. For galaxies with a rotation component, σ_* measured from a single aperture spectrum can vary by up to ~20%, depending on the size of the adopted extraction aperture. To correct for the rotational broadening, we derive luminosity-weighted σ_* within the effective radius of each galaxy, providing uniformly measured velocity dispersions to improve the M_(BH)-σ_* relation

Dobrava-Belgrade Hantavirus from Germany Shows Receptor Usage and Innate Immunity Induction Consistent with the Pathogenicity of the Virus in Humans

BACKGROUND: Dobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. DOBV-associated clinical cases typically occur also in the northern part of Germany where the virus is carried by the striped field mouse (Apodemus agrarius). However, the causative agent responsible for human illness has not been previously isolated. METHODOLOGY/PRINCIPAL FINDINGS: Here we report on characterization of a novel cell culture isolate from Germany obtained from a lung tissue of "spillover" infected yellow necked mouse (A. flavicollis) trapped near the city of Greifswald. Phylogenetic analyses demonstrated close clustering of the new strain, designated Greifswald/Aa (GRW/Aa) with the nucleotide sequence obtained from a northern German HFRS patient. The virus was effectively blocked by specific antibodies directed against β3 integrins and Decay Accelerating Factor (DAF) indicating that the virus uses same receptors as the highly pathogenic Hantaan virus (HTNV). In addition, activation of selected innate immunity markers as interferon β and λ and antiviral protein MxA after viral infection of A549 cells was investigated and showed that the virus modulates the first-line antiviral response in a similar way as HTNV. CONCLUSIONS/SIGNIFICANCE: In summary, our study reveals novel data on DOBV receptor usage and innate immunity induction in relationship to virus pathogenicity and underlines the potency of German DOBV strains to act as human pathogen

NIST Interlaboratory Study on Glycosylation Analysis of Monoclonal Antibodies: Comparison of Results from Diverse Analytical Methods

Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submit- Avenue, Silver Spring, Maryland 20993; 22Glycoscience Research Laboratory, Genos, Borongajska cesta 83h, 10 000 Zagreb, Croatia; 23Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacˇ ic´ a 1, 10 000 Zagreb, Croatia; 24Department of Chemistry, Georgia State University, 100 Piedmont Avenue, Atlanta, Georgia 30303; 25glyXera GmbH, Brenneckestrasse 20 * ZENIT / 39120 Magdeburg, Germany; 26Health Products and Foods Branch, Health Canada, AL 2201E, 251 Sir Frederick Banting Driveway, Ottawa, Ontario, K1A 0K9 Canada; 27Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama Higashi-Hiroshima 739–8530 Japan; 28ImmunoGen, 830 Winter Street, Waltham, Massachusetts 02451; 29Department of Medical Physiology, Jagiellonian University Medical College, ul. Michalowskiego 12, 31–126 Krakow, Poland; 30Department of Pathology, Johns Hopkins University, 400 N. Broadway Street Baltimore, Maryland 21287; 31Mass Spec Core Facility, KBI Biopharma, 1101 Hamlin Road Durham, North Carolina 27704; 32Division of Mass Spectrometry, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongwon-gu, Cheongju Chungbuk, 363–883 Korea (South); 33Advanced Therapy Products Research Division, Korea National Institute of Food and Drug Safety, 187 Osongsaengmyeong 2-ro Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, 363–700, Korea (South); 34Center for Proteomics and Metabolomics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; 35Ludger Limited, Culham Science Centre, Abingdon, Oxfordshire, OX14 3EB, United Kingdom; 36Biomolecular Discovery and Design Research Centre and ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Macquarie University, North Ryde, Australia; 37Proteomics, Central European Institute for Technology, Masaryk University, Kamenice 5, A26, 625 00 BRNO, Czech Republic; 38Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany; 39Department of Biomolecular Sciences, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany; 40AstraZeneca, Granta Park, Cambridgeshire, CB21 6GH United Kingdom; 41Merck, 2015 Galloping Hill Rd, Kenilworth, New Jersey 07033; 42Analytical R&D, MilliporeSigma, 2909 Laclede Ave. St. Louis, Missouri 63103; 43MS Bioworks, LLC, 3950 Varsity Drive Ann Arbor, Michigan 48108; 44MSD, Molenstraat 110, 5342 CC Oss, The Netherlands; 45Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787 Japan; 46Graduate School of Pharmaceutical Sciences, Nagoya City University, 3–1 Tanabe-dori, Mizuhoku, Nagoya 467–8603 Japan; 47Medical & Biological Laboratories Co., Ltd, 2-22-8 Chikusa, Chikusa-ku, Nagoya 464–0858 Japan; 48National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG United Kingdom; 49Division of Biological Chemistry & Biologicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158–8501 Japan; 50New England Biolabs, Inc., 240 County Road, Ipswich, Massachusetts 01938; 51New York University, 100 Washington Square East New York City, New York 10003; 52Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, United Kingdom; 53GlycoScience Group, The National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland; 54Department of Chemistry, North Carolina State University, 2620 Yarborough Drive Raleigh, North Carolina 27695; 55Pantheon, 201 College Road East Princeton, New Jersey 08540; 56Pfizer Inc., 1 Burtt Road Andover, Massachusetts 01810; 57Proteodynamics, ZI La Varenne 20–22 rue Henri et Gilberte Goudier 63200 RIOM, France; 58ProZyme, Inc., 3832 Bay Center Place Hayward, California 94545; 59Koichi Tanaka Mass Spectrometry Research Laboratory, Shimadzu Corporation, 1 Nishinokyo Kuwabara-cho Nakagyo-ku, Kyoto, 604 8511 Japan; 60Children’s GMP LLC, St. Jude Children’s Research Hospital, 262 Danny Thomas Place Memphis, Tennessee 38105; 61Sumitomo Bakelite Co., Ltd., 1–5 Muromati 1-Chome, Nishiku, Kobe, 651–2241 Japan; 62Synthon Biopharmaceuticals, Microweg 22 P.O. Box 7071, 6503 GN Nijmegen, The Netherlands; 63Takeda Pharmaceuticals International Co., 40 Landsdowne Street Cambridge, Massachusetts 02139; 64Department of Chemistry and Biochemistry, Texas Tech University, 2500 Broadway, Lubbock, Texas 79409; 65Thermo Fisher Scientific, 1214 Oakmead Parkway Sunnyvale, California 94085; 66United States Pharmacopeia India Pvt. Ltd. IKP Knowledge Park, Genome Valley, Shamirpet, Turkapally Village, Medchal District, Hyderabad 500 101 Telangana, India; 67Alberta Glycomics Centre, University of Alberta, Edmonton, Alberta T6G 2G2 Canada; 68Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 Canada; 69Department of Chemistry, University of California, One Shields Ave, Davis, California 95616; 70Horva´ th Csaba Memorial Laboratory for Bioseparation Sciences, Research Center for Molecular Medicine, Doctoral School of Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Egyetem ter 1, Hungary; 71Translational Glycomics Research Group, Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Veszprem, Egyetem ut 10, Hungary; 72Delaware Biotechnology Institute, University of Delaware, 15 Innovation Way Newark, Delaware 19711; 73Proteomics Core Facility, University of Gothenburg, Medicinaregatan 1G SE 41390 Gothenburg, Sweden; 74Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Institute of Biomedicine, Sahlgrenska Academy, Medicinaregatan 9A, Box 440, 405 30, Gothenburg, Sweden; 75Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Bruna Straket 16, 41345 Gothenburg, Sweden; 76Department of Chemistry, University of Hamburg, Martin Luther King Pl. 6 20146 Hamburg, Germany; 77Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba, Canada R3T 2N2; 78Laboratory of Mass Spectrometry of Interactions and Systems, University of Strasbourg, UMR Unistra-CNRS 7140, France; 79Natural and Medical Sciences Institute, University of Tu¨ bingen, Markwiesenstrae 55, 72770 Reutlingen, Germany; 80Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; 81Division of Bioanalytical Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands; 82Department of Chemistry, Waters Corporation, 34 Maple Street Milford, Massachusetts 01757; 83Zoetis, 333 Portage St. Kalamazoo, Michigan 49007 Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license. Received July 24, 2019, and in revised form, August 26, 2019 Published, MCP Papers in Press, October 7, 2019, DOI 10.1074/mcp.RA119.001677 ER: NISTmAb Glycosylation Interlaboratory Study 12 Molecular & Cellular Proteomics 19.1 Downloaded from https://www.mcponline.org by guest on January 20, 2020 ted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide communityderived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods. Molecular & Cellular Proteomics 19: 11–30, 2020. DOI: 10.1074/mcp.RA119.001677.L

Hantaviruses and the intrinsic antiviral interferon system

Infolge einer Infektion mit Hantaviren sterben bis zu 15% der mit hämorrhagischem Fieber mit renalem Syndrom und bis zu 40% der mit Hantaviralen Cardiopulmonalen Syndrom erkrankten Patienten. Die Pathogenitätsmechanismen die zu diesen Syndromen führen und Virulenzfaktoren der Hantaviren sind nur ansatzweise charakterisiert. Die erfolgreiche primäre Infektion nach der Virusaufnahme ist eine wesentliche Voraussetzung für die Pathogenese. In dieser Phase der Infektion vermehren sich pathogene Hantaviren in vitro deutlich effizienter als nicht pathogene. Im Rahmen der Studie wurden virale und zelluläre Faktoren identifiziert und charakterisiert, die für die Etablierung der primären Infektion und folglich auch für die Virulenz der Viren in vivo eine wichtige Rolle spielen. In einem ersten Schritt der Studie wurde eine Fokusaufreinigungsmethode für nicht zytolytische Viren entwickelt. Diese Methode erlaubt die Klonierung von Hantaviren und auf diese Weise auch die Entfernung von defekten interferierenden Viruspartikeln. Defekte Partikel können die Effizient der Virusvermehrung und auch angeborene Immunreaktionen modulieren. Im Rahmen der vorliegenden Studie konnte außerdem gezeigt werden, dass die Verwendung von Referenzviren mit unterschiedlichen Anteilen defekter Viruspartikel einen starken Einfluss auf die Quantifizierung Virus- neutralisierender Antikörper hat. Dieser Befund unterstreicht zusätzlich die Bedeutung der etablierten Fokusaufreinigungsmethode. Diese Methode bildet eine wichtige und solide Grundlage für den funktionellen Vergleich pathogener und nicht-pathogener Referenzviren. Um die Interaktion zwischen Hantaviren und dem angeborenen Immunsystem zu charakterisieren, wurde die Wirkung von Interferon- alpha (IFN) und Interferon-gamma (IFN) auf das hochpathogene HTNV bestimmt. Obwohl diese IFN-Typen teilweise unterschiedliche Gene induzieren, wurde HTNV durch beide IFNe mit der gleichen Effizienz gehemmt. Die Ergebnisse führten zu der Hypothese, dass die Hemmung von HTNV durch Gene vermittelt wird, die sowohl durch IFN als auch IFN moduliert werden. Frühere Studien hatten gezeigt, dass MxA per se ausreichend ist, um eine HTNV-Infektion in vitro zu verhindern. Im Gegensatz zu diesen Befunden, ergaben unsere Untersuchungen keine Hinweise auf einen Beitrag von MxA an der Hemmung von HTNV in IFN-behandelten Zellen. Die Effizienz der Hemmung von HTNV war unverändert, ungeachtet ob MxA gebildet wurde oder nicht. Dieses Ergebnis deutet darauf hin, dass redundante Mechanismen existieren, die für die antivirale Wirkung und die effiziente IFN-vermittelte Hemmung entscheidend sind. Diese Ergebnisse bestätigen die oben skizzierte Hypothese, dass die entscheidenden antiviralen Effektoren gegen HTNV sowohl durch IFN als auch durch IFN induziert werden sollten. Testsysteme für die Untersuchung der Mechanismen, die zu HFRS oder HCPS führen, sind nur ansatzweise entwickelt. Um Hinweise auf diese Mechanismen zu erhalten, wurde die Wechselwirkung zwischen Wirt und Virus - auf der einen Seite mit dem pathogenen HTNV und auf der anderen Seite mit dem nicht pathogenen PHV verglichen. Im Rahmen dieser Vergleichsstudie konnte festgestellt werden, dass pathogene und nicht pathogene Hantaviren angeborene Immunreaktionen über die Ubiquitin-Ligase TRAF3 auslösen. Weiterhin konnte erstmalig gezeigt werden, dass hoch-pathogene Hantaviren angeborene Immunreaktionen über TLR3 auslösen können. Auf Grundlage der differenziellen Virus-Wirt-Interaktion wurde folgendes Modell aufgestellt: Die durch nicht pathogene Hantaviren frühzeitig ausgelösten angeborenen antiviralen Immunreaktionen blockieren die Infektion vollständig. Pathogene Hantaviren hingegen lösen die antivirale Immunreaktion zu spät aus, sodass die Entwicklung einer primären und systemischen Infektion ermöglicht wird. In Folge der anhaltenden Virusproduktion, kommt es zu einer Entzündungsreaktion, die Effektorzellen des angeborenen und des erworbenen Immunsystems rekrutiert und aktiviert. Diese durch die Infektion ausgelöste systemische Immunreaktion könnte für die Pathogenese entscheidend sein. Reverse Genetik System sind bisher für Hantaviren nicht ethabliert. Die Herstellung und Isolierung von Reassortanten nach einer Ko-Infektion mit mehreren Viren ist gegenwärtig der einzige Weg, mit dessen Hilfe definierte Hantavirusvarianten hergestellt werden können. Um Virulenzfaktoren eindeutig zu identifizieren, wurden Reassortanten zwischen einem pathogenen und einem nicht pathogenen Hantavirus hergestellt. Die funktionelle Analyse dieser Reassortanten im Vergleich zu den parentalen Viren zeigte, dass die S-RNA, die für das Nukleokapsidprotein und die L-RNA, die für die RNA-abhängige RNA Polymerase kodieren, entscheidend sind für die Virusspezies-spezifische Virus-Wirt-Interaktion. Abgesehen von den immunogenen Eigenschaften der Glykoproteine des pathogenen PUUV, zeigte die hergestellte Reassortante denselben Phänotyp, wie das nicht pathogene parentale PHV. Um zu testen, ob diese Reassortante als Lebend-Impfstoff zum Schutz vor einer PUUV Infektion geeignet sein könnte sind weitere Studien erforderlich. Über diesen Aspekt hinaus, erlauben die erzielten Ergebnisse eine fokussierte Charakterisierung der molekularen Wirkmechanismen, die für die differenzielle Aktivierung antiviraler Immunreaktionen verantwortlich sind. Hantaviren vermehren sich primär in Endothelzellen können aber auch in alveolar Makrophagen und Dentritischen Zellen replizieren. Wie die Viren sich nach der primären Infektion im Wirt ausbreiten ist gegenwärtig nicht bekannt. Über die Migration infizierter dendritischer Zellen könnte das Virus in die Lymphknoten gelangen und von dort die systemische Infektion auslösen. Während der systemischen Infektion kommt es teilweise zu irreversiblen Schockzuständen, die i. d. R. tödlich verlaufen. Erstmalig konnten wir zeigen, dass in situ gereifte humane Mastzellen mit Hantaviren infiziert und durch die Infektion aktiviert werden können. Diese Ergebnisse begründen die Hypothese, dass auch Mastzellen im Zuge der systemischen Infektion infiziert werden und durch die Sezernierung von Entzündungsmediatoren an der Ausprägung der Symptomatik beteiligt sein könnten. Die therapeutische Stabilisierung von Mastzellen in dieser kritischen Phase der Infektion könnte geeignet sein, die Ausprägung irreversibler Schockzustände und letale Krankheitsverläufe zu verhindern. In dieser Arbeit sind Studien zusammengefasst, auf deren Grundlage konkrete Hypothesen zur Virulenz und Pathogenese der Hantaviren im Menschen aufgestellt werden konnten. Eine Fortführung der Untersuchungen, angelehnt an diese Hypothesen, kann zur Entwicklung neuer Hantavirus-Impfstoffe und zur Verbesserung der Behandlungsoptionen für infizierte Patienten führen.Hantavirus infection can cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome with case fatality ratios up to 15% and 40%, respectively. The virulence factors and mechanisms responsible for these syndromes are not known. Successful primary infection after uptake of the virus is crucial for development of syndromes. During primary infection pathogenic hantaviruses propagate with higher efficiency compared to non pathogenic in type I interferon (IFN) -competent cells. In the presented study viral and cellular factors important for establishment of primary infection were identified. These factors might be important also for the virulence of hantaviruses in humans. Initially a focus purification method was established for non cytolytic viruses. This method allows removing of defective interfering virus particles and cloning of infectious hantaviruses. Defective particles can modulate the efficiency of virus propagation and innate immune reactions. Furthermore, different amounts of defective particles present in reference virus material can have a significant influence on quantification of neutralizing antibodies. This finding underscores the importance of the established focus purification method, which is an important and solid basis for the functional analysis of pathogenic and non-pathogenic hantaviruses. To characterize the interaction of hantaviruses and the innate immune system the effect of IFN and IFN on the pathogenic Hantaan virus (HTNV) was determined. IFNs induce a huge set of different genes and at least some of these genes are induced both by IFN and IFN. Replication of HTNV was blocked with the same efficiency. This finding suggest that the observed inhibition is mediated by genes which are induced by both IFNs. Previous studies indicated that the IFN-inducible MxA protein can prevent HTNV infection in vitro. In our studies MxA was not decisive for IFN-induced inhibition of HTNV. Irrespectively whether MxA was expressed or not, the antiviral efficiency was not impaired. This result implies that redundant mechanisms contribute to prevent HTNV propagation. This interpretation is consistent with the hypothesis that decisive antiviral effectors are induced both by IFN and IFN. Experimental systems to analyze the mechanisms responsible for hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome are not available. We analysed the interaction of the host cell with pathogenic and non pathogenic hantaviruses in vitro to get an idea about the mechanism which might be decisive for the virulence in vitro. This study revealed that pathogenic and non pathogenic hantaviruses elicit innate responses via recruitment of the ubiquitin ligase TRAF3. Furthermore, the study revealed that pathogenic hantaviruses can be recognized by TLR3. Based on this finding it was proposed that early activation of antiviral responses by non pathogenic hantaviruses prevent infection completely. However, pathogenic hantaviruses induce antiviral immune reactions in a retarded manner which might allow establishment of primary infection, propagation, and dissemination in vivo. Systemic infection might cause inflammatory immune reactions and recruitment of effector cells of the innate and acquired immune system. Thus, modulation of the immediate antiviral immune response seems to be a key factor for the virulence of hantaviruses in humans. Reverse genetic systems are not available for hantaviruses. Isolation of reassortants after coinfection of cells with different viruses currently is the only way to produce defined hantavirus variants. To identify virulence factors reassortants between pathogenic and non pathogenic hantaviruses were produced. Functional analysis of these reassortants in line with the parental viruses demonstrated that the S-RNA, coding for the nucleocapsid protein and the L-RNA, coding for the RNA-dependent RNA polymerase, determine the observed virus species specific virus host interaction. The produced reassortant revealed the immunogenic properties of the pathogenic Puumal hantavirus but all other characteristic features of the non pathogenic Prospect Hill hantavirus. Further studies are required to test whether the reassortant might be used as attenuated vaccine against an infection with Puumala virus. Furthermore, these results allow a focused characterisation of the molecular mechanisms responsible for the differential activation of antiviral immune reactions. Hantaviruses primarily replicate in endothelial cells, but also alveolar macrophages and dendritic cells have been reported to support viral replication. How viruses disseminate after primary infection is unclear. With infected macrophages and dendritic cells the virus might be transported to lymph nodes and spread further to establish a systemic infection. During systemic infection irreversible shock is observed in