La GTPasa endosomal RhoB regula la recuperación de la barrera endotelial durante la inflamación

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 23-10-2015El endotelio forma la capa más interna de los vasos sanguíneos y separa el torrente circulatorio de los tejidos subyacentes. Su integridad es un requisito para el correcto desarrollo y terminación de la respuesta inflamatoria. Sin embargo, durante el transcurso de ésta, la función de la monocapa endotelial se ve comprometida debido a la acción combinada de las citoquinas pro-inflamatorias y las células inmunes. La inflamación es un componente de la mayoría de patologías de más prevalencia en nuestra sociedad y la disfunción endotelial es la base para el desarrollo de enfermedades inflamatorias crónicas. Con el objetivo de identificar nuevas proteínas claves en la respuesta inflamatoria humana, hemos descubierto que la GTPasa RhoB aumenta su expresión en respuesta a estímulos pro-inflamatorios y es expresada abundantemente en el endotelio de muestras de tejidos humanos de enfermedades inflamatorias crónicas. RhoB, junto con sus homólogas RhoA y RhoC, presentan funciones aditivas en el mantenimiento de la barrera endotelial, redundantes en la polimerización de actina en condiciones de reposo o inflamadas y no están implicadas en el aumento de permeabilidad a largo plazo inducido por TNF o en la trasnmigración del linfocito in vitro. Sin embargo, RhoB juega un papel específico y relevante en la restauración de la función de barrera tras la acción de agentes pro-coagulantes. RhoB favorece la disfunción endotelial al prevenir la expansión de la célula sobre el sustrato tras la contracción endotelial aguda. Durante la recuperación, detectamos un incremento en el tráfico de vesículas de RhoB hacia y desde protrusiones nacientes de la membrana plasmática y demostramos que RhoB controla el tráfico intracelular de miembros de la maquinaria proteica que regulan la formación de extensiones de membrana. RhoB co-localiza con Rac en vesículas intracelulares e inhibe su activación y el tráfico de esta GTPasa hacia la membrana plasmática. Así mismo, RhoB inhibe la actividad de la serina quinasa Akt y evidencias sugieren que también podría impedir su tráfico hacia la periferia celular. La inhibición directa tanto de Rac como de Akt retrasa la recuperación de la barrera, que además se ve severamente afectada por inhibidores globales del tráfico intracelular. En cambio, la inducción de la translocación de Rac a la membrana plasmática acelera la reformación de la monocapa. En conclusión, nuestros resultados indican que la regulación específica del tráfico intracelular de Rac y Akt por parte de RhoB controla la integridad de la barrera endotelial durante la inflamación, actuando esta GTPasa como un promotor de la disfunción endotelialThe endothelium forms a monolayer of cells that lines on the intimal surface of the blood vessels and physically separates the bloodstream from the underlying tissues. Preserving endothelial integrity is required for the correct termination of the inflammatory reactions. Inflammation is present in some of the most prevalent diseases in our society. Endothelial barrier function could be endangered due to the combined action of pro-inflammatory cytokines and leukocytes , which could lead to an uncontrolled and pathologic inflammatory response. Indeed, endothelial barrier dysfunction underlies chronic inflammatory diseases. In searching for new proteins essential for the human endothelial inflammatory response, we have found that the endosomal Rho GTPase RhoB is upregulated in response to inflammatory cytokines and expressed in the endothelium of chronically inflamed tissues. RhoB, and the closely related RhoA and RhoC, play redundant roles in regulating F-actin levels and additive roles in the maintenance of barrier integrity in unstimulated HUVECs. None of the proteins had relevant roles in long-term barrier disruption in response to TNF or in leukocyte transmigration in vitro. However, RhoB specifically inhibits barrier restoration after acute cell contraction by preventing plasma membrane extension. During barrier restoration, a two-way RhoB trafficking between vesicles containing RhoB nanoclusters and nascent plasma membrane protrusions is induced. We show that RhoB regulates the intracellular trafficking of proteins that controls membrane spreading. We further show that RhoB colocalizes with Rac in Rab5-positive endosomes and negatively regulates Rac1 activity and trafficking to the plasma membrane during barrier recovery. Furthermore, inhibition of endosomal trafficking impairs, whereas induction of Rac translocation to the plasma membrane accelerates, barrier reformation. In addition, we show that RhoB controls Akt activation and we have evidences that RhoB could also regulate Akt trafficking towards plasma membrane during recovery. In conclusion, RhoB-specific regulation of Rac and Akt intracellular trafficking controls endothelial barrier integrity during inflammation. RhoB upregulation exacerbates endothelial responses to stimuli inducing acute contractio

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEThe Progeria Research FoundationMinisterio de Ciencia e Innovaciónpu

Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function.

