Raising awareness of sex and gender bias in artificial intelligence and health

Historically, biomedical research has been led by and focused on men. The recent introduction of Artificial Intelligence (AI) in this area has further proven this practice to be discriminatory for other sexes and genders, more noticeably for women. To move towards a fair AI development, it is essential to include sex and gender diversity both in research practices and in the workplace. In this context, the Bioinfo4women (B4W) program of the Barcelona Supercomputing Center (i) promotes the participation of women scientists by improving their visibility, (ii) fosters international collaborations between institutions and programs and (iii) advances research on sex and gender bias in AI and health. In this article, we discuss methodology and results of a series of conferences, titled “Sex and Gender Bias in Artificial Intelligence and Health, organized by B4W and La Caixa Foundation from March to June 2021 in Barcelona, Spain. The series consisted of nine hybrid events, composed of keynote sessions and seminars open to the general audience, and two working groups with invited experts from different professional backgrounds (academic fields such as biology, engineering, and sociology, as well as NGOs, journalists, lawyers, policymakers, industry). Based on this awareness-raising action, we distilled key recommendations to facilitate the inclusion of sex and gender perspective into public policies, educational programs, industry, and biomedical research, among other sectors, and help overcome sex and gender biases in AI and health

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare

Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.This work is written on behalf of the Women’s Brain Project (WBP) (www.womensbrainproject.com/), an international organization advocating for women’s brain and mental health through scientific research, debate and public engagement. The authors would like to gratefully acknowledge Maria Teresa Ferretti and Nicoletta Iacobacci (WBP) for the scientific advice and insightful discussions; Roberto Confalonieri (Alpha Health) for reviewing the manuscript; the Bioinfo4Women programme of Barcelona Supercomputing Center (BSC) for the support. This work has been supported by the Spanish Government (SEV 2015–0493) and grant PT17/0009/0001, of the Acción Estratégica en Salud 2013–2016 of the Programa Estatal de Investigación Orientada a los Retos de la Sociedad, funded by the Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (ERDF). EG has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement No 116030 (TransQST), which is supported by the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).Peer ReviewedPostprint (published version

Genetic removal of synaptic Zn2+ impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity

Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Here we report that the genetic removal of synaptic Zn2+ results in progressive impairment of hippocampal-dependent memory, reduces activity-dependent increase in Erk phosphorylation and BDNF mRNA, alters regulation of Erk activation by NMDAR subunits, increases neuronal spiking, and induces biochemical and morphological alterations consistent with increasing epileptiform activity and neurodegeneration as ZnT3KO mice age. Our study shows that disruption of synaptic Zn2+ triggers neurodegenerative processes and is a potential pathway through which AβO trigger altered expression of neurotrophic proteins, along with reduced hippocampal synaptic density and degenerating neurons, neuronal spiking activity, and cognitive impairment and supports efforts to develop therapeutics to preserve synaptic zinc homeostasis in the brain as potential treatments for AD

Neuroplasticity-targeted therapy for Down syndrome: a translational approach

This Thesis aims at addressing the therapeutic potential of a neuroplasticity-targeted treatment for intellectual disability (ID) in Down syndrome (DS). The therapy consisted of the administration of the green tea catechin Epigallocatechin-3-gallate (EGCG), which is a natural modulator of Hsa21 candidate genes Dyrk1A and APP, in combination with cognitive stimulation. The assessment of the therapeutic efficacy of this intervention was performed using a translational approach, including preclinical studies with a mouse model of DS and clinical trials with humans with DS. In this work we show for the first time that this combined therapy significantly ameliorates cognitive deficits in mice and young adults with DS, by modifying brain neuronal networks structure and function.Esta Tesis tiene como objetivo examinar el potencial terapéutico de una intervención orientada a mejorar la neuroplasticidad cerebral, propuesta para mitigar la discapacidad intelectual (DI) en el síndrome de Down (SD). La terapia consistió en la administración de la catequina del té verde, Epigalocatequina-3-galato (EGCG), que es un modulador natural de dos genes candidatos que se encuentran en Hsa21, Dyrk1A y APP, en combinación con estimulación cognitiva. La evaluación de la eficacia terapéutica de esta intervención se realizó utilizando un enfoque de la translacional, incluyendo estudios preclínicos con un modelo de ratón de SD y ensayos clínicos con adultos jóvenes con SD. Este trabajo demuestra por primera vez que esta terapia combinada atenúa significativamente los déficits cognitivos en ratones y adultos jóvenes con SD, mediante la modificación de la estructura y función de redes neuronales en el cerebro

Neuroplasticity-targeted therapy for Down syndrome: a translational approach

This Thesis aims at addressing the therapeutic potential of a neuroplasticity-targeted treatment for intellectual disability (ID) in Down syndrome (DS). The therapy consisted of the administration of the green tea catechin Epigallocatechin-3-gallate (EGCG), which is a natural modulator of Hsa21 candidate genes Dyrk1A and APP, in combination with cognitive stimulation. The assessment of the therapeutic efficacy of this intervention was performed using a translational approach, including preclinical studies with a mouse model of DS and clinical trials with humans with DS. In this work we show for the first time that this combined therapy significantly ameliorates cognitive deficits in mice and young adults with DS, by modifying brain neuronal networks structure and function.Esta Tesis tiene como objetivo examinar el potencial terapéutico de una intervención orientada a mejorar la neuroplasticidad cerebral, propuesta para mitigar la discapacidad intelectual (DI) en el síndrome de Down (SD). La terapia consistió en la administración de la catequina del té verde, Epigalocatequina-3-galato (EGCG), que es un modulador natural de dos genes candidatos que se encuentran en Hsa21, Dyrk1A y APP, en combinación con estimulación cognitiva. La evaluación de la eficacia terapéutica de esta intervención se realizó utilizando un enfoque de la translacional, incluyendo estudios preclínicos con un modelo de ratón de SD y ensayos clínicos con adultos jóvenes con SD. Este trabajo demuestra por primera vez que esta terapia combinada atenúa significativamente los déficits cognitivos en ratones y adultos jóvenes con SD, mediante la modificación de la estructura y función de redes neuronales en el cerebro

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies

Re-establishment of the epigenetic state and rescue of kinome deregulation in Ts65Dn mice upon treatment with green tea extract and environmental enrichment

Down syndrome (DS) is the main genetic cause of intellectual disability due to triplication of human chromosome 21 (HSA21). Although there is no treatment for intellectual disability, environmental enrichment (EE) and the administration of green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mouse models and individuals with DS. Using proteome, and phosphoproteome analysis in the hippocampi of a DS mouse model (Ts65Dn), we investigated the possible mechanisms underlying the effects of green tea extracts, EE and their combination. Our results revealed disturbances in cognitive-related (synaptic proteins, neuronal projection, neuron development, microtubule), GTPase/kinase activity and chromatin proteins. Green tea extracts, EE, and their combination restored more than 70% of the phosphoprotein deregulation in Ts65Dn, and induced possible compensatory effects. Our downstream analyses indicate that re-establishment of a proper epigenetic state and rescue of the kinome deregulation may contribute to the cognitive rescue induced by green tea extracts.This work was supported by the Fondation Jérôme Lejeune Foundation (Project #1347 “Elucidation of the mechanism of action of epigallocatechin-3-gallate as a therapeutic agent on the cognitive phenotype in Down Syndrome mice models”), Agencia Estatal de Investigación (AEI) (PID2019-110755RB-I00/AEI/10.13039/501100011033), H2020 SC1 Gene overdosage and comorbidities during the early lifetime in Down Syndrome GO-DS21-848077, Fundació La Marató De TV3 (201620-31_MDierssen), EU (JPND HEROES (tHE cRossroad Of dEmentia Syndromes), NIH (Grant Number: 1R01EB 028159-01). The CRG is a Center of Excellence Severo Ochoa. The CIBER of Rare Diseases is an initiative of the ISCIII. The laboratories of M. Dierssen and E. Sabidó are supported by DIUE de la Generalitat de Catalunya (Grups consolidats 2017SGR926, 2017SGR595). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We also acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus.This research was supported by DIUE of Generalitat de Catalunya (Grups consolidats SGR 2014/1125); Fondation Jérôme Lejeune (Paris, France); Spanish Ministry of Economy and Finance (MINECO) grants SAF2013-49129-C2-1-R, BFU2011-28575, and MTM2015-64465-C2-1-R CDTI (“Smartfoods”); the CIBER of Rare Diseases (ISCIII initiative); and EU-Era Net Neuron PCIN-2013-060. The CRG has received support as a Severo Ochoa Center of Excellence SEV- 2012-O208. S.C.-S. received a FPI doctoral Fellowship from the MINECO (SAF2010-16427)

Combined treatment with environmental enrichment and (-)-epigallocatechin-3-gallate ameliorates learning deficits and hippocampal alterations in a mouse model of Down Syndrome

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus.Peer Reviewe

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus.This research was supported by DIUE of Generalitat de Catalunya (Grups consolidats SGR 2014/1125); Fondation Jérôme Lejeune (Paris, France); Spanish Ministry of Economy and Finance (MINECO) grants SAF2013-49129-C2-1-R, BFU2011-28575, and MTM2015-64465-C2-1-R CDTI (“Smartfoods”); the CIBER of Rare Diseases (ISCIII initiative); and EU-Era Net Neuron PCIN-2013-060. The CRG has received support as a Severo Ochoa Center of Excellence SEV- 2012-O208. S.C.-S. received a FPI doctoral Fellowship from the MINECO (SAF2010-16427)