DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit a-calcitonin gene-related peptide (a-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of a-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt a-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit a-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target. © 202

Babinet principle applied to the design of metasurfaces and metamaterials

The electromagnetic theory of diffraction and the Babinet principle are applied to the design of artificial metasurfaces and metamaterials. A new particle, the complementary split rings resonator, is proposed for the design of metasurfaces with high frequency selectivity and planar metamaterials with a negative dielectric permittivity. Applications in the fields of frequency selective surfaces and polarizers, as well as in microwave antennas and filter design, can be envisaged. The tunability of all these devices by an applied dc voltage is also achievable if these particles are etched on the appropriate substrate

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.667+2_667+23del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.667+2_667+23del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family

Automated synthesis of transmission lines loaded with complementary split ring resonators (CSRRs) and open complementary split ring resonators (OCSRRs) through aggressive space mapping (ASM)

This paper is focused on the application of space mapping optimization to the automated synthesis of transmission lines loaded with complementary split ring resonators (CSRRs) and open complementary split ring resonators (OCSRRs). These structures are of interest for the implementation of resonant-type metamaterial transmission lines and for the design of planar microwave circuits based on such complementary resonators. The paper presents a method to generate the layouts of CSRR- and OCSRR-loaded microstrip lines from the elements of their equivalent circuit models. Using the so-called aggressive space mapping, a specific implementation that uses quasi-Newton type iteration, we have developed synthesis algorithms that are able to provide the topology of these CSRR and OCSRR-loaded lines in few steps. The most relevant aspect, however, is that this synthesis process is completely automatic, i.e., it does not require any action from the designers, other than initiating the algorithm. Moreover, this technique can be translated to other electrically small planar elements described by lumped element equivalent circuit models.This work has been partially supported by MICIIN-Spain (Projects TEC2010-17512 METATRANSFER, TEC2010-21520-C04-01 AVANSAT, CONSOLIDER EMET CSD2008-00066, and Grant AP2008-04707), Generalitat de Catalunya (Project 2009SGR-421), and MITyC-Spain (Project TSI-020100-2010-169 METASINTESIS). Ferran Martin is in debt to ICREA for supporting his work through an ICREA Academia Award (calls 2008 and 2013).Selga, J.; Rodríguez Pérez, AM.; Orellana, M.; Boria Esbert, VE.; Martín, F. (2014). Automated synthesis of transmission lines loaded with complementary split ring resonators (CSRRs) and open complementary split ring resonators (OCSRRs) through aggressive space mapping (ASM). Applied Physics A. 117(2):557-565. https://doi.org/10.1007/s00339-014-8703-xS5575651172G.V. Eleftheriades, K.G. Balmain, Negative Refraction Metamaterials: Fundamental Principles and Applications (Wiley, New Jersey, 2005)C. Caloz, T. Itoh, Electromagnetic Metamaterials: Transmission Line Theory and Microwave Applications (Wiley, New Jersey, 2006)R. Marqués, F. Martín, M. Sorolla, Metamaterials with Negative Parameters: Theory, Design and Microwave Applications (Wiley, New Jersey, 2008)F. Martín, Artificial Transmission Lines for RF and Microwave Applications. (Wiley, New Jersey) (to be published)M.A. Antoniades, G.V. Eleftheriades, A broadband series power divider using zero-degree metamaterial phase shifting lines. IEEE Microw. Wirel. Compon. Lett. 15, 808–810 (2005)H. Okabe, C. Caloz, T. Itoh, A compact enhanced bandwidth hybrid ring using an artificial lumped element left handed transmission line section. IEEE Trans. Microw. Theory Tech. 52, 798–804 (2004)G. Sisó, J. Bonache, M. Gil, F. Martín, Application of resonant-type metamaterial transmission lines to the design of enhanced bandwidth components with compact dimensions. Microw. Opt. Technol. Lett. 50, 127–134 (2008)I.H. Lin, M. De Vincentis, C. Caloz, T. Itoh, Arbitrary dual-band components using composite right/left handed transmission lines. IEEE Trans. Microw. Theory Tech. 52, 1142–1149 (2004)A.C. Papanastasiou, G.E. Georghiou, G.V. Eleftheriades, A quad-band Wilkinson power divider using generalized NRI transmission lines. IEEE Microw. Wirel. Compon. Lett. 18, 521–523 (2008)M. Durán-Sindreu, G. Sisó, J. Bonache, F. Martín, Planar