Producing progress? Issues to consider

Existeix una creixent llacuna en la productivitat de la indústria biofarmacèutica: els diners gastats en el desenvolupament de nous fàrmacs ha augmentat molt, però el gran augment esperat de noves teràpies basades en les revolucions recents de la biologia molecular i la genètica encara no s'han materialitzat. El llarg temps d'aprovació de nous fàrmacs, l'alt índex de fracassos, i l'alt nivell de competència són algunes de les raons d'aquesta situació. Hi ha qui sosté que els empresaris no estan promovent nous descobriments fonamentals i senzillament es beneficien del coneixement que es genera al món acadèmic. De fet, la investigació finançada amb fons públics està liderant un camp completament nou i el desenvolupament d'un nou escenari per a la medicina. El coneixement adquirit ha canviat enormement la nostra manera d'encarar les malalties. Com a resposta a aquest canvi, cal un nou model que tingui en compte com s'inverteix en innovació, i també com es fa la innovació.There is a growing gap in productivity in the biopharmaceutical industry. The money spent on developing new drugs has increased substantially, but the hoped-for dramatic increase in new therapies based on recent revolutions in molecular biology and genetics has yet to materialize. Long approval times, high-failures rates, and high-competition account in part for this situation. Some argue that entrepreneurs are not promoting fundamental, new discoveries and instead are simply profiting from the knowledge generated by academia. In fact, publicly funded research is driving progress in a completely new field and the development of a completely new landscape of medicine. The knowledge thereby acquired has dramatically changed the approach to targeting disease. In response, a new model is needed, one that addresses how investment in innovation is driven, but also how innovation is done. [Contrib Sci 10:29-34 (2014)

Top ten discoveries of the year: Neurodevelopmental disorders

Developmental brain disorders, a highly heterogeneous group of disorders with a prevalence of around 3% of worldwide population, represent a growing medical challenge. They are characterized by impaired neurodevelopmental processes leading to deficits in cognition, social interaction, behavior and motor functioning as a result of abnormal development of brain. This can include developmental brain dysfunction, which can manifest as neuropsychiatric problems or impaired motor function, learning, language or non-verbal communication. Several of these phenotypes can often co-exist in the same patient and characterize the same disorder. Here I discuss some contributions in 2019 that are shaking our basic understanding of the pathogenesis of neurodevelopmental disorders. Recent developments in sophisticated in-utero imaging diagnostic tools have raised the possibility of imaging the fetal human brain growth, providing insights into the developing anatomy and improving diagnostics but also allowing a better understanding of antenatal pathology. On the other hand, advances in our understanding of the pathogenetic mechanisms reveal a remarkably complex molecular neuropathology involving a myriad of genetic architectures and regulatory elements that will help establish more rigorous genotype-phenotype correlations

Neurociencia y repercusión biopolítica del conocimiento sobre la discapacidad intelectual

La neurociencia requiere un escenario multidisciplinar con planteamientos y puntos de vista filosóficos, sociológicos, psiquiátricos, psicólogos, políticos, o biológicos: cada uno de ellos con una mirada complementaria y necesaria para abordar la relación entre mente, cerebro, y comportamiento humano. Ciertamente, los científicos no deben dejarse influir por objetivos de tipo político o cultural que nada tiene que ver con la esencia de nuestra profesión. La neurociencia nos provee de información que nos hace conscientes de nuestros sesgos subjetivos y nos permite estar alerta frente a nuestros miedos y a cómo éstos condicionan nuestra conducta y nuestra toma de decisiones. Es decir, nos permite luchar contra los estereotipos, y mejorar la aceptación social de la diversidad funcional

The AE-BKH Disputatio of Barcelona 2013-2016

The Barcelona Knowledge Hub of the Academia Europaea (AE- BKH)was set up in Barcelona in 2013 as the office for the Southern European region and the Mediterranean. The Academia Europaea is a pan-European, nongovernmental, not-for-profit association of over 4000 individual scien- tists and scholars who are recognized as experts and leaders in their own fields. It is committed to identifying topics of trans-European importance to science and scholarship, and provides, where appropriate, its expertise and its independent and impartial advice to European institutions, governments and international agencies concerning matters affecting science, scholarship and academic life in Europe. The AE-BKH organizes multidisciplinary activities that consider the perspective of the social sciences and the humanities, with scholarly aims as well as the goal of promoting the dissemination of science. One of the very special activities of the AE-BKH is the celebration of the pres- ent-day Disputatio of Barcelona as a remembrance of the original Disputatio of Barcelona held in 1263.Until present, four moder-day Disputationes have been held, from 2013 until 2016 [Contrib Sci 12:xx-xx (2016)

Neurodevelopmental disorders: 2021 update

One of the current challenges in the field of neurodevelopmental disorders (NDDs) is still to determine their underlying aetiology and risk factors. NDDs comprise a diverse group of disorders primarily related to neuro-developmental dysfunction including autism spectrum disorder (ASD), developmental delay, intellectual dis-ability (ID), and attention-deficit/hyperactivity disorder (ADHD) that may present with a certain degree of cognitive dysfunction and high prevalence of neuropsychiatric outcomes. Last year, advances in human ge-nomics have begun to shed light on the genetic architecture of these disorders and large-scale sequencing studies are starting to reveal mechanisms that range from unique genomic DNA methylation patterns (i.e. “episignatures”) to highly polygenic conditions. In addition, the contribution of de novo somatic mutations to neurodevelopmental diseases is being recognized. However, progressing from genetic findings to underlying neuropathological mechanisms has proved challenging, due to the increased resolution of the molecular and genetic assays. Advancement in modelling tools is likely to improve our understanding of the origin of neuro-developmental disorders and provide insight into their developmental mechanisms. Also, combined in vivo editing of multiple genes and single-cell RNA-sequencing (scRNA-seq) are bringing us into a new era of un-derstanding the molecular neuropathology of NDDs

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome: a randomized phase Ib clinical trial (PERSEUS study)

© 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. Methods: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. Results: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in theEGCGgroup and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. Conclusion: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population.Peer ReviewedArticle signat per 26 autors/es: Cécile Cieuta-Walti, Aida Cuenca-Royo, Klaus Langohr, Claire Rakic, Ma Ángeles López-Vílchez, Julián Lirio, Domingo González-Lamuño Leguina, Teresa Bermejo González, Jordi García García, Maria Rimblas Roure, Ana Aldea-Perona, Laura Forcano, Maria Gomis-Gonzalez, Sebastià Videla Cés, Florence Lacaille, Aimé Ravel, Clotilde Mircher, Hervé Walti, Nathalie Janel, Julien Dairou, Marilyne Lévy, Sophie Durand, Mara Dierssen, Silvia Sacco, Rafael de la Torre Fornell, PERSEUS Study GroupPostprint (author's final draft

Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A)

BACKGROUND: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. CONCLUSIONS/SIGNIFICANCE: The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21

Effect of epigallocatechin gallate on the body composition and lipid profile of down syndrome individuals: implications for clinical management

© 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Peer ReviewedPostprint (author's final draft

New Perspectives for the Rescue of Cognitive Disability in Down Syndrome

Down syndrome (DS) is a relatively common genetic condition caused by the triplication of human chromosome 21. No therapies currently exist for the rescue of neurocognitive impairment in DS. This review presents exciting findings showing that it is possible to restore brain development and cognitive performance in mouse models of DS with therapies that can also apply to humans. This knowledge provides a potential breakthrough for the prevention of intellectual disability in DS

Increased Opioid Dependence in a Mouse Model of Panic Disorder

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients