Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells

HIV infections; Restriction factorsInfecciones por VIH; Factores de restricciónInfeccions pel VIH; Factors de restriccióLatency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1-infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal.This work was supported by following grants: M.K.I., JSPS Oversea Research Fellowship and Takeda Science Foundation; A.E.C., PT17/0009/0019 (ISCIII/MINECO and FEDER); M.J.B., RTI2018-101082-B-I00 and PID2021-123321OB-I00 [MINECO/FEDER]), and the Miguel Servet program by ISCIII (CP17/00179 and CPII22/00005); C.B., M.R.R., C.D.C., European Union’s Horizon 2020 research and innovation program under grant agreement 681137-EAVI2020 and NIH grant P01-AI131568; J.D., the Spanish Ministry of Science and Innovation (PID2019106959RB-I00/AEI/10.13039/501100011033); A.M., the Spanish Ministry of Science and Innovation (PID2019-106323RB-I00 AEI//10.13039/501100011033) and the institutional “María de Maeztu” Programme for Units of Excellence in R&D (CEX2018-000792-M)

Biplanar High-Speed Fluoroscopy of Pony Superficial Digital Flexor Tendon (SDFT)-An In Vivo Pilot Study.

The superficial digital flexor tendon (SDFT) is the most frequently injured structure of the musculoskeletal system in sport horses and a common cause for early retirement. This project's aim was to visualize and measure the strain of the sound, injured, and healing SDFTs in a pony during walk and trot. For this purpose, biplanar high-speed fluoroscopic kinematography (FluoKin), as a high precision X-ray movement analysis tool, was used for the first time in vivo with equine tendons. The strain in the metacarpal region of the sound SDFT was 2.86% during walk and 6.78% during trot. When injured, the strain increased to 3.38% during walk and decreased to 5.96% during trot. The baseline strain in the mid-metacarpal region was 3.13% during walk and 6.06% during trot and, when injured, decreased to 2.98% and increased to 7.61%, respectively. Following tendon injury, the mid-metacarpal region contributed less to the overall strain during walk but showed increased contribution during trot. Using this marker-based FluoKin technique, direct, high-precision, and long-term strain measurements in the same individual are possible. We conclude that FluoKin is a powerful tool for gaining deeper insight into equine tendon biomechanics

Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells

Latency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1-infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal.We thank Drs Yingying Li, Feng Gao and Beatrice H. Hahn for providing codon-optimized HIV-1 Gag expression vector, Drs James Hoxie and Susan Zolla-Pazner for supplying anti-Nef and -p24 antibodies, respectively through the NIH AIDS reagent program. We also thank Dr Song Gao for providing SLFN13-tRNA structure information, and Dr Maria-Eugenia Gas Lopez and Dr Ester Gea-Mallorquí for advise. This work was supported by following grants: M.K.I., JSPS Oversea Research Fellowship and Takeda Science Foundation; A.E.C., PT17/0009/0019 (ISCIII/MINECO and FEDER); M.J.B., RTI2018-101082-B-I00 and PID2021-123321OB-I00 [MINECO/FEDER]), and the Miguel Servet program by ISCIII (CP17/00179 and CPII22/00005); C.B., M.R.R., C.D.C., European Union’s Horizon 2020 research and innovation program under grant agreement 681137-EAVI2020 and NIH grant P01-AI131568; J.D., the Spanish Ministry of Science and Innovation (PID2019106959RB-I00/AEI/10.13039/501100011033); A.M., the Spanish Ministry of Science and Innovation (PID2019-106323RB-I00 AEI//10.13039/501100011033) and the institutional “María de Maeztu” Programme for Units of Excellence in R&D (CEX2018-000792-M).info:eu-repo/semantics/publishedVersio

Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells

Latency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1-infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal. In cell lines and HIV-1 patient PBMCs, the Schlafen 12 protein (SLFN12) is shown to be an HIV-1 restriction factor that inhibits HIV-1 replication and virus reactivatio

