Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19587

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Impact of dapagliflozin on key pathophysiological pathways underlying chronic heart failure progression: the DAPA-MODA biomarker study.
(EDICIONES DOYMA SA, 2025-11-27) Martínez-Pina, Verónica; Bayés-Genís, Antoni; Nuñez, Julio; Riquelme-Pérez, Alejandro; Cebreiros-López, Iria; Morillas, Herminio; Cobo-Marcos, Marta; García-Pinilla, José M; Rodríguez-Palomares, Juan F; Dobarro, David; Restrepo-Córdoba, María A; González-Juanatey, José R; Zamorano, José L; Noguera-Velasco, José A; Pascual-Figal, Domingo A
Dapagliflozin improves clinical outcomes in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction. However, its effects on circulating biomarkers that reflect distinct pathophysiological pathways remain incompletely understood. DAPA-MODA is a prospective, multicenter, single-arm study that enrolled patients with stable chronic HF receiving optimized guideline-directed medical therapy, excluding sodium-glucose cotransporter-2 inhibitors. In a predefined biomarker substudy (n=156; 63.5% men; age 70.5±10.6 years; 67.9% with left ventricular ejection fraction > 40%), 11 biomarkers representing 5 key biological pathways (cardiac stress, inflammation, neurohormonal activation, congestion, and fibrosis) were measured at baseline, 1 month, and 6 months. At baseline, markers of myocardial stress were frequently elevated (NT-proBNP [95.5%] and MR-proANP [34.8%]), as was troponin for myocardial injury (73.5%). Inflammatory (IL-6 [40%], CRP [35%], GDF-15 [56%]) and neuro-endocrine stress (copeptin [43%]) markers were also commonly raised. In contrast, elevations in congestion (MR-proADM, CA-125) and fibrosis markers (ST2, PINP) were less frequent, reflecting diverse pathophysiological involvement. Dapagliflozin led to significant reductions in NT-proBNP and MR-proADM levels by 6 months. Reductions in MR-proANP, CRP, IL-6, copeptin, and PINP were confined to patients with elevated baseline levels. ST2 and CA-125 remained unchanged, while GDF-15 levels increased modestly. Dapagliflozin favorably modulates several key pathophysiological pathways involved in chronic HF progression, with differential effects among biomarkers by acting particularly on those that are elevated at baseline.
Titin-related familial dilated cardiomyopathy: factors associated with disease onset.
(OXFORD UNIV PRESS, 2025-12-22) Johnson, Renee; Fletcher, Robert A; Peters, Stacey; Ohanian, Monique; Soka, Magdalena; Smolnikov, Andrei; Abihider, Katherine E; Ackerman, Michael J; Ader, Flavie; Akhtar, Mohammed M; Amin, Ahmad S; Ashley, Euan A; Atherton, John J; Austin, Rachel; Baas, Annette F; Bagnall, Richard D; Ross, Samantha Barratt; Blouin, Jean-Louis; Brown, Emily E; Bundgaard, Henning; Cannie, Douglas; Chmielewski, Przemyslaw; Correnti, Gemma; Crespo-Leiro, Maria Generosa; Dal Ferro, Matteo; Dellefave-Castillo, Lisa M; Dominguez, Fernando; Dooijes, Dennis; Dybro, Anne M; Ed Demri, Youssef; El Hachmi, Mohamed; Escobar-Lopez, Luis; Foye, Sarah Jajesnica; Franaszczyk, Maria; Gigli, Marta; Lopez, Esther Gonzalez; Goudal, Adeline; Graw, Sharon; Guipponi, Michel; Haan, Eric; Haas, Jan; Hammersley, Daniel J; Hansen, Frederikke G; Hayward, Christopher S; Hey, Thomas Morris; Heymans, Stephane; Ho, Carolyn Y; Houweling, Arjan C; Ingles, Jodie; Ingrey, Angela; Jabbour, Andrew; James, Paul A; Jansweijer, Joeri A; Jongbloed, Jan D H; Keogh, Anne M; Larrañaga-Moreira, Jose M; Lekanne Deprez, Ronald H; Macciocca, Ivan; Macdonald, Peter S; Mansencal, Nicolas; Mansour, Julia; Martinez-Veira, Cristina; McDonough, Barbara; McGaughran, Julie; Medo, Kristen; Merlo, Marco; Michalak, Ewa; Monserrat, Lorenzo; Mountain, Helen; Muller, Steven A; Murphy, Anne