Pharmaceutical innovations: the grand challenges ahead

Copyright © 2020 Aroeira and Castanho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Lifestyles are evolving rapidly due to swiftly evolving technologies rapid exchange of information across the globe, and facilitated mobility of people across long distances. In addition, climate changes accelerate the geographical dynamics of disease. The result is that both communicable and non-communicable diseases pose challenges never faced before and the perception of the way pharmaceutical sciences are dealing with such changes is under unprecedented scrutiny. The discredit in science-based solutions has a tremendous societal impact and is detrimental to evidence-based pharmacology at large. Pharmaceutical innovation that target the needs of healthy living and meet the expectation of society are urgently needed and are a worthy effect of both industrial and academic researchers. A reflection on the grand challenges ahead in thus timely and appropriate.This work was supported by La Caixa Foundation (grant reference: IMM/BPD/107-2018 to RA).info:eu-repo/semantics/publishedVersio

Regulation of hippocampal postnatal and adult neurogenesis by adenosine A 2A receptor: Interaction with brain-derived neurotrophic factor

21 páginas, 7 figuras.Adenosine A2A receptor (A2A R) activation modulates several brain processes, ranging from neuronal maturation to synaptic plasticity. Most of these actions occur through the modulation of the actions of the neurotrophin brain-derived neurotrophic factor (BDNF). In this work, we studied the role of A2A Rs in regulating postnatal and adult neurogenesis in the rat hippocampal dentate gyrus (DG). Here, we show that A2A R activation with CGS 21680 promoted neural stem cell self-renewal, protected committed neuronal cells from cell death and contributed to a higher density of immature and mature neuronal cells, particularly glutamatergic neurons. Moreover, A2A R endogenous activation was found to be essential for BDNF-mediated increase in cell proliferation and neuronal differentiation. Our findings contribute to further understand the role of adenosinergic signaling in the brain and may have an impact in the development of strategies for brain repair under pathological conditions.Fundaç~ao para a Ciência e a Tecnologia, Grant/Award Numbers: IF/01227/2015, SFRH/BD/74662/2010, IMM/CT/35-2018, SFRH/BD/128280/2017, SFRH/BD/129710/2017; H2020-WIDESPREAD-05-2020-Twinning (EpiEpinet) under grant agreement No, Grant/Award Number: 9524; Ministerio de Ciencia e Innovaci on, Grant/Award Number: PID2019-111225RB-I00; Spanish MICIU, Grant/Award Number: SAF2015-70433-R; Generalitat Valenciana, Grant/Award Number: PROMETEO/2018/055; COST Action, Grant/Award Number: BM1402Peer reviewe

Can citation metrics predict the true impact of scientific papers?

© 2020 Federation of European Biochemical SocietiesBibliometric quantification is frequently used as metrics for the evaluation of the scientific performance of researchers and institutions. The researchers’ merit is usually assessed by the analysis of quantitative parameters such as the number of publications, the impact factor of journals, the total number of citations, or the h-index, although the limitations in translating these indicators into the impact of the outcome of scientific production are a matter of harsh criticism. To assess, based on factual evidences, the validity of traditional bibliometric analyses to conclude on the impact of papers to advance the state of the art, we carried out an innovative methodology on selected publications (test set). This methodology is based on identifying those citations of the test set papers that truly embed the methods, concepts, or hypotheses to build new knowledge and formulate conclusions. The results show that the percentage of citations that reflect the real impact of the papers of the test set has an average value of 12.4% of total citations and is not related to the impact factor of the journal where the test set papers were published. In conclusion, our analysis demonstrates factually, using experimental data, the total failure of using quantitative bulk citation analyses to conclude on the scientific impact of publications. Only a careful analysis of how the work described in papers was embedded on the subsequent work and/or conclusions of others can tell about the real contribution of a published work to the development of new knowledge and advancement of science.This work was supported by ‘La Caixa’ Foundation (grant reference: IMM/BPD/107-2018).info:eu-repo/semantics/publishedVersio

Can citation metrics predict the true impact of scientific papers?

© 2020 Federation of European Biochemical SocietiesBibliometric quantification is frequently used as metrics for the evaluation of the scientific performance of researchers and institutions. The researchers’ merit is usually assessed by the analysis of quantitative parameters such as the number of publications, the impact factor of journals, the total number of citations, or the h-index, although the limitations in translating these indicators into the impact of the outcome of scientific production are a matter of harsh criticism. To assess, based on factual evidences, the validity of traditional bibliometric analyses to conclude on the impact of papers to advance the state of the art, we carried out an innovative methodology on selected publications (test set). This methodology is based on identifying those citations of the test set papers that truly embed the methods, concepts, or hypotheses to build new knowledge and formulate conclusions. The results show that the percentage of citations that reflect the real impact of the papers of the test set has an average value of 12.4% of total citations and is not related to the impact factor of the journal where the test set papers were published. In conclusion, our analysis demonstrates factually, using experimental data, the total failure of using quantitative bulk citation analyses to conclude on the scientific impact of publications. Only a careful analysis of how the work described in papers was embedded on the subsequent work and/or conclusions of others can tell about the real contribution of a published work to the development of new knowledge and advancement of science.This work was supported by ‘La Caixa’ Foundation (grant reference: IMM/BPD/107-2018).info:eu-repo/semantics/publishedVersio

BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes

© 2015 Wiley Periodicals, Inc.Glycine transporters (GlyT), GlyT1 and GlyT2, are responsible for the termination of glycine-mediated synaptic activity through removal of neurotransmitter from synaptic cleft. Brain-derived neurotrophic factor (BDNF) activates its high affinity tropomyosin-related kinase (Trk) receptors, namely TrkB, which includes full length (TrkB-FL) and truncated (TrkB-T) isoforms. In this article we evaluated the influence of BDNF upon the activity of glycine transporters in astrocytes. We report that BDNF decreases GlyT1- and GlyT2- mediated [(3) H]glycine transport in primary cultures of astrocytes from rat cerebral cortex. BDNF decreased Vmax but not Km values of transport, which suggests that BDNF induces transporter internalization. Accordingly, dynasore, an inhibitor of dynamin/clathrin-dependent endocytosis, prevented the influence of BDNF upon GlyT-mediated transport. While quantifying mRNA and protein levels, we detected a predominance of truncated isoforms over the TrkB-FL receptor. The effect of BDNF was not abolished by specific inhibitors of PLCγ, PI3K and MAPK, indicating that it did not occur through TrkB-FL canonical pathways. However, BDNF action was lost in the presence of a Rho family-specific blocker (toxin B), a signaling pathway that has been associated to TrkB-T1. Furthermore, the effect of BDNF was abolished upon TrkB-T knockdown in astrocytes by RNA interference. Immunofluorescence assays confirmed an increased GlyT expression in endosomes upon BDNF incubation, which was prevented in the presence of either dynasore or toxin B. We conclude that BDNF, acting on TrkB-T1 receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism.Fundação para a Ciência e a Tecnologia (FCT), Portugal. Grant Number: SFRH/BD/62831/2009info:eu-repo/semantics/publishedVersio

BDNF modulates glycine uptake in hippocampal synaptosomes by decreasing membrane insertion of glycine transporter 2

© 2016 Elsevier Ltd. All rights reserved.Glycine transporter 2 (GlyT2) is localized in the nerve terminals of glycinergic neurons, promoting glycine uptake and ensuring the refilling of glycinergic vesicles. Brain-derived neurotrophic factor (BDNF) activates its high affinity TrkB receptors, which occur in two isoforms, full length (TrkB-FL) and truncated (TrkB-T1/T2). After BDNF binding to TrkB receptor, several intracellular cascades are triggered, specifically PLC, Akt and MAPK signalling pathways. We herein show that BDNF decreases [(3)H]glycine uptake mediated by GlyT2 in isolated nerve endings (synaptosomes) obtained from rat hippocampus, by reducing the maximum velocity (Vmax) of transport while not influencing the transporter affinity constant (Km) for glycine. Western Blot analysis detected both TrkB receptor isoforms in the synaptosomes but the BDNF effect seems to be mediated by TrkB-FL since: 1) the tyrosine kinase inhibitor, k252a, prevented the effect of BDNF, and 2) the effect of BDNF was lost in the presence of specific inhibitors of TrkB signalling pathways, namely U73122, LY294002 and U0126 (inhibitors of PLC, Akt and MAPK pathways, respectively). Monensin, a transporter recycling inhibitor, prevented the BDNF action upon glycine uptake, suggesting that BDNF reduces GlyT2 insertion in the plasma membrane. It is concluded that BDNF effect upon glycine uptake into glycinergic nerve terminals requires the activation of the TrkB-FL receptor and its canonical signalling pathways and occurs by inhibiting GlyT2 membrane incorporation.This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal. Rita I. Aroeira and Sandra H. Vaz were in receipt of fellowships from FCT, SFRH/BD/62831/2009 and SFRH/BPD/81627/2011, respectively. BDNF was a kind gift from Regeneron Pharmaceuticals.info:eu-repo/semantics/publishedVersio

Uptake and metabolism of arginine impact Plasmodium development in the liver

International audiencePrior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host's liver cells that depends on the parasite's ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg) uptake through the host cell's SLC7A2-encoded transporters is essential for the parasite's development and maturation in the liver. Our data suggest that the Arg that is taken up is primarily metabolized by the arginase pathway to produce the polyamines required for Plasmodium growth. Although the parasite may hijack the host's biosynthesis pathway, it relies mainly upon its own arginase-AdoMetDC/ODC pathway to acquire the polyamines it needs to develop. These results identify for the first time a pivotal role for Arg-dependent polyamine production during Plasmodium's hepatic development and pave the way to the exploitation of strategies to impact liver infection by the malaria parasite through the modulation of Arg uptake and polyamine synthesis

Evaluation of body posture in nursing students

Abstract OBJECTIVE To investigate the body posture of nursing students before and after clinical practice. METHOD The study was developed in two stages. Initially the body posture of students of the 2nd, 4th, 6th, and 8th periods were assessed through photogrammetry. All images were analyzed in a random and masked manner with CorporisPro® 3.1.3 software. Three evaluations were performed for each angle and then the mean value was calculated. Two years later, when the 4th period students had developed their clinical internships, their body posture was again evaluated. RESULTS The total sample consisted of 112 students. Comparison of their posture with the normality pattern showed that all the angles presented significant differences (p< 0.00), except for the angle of the Thales triangle. Reassessment of these students evidenced significant differences in the angles of the acromioclavicular joint (p=0.03), knee flexion (p< 0.00) and in the tibiotarsal angle (p< 0.00). CONCLUSION All the students presented alterations when compared to the normality values. The segments that presented significant differences between before and after practice were the acromioclavicular angle, knee flexion, and tibiotarsal angle; the latter two were in the rolling position