“Unidad de Excelencia María de Maeztu”, funded by the MCIU and the AEI (DOI: 10.13039/501100011033). Ref: CEX2018-000792-M
“Unidad de Excelencia María de Maeztu”, funded by the MCIU and the AEI (DOI: 10.13039/501100011033). Ref: CEX2018-000792-M
The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPα+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.
Reference: Domenjo-Vila E, Casella V, Iwabuchi R, Fossum E, Pedragosa M, Castellví Q, Cebollada Rica P, Kaisho T, Terahara K, Bocharov G, Argilaguet J, Meyerhans A (2023) XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections. Cell Rep. 28;42(2):112123. Doi: 10.1016/j.celrep.2023.112123.
Figure Legend: Human neuroblastoma cells were transfected with SURF4 siRNA or a plasmid to overexpress SURF4. Cells were treated with 10 µM oligomers of Aβ1-42 for 24 h and cell survival measured by MTT reduction. Data are the mean ± SEM of 3-10 independent experiments. *p<0.05 vs control by Student’s t test.
In a genome-wide investigation conducted in yeasts, our team has pinpointed 81 genes that increase and 157 genes that prevent Aβ1-42 toxicity. Our work unveiled crucial cellular processes influenced by Aβ oligomers, such as calcium regulation and protein translation. Particularly noteworthy is the discovery that SURF4, a regulator of store-operated calcium channels, exerts modulation on oAβ1-42 neurotoxicity by regulating calcium influx, thus opening promising therapeutic approaches for Alzheimer’s disease. This research has been undertaken collaboratively with six national and international research groups.
Reference: Picón-Pagès P, Bosch-Morató M, Subirana L, Rubio-Moscardó F, Guivernau B, Fanlo-Ucar H, Zeylan ME, Senyuz S, Herrera-Fernández V, Vicente R, Fernández-Fernández JM, García-Ojalvo J, Gursoy A, Keskin O, Oliva B, Posas F, de Nadal E, Muñoz FJ (2023) A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity. Int J Mol Sci. 24(2):1278. doi: 10.3390/ijms24021278.
Figure Legend: Stress-dependent inhibition of cell polarity in fission yeast. In the rod-shaped S. pombe cells, spatial distribution of regulators limits the local activity of the Rho GTPase Cdc42 at the cell poles and promotes cell growth by tip elongation during mitotic lifecycle. GEFs positive regulators (Gef1 and Scd1) are localized at cell tips, while GAPs negative regulators (Rga4 and Rga6) are positioned at cell sides. Upon environmental stress conditions the tip-localized Rga3 is activated by the MAP kinase Sty1 and promotes Cdc42 inactivation at the cell poles. Sty1 also prevents the function of Gef1 at the poles, creating a two-step safeguard mechanism that downregulates polarized cell growth at unfavorable conditions.
General stress responses, which sense environmental or endogenous signals, aim at promoting cell survival and fitness during adverse conditions. In eukaryotes, mitogen-activated protein (MAP) kinase-driven cascades trigger a shift in the cell’s gene expression program as a cellular adaptation to stress. Here, we review another aspect of activated MAP kinase cascades reported in fission yeast: the transient inhibition of cell polarity in response to oxidative stress. The phosphorylation by a stress-activated MAP kinase of regulators of the GTPase cell division cycle 42 (Cdc42) causes a transient inhibition of polarized cell growth. The formation of growth sites depends on limiting and essential polarity components. We summarize here some processes in which inhibition of Cdc42 may be a general mechanism to regulate polarized growth also under physiological conditions.
Reference: Salat-Canela C, Pérez, Ayté J, Hidalgo E (2023) Stress-induced cell depolarization through the MAP kinase-Cdc42 axis. Trends Cell Biol. 33:124-137. doi: 10.1016/j.tcb.2022.06.004.