M; Murray, Brittney; Oates, Emily C; Ormondroyd, Elizabeth; Pachter, Nicholas; Paldino, Alessia; Palmyre, Aurélien; Pereira, Naveen L; Picard, Kermshlise C; Poplawski, Nicola; Prasad, Sanjay; Proukhnitzky, Julie; Pruny, Jean-Francois; Reant, Patricia; Richard, Pascale; Ronan, Anne; Sedaghat-Hamedani, Farbod; Semsarian, Christopher; Storm, Garrett; Stroeks, Sophie; Syrris, Petros; Taylor, Matthew R G; Thomson, Kate; Thompson, Tina; van Tintelen, J Peter; Vissing, Christoffer Rasmus; Waddell-Smith, Kathryn E; Wallis, Mathew; Zentner, Dominica; Arnott, Clare; Marian, Ali J; Oh, Jaewon; Fokstuen, Siv; James, Cynthia A; Barriales-Villa, Roberto; Meder, Benjamin; Wahbi, Karim; Giudicessi, John R; Parikh, Victoria N; Ware, James S; Piriou, Nicolas; Rooryck, Caroline; Lakdawala, Neal K; Mestroni, Luisa; Sinagra, Gianfranco; Elliott, Perry M; Watkins, Hugh; McNally, Elizabeth M; Charron, Philippe; van Spaendonck-Zwarts, Karin Y; Garcia-Pavia, Pablo; Peña-Peña, Maria Luisa; Mogensen, Jens; Christensen, Alex Hoerby; Bilińska, Zofia T; Rasmussen, Torsten B; Seidman, Jonathan G; Seidman, Christine E; Te Riele, Anneline S J M; Verdonschot, Job A J; Pinto, Yigal M; Christiaans, Imke; Fatkin, Diane
Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.
Abstract 4365441: The Prevalence of Clinical Atherosclerosis in Denmark
(Lippincott Williams & Wilkins (LWW), 2025-11-04) Hasselbalch, Rasmus; Kragh, Maja Valentin; Perez-Garcia, Carlos; Eldrup, Nikolaj; Fuster, Jose; Boettcher, Morten; Iversen, Kasper; Kofoed, Klaus; Ibanez, Borja; Bundgaard, Henning
Functional interplay between endothelial nitric oxide synthase and membrane type 1 matrix metalloproteinase in migrating endothelial cells.
(Elsevier, 2007-10-15) Genís, Laura; Gonzalo, Pilar; Tutor, Antonio S; Gálvez, Beatriz G; Martínez-Ruiz, Antonio; Zaragoza, Carlos; Lamas, Santiago; Tryggvason, Karl; Apte, Suneel S; Arroyo, Alicia G
Nitric oxide (NO) is essential for vascular homeostasis and is also a critical modulator of angiogenesis; however, the molecular mechanisms of NO action during angiogenesis remain elusive. We have investigated the potential relationship between NO and membrane type 1-matrix metalloproteinase (MT1-MMP) during endothelial migration and capillary tube formation. Endothelial NO synthase (eNOS) colocalizes with MT1-MMP at motility-associated structures in migratory human endothelial cells (ECs); moreover, NO is produced at these structures and is released into the medium during EC migration. We have therefore addressed 2 questions: (1) the putative regulation of MT1-MMP by NO in migratory ECs; and (2) the requirement for MT1-MMP in NO-induced EC migration and tube formation. NO upregulates MT1-MMP membrane clustering on migratory human ECs, and this is accompanied by increased degradation of type I collagen substrate. MT1-MMP membrane expression and localization are impaired in lung ECs from eNOS-deficient mice, and these cells also show impaired migration and tube formation in vitro. Inhibition of MT1-MMP with a neutralizing antibody impairs NOinduced tube formation by human ECs, and NO-induced endothelial migration and tube formation are impaired in lung ECs from mice deficient in MT1-MMP. MT1-MMP thus appears to be a key molecular effector of NO during the EC migration and angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders.
Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity.
(DOYMA, 2023-11) Zatarain-Nicolás, Eduardo; Martín, Pilar; Márquez Rodas, Iván; Virizuela, Juan; Martín García, Ana; Mitroi, Cristina; Cosín Sales, Juan; Barrios, Vivencio; Sánchez-Cabo, Fátima; Ibañez, Borja; de Castro Carpeño, Javier; López Fernández, Teresa
Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12 months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT.
