Facilitating Creativity in Collaborative Work with Computational Intelligence Software

The use of computational intelligence for leveraging social creativity is a relatively new approach that allows organizations to find creative solutions to complex problems in which the interaction between stakeholders is crucial. The creative solutions that come from joint thinking-from the combined knowledge and abilities of people with diverse perspectives-contrast with traditional views of creativity that focus primarily on the individual as the main contributor of creativity. In an effort to support social creativity in organizations, in this paper we present computational intelligence software tools for that aim and an architecture for creating software mashups based on the concept of affinity space. The affinity space defines a digital setting to facilitate specific scenarios in collaborative business environments. The solution presented includes a set of free and open source software tools ranging from newly developed brainstorming applications to an expertise recommender for enhancing social creativity in the enterprise. The current paper addresses software design issues and presents reflections on the research work undertaken in the COLLAGE project between 2012 and 2015

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors

Fermented wheat germ extract inhibits glycolysis/pentoses cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T cell leukemia tumor cells

The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC(50) concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide- and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased (13)C incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC(50) (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects

Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells.

BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) involves activation of c-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) signaling, but little is known about the roles of proteins that regulate the activity of oncogenic KRAS. We investigated the activities of proteins that interact with KRAS in PDAC cells. METHODS: We used mass spectrometry to demonstrate that heterogeneous nuclear ribonucleoproteins (HNRNP) A2 and B1 (encoded by the gene HNRNPA2B1) interact with KRAS G12V. We used co-immunoprecipitation analyses to study interactions between HNRNPA2B1 and KRAS in KRAS-dependent and KRAS-independent PDAC cell lines. We knocked down HNRNPA2B1 using small hairpin RNAs and measured viability, anchorage-independent proliferation, and growth of xenograft tumors in mice. We studied KRAS phosphorylation using the Phos-tag system. RESULTS: We found that interactions between HRNPA2B1 and KRAS correlated with KRAS-dependency of some human PDAC cell lines. Knock down of HNRNPA2B1 significantly reduced viability, anchorage-independent proliferation, and formation of xenograft tumors by KRAS-dependent PDAC cells. HNRNPA2B1 knock down also increased apoptosis of KRAS-dependent PDAC cells, inactivated c-akt murine thymoma oncogene homolog 1 signaling via mammalian target of rapamycin, and reduced interaction between KRAS and phosphatidylinositide 3-kinase. Interaction between HNRNPA2B1 and KRAS required KRAS phosphorylation at serine 181. CONCLUSIONS: In KRAS-dependent PDAC cell lines, HNRNPA2B1 interacts with and regulates the activity of KRAS G12V and G12D. HNRNPA2B1 is required for KRAS activation of c-akt murine thymoma oncogene homolog 1-mammalian target of rapamycin signaling, interaction with phosphatidylinositide 3-kinase, and PDAC cell survival and tumor formation in mice. HNRNPA2B1 might be a target for treatment of pancreatic cancer

KRAS phosphorylation regulates cell polarization and tumorigenic properties in colorectal cancer.

Oncogenic mutations of KRAS are found in the most aggressive human tumors, including colorectal cancer. It has been suggested that oncogenic KRAS phosphorylation at Ser181 modulates its activity and favors cell transformation. Using nonphosphorylatable (S181A), phosphomimetic (S181D), and phospho-/dephosphorylatable (S181) oncogenic KRAS mutants, we analyzed the role of this phosphorylation to the maintenance of tumorigenic properties of colorectal cancer cells. Our data show that the presence of phospho-/dephosphorylatable oncogenic KRAS is required for preserving the epithelial organization of colorectal cancer cells in 3D cultures, and for supporting subcutaneous tumor growth in mice. Interestingly, gene expression differed according to the phosphorylation status of KRAS. In DLD-1 cells, CTNNA1 was only expressed in phospho-/dephosphorylatable oncogenic KRAS-expressing cells, correlating with cell polarization. Moreover, lack of oncogenic KRAS phosphorylation leads to changes in expression of genes related to cell invasion, such as SERPINE1, PRSS1,2,3, and NEO1, and expression of phosphomimetic oncogenic KRAS resulted in diminished expression of genes involved in enterocyte differentiation, such as HNF4G. Finally, the analysis, in a public data set of human colorectal cancer, of the gene expression signatures associated with phosphomimetic and nonphosphorylatable oncogenic KRAS suggests that this post-translational modification regulates tumor progression in patients

UTP and ATP increase extracellular signal-regulated kinase 1/2 phosphorylation in bovine chromaffin cells through epidermal growth factor receptor transactivation

Adenosine triphosphate (ATP) is coreleased with catecholamines from adrenal medullary chromaffin cells in response to sympathetic nervous system stimulation and may regulate these cells in an autocrine or paracrine manner. Increases in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation were observed in response to ATP stimulation of bovine chromaffin cells. The signaling pathway involved in ATP-mediated ERK1/2 phosphorylation was investigated via Western blot analysis. ATP and uridine 5′-triphosphate (UTP) increased ERK1/2 phosphorylation potently, peaking between 5 and 15 min. The mitogen-activated protein kinase (MAPK/ERK)-activating kinase (MEK) inhibitor PD98059 blocked this response. UTP, which is selective for G-protein-coupled P2Y receptors, was the most potent agonist among several nucleotides tested. Adenosine 5′-O-(3-thio) triphosphate (ATPγS) and ATP were also potent agonists, characteristic of the P2Y2 or P2Y4 receptor subtypes, whereas agonists selective for P2X receptors or other P2Y receptor subtypes were weakly effective. The receptor involved was further characterized by the nonspecific P2 antagonists suramin and reactive blue 2, which each partially inhibited ATP-mediated ERK1/2 phosphorylation. Inhibitors of protein kinase C (PKC), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and phosphoinositide-3 kinase (PI3K) had no effect on ATP-mediated ERK1/2 phosphorylation. The Src inhibitor PP2, epidermal growth factor receptor (EGFR) inhibitor AG1478, and metalloproteinase inhibitor GM6001 decreased ATP-mediated ERK1/2 phosphorylation. These results suggest nucleotide-mediated ERK1/2 phosphorylation is mediated by a P2Y2 or P2Y4 receptor, which stimulates metalloproteinase-dependent transactivation of the EGFR

SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage

We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO-conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus

Sectoral Differences in Wage Freezes and Wage Cuts : Evidence from a New Firm Survey

The paper provides evidence concerning incidence and sources of nominal wage rigidity in services and manufacturing, using a new and large employer survey on wage and price setting behaviour for Germany. We observe that wage freezes are more frequent in services than in manufacturing, whereas wage cuts are less frequent. The significant sector gaps do not vanish after controlling for relevant firm characteristics influencing the incidence of wage freezes and wage cuts, notably coverage by collective agreements and the degree of price competition on the product market. An analysis of firms’ view on the reasons preventing wage cuts suggests that specific fear of excess worker turnover could explain distinct wage setting behaviour in services

Ultrafast photochemistry produces superbright short-wave infrared dots for low-dose in vivo imaging

12 p.-5 fig.Optical probes operating in the second near-infrared window (NIR-II, 1,000-1,700 nm), where tissues are highly transparent, have expanded the applicability of fluorescence in the biomedical field. NIR-II fluorescence enables deep-tissue imaging with micrometric resolution in animal models, but is limited by the low brightness of NIR-II probes, which prevents imaging at low excitation intensities and fluorophore concentrations. Here, we present a new generation of probes (Ag2S superdots) derived from chemically synthesized Ag2S dots, on which a protective shell is grown by femtosecond laser irradiation. This shell reduces the structural defects, causing an 80-fold enhancement of the quantum yield. PEGylated Ag2S superdots enable deep-tissue in vivo imaging at low excitation intensities (<10 mW cm-2) and doses (<0.5 mg kg-1), emerging as unrivaled contrast agents for NIR-II preclinical bioimaging. These results establish an approach for developing superbright NIR-II contrast agents based on the synergy between chemical synthesis and ultrafast laser processing.Authors thank Dr A. Benayas (CICECO, U. Aveiro, Portugal), Prof G. Lifante and Prof J. García Sole (UAM) for helpful discussions. This work has been founded by Ministerio de Economı́a y Competitividad-MINECO (MAT2017-83111R and MAT2016-75362-C3-1-R) and the Comunidad de Madrid (B2017/BMD-3867 RENIM-CM) co-financed by European Structural and Investment Fund. D.M.-G. thanks UCM-Santander for a predoctoral contract (CT17/17-CT18/17). We thank the staff at the ICTS-National Centre for Electron Microscopy at the UCM for the help in the electron microscopy studies and C.M. at the beamline BL22-CLAESS of the Spanish synchrotron ALBA for his help in the XANES experiments. We also thank J.G.I at the Ultrafast Laser Laboratory at UCM for his help and fruitful discussion. Y.S. acknowledges the support from the China Scholarship Council (CSC File No. 201806870023). Additional funding was provided by the European Commission Horizon 2020 project NanoTBTech, the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP18_38 (2018/0265). Ajoy K. Kar and Mark D. Mackenzie acknowledge support from the UK Engineering and Physical Sciences Research Council (Project CHAMP, EP/M015130/1). C. Jacinto thanks the financial support of the Brazilian agencies: CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) through the grants: Projeto Universal Nr. 431736/2018-9 and Scholarship in Research Productivity 1C under the Nr. 304967/20181; FINEP (Financiadora de Estudos e Projetos) through the grants INFRAPESQ-11 and INFRAPESQ-12; FAPEAL (Fundação de Amparo à Pesquisa do Estado de Alagoas) grant Nr. 1209/2016. H. D. A. Santos was supported by a graduate studentship from CNPq and by a sandwich doctoral program (PDSE-CAPES) developed at Universidad Autonoma de Madrid, Spain, Project Nr. 88881/2016-01.Peer reviewe

Does labour regulation affect technical and allocative efficiency? Evidence from the banking industry

In light of the ongoing restructuring of the European banking industry and the challenging macroeconomic environment, banks have increased their efforts to reduce operating costs. Yet, the institutional features that affect banks’ ability to adjust costs and in particular personnel expenses, which comprise a significant part of banks’ non-interest cost structure, have not been adequately studied. This paper investigates the effect of labour market institutions and regulations on bank performance in 15 European countries over the period 2005-2010, using the Fraser index for labour regulation and its disaggregated sub-components. We propose a novel methodology to measure performance, based on the seminal work of Kumbhakar and Tsionas (2005), which allows the estimation of technical and allocative efficiency and the examination of the effect of labour market regulations in a single stage. Results indicate the existence of a positive relationship between the liberalization of EU labour markets and allocative efficiency, while the effect on technical efficiency appears to be negative, although not statistically significant. When looking at the disaggregated components of the labour index, we further confirm that different forces are at play