A Novel Requirement for Janus Kinases as Mediators of Drug Resistance Induced by Fibroblast Growth Factor-2 in Human Cancer Cells

The development of resistance to chemotherapy is a major cause of cancer-related death. Elucidating the mechanisms of drug resistance should thus lead to novel therapeutic strategies. Fibroblast growth factor (FGF)-2 signaling induces the assembly of a multi-protein complex that provides tumor cells with the molecular machinery necessary for drug resistance. This complex, which involves protein kinase C (PKC) ε, v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) and p70 S6 kinase β (S6K2), enhances the selective translation of anti-apoptotic proteins such as B-cell leukaemia/lymphoma-2 (BCL-2) and inhibitors of apoptosis protein (IAP) family members and these are able to protect multiple cancer cell types from chemotherapy-induced cell death. The Janus kinases (JAKs) are most noted for their critical roles in mediating cytokine signaling and immune responses. Here, we show that JAKs have novel functions that support their consideration as new targets in therapies aimed at reducing drug resistance. As an example, we show that the Janus kinase TYK2 is phosphorylated downstream of FGF-2 signaling and required for the full phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, TYK2 is necessary for the induction of key anti-apoptotic proteins, such as BCL-2 and myeloid cell leukemia sequence (MCL) 1, and for the promotion of cell survival upon FGF-2. Silencing JAK1, JAK2 or TYK2 using RNA interference (RNAi) inhibits FGF2-mediated proliferation and results in the sensitization of tumor cells to chemotherapy-induced killing. These effects are independent of activation of signal transducer and activator of transcription (STAT) 1, STAT3 and STAT5A/B, the normal targets of JAK signaling. Instead, TYK2 associates with the other kinases previously implicated in FGF-2-mediated drug resistance. In light of these findings we hypothesize that TYK2 and other JAKs are important modulators of FGF-2-driven cell survival and that inhibitors of these kinases will likely improve the effectiveness of other cancer therapies

Use of domesticated pigs by Mesolithic hunter-gatherers in northwestern Europe

Acknowledgements We thank the Archaeological State Museum Schleswig-Holstein, the Archaeological State Offices of Brandenburg, Lower Saxony and Saxony and the following individuals who provided sample material: Betty Arndt, Jo¨rg Ewersen, Frederick Feulner, Susanne Hanik, Ru¨diger Krause, Jochen Reinhard, Uwe Reuter, Karl-Heinz Ro¨hrig, Maguerita Scha¨fer, Jo¨rg Schibler, Reinhold Schoon, Regina Smolnik, Thomas Terberger and Ingrid Ulbricht. We are grateful to Ulrich Schmo¨lcke, Michael Forster, Peter Forster and Aikaterini Glykou for their support and comments on the manuscript. We also thank many institutions and individuals that provided sample material and access to collections, especially the curators of the Museum fu¨r Naturkunde, Berlin; Muse´um National d0 Histoire Naturelle, Paris; Smithsonian Institution, National Museum of Natural History, Washington D.C.; Zoologische Staatssammlung, Mu¨nchen; Museum fu¨r Haustierkunde, Halle; the American Museum of Natural History, New-York. This work was funded by the Graduate School ‘Human Development in Landscapes’ at Kiel University (CAU) and supported by NERC project Grant NE/F003382/1. Radiocarbon dating was carried out at the Leibniz Laboratory, CAU. This work is licensed under a Creative Commons AttributionNonCommercial-NoDerivs 3.0 Unported License.Peer reviewedPublisher PD

Multiplexed immunosensors for point-of-care diagnostic applications

Accurate, reliable, and cost-effective immunosensors are clinically important for the early diagnosis and monitoring of progressive diseases, and multiplexed sensing is a promising strategy for the next generation of diagnostics. This strategy allows for the simultaneous detection and quantification of multiple biomarkers with significantly enhanced reproducibility and reliability, whilst requiring smaller sample volumes, fewer materials, and shorter average analysis time for individual biomarkers than individual tests. In this opinionated review, we compare different techniques for the development of multiplexed immunosensors. We review the state-of-the-art approaches in the field of multiplexed immunosensors using electrical, electrochemical, and optical methods. The barriers that prevent translating this sensing strategy into clinics are outlined together with the potential solutions. We also share our vision on how multiplexed immunosensors will continue their evolution in the coming years

