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The lack of selectivity of anticancer drugs limits current chemotherapy. Light-activatable drugs, whose activity can be precisely controlled with external light, could provide a more localized action of the drugs in the tumor, thus decreasing side effects and increasing efficacy. Herein, we introduce a series of photoswitchable azobenzene histone deacetylase inhibitors (HDACis) whose activity can be controlled by external visible light. Initial HDACis isomerized under ultraviolet light and were up to >50-fold more active under illumination than in the dark in enzyme assays. These were then optimized toward compounds responding to more permeable and less harmful green light by introducing o-halogen atoms into the azobenzene. Selected compounds decreased cell viability only under illumination in four different cancer cell lines. Overall, we present photoswitchable HDACis with optimized activation wavelengths, which inhibit enzyme activity and cell viability only upon illumination with visible light, contributing to the still limited toolbox of photoswitchable anticancer drugs., L.J.-C. has received funding from the European Union’s Horizon2020 research and innovation programme under Marie Sklodowska-Curie Grant Agreement 841089. A.L. received funding from Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación 10.13039/501100011033 and ERDF A way of making Europe (Projects I+D+i CTQ2017-89222-R and PID2020-120499RB-I00), and the Catalan government (2017 SGR 1604). The authors thank Dr. Lourdes Muñoz from SimChem (IQAC-CSIC) for analytical and instrumental support. The authors thank Dr. Wiktor Szymanski (University of Groningen, Groningen, The Netherlands) for helpful discussions.

G-protein-coupled receptors (GPCRs) are a super-family of membrane proteins and major targets for drug development. However, many GPCRs drug candidates suffer from a lack of selectivity. Photopharmacology gives the possibility of modulating GPCR activity with an unprecedented local and temporal precision with the use of light. In this review, we compile and classify the different strategies in photopharmacology for GPCRs, we revise the different methods of analysis and characterization of light-regulated molecules used for GPCRs, and we give perspective of the impact of photopharmacology in research applications and in the development of new drugs.

Artificial control of neuronal activity enables the study of neural circuits and restoration of neural functions. Direct, rapid, and sustained photocontrol of intact neurons could overcome the limitations of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors (GluRs) to enable neuronal control in the auditory system. The new photoswitchable ligands induced photocurrents in untransfected neurons upon covalently tethering to endogenous GluRs and activating them reversibly with visible light pulses of a few milliseconds. As a proof of concept of these molecular prostheses, we applied them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method afforded the optical stimulation of auditory neurons of adult gerbils at hundreds of hertz without genetic manipulation that would be required for their optogenetic control. This indicates that the new photoswitchable ligands are also applicable to the spatiotemporal control of fast spiking interneurons in the brain., This research received funding from the European Union Research and Innovation Programme Horizon 2020─Human Brain Project SG3 (945539), DEEPER (ICT-36-2020–101016787), Agency for Management of University and Research Grants/Generalitat de Catalunya (CERCA Programme; 2017-SGR-1442 and 2017-SGR-1604 projects), Fonds Européen de Développement Économique et Régional (FEDER) funds, Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación and ERDF-FEDER European Fund (projects CTQ2017-89222-R and PID2020-120499RB-I00), and Fundaluce and “la Caixa” foundations (ID 100010434, agreement LCF/PR/HR19/52160010). The project Clúster Emergent del Cervell Humà (CECH, 001-P-001682) is cofinanced by the European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014–2020 with a grant of 50% of total eligible cost. A.G.-C. was supported by the fellowship BES-2014-068169 and Alexander von Humboldt Foundation. J.H. was supported by Agencia Estatal de Investigación (PID2019-106171RB-100/AEI/10.13039/501100011033) and Generalitat de Catalunya (2017 SGR00465). We thank chemical facility PCB staff (Unai Elezcano, Sònia Varon) and IBEC infrastructure staff (Isabel Oliveira, David Izquierdo). We thank Christiane Senger-Freitag, Sandra Gerke, and Sina Langer for technical support, Gerhard Hoch for his expert technical support, and Patricia Räke-Kügler for excellent administrative support. We thank Thomas Mager for providing the patch clamp setup. This work was funded by the European Research Council through the Advanced Grant “OptoHear” to T.M. under the European Union’s Horizon 2020 Research and Innovation program (grant agreement no. 670759), the Fraunhofer and Max-Planck Cooperation Program (NeurOpto grant) to T.M., was further supported by the German Research Foundation through the Priority Program 1926 “Next generation optogenetics” to A.H. and T.M., and the Leibniz Program (to T.M.) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy─EXC 2067/1-390729940 to A.H. and T.M. In addition, this research was supported by the Fakultätinternes Forschungförderungsprogramm from the Universitätsmedizin Göttingen, Georg-August-Universität Göttingen to A.H., and Fondation Pour l’Audition (FPA RD-2020-10) to T.M. Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. We thank Dr. Vladimir Belov, Jurgen Bienert, and Jan Seikowski for HPLC and LC–MS measurements of final TCPfast products.

