Western visitors at the Blätterhöhle (city of Hagen, southern Westphalia) during the Younger Dryas? A new final palaeolithic assemblage type in western Germany

Until now, it was considered certain that the last reindeer hunters of the Ahrensburgian (tanged point groups) existed exclusively in northwestern Central Europe during the Younger Dryas Cold Period (~ Greenland Stadial 1). The excavations carried out since 2006 on the forecourt (Vorplatz) of the small Blätterhöhle in Hagen on the northern edge of the Sauerland uplands of southern Westphalia (North Rhine-Westphalia, western Germany) have now changed this view. Beneath a surprisingly extensive sequence of Mesolithic find horizons, Pleistocene sediments could be reached whose excavations yielded a Final Palaeolithic lithic ensemble of the Younger Dryas, unusual for the region and beyond. It is characterised by numerous backed lithic projectile points of high variability. Comparisons suggest a typological-technological connection with the Western European Laborian / Late Laborian. Neither in the nearer nor in the wider surroundings has a comparable lithic find ensemble been found so far. In addition, there is a lack of clear evidence for the reindeer in the fauna. Surprisingly, the vast majority of radiocarbon dates of bones and charcoals from the investigated archaeological horizon of the Final Pleistocene proved to be significantly older than expected from their stratigraphic position. This phenomenon has not yet been clarified

Cueva de Ardales, Province of Malaga

Artículo recopilatorio sobre los principales hallazgos y descubrimientos llevados a cabo en la Cueva de Ardales

miR-34a as hub of T cell regulation networks

Background: Micro(mi)RNAs are increasingly recognized as central regulators of immune cell function. While it has been predicted that miRNAs have multiple targets, the majority of these predictions still await experimental confirmation. Here, miR-34a, a well-known tumor suppressor, is analyzed for targeting genes involved in immune system processes of leucocytes. Methods: Using an in-silico approach, we combined miRNA target prediction with GeneTrail2, a web tool for Multi-omics enrichment analysis, to identify miR-34a target genes, which are involved in the immune system process subcategory of Gene Ontology. Results: Out of the 193 predicted target genes in this subcategory we experimentally tested 22 target genes and confirmed binding of miR-34a to 14 target genes including VAMP2, IKBKE, MYH9, MARCH8, KLRK1, CD11A, TRAFD1, CCR1, PYDC1, PRF1, PIK3R2, PIK3CD, AP1B1, and ADAM10 by dual luciferase assays. By transfecting Jurkat, primary CD4+ and CD8+ T cells with miR-34a, we demonstrated that ectopic expression of miR-34a leads to reduced levels of endogenous VAMP2 and CD11A, which are central to the analyzed subcategories. Functional downstream analysis of miR-34a over-expression in activated CD8+ T cells exhibits a distinct decrease of PRF1 secretion. Conclusions: By simultaneous targeting of 14 mRNAs miR-34a acts as major hub of T cell regulatory networks suggesting to utilize miR-34a as target of intervention towards a modulation of the immune responsiveness of T-cells in a broad tumor context

Degenerations of Jordan Superalgebras

We describe degenerations of three-dimensional Jordan superalgebras over $\mathbb{C}$. In particular, we describe all irreducible components in the corresponding varieties.Comment: arXiv admin note: text overlap with arXiv:1611.0645

Wrinkle in the plan: miR-34a-5p impacts chemokine signaling by modulating CXCL10/CXCL11/CXCR3-axis in CD4+, CD8+ T cells, and M1 macrophages

Background In 2016 the first-in-human phase I study of a miRNA-based cancer therapy with a liposomal mimic of microRNA-34a-5p (miR-34a-5p) was closed due to five immune related serious adverse events (SAEs) resulting in four patient deaths. For future applications of miRNA mimics in cancer therapy it is mandatory to unravel the miRNA effects both on the tumor tissue and on immune cells. Here, we set out to analyze the impact of miR-34a-5p over-expression on the CXCL10/CXCL11/CXCR3 axis, which is central for the development of an effective cancer control. Methods We performed a whole genome expression analysis of miR-34a-5p transfected M1 macrophages followed by an over-representation and a protein–protein network analysis. In-silico miRNA target prediction and dual luciferase assays were used for target identification and verification. Target genes involved in chemokine signaling were functionally analyzed in M1 macrophages, CD4+ and CD8+ T cells. Results A whole genome expression analysis of M1 macrophages with induced miR-34a-5p over-expression revealed an interaction network of downregulated target mRNAs including CXCL10 and CXCL11. In-silico target prediction in combination with dual luciferase assays identified direct binding of miR-34a-5p to the 3′UTRs of CXCL10 and CXCL11. Decreased CXCL10 and CXCL11 secretion was shown on the endogenous protein level and in the supernatant of miR-34a-5p transfected and activated M1 macrophages. To complete the analysis of the CXCL10/CXCL11/CXCR3 axis, we activated miR-34a-5p transfected CD4+ and CD8+ T cells by PMA/Ionomycin and found reduced levels of endogenous CXCR3 and CXCR3 on the cell surface. Conclusions MiR-34a-5p mimic administered by intravenous administration will likely not only be up-taken by the tumor cells but also by the immune cells. Our results indicate that miR-34a-5p over-expression leads in M1 macrophages to a reduced secretion of CXCL10 and CXCL11 chemokines and in CD4+ and CD8+ T cells to a reduced expression of CXCR3. As a result, less immune cells will be attracted to the tumor site. Furthermore, high levels of miR-34a-5p in naive CD4+ T cells can in turn hinder Th1 cell polarization through the downregulation of CXCR3 leading to a less pronounced activation of cytotoxic T lymphocytes, natural killer, and natural killer T cells and possibly contributing to lymphocytopenia

La Cueva de la Güelga: (Cangas de Oní­s, Asturias)

Depto. de Prehistoria, Historia Antigua y ArqueologíaFac. de Geografía e HistoriaTRUEpu

Site formation and chronology of the new Paleolithic site Sima de Las Palomas de Teba, southern Spain

The newly identified Paleolithic site Sima de Las Palomas de Teba hosts an almost seven -m-thick sediment profile investigated here to elucidate the rock shelter's chronostratigraphy and formation processes. At its base, the sediment sequence contains rich archeological deposits recording intensive occupation by Neanderthals. Luminescence provides a terminus ante quem of 39.4 ± 2.6 ka or 44.9 ± 4.1 ka (OSL) and 51.4 ± 8.4 ka (TL). This occupation ended with a rockfall event followed by accumulation of archeologically sterile sediments. These were covered by sediments containing few Middle Paleolithic artifacts, which either indicate ephemeral occupation by Neanderthals or reworking as suggested by micromorphological features. Above this unit, scattered lithic artifacts of undiagnostic character may represent undefined Paleolithic occupations. Sediment burialagesbetweenabout23.0±1.5ka(OSL)and40.5±3.4ka(pIRIR)provideanUpperPaleolithicchronology for sediments deposited above the rockfall. Finally, a dung-bearing Holocene layer in the upper most part of the sequence contains a fragment of a human mandible dated to 4032 ± 39 14C yr BP. Overall, the sequence represents an important new site for studying the end of Neanderthal occupation in southern Spain

Quantitative and time-resolved miRNA pattern of early human T cell activation

T cells are central to the immune response against various pathogens and cancer cells. Complex networks of transcriptional and post-transcriptional regulators, including microRNAs (miRNAs), coordinate the T cell activation process. Available miRNA datasets, however, do not sufficiently dissolve the dynamic changes of miRNA controlled networks upon T cell activation. Here, we established a quantitative and time-resolved expression pattern for the entire miRNome over a period of 24 h upon human Tcell activation. Based on our time-resolved datasets, we identified central miRNAs and specified common miRNA expression profiles. We found the most prominent quantitative expression changes for miR155-5p with a range from initially 40 molecules/cell to 1600 molecules/cell upon T-cell activation. We established a comprehensive dynamic regulatory network of both the up- and downstream regulation of miR155. Upstream, we highlight IRF4 and its complexes with SPI1 and BATF as central for the transcriptional regulation of miR-155. Downstream of miR-155-5p, we verified 17 of its target genes by the time-resolved data recorded after T cell activation. Our data provide comprehensive insights into the range of stimulus induced miRNA abundance changes and lay the ground to identify efficient points of intervention for modifying the T cell response

GeneTrail 3: advanced high-throughput enrichment analysis

We present GeneTrail 3, a major extension of our web service GeneTrail that offers rich functionality for the identification, analysis, and visualization of deregulated biological processes. Our web service provides a comprehensive collection of biological processes and signaling pathways for 12 model organisms that can be analyzed with a powerful framework for enrichment and network analysis of transcriptomic, miRNomic, proteomic, and genomic data sets. Moreover, GeneTrail offers novel workflows for the analysis of epigenetic marks, time series experiments, and single cell data. We demonstrate the capabilities of our web service in two case-studies, which highlight that GeneTrail is well equipped for uncovering complex molecular mechanisms. GeneTrail is freely accessible at: http://genetrail.bioinf.uni-sb.de

Changes of Protein Expression after CRISPR/Cas9 Knockout of miRNA-142 in Cell Lines Derived from Diffuse Large B-Cell Lymphoma

Background: As microRNA-142 (miR-142) is the only human microRNA gene where mutations have consistently been found in about 20% of all cases of diffuse large B-cell lymphoma (DLBCL), we wanted to determine the impact of miR-142 inactivation on protein expression of DLBCL cell lines. Methods: miR-142 was deleted by CRISPR/Cas9 knockout in cell lines from DLBCL. Results: By proteome analyses, miR-142 knockout resulted in a consistent up-regulation of 52 but also down-regulation of 41 proteins in GC-DLBCL lines BJAB and SUDHL4. Various mitochondrial ribosomal proteins were up-regulated in line with their pro-tumorigenic properties, while proteins necessary for MHC-I presentation were down-regulated in accordance with the finding that miR-142 knockout mice have a defective immune response. CFL2, CLIC4, STAU1, and TWF1 are known targets of miR-142, and we could additionally confirm AKT1S1, CCNB1, LIMA1, and TFRC as new targets of miR-142-3p or -5p. Conclusions: Seed-sequence mutants of miR-142 confirmed potential targets and novel targets of miRNAs can be identified in miRNA knockout cell lines. Due to the complex contribution of miRNAs within cellular regulatory networks, in particular when miRNAs highly present in RISC complexes are replaced by other miRNAs, primary effects on gene expression may be covered by secondary layers of regulation