The Effects of Aphid Traits on Parasitoid Host Use and Specialist Advantage

Specialization is a central concept in ecology and one of the fundamental properties of parasitoids. Highly specialized parasitoids tend to be more efficient in host-use compared to generalized parasitoids, presumably owing to the trade-off between host range and hostuse efficiency. However, it remains unknown how parasitoid host specificity and host-use depends on host traits related to susceptibility to parasitoid attack. To address this question, we used data from a 13-year survey of interactions among 142 aphid and 75 parasitoid species in nine European countries. We found that only aphid traits related to local resource characteristics seem to influence the trade-off between host-range and efficiency: more specialized parasitoids had an apparent advantage (higher abundance on shared hosts) on aphids with sparse colonies, ant-attendance and without concealment, and this was more evident when host relatedness was included in calculation of parasitoid specificity. More traits influenced average assemblage specialization, which was highest in aphids that are monophagous, monoecious, large, highly mobile (easily drop from a plant), without myrmecophily, habitat specialists, inhabit non-agricultural habitats and have sparse colonies. Differences in aphid wax production did not influence parasitoid host specificity and host-use. Our study is the first step in identifying host traits important for aphid parasitoid host specificity and host-use and improves our understanding of bottom-up effects of aphid traits on aphid-parasitoid food web structure

A valley-spin qubit in a carbon nanotube

Although electron spins in III-V semiconductor quantum dots have shown great promise as qubits, a major challenge is the unavoidable hyperfine decoherence in these materials. In group IV semiconductors, the dominant nuclear species are spinless, allowing for qubit coherence times that have been extended up to seconds in diamond and silicon. Carbon nanotubes are a particularly attractive host material, because the spin-orbit interaction with the valley degree of freedom allows for electrical manipulation of the qubit. In this work, we realise such a qubit in a nanotube double quantum dot. The qubit is encoded in two valley-spin states, with coherent manipulation via electrically driven spin resonance (EDSR) mediated by a bend in the nanotube. Readout is performed by measuring the current in Pauli blockade. Arbitrary qubit rotations are demonstrated, and the coherence time is measured via Hahn echo. Although the measured decoherence time is only 65 ns in our current device, this work offers the possibility of creating a qubit for which hyperfine interaction can be virtually eliminated

Pleosporales

One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae

Modes of Foreign Entry under Asymmetric Information about Potential Technology Spillovers

This paper studies the effect of technology spillovers on the entry decision of a multinational enterprise into a foreign market. Two alternative entry modes for a foreign direct investment are considered: Greenfield investment versus acquisition. We find that with quantity competition a spillover makes acquisitions less attractive, while with price competition acquisitions become more attractive. Asymmetric information about potential spillovers always reduces the number of acquisitions independently of whether the host country or the entrant has private information. Interestingly, we find that asymmetric information always hurts the entrant, while it sometimes is in favor of the host country

The quest for stellar coronal mass ejections in late-type stars: I. Investigating Balmer-line asymmetries of single stars in Virtual Observatory data

Context. Flares and coronal mass ejections (CMEs) can have deleterious effects on their surroundings: they can Erode or completely destroy atmospheres of orbiting planets over time and also have high importance in stellar evolution. Most of the CME detections in the literature are single events found serendipitously sparse for statistical investigation. Aims. We aimed to gather a large amount of spectral data of M-dwarfs to drastically increase the number of known events to make statistical analysis possible in order to study the properties of potential stellar CMEs. Methods. Using archival spectral data we investigated asymmetric features of Balmer-lines, which could indicate the Doppler-signature of ejected material. Results. Of more than 5500 spectra we find 478 that have line asymmetries - including nine larger events, in terms of velocity and mass - on 25 objects, with 1.2-19.6 events per day on objects with line asymmetries. Most events are connected with enhanced peaks of Balmer-lines, indicating that these are connected to flares similar to solar events. In most cases the detected speed does not reach surface escape velocity: the typical observed maximum velocities are on the order of 100-300 km s -1 , while the typical masses of the ejecta were on the order of 10 15 -10 18 g. Statistical analysis of the events suggests that these events are more frequent on cooler stars with stronger chromospheric activity. Conclusions. If the detected events correspond to CMEs, the detected maximum velocities are lower than those observed on the Sun, while event rates were somewhat lower than we could expect from the solar case. If the velocities are not distorted significantly due to a projection effect, these findings may support the idea that most of the coronal mass ejections could be suppressed by a strong magnetic field. Alternatively, it is possible that we can observe only an early low-coronal phase of the events before being accelerated at higher altitudes. Our findings could indicate that later-type, active dwarfs could be a safer environment for exoplanetary systems CME-wise than previously thought, and atmosphere loss due to radiation effects would play a stronger role in exoplanetary atmosphere evolution than CMEs

Regional Genetic Structure in the Aquatic Macrophyte Ruppia cirrhosa Suggests Dispersal by Waterbirds

The evolutionary history of the genus Ruppia has been shaped by hybridization, polyploidisation and vicariance that have resulted in a problematic taxonomy. Recent studies provided insight into species circumscription, organelle takeover by hybridization, and revealed the importance of verifying species identification to avoid distorting effects of mixing different species, when estimating population connectivity. In the present study, we use microsatellite markers to determine population diversity and connectivity patterns in Ruppia cirrhosa including two spatial scales: (1) from the Atlantic Iberian coastline in Portugal to the Siculo-Tunisian Strait in Sicily and (2) within the Iberian Peninsula comprising the Atlantic-Mediterranean transition. The higher diversity in the Mediterranean Sea suggests that populations have had longer persistence there, suggesting a possible origin and/or refugial area for the species. The high genotypic diversities highlight the importance of sexual reproduction for survival and maintenance of populations. Results revealed a regional population structure matching a continent-island model, with strong genetic isolation and low gene flow between populations. This population structure could be maintained by waterbirds, acting as occasional dispersal vectors. This information elucidates ecological strategies of brackish plant species in coastal lagoons, suggesting mechanisms used by this species to colonize new isolated habitats and dominate brackish aquatic macrophyte systems, yet maintaining strong genetic structure suggestive of very low dispersal.Fundacao para a Cincia e Tecnologia (FCT, Portugal) [PTDC/MAR/119363/2010, BIODIVERSA/0004/2015, UID/Multi/04326/2013]Pew FoundationSENECA FoundationMurcia Government, Spain [11881/PI/09]FCT Investigator Programme-Career Development [IF/00998/2014]Spanish Ministry of Education [AP2008-01209]European Community [00399/2012]info:eu-repo/semantics/publishedVersio

How managers can build trust in strategic alliances: a meta-analysis on the central trust-building mechanisms

Trust is an important driver of superior alliance performance. Alliance managers are influential in this regard because trust requires active involvement, commitment and the dedicated support of the key actors involved in the strategic alliance. Despite the importance of trust for explaining alliance performance, little effort has been made to systematically investigate the mechanisms that managers can use to purposefully create trust in strategic alliances. We use Parkhe’s (1998b) theoretical framework to derive nine hypotheses that distinguish between process-based, characteristic-based and institutional-based trust-building mechanisms. Our meta-analysis of 64 empirical studies shows that trust is strongly related to alliance performance. Process-based mechanisms are more important for building trust than characteristic- and institutional-based mechanisms. The effects of prior ties and asset specificity are not as strong as expected and the impact of safeguards on trust is not well understood. Overall, theoretical trust research has outpaced empirical research by far and promising opportunities for future empirical research exist