server cases which generally lead to death of the patient. Our data demonstrate that hantaviruses can infect and activate in situ maturated human mast cells. These results lead to the hypothesis that mast cell can be infected during systemic infection and secretion of inflammatory mediators could contribute to the observed symptoms. If true stabilisation of mast cells in this critical phase of the infection might be an option to prevent shock and the lethal course of the disease. Taken together, this study provides the basis for a concrete hypothesis which can explain hantavirus species specific virulence and pathogenesis in humans. Based on the developed model further studies might lead to development of novel hantavirus vaccines and novel options to treat infected patient

Weight Loss Trajectories and Related Factors in a 16-Week Mobile Obesity Intervention Program: Retrospective Observational Study

BackgroundIn obesity management, whether patients lose ≥5% of their initial weight is a critical factor in clinical outcomes. However, evaluations that take only this approach are unable to identify and distinguish between individuals whose weight changes vary and those who steadily lose weight. Evaluation of weight loss considering the volatility of weight changes through a mobile-based intervention for obesity can facilitate understanding of an individual’s behavior and weight changes from a longitudinal perspective. ObjectiveThe aim of this study is to use a machine learning approach to examine weight loss trajectories and explore factors related to behavioral and app use characteristics that induce weight loss. MethodsWe used the lifelog data of 13,140 individuals enrolled in a 16-week obesity management program on the health care app Noom in the United States from August 8, 2013, to August 8, 2019. We performed k-means clustering with dynamic time warping to cluster the weight loss time series and inspected the quality of clusters with the total sum of distance within the clusters. To identify use factors determining clustering assignment, we longitudinally compared weekly use statistics with effect size on a weekly basis. ResultsThe initial average BMI value for the participants was 33.6 (SD 5.9) kg/m2, and it ultimately reached 31.6 (SD 5.7) kg/m2. Using the weight log data, we identified five clusters: cluster 1 (sharp decrease) showed the highest proportion of participants who reduced their weight by >5% (7296/11,295, 64.59%), followed by cluster 2 (moderate decrease). In each comparison between clusters 1 and 3 (yo-yo) and clusters 2 and 3, although the effect size of the difference in average meal record adherence and average weight record adherence was not significant in the first week, it peaked within the initial 8 weeks (Cohen d>0.35) and decreased after that. ConclusionsUsing a machine learning approach and clustering shape-based time series similarities, we identified 5 weight loss trajectories in a mobile weight management app. Overall adherence and early adherence related to self-monitoring emerged as potential predictors of these trajectories

Hantavirus-induced immunity in rodent reservoirs and humans

Contact: Fax: 1 49 3 8351 7192 e-mail: [email protected] audienceHantaviruses are predominantly rodent-borne pathogens, although recently novel shrew-associated hantaviruses were found. Within natural reservoir hosts, hantairuses do not cause obvious pathogenetic effects; transmission to humans, however, can lead to hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome, depending on the virus species involved. This review is focussed on the recent knowledge on hantavirus-induced immune responses in rodent reservoirs and humans and their impact on susceptibility, transmission, and outcome of hantavirus infections. In addition, this review incorporates a discussion on the potential role of direct cell-virus interactions in the pathogenesis of hantavirus infections in humans. Finally, questions for further research efforts on the immune responses in potential hantavirus reservoir hosts and humans are summarized