Rhythm, which refers to the sensation of isochrony conveyed by repeating patterns in speech, is key to add emotion and pragmatic meanings to the dialogues of, for example, voice assistants such as Siri and Alexa. Despite its importance, few papers tested new promising rhythm measures due to the technical challenges involved in this research. The present project aims at ameliorating these challenges by creating a database to study prosody cross-linguistically together with a set of scripts that output over 20 rhythm measures. With the help of undergraduate students majoring in different languages, the database will consist of TED talks in 8 languages, their orthographic transcriptions, and annotated speech wave forms (words, syllables, phonemes, and pauses). Speech annotations will be automatically generated by freely available aligners and sound editing programs. This database will be the input to the scripts that output the 20+ rhythm measures. Both tools, the database and scripts, together with a manual will be made available to the research community worldwide in order to promote international dialogue in this field.

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery and development. However, some drug metabolites can reach high plasma concentrations and display relevant in vivo activity, which can be distinct from its parent drug. Here, we use computational and experimental methods to comprehensively characterise the kinase polypharmacology of M324, the major metabolite of the FDA-approved PARP inhibitor rucaparib. We experimentally demonstrate that M324 displays a distinct in vitro kinome profile from its parent drug, characterized by potent in vitro inhibition of GSK3A and PLK2 at clinically-relevant concentrations. These confirmed kinase activities of M324 could have potential implications for the efficacy and safety of rucaparib and therefore warrant further clinical investigation. The study reported here highlights the importance of thoroughly characterizing the activity of significant drug metabolites to better understanding drug responses in the clinic and maximally exploit the current drug arsenal in personalized and precision medicine.

Neuropathic pain is a common health problem, resulting in exacerbated response to noxious and non noxious stimuli, as well as impaired emotional and cognitive responses. Unfortunately, neuropathic pain is also one of the most difficult pain syndromes to manage, highlighting the importance of better understanding of the brain regions and neuromodulatory mechanisms involved in its regulation. Among the many interconnected brain areas which process pain, the amygdala is known to play an important role in the integration of sensory and emotional pain signals. Here, we questioned the ability of a recently identified neuromodulatory mechanisms associated to the metabotropic glutamate receptors mGlu4in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy induced by a chronic constriction of the sciatic nerve, we demonstrate that pharmacological activation of amygdala mGlu4receptors efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of those symptoms, activating mGlu4receptors in the controlateral amygdala, relatively to the side of the mononeuropathy, is necessary and sufficient to relieve both sensory and depressive-like symptoms while ipsilateral activation solely reduces depressive-like symptoms. Furthermore, using photopharmacology, a recent strategy allowing a precise spatiotemporal photocontrol of deep brain endogenous targets, we further demonstrate the rapid and reversible action of mGlu4-mediated neuromodulation on neuropathic pain symptoms. Finally, coupling photopharmacology and analgesic conditioned place preference, we show an important pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu4activity to counteract neuropathy in the hope of improving existing treatments.

Beta-adrenoceptors (ß-AR) are prototypical G proteincoupled receptors and important pharmacological targets for many diseases. Indeed, a number of approved drugs target these receptors due to their key role on many physiological functions. Among other examples, we encounter ß1-AR antagonists (ß- Blockers), which constitute the first-line therapy for the treatment of heart diseases, and ß2-AR agonists, which act as bronchodilators for the treatment of breathing pathologies. Considering the relevance of these receptors, achieving a reversible and localised control of their activity would provide a powerful tool, both for its research applications and its clinical potential. In this context, photopharmacology arises as a potent approach. Photopharmacology is an emerging field based on the use of synthetic light-regulated molecules to allow reversible spatiotemporal control of target receptors in native tissues. These ligands have the potential to provide a precise and controllable therapeutic action with increased efficacy and reduced side effects. Moreover, the fine regulation on demand of the receptor activation state is of great interest for their study in non-modified cells, tissues and organisms. The present project provides the first proof of concept for beta-adrenoceptor photopharmacology. We first designed and synthesised libraries of lightregulated compounds in order to regulate ß-AR activity with spatiotemporal precision. Subsequent testing highlighted the successful development of compounds with promising pharmacological properties which can be reversibly and irreversibly controlled by light. The discovered molecules enable a fine control of ß-AR in their native environment that will certainly open the door to innovative research procedures and may inspire future personalized therapies targeting these receptors.