Representative pictures of immunohistochemical analyses of the three main areas of the HPC (CA1, CA3 and DG), showing PPAR-γ positive cells in red, GFAP positive cells in green and DAPI in blue. Total number of PPAR-γ positive cells in CA1. Total number of PPAR-γ and GFAP (co-localization of the two markers) positive cells in CA1,. (N= 5 mice/group). Data are presented as mean ± SEM. Significant differences between water and PLAE groups revealed by unpaired t-tests are represented * p<0.05. PPAR-γ, peroxisome proliferator activated receptor type gamma; GFAP, glial fibrillary acidic protein. Scale bar 100 μm.
Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.
Reference: Garcia-Baos A, Pastor A, Gallego-Landin I, de la Torre R, Sanz F, Valverde O. (2023) The role of PPAR-γ in memory deficits induced by prenatal and lactation alcohol exposure in mice. Mol Psychiatry 28(8):3373-3383. doi: 10.1038/s41380-023-02191-z.
The European eTRANSAFE project (Enhancing TRANslational SAFEty Assessment Through Integrative Knowledge Management), a pioneering initiative aimed at sharing
comprehensive data on medicines safety, has successfully reached its culmination after six years of execution (see NRDD paper).
This international initiative has been led by the UPF’s professor Ferran Sanz, and this collaborative effort has involved multiple stakeholders, including many pharmaceutical companies and academic institutions. The project has achieved a notable integration of information. Following in the footsteps of a previous project, eTOX, more than 10,000 pharmacological studies provided by renowned pharmaceutical companies have been shared and integrated merged into a knowledge platform. This platform, called ToxHub, is based on a series of databases containing clinical and preclinical data from public and private sources, and constitutes a system where all project members can explore and exploit information on drug safety.
Another notable UPF’s outcome of the eTRANSAFE project is Flame, an open-source machine learning application developed by the UPF’s professor Manuel Pastor, which is integrated into ToxHub. Flame has the ability to predict possible adverse effects of future drugs.
Reference: Sanz F, Pognan F, Steger-Hartmann T, et al. (2023) eTRANSAFE: data science to empower translational safety assessment. Nature Reviews Drug Discovery 22, 605-606. doi: https://doi.org/10.1038/d41573-023-00099-5
A generalized understanding of protein dynamics is an unsolved scientific problem, the solution of which is critical to the interpretation of the structure-function relationships that govern essential biological processes. Here, we approach this problem by constructing coarse-grained molecular potentials based on artificial neural networks and grounded in statistical mechanics. For training, we build a unique dataset of unbiased all-atom molecular dynamics simulations of approximately 9 ms for twelve different proteins with multiple secondary structure arrangements. The coarse-grained models are capable of accelerating the dynamics by more than three orders of magnitude while preserving the thermodynamics of the systems. Coarse-grained simulations identify relevant structural states in the ensemble with comparable energetics to the all-atom systems. Furthermore, we show that a single coarse-grained potential can integrate all twelve proteins and can capture experimental structural features of mutated proteins. These results indicate that machine learning coarse-grained potentials could provide a feasible approach to simulate and understand protein dynamics.
Reference: Majewski M, Pérez A, Thölke P, et al. (2023) Machine learning coarse-grained potentials of protein thermodynamics. Nat Commun 14, 5739, https://doi.org/10.1038/s41467-023-41343-1
Cranial ganglia are aggregates of sensory neurons that mediate distinct types of sensation. The statoacoustic ganglion (SAG) develops into several lobes that are spatially arranged to connect appropriately with hair cells of the inner ear. To investigate the cellular behaviours involved in the 3D organization of the SAG, we use high-resolution confocal imaging of single-cell, labelled zebrafish neuroblasts (NBs), photoconversion, photoablation, and genetic perturbations. We show that otic NBs delaminate out of the otic epithelium in an epithelial-mesenchymal transition-like manner, rearranging apical polarity and primary cilia proteins. We also show that, once delaminated, NBs require RhoGTPases in order to perform active migration. Furthermore, tracking of recently delaminated NBs revealed their directed migration and coalescence around a small population of pioneer SAG neurons. These pioneer SAG neurons, not from otic placode origin, populate the coalescence region before otic neurogenesis begins and their ablation disrupts delaminated NB migratory pathways, consequentially affecting SAG shape. Altogether, this work shows for the first time the role of pioneer SAG neurons in orchestrating SAG development.