T lymphocytes linking autoimmunity and cardiovascular disease in aging
(OAE PUBLISHING INC, 2025-05-30) Ortega-Sollero, Enrique; Ruíz-Fernández, Ignacio; Martín, Pilar
Aging alters the immune system, leading to immunosenescence characterized by impaired T cell functions. The balance between regulatory T cells and type 17 helper T (Th17) cells is crucial for maintaining peripheral immune homeostasis. Aging disrupts this balance, contributing to a systemic chronic proinflammatory environment that increases the prevalence of age-related diseases. The Treg/Th17 imbalance compromises self-tolerance, promoting autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Furthermore, chronic inflammation driven by aberrant T cell responses is a significant risk factor for the progression of cardiovascular diseases (CVD), including hypertension, atherosclerosis, myocardial infarction, and myocarditis. Autoimmune disorders further exacerbate the risk of CVD, which remains the leading cause of mortality among patients with autoimmune diseases. This review provides an in-depth analysis of the mechanisms driving Treg/Th17 imbalance during aging, highlighting its impact on immune homeostasis, autoimmunity, and cardiovascular health. It explores how inflammaging and T cell dysfunction contribute to diseases such as rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, and myocardial infarction, emphasizing shared pathways and therapeutic strategies to restore immune balance and mitigate chronic inflammation. Understanding these immune pathways highlights the therapeutic potential of restoring Treg/Th17 balance to restore immune tolerance and reduce chronic inflammation, thereby mitigating the onset and progression of these age-related conditions.
SILAC-based nuclear proteomics uncovers antitumor mechanisms of selenium nanoparticles with in vivo validation in a melanoma model
(Elsevier, 2025-09) Estevez, Hector; Garcia-Calvo, Estefania; Álvarez-Fernández Garcia, Roberto; Sanchez-Diaz, Raquel; Lazcano, Juan José; Martin, Pilar; Luque-Garcia, Jose L.
Chitosan-stabilized selenium nanoparticles (Ch-SeNPs) are promising agents for cancer therapy due to their unique physicochemical properties, including spherical morphology and uniform size distribution. This study investigates the molecular mechanisms underlying their antitumoral effects, with a focus on the nuclear proteome. Quantitative proteomic analysis revealed 343 nuclear proteins, 47 of which showed significant changes following Ch-SeNPs treatment. Key regulators such as CDK1 and CDC5 were implicated in cell cycle arrest and tumor suppression pathways. Ch-SeNPs also affected processes including mRNA metabolism and cytoskeleton organization. In addition, Ch-SeNPs significantly inhibited tumor growth in a murine melanoma model, supporting their therapeutic potential.
Anti-mmu-mir-721 as a therapeutic target for immune checkpoint inhibitor-associated myocarditis
(Oxford University Press, 2025-08-01) Ortega Sollero, E; Jimenez-Alejandre, R; Ortego-Molto, R; Sanchez-Diaz, R; Martin, P
A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
(Cell Press, 2026-02-10) Dunphy, Gillian; Adán-Barrientos, Irene; Fernández-Delgado, Irene; Villarroya-Beltri, Carolina; Heras-Murillo, Ignacio; Moya-Ruiz, Elena; Sánchez-Álvarez, Miguel; Jarit-Cabanillas, Aitor; Del Pozo, Miguel A; Guerra, Susana; Sánchez-Madrid, Francisco; Sancho, David
Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.
Myocardium and endocardium of the early mammalian heart tube arise from independent multipotent lineages specified at the primitive streak.
(Cell Press, 2025-09-22) Sendra, Miquel; McDole, Katie; de Dios Hourcade, Juan; Temiño, Susana; Raiola, Morena; Guignard, Léo; Keller, Philipp J; Domínguez, Jorge N; Torres, Miguel; Fundación La Caixa; Comunidad de Madrid (España)
The formation of the primitive heart tube from cardiomyocytes and endocardial cells is a key event in mammalian development. Previous studies suggested that cardiomyocytes and endocardial cells segregate from a shared cardiac progenitor around the onset of gastrulation, yet their lineage relationship with other mesodermal tissues remains unclear. Using retrospective and prospective clonal analyses in mouse embryos, we traced cardiomyocyte and endocardial progenitors from the primitive streak to the heart tube. Our results identify two independent mesodermal populations specified around gastrulation onset. While each of these populations is unipotent in producing cardiomyocytes or endocardium, they retain multipotency and contribute to different subsets of non-cardiac mesoderm. Nonetheless, live imaging identifies simultaneous ingression and intermingling of these two mesodermal lineages in the primitive streak, showing their coordinated specification and migration. The proposed model for cardiac progenitor specification will help understanding the origins of congenital heart diseases and designing tissue engineering strategies.
Impact of genotype-phenotype associations on prognosis in dilated cardiomyopathy.
