Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.

Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.HUVR-IBiS Biobanco del Sistema Sanitario Público de Andalucía y ISCIII-Red de Biobancos [PT13/0010/0056].FEDER from Regional Development European Funds (European Union), Ministerio de Economía y Competitividad, Plan Nacional de I+D+I 2008-2011, Plan Estatal de I+D+i 2013-2016, ISCIII [Fis: PI12/00137, PI13/02295, PI15/00045, RTICC: RD12/0036/0028].Consejería de Ciencia e Innovación [CTS-1848] y Consejería de Salud de la Junta de Andalucía [PI-0306-2012, PI-0096-2014]

CryoEM and stability analysis of virus-like particles of potyvirus and ipomovirus infecting a common host

Sweet potato feathery mottle virus (SPFMV) and Sweet potato mild mottle virus (SPMMV) are members of the genera Potyvirus and Ipomovirus, family Potyviridae, sharing Ipomoea batatas as common host, but transmitted, respectively, by aphids and whiteflies. Virions of family members consist of flexuous rods with multiple copies of a single coat protein (CP) surrounding the RNA genome. Here we report the generation of virus-like particles (VLPs) by transient expression of the CPs of SPFMV and SPMMV in the presence of a replicating RNA in Nicotiana benthamiana. Analysis of the purified VLPs by cryo-electron microscopy, gave structures with resolutions of 2.6 and 3.0 Å, respectively, showing a similar left-handed helical arrangement of 8.8 CP subunits per turn with the C-terminus at the inner surface and a binding pocket for the encapsidated ssRNA. Despite their similar architecture, thermal stability studies reveal that SPMMV VLPs are more stable than those of SPFMV

Extreme Floods in Small Mediterranean Catchments: Long-Term Response to Climate Variability and Change

Climate change implies changes in the frequency and magnitude of flood events. The influence of climate variability on flooding was evaluated by an analysis of sedimentary (palaeofloods) and documentary archives. A 500-year palaeoflood record at Montilea River (657 km(2) in catchment area), eastern Spain, revealed up to 31 palaeofloods with a range of discharges of 20-950 m(3) s(-1), and with at least five floods exceeding 740-950 m(3) s(-1). This information contrasts with the available gauged flood registers (since year 1971) with an annual maximum daily discharge of 129 m(3) s(-1). Our palaeoflood dataset indicates flood cluster episodes at (1) 1570-1620, (2) 1775-1795, (3) 1850-1890, and (4) 1920-1969. Flood rich periods 1 and 3 corresponded to cooler than usual (about 0.3 degrees C and 0.2 degrees C) climate oscillations, whereas 2 and 4 were characterised by higher inter-annual climatic variability (floods and droughts). This high inter-annual rainfall variability increased over the last 150 years, leading to a reduction of annual maximum flow. Flood quantiles (>50 years) calculated from palaeoflood+gauged data showed 30%-40% higher peak discharges than those using only instrumental records, whereas when increasing the catchment area (1500 km(2)) the discharge estimation variance decreased to-15%. The results reflect the higher sensitivity of small catchments to changes on flood magnitude and frequency due to climate variability whereas a larger catchment buffers the response due to the limited extent of convective storms. Our findings show that extended flood records provide robust knowledge about hazardous flooding that can assist in the prioritization of low-regret actions for flood-risk adaptation to climate change

Morphological Evolution of Spiders Predicted by Pendulum Mechanics

[Background] Animals have been hypothesized to benefit from pendulum mechanics during suspensory locomotion, in which the potential energy of gravity is converted into kinetic energy according to the energy-conservation principle. However, no convincing evidence has been found so far. Demonstrating that morphological evolution follows pendulum mechanics is important from a biomechanical point of view because during suspensory locomotion some morphological traits could be decoupled from gravity, thus allowing independent adaptive morphological evolution of these two traits when compared to animals that move standing on their legs; i.e., as inverted pendulums. If the evolution of body shape matches simple pendulum mechanics, animals that move suspending their bodies should evolve relatively longer legs which must confer high moving capabilities.[Methodology/Principal Findings] We tested this hypothesis in spiders, a group of diverse terrestrial generalist predators in which suspensory locomotion has been lost and gained a few times independently during their evolutionary history. In spiders that hang upside-down from their webs, their legs have evolved disproportionately longer relative to their body sizes when compared to spiders that move standing on their legs. In addition, we show how disproportionately longer legs allow spiders to run faster during suspensory locomotion and how these same spiders run at a slower speed on the ground (i.e., as inverted pendulums). Finally, when suspensory spiders are induced to run on the ground, there is a clear trend in which larger suspensory spiders tend to run much more slowly than similar-size spiders that normally move as inverted pendulums (i.e., wandering spiders).[Conclusions/Significance] Several lines of evidence support the hypothesis that spiders have evolved according to the predictions of pendulum mechanics. These findings have potentially important ecological and evolutionary implications since they could partially explain the occurrence of foraging plasticity and dispersal constraints as well as the evolution of sexual size dimorphism and sociality.This paper has been written under a Ramón y Cajal research contract from the Spanish Ministry of Science and Culture (MEC) to JML and a FPI scholarship (BES-2005-9234) to GC. This work has been funded by MEC grants CGL2004-03153 and CGL2007-60520 to JML and GC, as well as CGL2005-01771 to EMPeer reviewe

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Moku virus; a new Iflavirus found in wasps, honey bees and Varroa

There is an increasing global trend of emerging infectious diseases (EIDs) affecting a wide range of species, including honey bees. The global epidemic of the single stranded RNA Deformed wing virus (DWV), driven by the spread of Varroa destructor has been well documented. However, DWV is just one of many insect RNA viruses which infect a wide range of hosts. Here we report the full genome sequence of a novel Iflavirus named Moku virus (MV), discovered in the social wasp Vespula pensylvanica collected in Hawaii. The novel genome is 10,056 nucleotides long and encodes a polyprotein of 3050 amino acids. Phylogenetic analysis showed that MV is most closely related to Slow bee paralysis virus (SBPV), which is highly virulent in honey bees but rarely detected. Worryingly, MV sequences were also detected in honey bees and Varroa from the same location, suggesting that MV can also infect other hymenopteran and Acari hosts

A Replicating Viral Vector Greatly Enhances Accumulation of Helical Virus-Like Particles in Plants

The production of plant helical virus-like particles (VLPs) via plant-based expression has been problematic with previous studies suggesting that an RNA scaffold may be necessary for their efficient production. To examine this, we compared the accumulation of VLPs from two potexviruses, papaya mosaic virus and alternanthera mosaic virus (AltMV), when the coat proteins were expressed from a replicating potato virus X- based vector (pEff) and a non-replicating vector (pEAQ-HT). Significantly greater quantities of VLPs could be purified when pEff was used. The pEff system was also very efficient at producing VLPs of helical viruses from different virus families. Examination of the RNA content of AltMV and tobacco mosaic virus VLPs produced from pEff revealed the presence of vector-derived RNA sequences, suggesting that the replicating RNA acts as a scaffold for VLP assembly. Cryo-EM analysis of the AltMV VLPs showed they had a structure very similar to that of authentic potexvirus particles. Thus, we conclude that vectors generating replicating forms of RNA, such as pEff, are very efficient for producing helical VLPs