Beta-adrenoceptors (ß-AR) are prototypical G protein-coupled receptors (GPCR) and important pharmacological targets for numerous diseases. Indeed, a number of approved drugs target ß-AR, which are key regulators of many physiological functions. Among other examples, ß1-AR antagonists (known as ß-Blockers) are first-line therapies for the treatment of heart failure, and ß2-AR agonists, which act as bronchodilators, are widely used for the treatment of breathing pathologies. Considering the medical relevance of these receptors, achieving a reversible and localized control of their activity would provide a powerful research and clinical tool. GPCR signaling is currently recognized as a multidimensional process governed by molecular, spatial and temporal components. Uncovering the role of each of these dimensions is crucial to improve our knowledge on cell communication, to understand how different pathways give rise to cellular and physiological effects, and to know how can we interact with biological systems with precision using drugs. Photopharmacology is an emerging field in which light-sensitive molecules are used to control the function of a given target protein in native tissues. The modulation of the target activity is achieved by small, drug-like, photoregulated ligands. By the use of light, both spatial and temporal control of the compound activity can be achieved in unprecedented manners compared to conventional pharmacology. These ligands have the potential to provide highly precise and controllable therapeutic actions that may result in increased efficacies and reduced side effects. Importantly, photopharmacology may allow to gain mechanistic insight on the interplay between the activation time and the receptor location during signaling processes in non-modified cells, tissues and whole organisms. Our research focused on the generation of new molecular tools for beta-adrenoceptors photopharmacology will be presented in this communication. First, several libraries of light-sensitive compounds with the aim to regulate ß-AR activity with spatiotemporal precision were designed and synthesized. Subsequent testing in cell preparations demonstrated the successful development of compounds with promising pharmacological properties, which can be reversibly and irreversibly controlled by light. Among those, several hit compounds were identified as ligands for beta-1 and beta-2 adrenoceptors with low nanomolar activities. These libraries compounds were found to be active enough to become useful photopharmacological tools, so we also performed in vivo experiments to determine their research potential in physiological environments. Indeed, the discovered molecules enabled a fine control of ß-AR in their native environment. We believe that the results of these studies will certainly open the door to innovative research procedures and may inspire future therapies targeting ß-AR.

Metabotropic glutamate 5 receptors (mGlu

Lepidopteran pests are major factors limiting soybean productivity in South America. In some cases, the control of these species requires the use of foliar insecticides. For a sustainable use of these insecticides, they should be sprayed when insect population sizes reach an economic threshold. Since this estimation requires to determine the consumption of different species, this work aimed to integrate all the main factors, studying the consumption of small-and medium-size larvae of major lepidopteran pests to vegetative and reproductive tissues on Bt and non-Bt soybeans. The damage to vegetative tissues was tested in detached-leaf assays in grow chambers, and to reproductive structures was measured in greenhouse with infestation at early (flowering) and mid reproductive (mid grain filling) stages. Based on the feeding behavior of the species tested, they were cast in four groups: a) A. gemmatalis and C. includens, defoliating only the RR variety with the lowest consumption of foliar area; b) S. eridania, defoliating both RR and IPRO varieties, consuming twice than the species mentioned above; c) H. armigera, defoliating and being the most damaging species to pods in the RR variety; d) S. cosmioides and S. frugiperda, defoliating and damaging pods in both varieties. The species differed in their ability to feed on IPRO varieties, so a different economic threshould could be considered. This clasification contributes to a recommendation of insecticide use sustainable, taking into account the behavior of these species that are major soybeans pests in South America.

Although learning second language phonology is a difficult task, orthographic input may support the learning of difficult sound contrasts through a process known as orthographic facilitation. We extended this research by examining the effects of orthographic input together with individual differences in three different phonological learning processes, namely, the production of, perception of, and memorization of words containing three Marathi phonemic contrasts (i.e., [k-kh], [], and []) by native English speakers. Moreover, because the [] and [] contrasts were particularly challenging in previous auditory training studies (e.g., Polka, 1991), we used cross-modal training in order to enhance learning by pairing auditory perception tasks with visual orthographic information, the amplification of relevant acoustic cues, and proprioceptive descriptions to the articulation of target phonemes. Results showed significant learning from the pre- to the posttest across tasks and contrasts, supporting the effectiveness of cross-modal training. Furthermore, incongruent orthographic input could inhibit perception, and orthographic input generally supported memory for word pronunciations. Moreover, individual differences regarding phonological skills and nonspeech auditory discrimination predicted participants’ success in different phonological learning processes. These results provide a detailed picture of the complexity between different aspects of second language phonological learning and cross-modal training.

Catecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of the heart. Although both β

SummaryCatecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of the heart. Although both β1- and β2-AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1-AR have proven this receptor as the main target for the therapeutic effects of beta blockers in heart. Here, we report a new strategy for the spatiotemporal control of β1-AR activation by means of light-regulated drugs with a high level of β1-/β2-AR selectivity. All reported molecules allow for an efficient real time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo-2, can be reversibly photocontrolled. Strikingly, pAzo-2 also enables a dynamic cardiac rhythm management on alive zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1-AR in native environments using light.

Catecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of the heart. Although both β1 - and β2 -AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1 -AR have proven this receptor as the main target for the therapeutic effects of beta blockers in the heart. Here, we report a new strategy for the light-control of β1 -AR activation by means of photoswitchable drugs with a high level of β1 -/β2 -AR selectivity. All reported molecules allow for an efficient real-time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo-2, can be reversibly photocontrolled. Strikingly, pAzo-2 also enables a dynamic cardiac rhythm management on living zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1 -AR in native environments using light., We thank Ignacio Pérez (IQAC-CSIC, Barcelona), Yolanda Pérez (IQAC-CSIC, Barcelona), Lourdes Muñoz (SimChem, IQAC-CSIC, Barcelona) and Carme Serra (SimChem, IQAC-CSIC, Barcelona) for technical support. We thank Diana Baxter (Institute for Research in Biomedicine, IRB, Barcelona) for her thorough revision of the language of this manuscript. We thank Dr. Kees Jalink (The Netherlands Cancer Institute, Amsterdam, the Netherlands) for providing the plasmids encoding for the Epac-SH188 biosensor. We thank the University of Vic-Central University of Catalonia (UVic-UCC) and Dr. Marta Otero for the material assignment which helped in some biological assays. We thank Nikos Hatzakis for access to the Olympus IX81 confocal microscope (UCPH, DK). This work was supported by ERDF-FEDER European Fund and Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (projects CTQ2017-89222-R and PID2020-120499RB-I00) and by the Catalan government (2017 SGR 1604) to A.L. X.R. research was financed by the Spanish Ministry of Economy, Industry and Competitiveness (SAF2015-74132-JIN). D.R. research was supported by “Agencia Estatal de Investigación” from the Spanish Ministry of Science and Innovation (project PID2020-113371RB-C21) and IDAEA-CSIC, Severo Ochoa Centre of Excellence (CEX2018-000794-S), which financed M.F. A.D.C. received the support of a fellowship from “la Caixa” Foundation (ID 100010434) under the fellowship code LCF/BQ/DE18/11670012. K.L.M., A.D. and Y.M. were supported by the Novo Nordisk Foundation (NNF20OC0064565).

Neuropathic pain is a common health problem resulting in exacerbated response to noxious and non noxious stimuli, as well as impaired emotional and cognitive responses. Unfortunately, neuropathic pain is also one of the most difficult pain syndromes to manage, highlighting the importance of better understanding the brain regions and neuromodulatory mechanisms involved in its regulation. Among the many interconnected brain areas which process pain, the amygdala is known to play an important role in the integration of sensory and emotional pain signals. Here we questioned the ability of a recently identified neuromodulatory mechanism associated with the metabotropic glutamate receptors mGlu4 in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy, we demonstrate that pharmacological activation of amygdala mGlu4 efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of these symptoms. Activating mGlu4 in the contralateral amygdala relative to the side of the mononeuropathy, is necessary and sufficient to relieve both sensory and depressive-like symptoms, while ipsilateral activation solely reduces depressive-like symptoms. Furthermore, using photopharmacology, a recent strategy allowing precise photocontrol of endogenous proteins, we further demonstrate the dynamic alleviation of neuropathic pain through light-dependent facilitation of mGlu4 by a photoswitchable positive allosteric modulator. Finally, coupling photopharmacology and analgesic conditioned place preference, we show a significant pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu4 activity to counteract neuropathy reinforcing its therapeutic interest for the treatment of pathological pain., This work was supported by the International Emerging Action (IEA) from the Centre National de la Recherche Scientifique (CNRS) to CG and AL and by grants from the French National Research Agency (ANR): ANR-16-CE16–0010 to CG and ANR-17-NEU3–0001 under the frame of Neuron Cofund to CG and AL.

Lepidopteran pests are major factors limiting soybean productivity in South America. In some cases, effective management of these species requires the use of foliar insecticides. For sustainable use of these insecticides, they should only be applied when insect population size exceeds an economic threshold. Since this estimation requires to determine the consumption of different species, this work aimed to integrate all these factors, studying the consumption of small (less than 1 cm long) and medium (1 to 1.5 cm long) size larvae of major lepidopteran pests to vegetative and reproductive tissues on Bt (M7739IPRO variety, containing the event MON87701 which expresses the Cry1Ac protein from Bacillus thuringiensis) and non-Bt (BMX Desafio RR variety) soybeans. The feeding injury to vegetative tissues was tested in detached-leaf assays in grow chambers, and for reproductive structures the study was conducted in greenhouse with infestations at early (flowering) and mid reproductive (mid grain filling) stages. Based on the feeding behavior of the species tested, they were cast in four groups: a) Anticarsia gemmatalis and Chrysodeixis includens, defoliating only the RR variety with the lowest consumption of foliar area; b) Spodoptera eridania, defoliating both RR and IPRO varieties, consuming twice than the species mentioned above; c) Helicoverpa armigera, defoliating and being the most damaging species to pods in the RR variety; and d) S. cosmioides and S. frugiperda, defoliating and damaging pods in both varieties. The species differed in their ability to feed on IPRO varieties, so a different economic threshold should be considered. Consequently, in cases where more than one species are found simultaneously, the species composition should be considered in estimating the economic threshold. Additionally, our findings may contribute to a better decision-making to control insect feeding injury in IPRO varieties, because a slower larval growth provides more time to ensure the need of control with insecticides. In summary, this clasification contributes to an improved recommendation of sustainable insecticide use, taking into account the behavior of each species that are major soybeans pests in South America.

Including contributions from a team of world-renowned international scholars, this volume is a state-of-the-art survey of second language speech research, showcasing new empirical studies alongside critical reviews of existing influential speech learning models. It presents a revised version of Flege's Speech Learning Model (SLM-r) for the first time, an update on a cornerstone of second language research. Chapters are grouped into five thematic areas: theoretical progress, segmental acquisition, acquiring suprasegmental features, accentedness and acoustic features, and cognitive and psychological variables. Every chapter provides new empirical evidence, offering new insights as well as challenges on aspects of the second language speech acquisition process. Comprehensive in its coverage, this book summarises the state of current research in second language phonology, and aims to shape and inspire future research in the field. It is an essential resource for academic researchers and students of second language acquisition, applied linguistics and phonetics and phonology.

Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS-0208, an unprecedented arylthioether-phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α-galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’-OH and 3’-OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation., Financial support by the Ministry of Economy, Industry and Competitiveness (CTQ2014-57020-R and CTQ2011-29549-C02-01 grants) is gratefully acknowledged. Pre-doctoral FPU Spanish research and teaching fellowship from the Ministry of Education, Culture and Sport (FPU2013-01783 for R. Borràs-Tudurí grant and AP2007-01826 for A. Alcaide grant) are also acknowledged.

Stroke and traumatic injury in brain or spinal cord are often life-threating conditions and major causes of death or permanent disability with high impact in the health care system. There are several stages of intervention to improve the neurological outcome. Acutely, fast interventions aiming to reestablish cerebral blood flow in ischemic stroke, to stop bleeding after brain hemorrhage, and to reduce edema after contusions are amongst mandatory actions. Current studies aim to develop accompanying strategies for brain cell protection based on enhancing endogenous protective mechanism, blocking cell death pathways, or through immunomodulation. After the acute phase, interventions are intended to promote recovery of function using rehabilitation with state-of-the-art technologies enabled by robotics. Other advanced strategies include cell, gene, and immune therapies, and brain function modulation with the aid of smart nanotechnologies. There is great expectation in the fast evolving novel approaches for improvement of neurological deficits in these unpredictable and devastating condition

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Supplemental material, supplemental_material for Chinese-English Speakers’ Perception of Pitch in Their Non-Tonal Language: Reinterpreting English as a Tonal-Like Language by Marta Ortega-Llebaria and Zhaohong Wu in Language and Speech

We present an in-depth characterization of the polarimetric channel of the Large-Angle Spectrometric COronagraph LASCO-C2 onboard the Solar and Heliospheric Observatory (SoHO). The polarimetric analysis of the white-light images makes use of polarized sequences composed of three images obtained though three polarizers oriented at +60{\deg}, 0{\deg} and -60{\deg}, complemented by a neighboring unpolarized image, and relies on the formalism of Mueller. The Mueller matrix characterizing the C2 instrument was obtained through extensive ground-based calibrations of the optical components and global laboratory tests. Additional critical corrections were derived from in-flight tests relying prominently on roll sequences and on consistency criteria, mainly the tangential direction of polarization. Our final results encompass the characterization of the polarization of the white-light corona, of its polarized radiance, of the two-dimensional electron density, and of the K-corona over two solar cycles. They are in excellent agreement with measurements obtained at several solar eclipses except for slight discrepancies affecting the innermost part of the C2 field-of-view, probably resulting from an imperfect removal of the bright diffraction fringe surrounding the occulter., Comment: 72 pages, 51 figures

Supplemental material, supplemental_material for Chinese-English Speakers’ Perception of Pitch in Their Non-Tonal Language: Reinterpreting English as a Tonal-Like Language by Marta Ortega-Llebaria and Zhaohong Wu in Language and Speech

The spatiotemporal control of cellular dynamic processes has great fundamental interest but lacks versatile molecular tools. Dynamin is a key protein in endocytosis and an appealing target to manipulate cell trafficking using patterns of light. We have developed the first photoswitchable small-molecule inhibitors of endocytosis (dynazos), by a stepwise design of the photochromic and pharmacological properties of dynasore, a dynamin inhibitor. We have characterized their photochromism with UV-visible and transient absorption spectroscopy and their biological activity using fluorescence microscopies and flow cytometry. Dynazos are water-soluble, cell permeable, and photostable, and enable fast, single-wavelength photoswitchable inhibition of clathrin-mediated endocytosis at micromolar concentration.

In English, positions of lexical stress in disyllabic words are associated with word categories; that is, nouns tend to be stressed more often on the first syllable, whereas verbs are more likely to be stressed on the second syllable (i.e. subject (noun) vs. subject (verb)). This phenomenon, which is called the stress typicality effect, has been shown to facilitate word recognition to native English speakers. However, there is little research on whether it also facilitates word recognition to non-native speakers of English, in particular, to English learners with a tonal first language. To fill this research gap, the present study investigated whether the stress typicality effect modulated word recognition in native speakers of Chinese who learned English as a second language. Both visual grammatical classification and lexical decision tasks were administered to ESL learners with intermediate and advanced English proficiency. The results revealed that Chinese intermediate ESL learners were not sen...

Resumen Antecedentes y objetivo Los informes recientes sobre brotes de lipoatrofia semicircular (LS) en diversos paises han generado debate acerca del papel potencial de las caracteristicas ambientales de los puestos de trabajo en los nuevos edificios. El objetivo de este estudio fue investigar la sospecha de un brote de LS entre los ninos de una guarderia publica de Barcelona, lo cual genero una tremenda alarma. Metodos Realizamos una valoracion epidemiologica, incluyendo analisis descriptivo y de prevalencia, y una investigacion ambiental seguida de una valoracion psiquiatrica de acuerdo con los criterios de Small. Comparamos la prevalencia de LS y su intervalo de confianza del 95% entre los ninos y entre el personal de la guarderia en estudio, y con otros centros. Resultados Entre los 86 ninos que acudieron a la guarderia detectamos 11 casos confirmados y 2 casos posibles de LS (15,1%), y entre los 41 ninos que acudieron a otros centros identificamos 8 casos confirmados y 4 casos posibles (29,3%) (p = 0,10). Entre el personal de la guarderia, detectamos 8 casos de LS (66,7%), y entre las 19 mujeres que trabajaban en otros sitios identificamos 14 con la misma condicion que el personal (73,7%) (p = 0,98). Se clasificaron finalmente todas las lesiones como hendiduras con diferentes localizaciones. La evaluacion ambiental no identifico ningun factor de riesgo con relacion significativa con la aparicion del brote. Dicho brote compartio 13 de los criterios de Small en relacion con el trastorno somatoforme epidemico («histeria colectiva»). Conclusion La presencia de hendiduras puede considerarse como una variante de la normalidad en las extremidades inferiores de los ninos. El desarrollo caracteristico del proceso nos conduce a la conclusion de que este brote fue un trastorno somatoforme epidemico.

Resumen: Este trabajo describe el proceso de revisión del catálogo de servicios de salud pública de la ciudad de Barcelona para responder a la reducción presupuestaria producida a partir de 2010 en las administraciones públicas en España. Se basó en un grupo de trabajo que revisó las diferentes líneas de actividad, teniendo en cuenta los gastos y los ingresos asociados y su razón de ser, valorando factores como la obligación legal de desempeño, la financiación finalista, la petición explícita por las administraciones fundadoras y la existencia o no de otros actores capaces de asumirla. Se describen los cambios y sus consecuencias. Se valora que el nuevo catálogo está consolidado y se considera ratificado por los órganos de gobierno, que se han renovado tras los relevos políticos. Creemos que esto es fruto de haberlo basado en el consenso profesional y los criterios de gestión, claves para el buen funcionamiento de un organismo autónomo ejecutivo de carácter público. Abstract: This paper describes the review process of the Agency of Public Health of Barcelona's service portfolio in response to the budget cuts introduced since 2010 in the public administrations in Spain. A working group reviewed the different business activities, taking into account their costs and generated revenue and their justification, assessing factors such as the existence of legal constraints, tied funding, explicit demands from the founding administrations and other actors that may be capable of undertaking particular activities. The changes and their consequences are described. The new service portfolio has been consolidated and is considered ratified by the Agency board, which was renewed after political changes. We conclude that this is because it was based on professional consensus and management criteria, which are key for the smooth operation of a public autonomous executive organisation. Palabras clave: Administración de salud pública, Organización y administración, Administración pública, Práctica de la salud pública, Keywords: Public health administration, Organisation and administration, Public administration, Public health practice

International audience; Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences.

Optopharmacology is a very promising approach based on the use of light-deliverable drugs, which allows manipulating physiological processes with high spatiotemporal resolution. Light-dependent drugs (i.e. caged-compounds) targeting G protein-coupled receptors (GPCRs) have been developed to provide great pharmacological precision on the control of pain. Metabotropic glutamate type 5 (mGlu

Optopharmacology is a very promising approach based on the use of light-deliverable drugs, which allows manipulating physiological processes with high spatiotemporal resolution. Light-dependent drugs (i.e. caged-compounds) targeting G protein-coupled receptors (GPCRs) have been developed to provide great pharmacological precision on the control of pain. Metabotropic glutamate type 5 (mGlu5) receptors are widely expressed through the pain neuraxis and play a key role in pain transmission. In line with this, selective mGlu5 receptor negative allosteric modulators (NAMs) have consistently shown analgesic activity in experimental animal models of inflammatory pain. Accordingly, we synthesized a light-deliverable drug (i.e. caged compound) using the chemical structure of raseglurant, a mGlu5 receptor NAM, as a molecular scaffold. And thereafter, we evaluated the analgesic activity of the caged compound in formalin-injected (hind paw) mice upon light irradiation (405 nm). Of note, light was both delivered at the peripheral (i.e. hind paw) and central level (i.e. thalamus), by means of brain-implanted fiber-optics. The novel light-deliverable drug, JF-NP-26, showed antinociceptive activity upon violet light irradiation either of the hind paw or the thalamus, demonstrating the ability of precisely activating, in time and space, the caged compound. Here, we describe in detail the protocol used to perform a reliable and reproducible formalin nociception test in mice using an optopharmacology approach (i.e. light-deliverable compounds).