Reference: Bañón A, Alsina B (2023) Pioneer statoacoustic neurons guide neuroblast behaviour during otic ganglion assembly. Development. 150(21):dev201824. doi: 10.1242/dev.201824.
Background: Cannabis addiction is a chronically relapsing disorder lacking effective treatment. Regular cannabis consumption typically begins during adolescence, and this early cannabinoid exposure may increase the risk for drug addiction in adulthood.
Objective: This study investigates the development of cannabis addiction-like behavior in adult mice after adolescent exposure to the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC).
Methods: Adolescent male mice were exposed to 5 mg/kg of THC from postnatal days 37 to 57. Operant self-administration sessions of WIN 55,212-2 (12.5 μg/kg/infusion) were conducted for 10 days. Mice were tested for three addiction-like criteria (persistence of response, motivation, and compulsivity), two parameters related to craving (resistance to extinction and drug-seeking behavior), and two phenotypic vulnerability traits related to substance use disorders (impulsivity and reward sensitivity). Additionally, qPCR assays were performed to detect differentially expressed genes in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HPC) of “addicted” and “non-addicted” mice.
Results: Adolescent THC exposure did not modify WIN 55,212-2 reinforcement nor the development of cannabis addiction-like behavior. Inversely, THC pre-exposed mice displayed impulsive-like behavior in adulthood, which was more pronounced in mice that developed the addiction-like criteria. Moreover, downregulated drd2 and adora2a gene expression in NAc and HPC was revealed in THC pre-exposed mice, as well as a downregulation of drd2 expression in mPFC of vehicle pre-treated mice that developed addiction-like behaviors.
Discussion: These findings suggest that adolescent THC exposure may promote impulsivity-like behavior in adulthood, associated with downregulated drd2 and adora2a expression in NAc and HPC.
Keywords: THC; WIN 55,212-2 self-administration mouse model; adolescence; adora2a; cannabis addiction; drd2; impulsivity.
Reference: Cajiao-Manrique MDM, Casadó-Anguera V, García-Blanco A, Maldonado R, Martín-García E (2023) THC exposure during adolescence increases impulsivity-like behavior in adulthood in a WIN 55,212-2 self-administration mouse model. Front Psychiatry. 14:1148993. doi: 10.3389/fpsyt.2023.1148993.
Cebus unicolor, Brasil (Rebecca Still); Cacajao homomi, Venezuela (Jan Dungel); Saimiri cassiquiarensis ssp. Cassiquiarensis and Plecturocebus vieirai, Brasil (Marcelo Santana).
The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.
Reference: Kuderna LKF et al., Marquès-Bonet T (2023) A global catalog of whole-genome diversity from 233 primate species. Science 380,906-913 .DOI:10.1126/science.abn7829
SLC30A9 encodes a ubiquitous zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.
Reference: Roca-Umbert A, Garcia-Calleja J, Vogel-González M, Fierro-Villegas A, Ill-Raga G, Herrera-Fernández V, Bosnjak A, Muntané G, Gutiérrez E, Campelo F, Vicente R, Bosch E (2023). Human genetic adaptation related to cellular zinc homeostasis. PLOS Genetics 19(9): e1010950. doi: 10.1371/journal.pgen.1010950.
