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Amyloid-beta (Abeta) peptide deposits and hyperphosphorylated tau protein (phospho-tau) accumulate in Alzheimer's disease (AD) brains. These abnormal protein aggregates leads to glial activation, synaptic dysfunction, neuronal loss and cognitive decline. While microglial response has mostly been analyzed in relation to Abeta accumulation, little is still known about inflammatory processes associated with tau pathology. Microglial reactivity and defective glial responses have been involved in these proteinopathies. Our aim is to clarify the effects of Abeta and tau separately, in order to improve the comprehension of their differential contribution to neuroinflammation and neurodegeneration. We compared the progression of these processes in an amyloidogenic AD model (APPSL/PS1M146L) and two different models of tauopathy (ThyTau22 and hP301S) from 2 to 18 months of age. Accumulation of aggregated proteins was assessed using specific anti- Abeta and phospho-tau antibodies. Inflammatory response was studied using a battery of microglial markers (Iba1, CD45, CD68, Trem2 and Gal-3). In the hippocampus of these models, Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Neuritic plaques induced a strong microglial activation associated to plaques in APP/PS1 mice. Interestingly, inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to not only APP/PS1, but also to P301S mice, which displayed a prominent microglial response. Deciphering the specific effects of Abeta, tau and their different toxic species, would indeed enable the development of novel therapeutic strategies and drugs targeting neuroinflammatory pathways related to these proteinopathies. ; Universidad de Málaga. Campus de excelencia Andalucía-Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and by grant PPIT.UMA.B1.2017/26 (RS-V).

Since it has been imposed in the academic and public debate, social innovation constitutes an ambivalent concept. However, many interpretations agree on the positive relationship between bottom-up processes and institutional learning.In marginal contexts, practices of collective activation are often weak, evanescent and they remain into the informal domain due to the scarcity of cultural, political and economic resources of the agents, with very few possibilities of affecting the institutional level. Researching on social innovation and community-based planning in the perspective of marginal populations requires to not overestimate the capacity of the inhabitants to activate. On the contrary, intermediary actors and networks could carry out a strategic role in leading community-based planning processes.The paper aims at reflecting on the political and territorial implications of community planning processes in two public housing neighbourhoods in the city of Milan - San Siro and Giambellino - where the third sector organizations, promoting neighbourhood networks, started claiming for urban regeneration. Gathering together professionals, activists and inhabitants, they play a twofold role of service providers and representatives of the inhabitants.Analysing these processes in the framework of the transformation of welfare provision at the local level, what worth to notice is that community processes impact on the participant's life and professional paths, more than on the neighbourhoods.Associating a policy analysis approach with the qualitative network analysis of social relations and biographic paths of some of the members of these networks, common patterns of activation and engagement seem to emerge.In conclusion, the paper reflects on communitybased planning and social innovation in marginal neighbourhoods starting from the recognition of new roles that are redefining the meaning of these processes and the perspectives of institutional change.

Until now, the general construction of the plasticizing system has assumed placing the screw in a fixed barrel. However, at the end of the 20th century, a completely new concept of the design of an extruder was put forward, which had never been used before in the industry or in experimental machines. This new solution consisted in kinematic activation of the barrel itself, which meant it could rotate in the direction identical or opposite to the direction of screw rotation. So far, several design solutions concerning kinematic activation of the barrel of the plasticizing system have been proposed. The idea of this solution is presented in the picture. As a result of the implementation of the international NEWEX project within H2020-MSCA-RISE several new construction concepts were developed for which CAD models were created using the SolidWorks programme. All CAD models were made in such a way that they could constitute the modification of W-25 single-screw extruder, and all of them present a classic or modified screw placed in the barrel plasticizing system, therefore screw diameter D equals 25 mm. The joint length of rotational barrel elements equals 4D. The main reason for using such constructional solutions is the intensification of the mixing process and the increase of homogenization of the processed polymer, filled polymer or a composite. The strength and thermal calculations of selected models were carried out and computer simulations were performed concerning the optimization of the adopted solutions. The most important aim is to maximize the mixing, quantified here by WATS, with little changes in the remaining criteria, i.e., output, melt temperature at die exit (Tmelt), mechanical power consumption (Power), length of the screw required for melting (Lmelting) and viscous dissipation ; European Union

[EN] This paper presents a novel method that combines coupled hidden Markov models (HMM) and non Gaussian mixture models based on independent component analyzer mixture models (ICAMM). The proposed method models the joint behavior of a number of synchronized sequential independent component analyzer mixture models (SICAMM), thus we have named it generalized SICAMM (G-SICAMM). The generalization allows for flexible estimation of complex data densities, subspace classification, blind source separation, and accurate modeling of both local and global dynamic interactions. In this work, the structured result obtained by G-SICAMM was used in two ways: classification and interpretation. Classification performance was tested on an extensive number of simulations and a set of real electroencephalograms (EEG) from epileptic patients performing neuropsychological tests. G-SICAMM outperformed the following competitive methods: Gaussian mixture models, HMM, Coupled HMM, ICAMM, SICAMM, and a long short-term memory (LSTM) recurrent neural network. As for interpretation, the structured result returned by G-SICAMM on EEGs was mapped back onto the scalp, providing a set of brain activations. These activations were consistent with the physiological areas activated during the tests, thus proving the ability of the method to deal with different kind of data densities and changing non-stationary and non-linear brain dynamics. (C) 2019 Elsevier Ltd. All rights reserved. ; This work was supported by Spanish Administration (Ministerio de Economia y Competitividad) and European Union (FEDER) under grants TEC2014-58438-R and TEC2017-84743-P. ; Safont Armero, G.; Salazar Afanador, A.; Vergara Domínguez, L.; Gomez, E.; Villanueva, V. (2019). Multichannel dynamic modeling of non-Gaussian mixtures. Pattern Recognition. 93:312-323. https://doi.org/10.1016/j.patcog.2019.04.022 ; S ; 312 ; 323 ; 93

Novozym 435 (N435) is a commercially available immobilized lipase produced by Novozymes. It is based on immobilization via interfacial activation of lipase B from Candida antarctica on a resin, Lewatit VP OC 1600. This resin is a macroporous support formed by poly(methyl methacrylate) crosslinked with divinylbenzene. N435 is perhaps the most widely used commercial biocatalyst in both academy and industry. Here, we review some of the success stories of N435 (in chemistry, energy and lipid manipulation), but we focus on some of the problems that the use of this biocatalyst may generate. Some of these problems are just based on the mechanism of immobilization (interfacial activation) that may facilitate enzyme desorption under certain conditions. Other problems are specific to the support: mechanical fragility, moderate hydrophilicity that permits the accumulation of hydrophilic compounds (e.g., water or glycerin) and the most critical one, support dissolution in some organic media. Finally, some solutions (N435 coating with silicone, enzyme physical or chemical crosslinking, and use of alternative supports) are proposed. However, the N435 history, even with these problems, may continue in the coming future due to its very good properties if some simpler alternative biocatalysts are not developed. ; We gratefully recognize the financial support from MINECO from the Spanish Government (project number CTQ2017-86170-R, Colciencias, Ministerio de Educación Nacional, Ministerio de Industria, Comercio y Turismo e ICETEX, Convocatoria Ecosistema Científico – Colombia Científica. Fondo Francisco José de Caldas, Contrato RC-FP44842-212-2018 and Colciencias (Colombia) (project number FP44842-076-2016), Generalitat Valenciana (PROMETEO/2018/076), FAPERGS (project number 17/2551-0000939-8), CONICET (R. Argentina), FUNCAP (project number BP3-0139-00005.01.00/18) and ANPCyT (PICT 2015-0932 and PICT CABBIO 4687).

Supported by grants from North West Cancer Research (Grant number: CR945), The Wellcome Trust (Grant number: 074287/Z/03/Z) and a research studentship (HG) from the Libyan Government. ; Matrix metalloproteinase (MMP)‐7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP‐7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP‐7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP‐7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP‐7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3‐kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP‐7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP‐7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino‐ and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP‐7 knockdown and immunoneutralization. Thus, MMP‑7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3‐kinase. Secreted MMP‐7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion. ; Publisher PDF ; Peer reviewed

Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow-derived cells (BMDCs) from Sos1 fl/fl mice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR-ABL. ; This work has been supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC 10168 and 18621), the Italian Ministries of Education- University-Research (MIUR-PRIN-2009X23L78), the International Association For Cancer Research (AICR-09-0582 and 14-0335), the CARIPLO Foundation (2010-0737) and the European Research Council (Advanced-ERC268836). ALI was supported by a Grant from der German Jose Carreras Stiftung (DJCLS R14/22) and a Grant from the Government Baden-Württemberg (MWK). CM was supported form a AECC fellowship, Spain. ; Peer Reviewed

This is the author accepted manuscript. The final version is available from Frontiers Media via the DOI in this record. ; Oxygen sensing mechanisms are vital for homeostasis and survival. When oxygen levels are too low (hypoxia), blood flow has to be increased, metabolism reduced, or a combination of both, to counteract tissue damage. These adjustments are regulated by local, humoral or neural reflex mechanisms. The kidney and the carotid body are both directly sensitive to falls in the partial pressure of oxygen and trigger reflex adjustments and thus act as oxygen sensors. We hypothesize a cooperative oxygen sensing function by both the kidney and carotid body to ensure maintenance of whole body blood flow and tissue oxygen homeostasis. Under pathological conditions of severe or prolonged tissue hypoxia, these sensors may become excessively activated continuously and increase perfusion pressure chronically. Consequently, persistence of their activity could become a driver for the development of hypertension and cardiovascular disease. Hypoxia-mediated renal and carotid body afferent signaling triggers unrestrained activation of the renin angiotensin-aldosterone system (RAAS). Renal and carotid body mediated responses in arterial pressure appear to be synergistic as interruption of either afferent source has a summative effect of reducing blood pressure in renovascular hypertension. We discuss that this cooperative oxygen sensing system can activate/sensitize their own afferent transduction mechanisms via interactions between the RAAS, hypoxia inducible factor and erythropoiesis pathways. This joint mechanism supports our view point that the development of cardiovascular disease involves afferent nerve activation. ; This work was supported by the British Heart Foundation (FS/14/2/30630, RG/12/6/29670 and PG/15/68/31717) and the European Union, Seventh Framework Programme, Marie Curie Actions (CARPEDIEM - No 612280).

In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1. ; Our laboratory is funded by grants from Ministerio de Economía y Competitividad (SAF2011-23800 and SAF2014-55511R), the European Union (H2020-MSCA Programme, Grant agreement 64183-ONCORNET), The Cardiovascular Network of Ministerio Sanidad y Consumo-Instituto Carlos III (RD12/0042/0012), Comunidad de Madrid (S-2010/BMD-2332) to F.M and Instituto Carlos III (PI11/00859, PI14-00435, PIE-13-00041), Fundación Ramón Areces and Fundación Rodríguez Pascual to P.P. Dr.MartaMendiola is supported by a postdoctoral research contract of Fondo de Investigación Sanitaria (FIS) ('Sara Borrell' Program), Instituto de Salud Carlos III

AbstractLong‐chain polyunsaturated fatty acids (LCPUFA) have been shown to be necessary for early retinal and brain development, but long‐term cognitive benefits of LCPUFA in infancy have not been definitively established. The present study sought to determine whether LCPUFA supplementation during the first year of life would result in group differences in behavior and event‐related potentials (ERPs) while performing a task requiring response inhibition (Go/No‐Go) at 5.5 years of age. As newborns, 69 children were randomly assigned to infant formulas containing either no LCPUFA (control) or formula with 0.64% of total fatty acids as arachidonic acid (ARA; 20:4n6) and various concentrations of docosahexaenoic acid (DHA; 22:6n3) (0.32%, 0.64% or 0.96%) for the first 12 months of life. At 5.5 years of age, a task designed to test the ability to inhibit a prepotent response (Go/No‐Go) was administered, yielding both event‐related potentials (ERPs) and behavioral data. Behavioral measures did not differ between groups, although reaction times of supplemented children were marginally faster. Unsupplemented children had lower P2 amplitude than supplemented children to both Go and No‐Go conditions. N2 amplitude was significantly higher on No‐Go trials than Go trials, but only for supplemented children, resulting in a significant Group × Condition interaction. Topographical analysis of the ERPs revealed that the LCPUFA‐supplemented group developed a novel period of synchronous activation (microstate) involving wider anterior brain activation around 200 ms; this microstate was not present in controls. These findings suggest that LCPUFA supplementation during the first 12 months of life exerts a developmental programming effect that is manifest in brain electrophysiology. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=oM2leg4sevs.

This work analyzes the Councils of State and more in general the administrative courts as political actors. Councils of State are peculiar unelected bodies that present a double, "amphibious" nature. As advisory boards of the government on legislation, they belong to the executive. However, as highest courts responsible for the judicial review of administrative acts, they are also part of the judiciary. Adopting a strategic approach to the analysis of the relations between the legislature and the judiciary, the research investigates the interaction between government and the Council of State in the Italian case. The first question I intend to answer is if the interaction between the two institutions in the process of implementation of primary laws produces different outcomes, according to the political circumstances. More precisely, I analyze the extent to which the level of government ideological heterogeneity and the size of alternation affect the probability to activate the Council of State as Advisor. Second, I try to answer if the political factors that determine the activation of the Council of State in Italy also play a role in influencing the institutional characteristics of courts that review administrative acts in other countries. Following the game theoretical framework adopted for the Italian case, I examine the characteristics of courts that review administrative acts in fifteen European countries, showing the correlation between courts' institutional features and the prevailing political conditions (taking into consideration the post-Second World War period through the end of the 1990s). The data seem to suggest that the causal mechanisms that explain the activation of the Italian Council of State as Advisor can be behind the different role played by the administrative judiciary in the executive politics in other European Countries.

The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC. ; We are grateful to Reidar Grenman, Silvio Gutkind, Nahum Sonenberg, Gordon Peters, David Sabatini and Mariano Barbacid for sharing critical reagents. We also thank Aurora Astudillo, Aitana Vallina, Laura Alonso-Dura ́n and Eva Allonca for excellent technical assistance. Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy (SAF) co-funded by the European Regional Development Fund, the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund, the Botin Foundation and BancoSantander (Santander Universities Global Division), the Ramon Areces Foundation an the AXA Foundation. Work in the laboratory of J.M.G.-P. and J.P.R. was supported bygrants from Plan Nacional de DþI 2013–2016 ISCIII (CP13/00013 andPI13/00259),RD12/0036/0015 of Red Tematica de Investigacio ́n Cooperativa en Cancer (RTICC), Spain and the FEDER Funding Program from the European Union ; Sí

The electrical properties of polycrystalline NiZn ferrite, Zn0.44Ni0.38Fe2.18O4, were investigated by impedance spectroscopy over the frequency and temperature ranges, 5 Hz to 2 MHz and 10-600 K and by magnetic permeability measurements at room temperature. Samples were sintered in either conventional or solar furnaces followed by quenching or slow cooling to ambient temperature. Depending on processing conditions, the room-temperature electrical resistivity of conventionally sintered samples varied by seven orders of magnitude, from 5 ohm cm for a sample quenched from 1250 degrees C to 10 Mohm cm for a sample quenched from 400 degrees C. These differences were attributed to variations in oxygen content of the ferrite which decreased with increasing quench temperature. Oxygen deficiency led to mixed valence of Fe in the octahedral B sites of the spinel structure and was responsible for high electronic conductivity with low activation energy at low temperatures in oxygen-deficient samples. By contrast, in oxygen-stoichiometric samples, Fe on the tetrahedral A sites was believed to be divalent and Fe on the octahedral B sites to be entirely trivalent. Electron hopping between A and B sites had much higher activation energy and dominated the conductivity at high temperature for all samples. Samples sintered in the solar furnace were much more conductive than ones that were slow-cooled after conventional sintering and this is attributed to the relatively rapid cooling rate after exposure in the solar furnace, which preserved some of the oxygen deficiency present at high temperature. For the same reason, samples that were slow cooled in N-2 were also much more conductive. ; The authors thank the regional (Comunidad Autonoma de Madrid) government (MATERYENER3CM S2013/MIT-2753) and the national government (MINECO) (MAT2013-46452-C4-3R) for financial support.

Purpose
– The dote system is the most recent and only way to finance and deliver services in the training and labour policy field in Lombardy (Italy), strengthening the regional quasi-market approach. The purpose of this paper is to analyse its logic and highlight the implications for the policy system.


Design/methodology/approach
– Qualitative case-study including preliminary documentation, analysis of administrative data, in-depth interviews with stakeholders and practitioners.


Findings
– The dote system is based on a strongly pre-structured and pure performance logic. It predefines forms, ways and steps towards people's "autonomy", further categorising the policy system and establishing a combination of individualisation without personalisation. The strict regulation makes it difficult to design accessible, high-quality and tailor-made interventions. Dote could represent an interesting innovation for high-profile measures, but as a universal equivalent it often fails to match the needs of people and the labour market.


Research limitations/implications
– The self-funded research is limited to a regional context, analysed against the background of European welfare transformations. Greater effort in qualitative research could improve the knowledge about the implications of NPM and quasi-markets.


Practical implications
– Regional centralism is strengthened; local authorities and private bodies are excluded from planning; freedom of choice is limited. A marriage of convenience between providers and users increases the level of stress and the dispersion of resources.


Originality/value
– Dote is a particular experiment in the panorama of activation. It works in a unique way, impacting on governance and activation modes. The paper is addressed to researchers, practitioners and policy makers interested in gaining better understanding of the implications of quasi-markets and NPM.

Long-term potentiation (LTP) of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca2+ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR) and metabotropic glutamate receptor (mGluR) activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca2+ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP) also involves mGluR activation. Astrocyte Ca2+ elevations and LTP are absent in IP3R2 knock-out mice. Downregulating astrocyte Ca2+ signal by loading astrocytes with BAPTA or GDPbS also prevents LTP, which is restored by simultaneous astrocyte Ca2+ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca2+ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergicinduced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca2+ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca2+ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information ; Supported by grants from Ministerio de Ciencia e Innovacio´n (BFU2010-15832, BFU2008-03488, BFU2008-04196, CSD2010-00045), Spain, European Union (HEALTH-F2-2007-202167) and Cajal Blue Brain. G.P. is supported by a Marie Curie Fellowship (FP7-253635). E.D.M. is supported by INCRECyT project from European Social Fund and JCCM.