multi-band microwave components based on the generalized composite right/left handed transmission line concept. IEEE Trans. Microw. Theory Tech. 58(12), 3882–3891 (2010)J. Bonache, I. Gil, J. García-García, F. Martín, Novel microstrip band pass filters based on complementary split ring resonators. IEEE Trans. Microw. Theory Tech. 54, 265–271 (2006)M. Gil, J. Bonache, J. García-García, J. Martel, F. Martín, Composite right/left handed (CRLH) metamaterial transmission lines based on complementary split rings resonators (CSRRs) and their applications to very wide band and compact filter design. IEEE Trans. Microw. Theory Tech. 55, 1296–1304 (2007)S. Lim, C. Caloz, T. Itoh, Metamaterial-based electronically-controlled transmission line structure as a novel leaky-wave antenna with tunable angle and beamwidth. IEEE Trans. Microw. Theory Tech. 52(12), 2678–2690 (2004)G. Zamora, S. Zuffanelli, F. Paredes, F. Javier Herraiz-Martínez, F. Martín, J. Bonache, Fundamental mode leaky-wave-antenna (LWA) using slot line and split-ring-resonator (SRR) based metamaterials. IEEE Antennas Wirel. Propag. Lett. 12, 1424–1427 (2013)A.K. Iyer, G.V. Eleftheriades, Negative refractive index metamaterials supporting 2-D waves. in IEEE-MTT Int’l Microwave Symposium, vol 2, Seattle, WA, pp. 412–415 (2002)A.A. Oliner, A periodic-structure negative-refractive-index medium without resonant elements. In URSI Digest, IEEE-AP-S USNC/URSI National Radio Science Meeting, San Antonio, TX, pp. 41 (2002)C. Caloz, T. Itoh, Application of the transmission line theory of left-handed (LH) materials to the realization of a microstrip LH transmission line. in Proceedings of IEEE-AP-S USNC/URSI National Radio Science Meeting, vol 2, San Antonio, TX, pp. 412–415 (2002)F. Martín, F. Falcone, J. Bonache, R. Marqués, M. Sorolla, Split ring resonator based left handed coplanar waveguide. Appl. Phys. Lett. 83, 4652–4654 (2003)F. Falcone, T. Lopetegi, M.A.G. Laso, J.D. Baena, J. Bonache, R. Marqués, F. Martín, M. Sorolla (2004) Babinet principle applied to the design of metasurfaces and metamaterials. Phys. Rev. Lett. 93, paper 197401M. Durán-Sindreu, A. Vélez, F. Aznar, G. Sisó, J. Bonache, F. Martín, Application of open split ring resonators and open complementary split ring resonators to the synthesis of artificial transmission lines and microwave passive components. IEEE Trans. Microw. Theory Tech. 57, 3395–3403 (2009)A. Vélez, F. Aznar, M. Durán-Sindreu, J. Bonache, F. Martín, Stop-band and band-pass filters in coplanar waveguide technology implemented by means of electrically small metamaterial-inspired open resonators. IET Microw. Antennas Propag. 4, 712–716 (2004)J.D. Baena, J. Bonache, F. Martín, R. Marqués, F. Falcone, T. Lopetegi, M.A.G. Laso, J. García, I. Gil, M. Flores-Portillo, M. Sorolla, Equivalent circuit models for split ring resonators and complementary split rings resonators coupled to planar transmission lines. IEEE Trans. Microw. Theory Tech. 53, 1451–1461 (2005)M. Gil, J. Bonache, J. Selga, J. García-García, F. Martín, Broadband resonant type metamaterial transmission lines. IEEE Microw. Wirel. Compon. Lett. 17, 97–99 (2007)M. Durán-Sindreu, P. Vélez, J. Bonache, F. Martín, Broadband microwave filters based on open split ring resonators (OSRRs) and open complementary split ring resonators (OCSRRs): improved models and design optimization. Radioengineering 20, 775–783 (2011)P. Vélez, J. Naqui, M. Durán-Sindreu, J. Bonache, F. Martín, Broadband microstrip bandpass filter based on open complementary split ring resonators. Int. J. Antennas Propag. 2012, 6 (2012)J.W. Bandler, R.M. Biernacki, S.H. Chen, P.A. Grobelny, R.H. Hemmers, Space mapping technique for electromagnetic optimization. IEEE Trans. Microw. Theory Tech. 42, 2536–2544 (1994)J.W. Bandler, R.M. Biernacki, S.H. Chen, R.H. Hemmers, K. Madsen, Electromagnetic optimization exploiting aggressive space mapping. IEEE Trans. Microw. Theory Tech. 43, 2874–2882 (1995)J.W. Bandler, Q.S. Cheng, S.A. Dakroury, A.S. Mohamed, M.H. Bakr, K. Madsen, J. Søndergaard, Space mapping: the state of the art. IEEE Trans. Microw. Theory Tech. 52, 337–361 (2004)C.G. Broyden, A class of methods for solving nonlinear simultaneous equations. Math. Comput. 19(92), 577–593 (1965)J. Selga, A. Rodríguez, V.E. Boria, F. Martín, Synthesis of split rings based artificial transmission lines through a new two-step, fast converging, and robust aggressive space mapping (ASM) algorithm. IEEE Trans. Microw. Theory Tech. 61(6), 2295–2308 (2013)A. Velez, F. Aznar, J. Bonache, M.C. Velázquez-Ahumada, J. Martel, F. Martín, Open complementary split ring resonators (OCSRRs) and their application to wideband CPW band pass filters. IEEE Microw. Wirel. Compon. Lett. 19, 197–199 (2009)D.M. Bates, D.G. Watts, Nonlinear Regression Analysis and Its Applications (Wiley, New York, 1998

