"HAART-Attack" bei junger HIV-Patientin

Zusammenfassung: Seit der Einführung der hochaktiven antiretroviralen Therapie (HAART) hat sich die Prognose von Patienten mit einer HIV-Infektion dramatisch verbessert. Morbidität und Mortalität HIV-assoziierter Infektionen konnten reduziert werden. Als Nebenwirkung dieser Therapie sind metabolische Komplikationen bekannt, die eine akzelerierte Atherosklerose mit Auftreten koronarer und zerebrovaskulärer Ereignisse bewirken können. Dies betrifft auch junge Patienten speziell bei Vorliegen zusätzlicher kardiovaskulärer Risikofaktoren. Wir berichten über eine 30-jährige HIV-Patientin mit einem akutem Myokardinfark

Host origin of plastid solute transporters in the first photosynthetic eukaryotes

Analysis of plastid transporter proteins in Arabidopsis suggests a host origin and provides new insights into plastid evolution

C-Terminal regions of topoisomerase IIα and IIβ determine isoform-specific functioning of the enzymes in vivo

Topoisomerase II removes supercoils and catenanes generated during DNA metabolic processes such as transcription and replication. Vertebrate cells express two genetically distinct isoforms (α and β) with similar structures and biochemical activities but different biological roles. Topoisomerase IIα is essential for cell proliferation, whereas topoisomerase IIβ is required only for aspects of nerve growth and brain development. To identify the structural features responsible for these differences, we exchanged the divergent C-terminal regions (CTRs) of the two human isoforms (α 1173-1531 and β 1186-1621) and tested the resulting hybrids for complementation of a conditional topoisomerase IIα knockout in human cells. Proliferation was fully supported by all enzymes bearing the α CTR. The α CTR also promoted chromosome binding of both enzyme cores, and was by itself chromosome-bound, suggesting a role in enzyme targeting during mitosis. In contrast, enzymes bearing the β CTR supported proliferation only rarely and when expressed at unusually high levels. A similar analysis of the divergent N-terminal regions (α 1-27 and β 1-43) revealed no role in isoform-specific functions. Our results show that it is the CTRs of human topoisomerase II that determine their isoform-specific functions in proliferating cells. They also indicate persistence of some functional redundancy between the two isoforms

Deficiency of the Fanconi anemia E2 ubiqitin conjugase UBE2T only partially abrogates Alu-mediated recombination in a new model of homology dependent recombination

The primary function of the UBE2T ubiquitin conjugase is in the monoubiquitination of the FANCI-FANCD2 heterodimer, a central step in the Fanconi anemia (FA) pathway. Genetic inactivation of UBE2T is responsible for the phenotypes of FANCT patients; however, a FANCT patient carrying a maternal duplication and a paternal deletion in the UBE2T loci displayed normal peripheral blood counts and UBE2T protein levels in B-lymphoblast cell lines. To test whether reversion by recombination between UBE2T AluYa5 elements could have occurred in the patient's hematopoietic stem cells despite the defects in homologous recombination (HR) in FA cells, we constructed HeLa cell lines containing the UBE2T AluYa5 elements and neighboring intervening sequences flanked by fluorescent reporter genes. Introduction of a DNA double strand break in the model UBE2T locus in vivo promoted single strand annealing (SSA) between proximal Alu elements and deletion of the intervening color marker gene, recapitulating the reversion of the UBE2T duplication in the FA patient. To test whether UBE2T null cells retain HR activity, the UBE2T genes were knocked out in HeLa cells and U2OS cells. CRISPR/Cas9-mediated genetic knockout of UBE2T only partially reduced HR, demonstrating that UBE2T-independent pathways can compensate for the recombination defect in UBE2T/FANCT null cells

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

The authors would like to thank the Deutsche José Carreras Leukämie-Stiftung, Inocente Inocente Foundation, the Ministry of Economy of Spain (SAF2015- 67919-R), Consejería de Salud de la Junta de Andalucía (Pl-0245-2017, CS2016- 3), BBVA Foundation, Francisco-Cobos Foundation, Fero Foundation and AECC Foundation for funding Pedro P. Medinas’s lab. Álvaro Andrades is supported by an FPU17/00067 PhD fellowship, Alberto M. Arenas is supported by an FPU17/01258 PhD fellowship, Paola Peinado is supported by a La Caixa Foundation PhD Fellowship (LCF/BQ/DE15/10360019), Isabel F. Coira was supported by a PhD FPI-fellowship (BES-2013-064596), Daniel J. García is supported by a Fundación Benéfica Anticáncer Santa Cándida y San Francisco Javier PhD fellowship and Juan Carlos Álvarez-Pérez is supported by a Marie Sklodowska Curie action (H2020-MSCA-IF-2018). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors would also like to thank the Biobanc de l’Hospital Infantil Sant Joan de Déu per a la Investigació, integrated in the Spanish Biobank Network of ISCIII, as well as Asociación Malagueña para la Investigación en Leucemias (AMPILE), for the sample and data procurement

Success Factors of Small and Medium-Sized International Enterprises in the Chinese Market from the Perspective of Polish Direct Investment (Cultural Approach)

Globalization has resulted in increasing transfer of firms operations, regardless of their size, to other countries. The recent dynamic emergence of China in the global economy, connecting with the vast inflows of foreign direct investment in their territory and common adjustments problems of many Western companies, has resulted in growing interest for best suitable business practices to this culturally and socially different environment. In this article, the key factors critical to the success of international companies in this region are introduced, with particular consideration to indigenous cultural elements and specific operation requirements of small and medium-sized enterprises in Business-to-Business sectors. The presented information are based on the broad literature review, five years of direct observation and thirty eight interviews conducted with Polish managers directly residing in China. In addition, some practical recommendations for managers and further research are given.Globalizacja wymusza na firmach, niezależnie od ich wielkości, coraz częstsze przenoszenie operacji do innych krajów. Dynamiczne pojawienie się Chin w światowej gospodarce i szeroki napł;yw zagranicznych inwestycji bezpośrednich na ich teren oraz problemy adaptacyjne wielu zachodnich przedsiębiorstw, spowodował;y zainteresowanie najlepszymi praktykami biznesowymi dostosowanymi do tego odmiennego kulturowo i społ;ecznie otocznia. W artykule zaprezentowane został;y najważniejsze czynnik mające wpł;yw na osiągnięcie sukcesu przez firmy międzynarodowe na tym obszarze, ze szczególnym uwzględnieniem aspektów kulturowych i specyfiki dział;ania mał;ych i średnich podmiotów na rynkach B2B. Prezentowane informacje są oparte na przeglądzie literatury, pięcioletnich obserwacjach bezpośrednich oraz trzydziestu ośmiu wywiadach przeprowadzonych z menadżerami polskich przedsiębiorstw odpowiedzialnymi za operacje w Chinach. Dodatkowo wskazano kilka praktycznych rekomendacji menadżerskich oraz możliwości dalszych badań

Multilayer Modelling of Lubricated Contacts: A New Approach Based on a Potential Field Description

A first integral approach, derived in an analogous fashion to Maxwell’s use of potential fields, is employed to investigate the flow characteristics, with a view to minimising friction, of shear-driven fluid motion between rigid surfaces in parallel alignment as a model for a lubricated joint, whether naturally occurring or engineered replacement. For a viscous bilayer arrangement comprised of immiscible liquids, it is shown how the flow and the shear stress along the separating interface is influenced by the mean thickness of the layers and the ratio of their respective viscosities. Considered in addition, is how the method can be extended for application to the more challenging problem of when one, or both, of the layers is a viscoelastic material

Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD-program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical and virological data from 4,140 antiretroviral-naive HIV-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002-2007. Baseline susceptibility to antiretroviral drugs was predicted using Stanford HIVdb v7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95%CI 7.2-9.5) in 2008-2010. The most frequent indicators of TDR were NRTI-mutations (4.5%), followed by NNRTI-mutations (2.9%) and PI-mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affecte

HIV-1 Infection in Cyprus, the Eastern Mediterranean European Frontier: A Densely Sampled Transmission Dynamics Analysis from 1986 to 2012

Since HIV-1 treatment is increasingly considered an effective preventionstrategy, it is important to study local HIV-1 epidemics to formulate tailored preventionpolicies. The prevalence of HIV-1 in Cyprus was historically low until 2005. To investigatethe shift in epidemiological trends, we studied the transmission dynamics of HIV-1 in Cyprususing a densely sampled Cypriot HIV-1 transmission cohort that included 85 percent ofHIV-1-infected individuals linked to clinical care between 1986 and 2012 based on detailedclinical, epidemiological, behavioral and HIV-1 genetic information. Subtyping andtransmission cluster reconstruction were performed using maximum likelihood and Bayesianmethods, and the transmission chain network was linked to the clinical, epidemiological andbehavioral data. The results reveal that for the main HIV-1 subtype A1 and B sub-epidemics,young and drug-naïve HIV-1-infected individuals in Cyprus are driving the dynamics of thelocal HIV-1 epidemic. The results of this study provide a better understanding of thedynamics of the HIV-1 infection in Cyprus, which may impact the development of preventionstrategies. Furthermore, this methodology for analyzing densely sampled transmissiondynamics is applicable to other geographic regions to implement effective HIV-1 preventionstrategies in local settings