OptoGluNAM4.1, a negative allosteric modulator (NAM) of metabotropic glutamate receptor 4 (mGlu4) contains a reactive group that covalently binds to the receptor and a blue-light-activated, fast-relaxing azobenzene group that allows reversible receptor activity photocontrol in vitro and in vivo. OptoGluNAM4.1 induces light-dependent behavior in zebrafish and reverses the activity of the mGlu4 agonist LSP4-2022 in a mice model of chronic pain, defining a photopharmacological tool to better elucidate the physiological roles of the mGlu4 receptor in the nervous system. © 2016 Elsevier Ltd, We are grateful to C. Serra, L. Muñoz, J. Hernando, F. Malhaire, Y. Pérez, M. Izquierdo-Serra, F. Aguado, S. Laffray, E. Bourinet, F.Codony (GenIUL), and Y. Chomis (Viewpoint) for helpful discussions and technical support. A.F. is supported by a Fondation Lefoulon Delalande postdoctoral fellowship , C.J. by a grant from INSERM ATIP-AVENIR and Marie Curie CIG ( PCIG12-GA-2012-332772 ). A.F. and C.J. are members of the Laboratory of Excellence Ion Channel Science and Therapeutics supported by a grant from the ANR . J.-P.P. is a member of the Laboratory of Excellence Epingenmed. We acknowledge financial support from the European Union's Seventh Framework Program for research, technological development, and demonstration under grant agreements 270483 (Focus), 210355 (Opticalbullet), and 335011 (Theralight) to P.G.; the Federation of European Biochemical Societies ; the Catalan government ( 2012FI_B 01122 to S.P., 2014SGR-1251 to P.G., and 2014SGR-0109 to A. Llebaria); the Spanish Government ( SAF2014-58396-R to J.G., CTQ2014-57020-R to A.L., and CTQ2013-43892R to P.G.); the ERANET Neuron LIGHTPAIN project (to A.L., J.G., and J.-P.P.); the Ramón Areces Foundation , the ERANET SynBio Modulightor project (to P.G.); the HBP Wavescales project (to P.G.); the Fondation Recherche Médicale (FRM team DEQ20130326522 to J.P.P.); the Agence Nationale de la Recherche ( ANR-13-BSV1-006 to C.G.) and the Beatriu de Pinós program of Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) for the support of X.R.

DERMATOFIBROSARCOMA PROTUBERANS - Tumor cutáneo raro, de lento crecimiento, asintomático, localmente agresivo, con tendencia a la recurrencia. Rara vez metastatiza. - Puede aparecer a cualquier edad, pero es más frecuente entre los 20 y los 50 años. Leve prevalencia en los hombres.

Cross-language studies have shown that English speakers use suprasegmental cues to lexical stress less consistently than speakers of Spanish and other Germanic languages ; accordingly, these studies have attributed this asymmetry to a possible trade-off between the use of vowel reduction and suprasegmental cues in lexical access. We put forward the hypothesis that this “cue trade-off” modulates intonation processing as well, so that English speakers make less use of suprasegmental cues in comparison to Spanish speakers when processing intonation in utterances causing processing asymmetries between these two languages. In three cross-language experiments comparing English and Spanish speakers’ prediction of hypo-articulated utterances in focal sentences and reporting speech, we have provided evidence for our hypothesis and proposed a mechanism, the Cue-Driven Window Length model, which accounts for the observed cross-language processing asymmetries between English and Spanish at both lexical and utterance levels. Altogether, results from these experiments illustrated in detail how different types of low-level acoustic information (e.g., vowel reduction versus duration) interacted with higher-level expectations based on the speakers’ knowledge of intonation providing support for our hypothesis. These interactions were coherent with an active model of speech perception that entailed real-time adjusting to feedback and to information from the context, challenging more traditional models that consider speech perception as a passive, bottom-up pattern-matching process.

New technologies for spatial and temporal remote control of G protein-coupled receptors (GPCRs) are necessary to unravel the complexity of GPCR signalling in cells, tissues and living organisms. An effective approach, recently developed, consists on the design of light-operated ligands whereby light-dependent GPCR activity regulation can be achieved. In this context, the use of light provides an advantage as it combines safety, easy delivery, high resolution and it does not interfere with most cellular processes. In this review we summarize the most relevant successful achievements in GPCR photopharmacology. These recent findings constitute a significant advance in research studies on the molecular dynamics of receptor activation and their physiological roles in vivo. Moreover, these molecules hold potential toward clinical uses as light-operated drugs, which can overcome some of the problems of conventional pharmacology. © 2019 Elsevier B.V., We acknowledge financial support from the ERANET Neuron LIGHTPAIN and MAGNOLIA projects, the Spanish Ministry of Science, Innovation and Universities (CTQ2014-57020-R and CTQ2017-89222-R), cofinanced by the European Regional Development Fund and the Catalan Government (2017SGR01604).

This paper, “Reconstruction d'images spatiales a haute resolution temporelle," was presented as part of International Conference on Space Optics—ICSO 1997, held in Toulouse, France.

Glutamate is the major excitatory neurotransmitter of the mammalian central nervous system (CNS). Its actions are mediated by two broad classes of receptors: ligand-gated ion channels and G-protein-coupled receptors (GPCRs), named ionotropic and metabotropic glutamate receptors (mGluRs), respectively. The mGluR family consists of eight subtypes which are responsible for glutamate neuromodulatory actions throughout the CNS. These receptors are complex allosteric machines, offering multiple possibilities to regulate their activity. Their structure is composed of a seven-helix transmembrane domain, common to all GPCRs, and a large bilobate extracellular domain (ECD) where glutamate binds. Moreover, mGluRs are constitutive dimers crosslinked by a disulfide bridge. This chapter will provide an overview of mGluR structure, dynamics, and pharmacology, describing the different types of pharmacological tools that modulate mGluRs function, from orthosteric to allosteric molecules, including nanobodies, ions, and light-operated ligands.

Long-term experience with a tonal language shapes pitch perception in specific ways, and consequently Chinese speakers may not process pitch in English words – e.g., “Rose?” spoken as a question versus “Rose” spoken as a statement – in the same way as native speakers of non-tonal languages do. If so, what are those pitch processing differences and how do they affect Chinese recognition of English words? We investigated these questions by administering a primed lexical-decision task in English to proficient Chinese–English bilinguals and two control groups, namely, Spanish–English and native English speakers. Prime-target pairs differed in one sound and/or in pitch. Results showed specific cross-language differences in pitch processing between the Chinese speakers and the control groups, confirming that experience with a tonal language shaped the perception of English words' intonation. Moreover, such experience helps to incorporate pitch into models of word-recognition for bilinguals of tonal and non-tonal languages.

This paper documents for the first time the intonation system of Tucumán Spanish, an understudied variety of Argentinian Spanish. Semi-spontaneous speech illustrating the intonation of main sentence types, i.e. broad focus statements, partial and absolute interrogatives, and imperatives and vocatives, was elicited from 31 native speakers of Tucumán Spanish via an adapted version of the Argentinian Intonation Survey (Prieto and Roseano, 2009-2013). The two authors listened to the recordings and transcribed them using the Tones and Break Indexes conventions (ToBI) (Beckman et al. 2002, Prieto and Roseano 2010, Hualde and Prieto 2015). Transcriptions of prenuclear and nuclear configurations together with their respective frequencies allowed both an appreciation of the most used configurations within each sentence type along with detailed variation at the phonetic level. For example, yes/no questions were consistently realized with a low nuclear pitch accent L* and an ascending boundary tone. However, there was variation in the height of the boundary tones yielding the frequent contour L* ¡H%, and the less frequent L* H%. Altogether, these detailed patterns document the systematic phonetic variation of the intonation system of TS and provide a basis for future research to determine the phonological status of this variation.

The metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) that modulate synaptic activity and plasticity throughout the mammalian brain. Signal transduction is initiated by glutamate binding to the venus flytrap domains (VFT), which initiates a conformational change that is transmitted to the conserved heptahelical domains (7TM) and results ultimately in the activation of intracellular G proteins. While both mGlu1 and mGlu5 activate Gαq G-proteins, they also increase intracellular cAMP concentration through an unknown mechanism. To study directly the G protein coupling properties of the human mGlu5 receptor homodimer, we purified the full-length receptor, which required careful optimisation of the expression, N-glycosylation and purification. We successfully purified functional mGlu5 that activated the heterotrimeric G protein Gq. The high-affinity agonist-PAM VU0424465 also activated the purified receptor in the absence of an orthosteric agonist. In addition, it was found that purified mGlu5 was capable of activating the G protein Gs either upon stimulation with VU0424465 or glutamate, although the later induced a much weaker response. Our findings provide important mechanistic insights into mGlu5 G protein-dependent activity and selectivity.

In Mandarin Chinese pitch is used to express both lexical meanings via tones and sentence-level meanings via pitch-accents raising the question of which information is processed first. While research with meaningful sentence materials suggested a general processing advantage of tone over pitch-accents, research on pure tones and nonce speech in pre-attentive processing found that the f0-shape led to timing and site processing differences. The current study reconciles these results by exploring whether the tone advantage found in meaningful speech materials is modulated by the f0-shape by establishing via a gating paradigm the relative timing of tone and pitch-accent identification. Target words containing static (T1) and dynamic (T2, T4) tones were embedded into meaningful sentences and were divided into 50 ms gates which were added incrementally either from the left- or right-edge of the target word. Results showed that dynamic targets had either a tone or pitch-accent advantage contingent on the direction of gate processing. In contrast, for static T1 targets, tone and pitch-accent were identified simultaneously regardless of the direction of gate processing. Altogether, these results indicate that the f0-shape, as defined by pitch dimensions of f0 and pitch range, mediates the timing of tone and pitch-accent identification in meaningful speech supporting highly interactive models of speech perception.

Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug’s release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders. © Font et al., This work was supported by MINECO/ISCIII (SAF2014-55700-P, PCIN-2013–019 C03-03 and PIE14/ 00034), the Catalan Government (2014 SGR 1054), ICREA (ICREA Academia-2010), Fundació la Marató de TV3 (Grant 20152031) and IWT (SBO-140028) to FC. MINECO (PCIN-2013–018 C03-02 and SAF2014-58396-R) to JG. MINECO (PCIN-2013–017 C03-01 and CTQ2014-57020-R), the Catalan Government (2014SGR109 and 2014CTP0002) to AL. ERANET Neuron project ‘LIGHTPAIN’ (to AL, JG, PC and FN). MINECO (CTQ2013-48767-C3-1-R and CTQ2015-71896-REDT), the Catalan Government (2014SGR304) to SN RB-O thanks the European Social Funds and the SUR del DEC de la Generalitat de Catalunya for a predoctoral fellowship (2016 FI_B1 00021).