How do MNC R&D laboratory roles affect employee international assignments?

Research and development (R&D) employees are important human resources for multinational corporations (MNCs) as they are the driving force behind the advancement of innovative ideas and products. International assignments of these employees can be a unique way to upgrade their expertise; allowing them to effectively recombine their unique human resources to progress existing knowledge and advance new ones. This study aims to investigate the effect of the roles of R&D laboratories in which these employees work on the international assignments they undertake. We categorise R&D laboratory roles into those of the support laboratory, the locally integrated laboratory and the internationally interdependent laboratory. Based on the theory of resource recombinations, we hypothesise that R&D employees in support laboratories are not likely to assume international assignments, whereas those in locally integrated and internationally interdependent laboratories are likely to assume international assignments. The empirical evidence, which draws from research conducted on 559 professionals in 66 MNC subsidiaries based in Greece, provides support to our hypotheses. The resource recombinations theory that extends the resource based view can effectively illuminate the international assignment field. Also, research may provide more emphasis on the close work context of R&D scientists rather than analyse their demographic characteristics, the latter being the focus of scholarly practice hitherto

Sistema para el Seguimiento del funcionamiento de ecosistemas en la Red de Parques Nacionales de España mediante Teledetección

Revista oficial de la Asociación Española de Teledetección[EN] Management of protected areas in the current context of global change requires approaches to characterize and to monitor ecosystem functioning. Remote sensing provides adequate tools for that because it provides índices that inform repeatedly and for large areas of land, about matter and energy exchanges between the biota and land surface. Considering this principle, and the continuous improvements in the availability of satellite data of higher quality and friendly use, we have developed with the Autonomous Organization of National Parks of Spain (OAPN), a monitoring system that complements other monitoring initiatives from this agency to inform about the conservation status of national parks. The system, called REMOTE, is based on the most used spectral vegetation indices on scientific literature, EVI (Enhanced Vegetation Index) and NDVI (Normalized Difference Vegetation Index), derived from the time series of satellite images of the MODIS-Terra sensor. The systems allows to progress in identification of reference conditions to understand and predict ecosystems response against environmental perturbations or management actions, and their directional changes (trends) they are experiencing. Likewise, establishment of reference conditions helps to identify anomalies that warn of sudden changes in ecosystem functioning. The system uses as ecosystem functioning indicators three attributes related to the annual carbon gains (net primary production) by the canopy, their seasonality and phenology. In addittion, Remote has been designed and programmed on open and free software allowing future modifications and improvements in an easy way. The implementation of this system aims to inform decision-makers and managers of the Network of National Parks of Spain about the health and conservation status of ecosystems.[ES] La gestión de las áreas protegidas en el actual contexto de cambio global requiere de aproximaciones que permitan caracterizar y seguir el funcionamiento de los ecosistemas. La teledetección ofrece herramientas para ello, ya que proporciona índices que informan reiteradamente y para grandes porciones de territorio, de los intercambios de materia y energía que tienen lugar entre la biota y la superficie terrestre. Considerando este principio, y la cada vez mayor disponibilidad de información satelital de calidad y facilidad de uso, desarrollamos junto con el Organismo Autónomo de Parques Nacionales de España (OAPN), un sistema de seguimiento que complementa a otras iniciativas desarrolladas por este organismo para informar del estado de conservación de los parques nacionales. El sistema, denominado REMOTE, se basa en el empleo de los índices de vegetación espectrales (IVs) de uso más extendido (EVI -índice de vegetación mejorado- y NDVI -índice de vegetación normalizado-), derivados de la serie temporal de imágenes satelitales del sensor MODIS-Terra. El sistema permite avanzar en la identificación de las condiciones de referencia para la comprensión y predicción de las respuestas de los ecosistemas frente a perturbaciones e interven-ciones, y de los cambios direccionales que éstos están experimentando (tendencias). Así mismo ayuda a la detección de anomalías recientes que alertan de cambios bruscos en el funcionamiento de los ecosistemas. REMOTE se carac-teriza porque usa como indicadores tres atributos relacionados con las ganancias de carbono anuales (productividad primaria neta) por parte del dosel vegetal, su estacionalidad y fenología. Además, está diseñado y programado con software libre y gratuito, lo que permitirá modificar o implementar mejoras en él fácilmente. Su implementación tiene como objetivo informar a los tomadores de decisiones y gestores de la Red de Parques Nacionales de España de la salud y estado de conservación de los ecosistemas.Los trabajos han sido financiados por el Organismo Autónomo de Parques Nacionales (OAPN), y el Centro Andaluz para la Evaluación y Seguimiento del Cambio Global (CAESCG).Cabello, J.; Alcaraz-Segura, D.; Reyes, A.; Lourenço, P.; Requena, JM.; Bonache, J.; Castillo, P.... (2016). System for monitoring ecosystem functioning of Network of National Parks of Spain with remote sensing. Revista de Teledetección. (46):119-131. doi:10.4995/raet.2016.5731.SWORD1191314

Nucleophile-Catalyzed Additions to Activated Triple Bonds. Protection of Lactams, Imides, and Nucleosides with MocVinyl and Related Groups

Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or N-methoxy-N-methylpropynamide in the presence of many potential catalysts were examined. DABCO and, second, DMAP appeared to be the best (highest reaction rates and E/Z ratios), while RuCl3, RuClCp*(PPh3)2, AuCl, AuCl(PPh3), CuI, and Cu2(OTf)2 were incapable of catalyzing such additions. The groups incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties. Deprotections were accomplished via exchange with good nucleophiles: the 1-dodecanethiolate anion turned out to be the most general and efficient reagent, but in some particular cases other nucleophiles also worked (e.g., MocVinyl-inosines can be cleaved with succinimide anion). Some structural and mechanistic details have been accounted for with the help of DFT and MP2 calculations

Careers of highly educated self-initiated expatriates : observations from studies among Finnish business professionals

This chapter reviews existing literature about the careers of self-initiated expatriates and analyzes the different studies carried out among university level educated Finnish business professionals. A series of studies carried out among members of the Finnish Association of Business School Graduates during the last 15 years was cross-analyzed. The studies are based on three surveys and further interviews among their expatriate members (1999, 2004 and a follow-up study in 2012) also involving SIEs. Therefore, this chapter provide an overview of what we know about the careers of Finnish SIEs and show evidence of (1) their career motives, (2) the role of family considerations in the career decision making of SIEs, (3) the development of career capital and social capital during SIE-experiences, and also (4) longer-term career impacts of SIE-experiences. Based on the literature review and analysis of above mentioned studies we highlight the gaps in in the knowledge about SIEs and suggest areas where further research is needed.fi=vertaisarvioitu|en=peerReviewed

DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

15 pags, 8 figs, 3 tabs. -- Supplementary data to this article can be found online at https://doi.org/10.1016/j.bioorg.2021.105231.The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit α-calcitonin gene-related peptide (α-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of α-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt α-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit α-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER), RTI2018-097189-C2 and CTQ2017-84371-P), and the Spanish National Research Council (CSIC, 201880E109, 201980E030). The NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB. We thank Prof. Josep Rizo and R. Voleti (Dept. Biophysics, Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, USA) for providing the clones required for expressing Syt1 and Syt7 proteins. SG-R and AB belong to the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).Peer reviewe