Background Cell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS). Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function. Results Platelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry. The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing. Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function. Conclusions Plasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.This work was supported by grants from The Progeria Research Foundation (PRF 2016-65) and the Spanish MINECO (PID2019-106279RB-I00, PID2019-108489RBI00). The authors thank Fundación La Caixa (A.G.), CEI Moncloa (N.I.M.-R.), MINECO (F.J.O.-N. and M.B.) and Ministerio de Ciencia, Innovación y Universidades (N.K.-F.) for predoctoral fellowships. The authors thank C. López-Otín for kindly donating LmnaG609G/G609G progeroid and their corresponding wild-type fibroblasts and UCM’s CAIs Cytometry and Fluorescence Microscopy, Genomics, NMR, and Mass Spectrometry, for their assistance. The CNIC is supported by the Ministerio de Ciencia e Innovación, the Instituto de Salud Carlos III, and the pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant SEV-2015- 0505). The generation of the antiprogerin antibody was funded by the Wellcome Trust (098291/Z/12/Z to S.N.).S

Polo-like kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction

Purpose: BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds. Experimental Design: We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dualtumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database. Results: The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells. Conclusions: We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.Fil: Carbajosa González, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Paviolo, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Castellaro, Andrés Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Andino, Diego Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Nigra, Ayelén Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Racca, Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Rodriguez, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Angiolini, Virginia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Guantay, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Villafañez, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Federico, Maria Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rodríguez, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Caputto, Beatriz Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Drewes, Gerard. Cellzome AG; AlemaniaFil: Madauss, Kevin P.. Global Observatory on Health Research and Development; Estados UnidosFil: Gloger, Israel. Global Observatory on Health Research and Development; Estados UnidosFil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Soria, Ramiro Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Los concejales de mandato cumplido y la ejecución presupuestaria. El caso de la Cuenca Carbonífera.

The work of city councilors, as they participate in the budget process, is involved in a series of problems that are specific to them. And this affects the community they represent if they are unable to overcome these issues. The councillors carry out their work as long as it is relatively regulated by the regulations in force. The frequent situations they encounter indicate that there is a gap between the real issues they deal with and the rules. The objective is focused on identifying the existence of the gap between both circumstances and its effects on the work of the councilors in office in the Carboniferous Basin. Therefore, our main question is: is there a gap between the regulations and the actual work done by councilors when they are in the process of approving the budget that comes from the municipal executive branch? We understand that this affects the decision making of the main work tool that affects both populations. To address this question we used a questionnaire addressed to the councilmen who are no longer in office, consisting of six axes of questioning.  In this way, we gained access to their personal experiences and the different visions and ways of approaching the issue. The answers led to situations in which problems derived mainly from political, informational, resource and personal preparation for the positions of councilors predominated. Considering this, the situation of the existence of the gap is demonstrated and the next step will be to establish whether the councilors and the community accept and maintain these peculiarities for the budget. The next lines of research will be related to the possible changes to be introduced in the process at the practical and normative level.El trabajo de los ediles, en tanto participan del proceso presupuestario, se ve envuelto en una serie de problemáticas que le son propias. Y ello afecta a la comunidad a la cual representan, si no pueden sortear dichas cuestiones. Los ediles realizan su trabajo, en tanto se encuentra relativamente normado por la reglamentación vigente. Las frecuentes situaciones que se encuentran nos indican que entre las cuestiones reales con las que se manejan y las normas existe un distanciamiento o brecha. El objetivo se centra en identificar la existencia de la brecha entre ambas circunstancias y sus efectos en la labor de los concejales de mandato cumplido en la Cuenca Carbonífera. Por lo tanto, nuestra pregunta principal es ¿existe una brecha entre lo normado y el trabajo real que realizan los concejales cuando se encuentran en el proceso de aprobación del presupuesto que deviene del poder ejecutivo municipal? Entendemos que esto afecta la toma de decisiones de la principal herramienta de trabajo que afecta a ambas poblaciones. Para afrontar dicha pregunta se utilizó un cuestionario dirigido a los concejales que ya no están en funciones, constando de seis ejes de preguntas.  Con ello accedimos a sus experiencias personales y de las distintas visiones y maneras de abordar la cuestión. Las respuestas condujeron a situaciones donde predominaron problemáticas derivadas principalmente de las líneas políticas, informacionales, recursos y de preparación personal para los cargos de ediles. Teniendo en cuenta ello, la situación de la existencia de la brecha queda demostrada y el paso siguiente será establecer si los ediles y la comunidad aceptan y mantienen estas peculiaridades para el presupuesto. Las próximas líneas de investigación serán relativas a los posibles cambios a introducir en el proceso a nivel práctico y normativo

Adherens junctions connect stress fibres between adjacent endothelial cells

<p>Abstract</p> <p>Background</p> <p>Endothelial cell-cell junctions maintain endothelial integrity and regulate vascular morphogenesis and homeostasis. Cell-cell junctions are usually depicted with a linear morphology along the boundaries between adjacent cells and in contact with cortical F-actin. However, in the endothelium, cell-cell junctions are highly dynamic and morphologically heterogeneous.</p> <p>Results</p> <p>We report that endothelial cell-cell junctions can attach to the ends of stress fibres instead of to cortical F-actin, forming structures that we name discontinuous adherens junctions (AJ). Discontinuous AJ are highly dynamic and are increased in response to tumour necrosis factor (TNF)-α, correlating with the appearance of stress fibres. We show that vascular endothelial (VE)-cadherin/β-catenin/α-catenin complexes in discontinuous AJ are linked to stress fibres. Moreover, discontinuous AJ connect stress fibres from adjacent cells independently of focal adhesions, of which there are very few in confluent endothelial cells, even in TNF-α-stimulated cells. RNAi-mediated knockdown of VE-cadherin, but not zonula occludens-1, reduces the linkage of stress fibres to cell-cell junctions, increases focal adhesions, and dramatically alters the distribution of these actin cables in confluent endothelial cells.</p> <p>Conclusions</p> <p>Our results indicate that stress fibres from neighbouring cells are physically connected through discontinuous AJ, and that stress fibres can be stabilized by AJ-associated multi-protein complexes distinct from focal adhesions.</p

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio