Estimation of Signal Parameters using Deep Convolutional Neural Networks

This paper introduces a Deep Learning approach for signal parameter estimation in the context of wireless channel modeling. Our work is capable of multidimensional parameter estimation from a signal containing an unknown number of paths. The signal parameters are estimated relative to a predefined grid, providing quasi grid-free, hence, more accurate estimates than previous grid-limited approaches. It requires no prior knowledge of the number of paths, giving it an advantage in terms of complexity compared to existing solutions. Along with the description, we provide an initial performance analysis and a comparison with State-of-the-Art techniques and discuss future research directions

TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia

Abstract Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori's protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critically and nonredundantly to H. pylori's tolerizing effects on murine DCs in vitro and in vivo. The tolerance-promoting effects of both factors are independent of their described suppressive activity on T cells. Isogenic H. pylori mutants lacking either GGT or VacA are incapable of preventing LPS-induced DC maturation and fail to drive DC tolerization as assessed by induction of Treg properties in cocultured naive T cells. The Δggt and ΔvacA mutants colonize mice at significantly reduced levels, induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses, and/or trigger more severe gastric pathology. Both factors promote the efficient induction of Tregs in vivo, and VacA is required to prevent allergen-induced asthma. The defects of the Δggt mutant in vitro and in vivo are phenocopied by pharmacological inhibition of the transpeptidase activity of GGT in all readouts. In conclusion, our results reveal the molecular players and mechanistic basis for H. pylori-induced immunomodulation, promoting persistent infection and conferring protection against allergic asthma

Agricultural expansion and the ecological marginalization of forest-dependent people

Agricultural expansion into subtropical and tropical forests causes major environmental damage, but its wider social impacts often remain hidden. Forest-dependent smallholders are particularly strongly impacted, as they crucially rely on forest resources, are typically poor, and often lack institutional support. Our goal was to assess forest-smallholder dynamics in relation to expanding commodity agriculture. Using high-resolution satellite images across the entire South American Gran Chaco, a global deforestation hotspot, we digitize individual forest-smallholder homesteads (n = 23,954) and track their dynamics between 1985 and 2015. Using a Bayesian model, we estimate 28,125 homesteads in 1985 and show that forest smallholders occupy much larger forest areas (>45% of all Chaco forests) than commonly appreciated and increasingly come into conflict with expanding commodity agriculture (18% of homesteads disappeared; n = 5,053). Importantly, we demonstrate an increasing ecological marginalization of forest smallholders, including a substantial forest resource base loss in all Chaco countries and an increasing confinement to drier regions (Argentina and Bolivia) and less accessible regions (Bolivia). Our transferable and scalable methodology puts forest smallholders on the map and can help to uncover the land-use conflicts at play in many deforestation frontiers across the globe. Such knowledge is essential to inform policies aimed at sustainable land use and supply chains.Instituto de Investigación Animal del Chaco SemiáridoFil: Levers, Christian. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Levers, Christian. University of British Columbia. Institute for Resources, Environment and Sustainability; CanadáFil: Levers, Christian. Vrije Universiteit Amsterdam. Department of Environmental Geography. Institute for Environmental Studies; Países BajosFil: Romero Muñoz, Alfredo. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Baumann, Matthias. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: De Marzo, Teresa. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Fernandez, Pedro David. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Fernandez, Pedro David. Universidad Nacional de Tucumán. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; ArgentinaFil: Gasparri, Nestor Ignacio. Universidad Nacional de Tucumán. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; ArgentinaFil: Gavier Pizarro, Gregorio Ignacio. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; ArgentinaFil: de Waroux, Yann le Polain. McGill University. Institute for the Study of International Development. Department of Geography; CanadáFil: Piquer Rodríguez, María. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Piquer Rodríguez, María. Universidad Nacional de Tucumán. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; ArgentinaFil: Piquer Rodríguez, María. Freie Univeristät Berlin. Latinamerika-Institut; AlemaniaFil: Semper Pascual, Asunción. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Semper Pascual, Asunción. Norwegian University of Life Sciences. Faculty of Environmental Sciences and Natural Resource Management; NoruegaFil: Kuemmerle, Tobias. Humboldt-Universität zu Berlin. Geography Department; AlemaniaFil: Kuemmerle, Tobias. Humboldt-University Berlin. Integrative Research Institute on Transformations in Human-Environment Systems; Alemani

TYK2^K923E protein level is reduced and TYK2 differs organ-specifically.

<p>A. WT, <i>Tyk2^−/−</i> and <i>Tyk2^K923E</i> mice were used to prepare whole cell extracts from BMMΦs, T cells and various organs (as indicated). Levels of expression of TYK2 and JAK1 were determined by immunoprecipitation and Western blot analysis. NFκB-p65 was used as input control. TYK2^K923E protein levels were quantified using ImageJ software for Mac OS X (open source, <a href="http://rsb.info.nih.gov/ij/index.html" target="_blank">http://rsb.info.nih.gov/ij/index.html</a>) and were between 13% and 30% in BMMΦs and approximately 58% in T cells compared to WT. B. Total RNA was isolated from WT and <i>Tyk2^K923E</i> BMMΦs and cDNA was used to analyse Tyk2 mRNA expression normalized to the housekeeping gene <i>Ube2D2</i>. Results from 4 independent experiments are shown (n = 6 per genotype). C. BMMΦs were treated with the proteasomal inhibitor MG-132 (50 µM), the autophagy-lysosome inhibitor 3-MA (10 mM) or the lysosome-acidification inhibitor bafilomycin A₁ (80 nM) for the indicated period of time (upper panel), for 11 h (middle panel) or 48 h (lower panel). Whole cell extracts were used to determine TYK2 and JAK1 expression levels by immunoprecipitation and Western blot analysis. As a control, a Western blot for HO-1 was performed. D. From day 5 after isolation of WT BMMΦs, cells were treated with JAK inhibitor I (panJAK inhibitor; 15 nM upper panel and 300 nM lower panel) for the indicated period of time. TYK2 and JAK2 expression levels were analysed as described in (A and C); NFκB-p65 was used as input control.</p

Transcriptional induction of IFN-responsive genes is similar in <i>Tyk2^K923E</i> and <i>Tyk2^−/−</i> cells.

<p>A.-C. WT, <i>Tyk2^−/−</i> and <i>Tyk2^K923E</i> BMMΦs were treated with IFNα (500 U/ml), IFNβ (100 U/ml) or IFNγ (100 U/ml) for 6 h or left untreated. Total RNA was extracted, reverse-transcribed and analysed by RT-qPCR for expression of <i>Oas1a</i>, <i>Ifit1</i> (A), <i>Cxcl1</i>, <i>Socs1</i> (B) and <i>Irf7, Tap1</i> (C). <i>Ube2D2</i> was used for normalization and expression levels were calculated relative to untreated WT cells. Data are derived from three independent experiments and depicted as mean values (+/− SE). D. WT, <i>Tyk2^−/−</i> and <i>Tyk2^K923E</i> BMMΦs were treated with indicated doses of IFNβ for 6 h. Target gene expression was determined as described in A-C. Mean values (+/− SD) derived from two independent experiments are depicted. Note that due to sample size a statistical analysis was not performed.</p