SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons

yesMultiple pathways participate in the AMPA receptor trafficking that underlies long-term potentiation (LTP) of synaptic transmission. Here we demonstrate that protein SUMOylation is required for insertion of the GluA1 AMPAR subunit following transient glycine-evoked increase in AMPA receptor surface expression (ChemLTP) in dispersed neuronal cultures. ChemLTP increases co-localisation of SUMO-1 and the SUMO conjugating enzyme Ubc9 and with PSD95 consistent with the recruitment of SUMOylated proteins to dendritic spines. In addition, we show that ChemLTP increases dendritic levels of SUMO-1 and Ubc9 mRNA. Consistent with activity dependent translocation of these mRNAs to sites near synapses, levels of the mRNA binding and dendritic transport protein CPEB are also increased by ChemLTP. Importantly, reducing the extent of substrate protein SUMOylation by overexpressing the deSUMOylating enzyme SENP-1 or inhibiting SUMOylation by expressing dominant negative Ubc9 prevent the ChemLTP-induced increase in both AMPAR surface expression and dendritic SUMO-1 mRNA. Taken together these data demonstrate that SUMOylation of synaptic protein(s) involved in AMPA receptor trafficking is necessary for activity-dependent increases in AMPAR surface expression.Medical Research Council, the European Research Council and the Wellcome Trus

Liposome Circulation Time is Prolonged by CD47 Coating.

INTRODUCTION: Bio-degradable nano-particles have many applications as drug delivery vehicles because of their good bio-availability, controlled release, low toxicity and potential for encapsulation. However, the most important obstacle to nanoparticulate drug delivery is elimination by macrophages which reduces the residence time of nanoparticles in the blood. To overcome this problem, the surface of the nanoparticle can be passivated by coating with Polyethylene glycol (PEG). However, the use of PEG has its own disadvantages. CD47 receptor acts as a self marker on the surface of many cells and inhibits phagocytosis. This study used a CD47 mimicry peptide as a substitute for PEG to fabricate "stealth" nanoliposome with reduced macrophage clearance. METHODS: Doxorubibin was used as a model drug because of its inherent fluorescence. Doxorubicin-containing liposomes were coated with different percentages of CD47 mimicry peptide (0.5% and 1%). PEGfunctionalized doxorubicin-containing liposomes, were used as a comparator. The liposomal formulations were intravenously injected into mice. Serum was collected at pre-defined time points and tissue samples were taken at 24 hours. Fluorescence was used to determine the concentration doxorubicin in serum, heart, spleen, kidney, liver and lung tissues. RESULTS: Tissue biodistribution and serum kinetic studies indicated that compared with PEG, the use of CD47 mimicry peptide increased the circulation time of doxorubicin in the circulation. Moreover, unwanted accumulation of doxorubicin in the reticuloendothelial tissues (liver and spleen), kidney and heart was significantly decreased by the CD47 mimicry peptide. CONCLUSION: The use of a CD47 mimicry peptide on the surface of nanoliposomes improved the residence time of liposomal doxorubicin in the circulation. The accumulation of drug in non-target tissues was reduced, thereby potentially reducing toxicity

Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

Visceral leishmaniasis (VL), a vector-transmitted disease caused by Leishmania donovani, is potentially fatal if left untreated. Vaccination against VL has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine is pressing for the control of the disease. Earlier, we observed protective efficacy using leishmanial antigen (Ag) in the presence of either cationic liposomes or monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) against experimental VL through the intraperitoneal (i.p.) route of administration in the mouse model. However, this route of immunization is not adequate for human use. For this work, we developed vaccine formulations combining cationic liposomes with MPL-TDM using recombinant GP63 (rGP63) as protein Ag through the clinically relevant subcutaneous (s.c.) route. Two s.c. injections with rGP63 in association with cationic liposomes and MPL-TDM showed enhanced immune responses that further resulted in high protective levels against VL in the mouse model. This validates the combined use of MPL-TDM as an immunopotentiator and liposomes as a suitable vaccine delivery system

SUMOylation of Syntaxin1A regulates presynaptic endocytosis

Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity-dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function

PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity

Dendritic spine remodelling involves regulated actin dynamics and is essential for synaptic plasticity. The Arp2/3 inhibitor PICK1 is here shown to regulate spine size: inducing shrinkage during long-term depression

Application of the ANP to the prioritization of project stakeholders in the context of responsible research and innovation

[EN] This paper presents a methodology to assess the stakeholders¿ influence in a research project within the context of responsible research and innovation. The methodology is based on a combination of the multicriteria decision making technique analytic network process and the key areas of responsible research. The method allows ranking and ordering the project¿s stakeholders based on their influence upon its responsibility. The purpose of such an assessment is to help research teams to more efficiently devote their limited resources to stakeholder management. The procedure is applied to a case study of the Information and Communication Technology business sector. It is an ongoing project at an early phase of development. Influential stakeholders have been identified first, and have been further classified into groups based on their relative importance. The assessment of their influence has been based on up to 16 different criteria, mainly belonging to the framework of responsible research and innovation. In the case study, the most influential criterion was the Capability to promote public engagement, while Developers were found to be the stakeholders most contributing to the research project responsibility. However, as explained, this is a temporary situation, valid for the current project development situation. It may vary over time as criteria vary in weight and stakeholders vary in influence.The authors would like to thank to our anonymous referees for their constructive comments and suggestions that helped us to improve the quality of the paper. Also, to the “Bolívar Gana con Ciencia” program from the Gobernación de Bolívar (Colombia) for the financial support. For the same reason, the authors are grateful to the Spanish Agencia Estatal de Investigación for its support of the project Propuesta de Indicadores para Impulsar el Diseño de Una Política Orientada al Desarrollo de Investigación e Innovación Responsable en España (CSO2016-76828-R)Ligardo-Herrera, I.; Gómez-Navarro, T.; Gonzalez-Urango, H. (2018). Application of the ANP to the prioritization of project stakeholders in the context of responsible research and innovation. Central European Journal of Operations Research. 1-23. https://doi.org/10.1007/s10100-018-0573-4S123Akbari N, Irawan CA, Jones DF, Menachof D (2017) A multi-criteria port suitability assessment for developments in the offshore wind industry. Renew Energy 102:118–133. https://doi.org/10.1016/j.renene.2016.10.035Aragonés-Beltrán P, García-Melón M, Montesinos-Valera J (2017) How to assess stakeholders’ influence in project management? A proposal based on the analytic network process. 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Evaluation of Leishmania donovani Protein Disulfide Isomerase as a Potential Immunogenic Protein/Vaccine Candidate against Visceral Leishmaniasis

In Leishmania species, Protein disulfide isomerase (PDI) - a redox chaperone, is reported to be involved in its virulence and survival. This protein has also been identified, through proteomics, as a Th1 stimulatory protein in the soluble lysate of a clinical isolate of Leishmania donovani (LdPDI). In the present study, the molecular characterization of LdPDI was carried out and the immunogenicity of recombinant LdPDI (rLdPDI) was assessed by lymphocyte proliferation assay (LTT), nitric oxide (NO) production, estimation of Th1 cytokines (IFN-γ and IL-12) as well as IL-10 in PBMCs of cured/endemic/infected Leishmania patients and cured L. donovani infected hamsters. A significantly higher proliferative response against rLdPDI as well as elevated levels of IFN-γ and IL-12 were observed. The level of IL-10 was found to be highly down regulated in response to rLdPDI. A significant increase in the level of NO production in stimulated hamster macrophages as well as IgG2 antibody and a low level of IgG1 in cured patient's serum was observed. Higher level of IgG2 antibody indicated its Th1 stimulatory potential. The efficacy of pcDNA-LdPDI construct was further evaluated for its prophylactic potential. Vaccination with this construct conferred remarkably good prophylactic efficacy (∼90%) and generated a robust cellular immune response with significant increases in the levels of iNOS transcript as well as TNF-α, IFN-γ and IL-12 cytokines. This was further supported by the high level of IgG2 antibody in vaccinated animals. The in vitro as well as in vivo results thus indicate that LdPDI may be exploited as a potential vaccine candidate against visceral Leishmaniasis (VL)

La Relación Entre la Motivación Docente y Variables de la Organización: Revisión de la Literatura

Abstract Teacher motivation plays a central role in education because ofitsimpacton student motivation. Previous reviews of teacher motivation have focused on individual variables and psychopathology indicators. However, it is also important to understand the effect of organizational variableson teacher motivationbecause these highlightthe contextthat the teacher is a part of(i.e.,the school). The literature review in this paper analysed studies related to teacher motivation and a pre-defined group of organizational variablesthat werepublished between 1990 and 2014 in several electronic databases.The study found that organizational culture was the most studied variable associated with teacher motivationand most studies in this area were published between 2010 and 2014.Further,there was a prevalence of quantitative studies. This paper concludes with the theoreticaland practical implications of the results,as well assuggestions for future research directions