According to the International Labour Organization, in 2022, 53·7% of workers in Latin America and the Caribbean region engaged in informal employment, while in North America and Europe (excluding eastern Europe) the figures are 9·6% and 13%, respectively. Informality often deprives people of decent work and dignified living. Informal employment is a continuum from the opposite of decent work arrangement and represents the maximum deterioration of working and employment conditions. Transition to employment formality might be reached by economic growth and the combination of strategies and policies, including extending social protection to all workers, increasing income of the informally employed, promoting social dialogue, training, and education, and strengthening institutions, such as labour inspections.
Reference: Merino-Salazar P, Avila Assunção A, Amable M, Benavides FG, Gimeno Ruiz de Porras D (2023) Informal employment as a fundamental determinant of mental health in Latin America and the Caribbean. The Lancet. 402, 10410: 1309-1311, doi.org/10.1016/S0140-6736(23)02051-2.
We investigate how knowledge, skills and competences obtained during science communication postgraduate programmes impact alumni’s experience in entering the workforce and in practicing their roles. Spanish programmes have been analysed with a double methodology: semi-structured interviews with programme directors (12 out of a total of 13) and a survey for programme alumni (134 answers). Results show these training programmes are useful for alumni to find and practice a job in the field. The study also identifies which knowledge, skills and competences are considered the most useful for alumni.
Reference: Saladie N, Llorente C, Revuelta G (2023). Is training in science communication useful to find and practice a specialised job? JCOM 22(06), A03. doi.org/10.22323/2.22060203
The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms, but remains largely elusive in humans due to ethical and technical limitations. Despite recent advances with pluripotent stem cell (PSC)-based approaches1-5, models that robustly recapitulate human somitogenesis in both space and time are still largely missing. Here, we introduce a PSC-derived mesoderm-based 3D model of human segmentation and somitogenesis, which we termed ‘axioloid’, that captures accurately the oscillatory dynamics of the segmentation clock as well as the morphological and molecular characteristics of segmentation and sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF/WNT signaling gradients and Retinoic Acid (RA) signaling components. Importantly, comparative analysis demonstrates striking similarities of axioloids to the human embryo, further validated by the presence of a HOX code in axioloids. We also demonstrate the use of the axioloid system to study the pathogenesis of human congenital diseases of the spine, by using patient-like iPSC cells with mutations in HES7 and MESP2, which revealed disease-associated phenotypes including loss of epithelial somite formation and abnormal rostrocaudal patterning. These results suggest that axioloids represent a promising novel platform to study axial development and disease in humans.
Reference: Yamanaka Y, et al., Martinez-Arias A, Tsujimura T, Alev C (2023) Reconstituting human somitogenesis in vitro. Nature. 614 (7948), 509-520. doi: 10.1038/s41586-022-05649-2.
Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 is an effector protein that targets invading DNA and plays a major role in the prokaryotic adaptive immune system. Although Streptococcus pyogenes CRISPR–Cas9 has been widely studied and repurposed for applications including genome editing, its origin and evolution are poorly understood. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species that last lived 2.6 billion years before the present. We demonstrate that these ancient forms were much more flexible in their guide RNA and protospacer-adjacent motif requirements compared with modern-day Cas9 enzymes. Furthermore, anCas portrays a gradual palaeoenzymatic adaptation from nickase to double-strand break activity, exhibits high levels of activity with both single-stranded DNA and single-stranded RNA targets and is capable of editing activity in human cells. Prediction and characterization of anCas with a resurrected protein approach uncovers an evolutionary trajectory leading to functionally flexible ancient enzymes.
Reference: Alonso-Lerma B, Jabalera Y, Samperio S, Morin M, Fernandez A, Hille LT, Silverstein RA, Quesada-Ganuza A, Reifs A, Fernández-Peñalver S, Benitez Y, Soletto L, Gavira JA, Diaz A, Vranken W, Sanchez-Mejias A, Güell M, Mojica FJM, Kleinstiver BP, Moreno-Pelayo MA, Montoliu L, Perez-Jimenez R (2023). Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins. Nature microbiology 8 (1), 77-90. https://doi.org/10.1038/s41564-022-01265-y