Designing Sustainable Urban Futures

Many 21st century cities have the potential to be sustainable and resource-saving living spaces when multifunctional structures, well-integrated transportation infrastructure, and democratic governance processes are present. Sustainable urban futures require a focus on the needs of humans and environmental best practices, as well as on the creative scope for community-driven sustainability innovations. This book is based on contributions from science and practice to the international symposium on “Sustainable Urban Development at Different Scales” organized by the Institute for Technology Assessment and Systems Analysis at the Karlsruhe Institute of Technology, Karlsruhe, Germany, in May 2014. The symposium used the global urbanization and reurbanization trend as an opportunity to examine cities as sustainable living spaces. This book identifi es concepts, analytic approaches, and practical applications for the design of sustainable urban futures among multiple disciplines and cultural backgrounds.Viele Städte des 21. Jahrhunderts haben das Potenzial, ein nachhaltiger und ressourcenschonender Lebensraum zu sein, wenn multifunktionale Strukturen, eine gut integrierte Verkehrsinfrastruktur und demokratische Stadtentwicklungsprozesse gegeben sind. Nachhaltige Stadtzukünfte erfordern einen starken Fokus auf die Berücksichtigung menschlicher Bedürfnissen an ihren Lebensraum, auf Umweltfreundlichkeit und Gesundheit sowie die gemeinsame Gestaltung kreativer Freiräume für nachhaltige Praktiken. Diese Buch basiert auf Beiträgen aus Wissenschaft und Praxis zum internationalen Symposium „Sustainable Urban Development at Different Scales“, das im Mai 2014 am Institut für Technikfolgenabschätzung und Systemanalyse am Karlsruher Institut für Technologie stattfand. Das Symposium nahm den globalen Urbanisierungsund Reurbanisierungstrend zum Anlass, um Städte auf unterschiedlichen Maßstabsebenen als nachhaltige Lebensräume zu diskutieren. Dieses Buch bietet Analysen, Konzepte und Ansätze zur Gestaltung nachhaltiger Stadtzukünfte aus der Sicht multipler Disziplinen und vor unterschiedlichen kulturellen Hintergründen

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca2+ mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca2+ channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca2+ overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca2+ overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias

Wenn Man(n) Vater wird ...

Die väterliche Perspektive bezüglich Schwangerschaft, Geburt und Elternschaft ist erst seit kurzem Gegenstand der wissenschaftlichen Forschung. Die vorliegende Arbeit widmet sich deshalb dem subjektiven Erleben von werdenden Vätern während der Zeit der Schwangerschaft, unter besonderer Berücksichtigung ihrer Auseinandersetzung mit der Vateridentität. Zusätzlich sollen darauf einflussnehmenden Faktoren untersucht werden. Entwickelt wurde die Untersuchung in Anlehnung an die Studie „Übergang zur Vaterschaft“ von Martin (2008), wobei durch Rekrutierung einer größeren Stichprobe repräsentativere Ergebnisse erzielt werden sollten. Insgesamt konnten durch eine Querschnittserhebung mittels Fragebögen, im Zeitraum von Juni bis September 2011, Daten von 134 Vätern, die ihr erstes Kind erwarteten und zwischen 20 und 45 Jahre alt waren, gewonnen werden. Als Erhebungsinstrument diente eine – entsprechend den interessierenden Forschungsfragen – überarbeitete Version des von Martin (2008) konstruierten „Fragebogens zur Erfassung der Auseinandersetzung mit der Vateridentität“, sowie der Fragebogen zur Erfassung der Zufriedenheit in der Paarbeziehung (ZIP) von Hassebrauck (1991). Die Untersuchung konnte keinen signifikanten Einfluss der aktuellen Schwangerschaftswoche auf die Auseinandersetzung mit der Vateridentität nachweisen. Ebenso machte der Umstand, ob das Kind geplant war oder nicht für die Auseinandersetzung mit der Vateridentität keinen Unterschied. Hingegen zeigte sich die Partnerschaftszufriedenheit als bedeutsam für die väterliche Vorstellung zur Vereinbarkeit von Familie und Beruf sowie für die Auseinandersetzung mit der Vateridentität. Außerdem konnte belegt werden, je höher die Bereitschaft zur Auseinandersetzung mit der Vateridentität, desto mehr Verhaltensaktivitäten werden von dem werdenden Vater während der Schwangerschaft durchgeführt. Ebenso stellte sich heraus, je mehr sich jemand auf die Geburt und das Leben zu Dritt vorbereitet, desto geringer ist seine Überforderung bzw. größer ist seine Bereitschaft und Reflexion bezüglich der zukünftigen Vaterrolle. Auch steigt mit einer intensiven pränatalen Beziehung zum Kind die Auseinandersetzung mit der Vateridentität an. Die Stärke aller gefundenen Zusammenhänge war jedoch sehr gering. Schlussendlich zeigte sich, dass jüngere sowie verheiratete Väter eine höhere Bereitschaft zur Auseinandersetzung mit der Vateridentität aufweisen und Väter, die nicht bei der Geburt dabei sein möchten, offenbar damit überfordert sind.The paternal perspective on pregnancy, birth and parenthood has only recently become the subject of scientific research. Consequently the present work focuses on the subjective experience of expectant fathers during the time of pregnancy, with special regard to their involvement with the father identity. In addition, main influencing factors should be investigated. The development of this evaluation was based on the study "Übergang zur Vaterschaft" by Martin (2008), whereas more representative results should be achieved by recruiting a larger sample. In total, by means of a cross-sectional survey using questionnaires, in the period from June to September 2011, data from 134 expectant fathers, who were between 20 and 45 years old, were obtained. According to the interest of research questions, the survey instrument used was a revised version of the „Fragebogen zur Erfassung der Auseinandersetzung mit der Vateridentität“ constructed by Martin (2008) and the Fragebogen zur Erfassung der Zufriedenheit in der Paarbeziehung (ZIP) of Hassebrauck (1991). The study could not detect any significant effect of the current week of pregnancy on the involvement with the father identity. Likewise, the fact whether the child was planned or not, made no difference to the involvement with the father identity. In contrast, the relationship satisfaction turned out to be important for the paternal idea for reconciling work and family life and for the involvement with the father identity. Moreover it was verified, the higher the willingness to deal with the father identity, the more behavioral activities are carried out by the expectant father during pregnancy. Similarly, the more someone turned out to be prepared for the birth and life with a child, the lower is his excessive demand or greater is his willingness and reflection regarding the future role of father. In addition, it was shown that simultaneously with an intensive prenatal relationship with the child, the involvement with the father identity increases. However, the strength of all correlations found was very low. Finally, it was found that younger and married fathers have a higher willingness to engage with the father identity and fathers who do not want to be present at the birth, are apparently overwhelmed

TEACCH sem verkfæri í stuðningi einhverfra barna og í námi fyrir alla í leikskólanum

Ritgerðin er lokaverkefni til BA-prófs í þroskaþjálfafræði við Deild menntunar og margbreytileika á Menntavísindasviði Háskóla Íslands. Fjallað verður um hugtakið „TEACCH“ sem er skammstöfun og stendur fyrir Treatment and Education of Autistic and related Communication-handicapped CHildren. Rannsóknarspurningin í þessari ritgerð er hvernig TEACCH sem framúrskarandi verkfæri í stuðningi einhverfra barna virkar og hvernig það er sömuleiðis frábær möguleiki í námi fyrir alla í leikskólanum. Áherslan er fyrst og fremst lögð á hugmyndafræðin TEACCH sem er hannað fyrir einhverf börn og verður fjallað um helstu einkenni einhverfurófs og hvernig skipulögð kennsla og sjónræn fyrirmæli henta við kennslu og stuðning með þessum hópi barna. En fremur er lögð áhersla á þarfir allra barna, hvað mikilvægt er að huga að þegar unnið er með margbreytilegan hóp barnanna í leikskólanum og hvernig algild hönnun náms – einnig nefnd altæk hönnun náms – kemur til móts við þau í samspili við skipulagða kennslu. Sýnd verða einnig praktískt dæmi úr vinnuumhverfi höfundar ritgerðar, sem ætlað er að undirstrika hvernig skipulögð kennsla nýtist einhverfum börnum, jafnt sem öðrum börnum. Niðurstaða rannsóknar er að öryggi er mikilvægt skilyrði og grunnvöllur þess að börn nái að blómstra og dafna. Það sem er lífsnauðsynlegt fyrir einhverf börn – að nota sjónrænar aðferðir sem þau eru hæf til að vinna auðveldlega úr til að skilja hvað gerist í umhverfinu og að fylgjast virk með í daglegu ferli – gagnast líka öllum börnum svo allir geta fylgt upplýsingum sjálfstætt og áttað sig á öllu sem gerist og skapar mikið sjálfsöryggi. Þannig er TEACCH framúrskarandi verkfæri í stuðningi einhverfra barna og í námi fyrir alla og er skipulögð kennsla með sjónrænum áherslum bæði góð og nauðsynleg fyrir öll börn í leikskólum

Klimawandel und Migration: Ein konzeptioneller und methodologischer Ansatz am Beispiel Mexikos

Schmidt-Verkerk K. Klimawandel und Migration: Ein konzeptioneller und methodologischer Ansatz am Beispiel Mexikos. In: Felgentreff C, Geiger M, eds. Migration und Umwelt. IMIS Beiträger. Vol 44. Universität Osnabrück: Institut für Migrationsforschung und Interkulturelle Studien (IMIS); 2013