(Elsevier, 2025-12) Stroeks, Sophie L V M; Wang, Ping; Merlo, Marco; Muller, Steven; Paldino, Alessia; Mora-Ayestaran, Nerea; Jason, Max; Ferro, Matteo Dal; Pio Loco Detto Gava, Carola; Dominguez, Fernando; Gonzalez-Lopez, Esther; van den Wijngaard, Arthur; Venner, Max F G H M; Sikking, Maurits; Minten, Michiel; Nihant, Bastien; Beelen, Nina; Graw, Sharon; Medo, Kristen; de Koning, Bart; Taylor, Matthew; van Tintelen, J Peter; Mestroni, Luisa; Sinagra, Gianfranco; Te Riele, Anneline S J M; Garcia-Pavia, Pablo; Heymans, Stephane; Verdonschot, Job A J
Dilated cardiomyopathy (DCM) has a monogenic aetiology in up to 40% of patients. Understanding the spectrum of genotype-phenotype associations in DCM is crucial for risk stratification and personalized treatment. We aimed to (i) characterize genotype-specific features, (ii) evaluate whether phenotype-based clustering reflects underlying genotype, and (iii) compare the prognostic value of genotype- versus phenotype-based approaches. A multicentre cohort of 534 DCM patients with a (likely) pathogenic variant were grouped by genotype (genotype-first approach) and clustered by clinical phenotype (phenotype-first approach). We compared clinical characteristics, identified genotype-phenotype associations, and evaluated outcomes, including all-cause mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias. Using the genotype-first approach, significant genotype-phenotype associations were found for 10 genes. FLNC, LMNA, DSP, and PLN variants were linked to arrhythmias. BAG3, TNNT2, DMD, and TTN were associated with increased cardiac volumes and decreased left ventricular ejection fraction (LVEF). Clustering identified four phenotypic clusters: (1) young, moderately reduced LVEF; (2) arrhythmias, moderate reduced LVEF; (3) low LVEF; (4) arrhythmias, low LVEF. There were no clear correlations between phenotypic clusters and genotype. The genotype-first approach showed that LMNA, FLNC, and BAG3 variants had the highest risk for heart failure and arrhythmogenic adverse outcomes. The phenotype-first approach indicated that clusters 3 and 4 were associated with the worst prognosis. Overall, genotype was the strongest predictor of outcome. Patients with a genetic form of DCM exhibit clinical and genetic heterogeneity. Genotype-based risk stratification is more accurate compared to a phenotype-first approach, highlighting the importance of broad genetic screening among patients with DCM. Additionally, gene-specific risk prediction should become more prominent in current guidelines on management of genetic DCM patients.
Current clinical applications of AAV-mediated gene therapy.
(Cell Press, 2025-06-04) Byrne, Barry J; Flanigan, Kevin M; Matesanz, Susan E; Finkel, Richard S; Waldrop, Megan A; D'Ambrosio, Eleonora S; Johnson, Nicholas E; Smith, Barbara K; Bönnemann, Carsten; Carrig, Sean; Rossano, Joseph W; Greenberg, Barry; Lalaguna, Laura; Lara-Pezzi, Enrique; Subramony, Sub; Corti, Manuela; Mercado-Rodriguez, Claudia; Leon-Astudillo, Carmen; Ahrens-Nicklas, Rebecca; Bharucha-Goebel, Diana; Gao, Guangping; Gessler, Dominic J; Hwu, Wuh-Liang; Chien, Yin-Hsiu; Lee, Ni-Chung; Boye, Sanford L; Boye, Shannon E; George, Lindsey A
Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic disease that in vivo delivers a functional copy of the aberrant gene is an intuitive solution that has thus far taken 3 decades to reduce to clinical practice, predominantly using adeno-associated viral (AAV) vectors. Among available viral and non-viral gene delivery approaches, AAV vectors remain the most efficient means for in vivo delivery of DNA to the nucleus. AAV vectors now constitute a bone fide novel therapeutic drug class composed of seven US Food and Drug Administration-approved products with over 10-fold more in clinical development for an expanding number of disease indications and an identified list of problems to overcome for widespread clinical application. Here, we review current progress in clinical AAV gene therapy, including for neuromuscular disorders, hemophilia, primary cardiovascular disorders, or disorders with cardiovascular manifestations, lysosomal storage disorders, mucopolysaccharide disorders, primary central nervous systemic disorders, and ocular disorders.
Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.
(2024-12-16) Garcia-Pavia, Pablo; Oręziak, Artur; Masri, Ahmad; Barriales-Villa, Roberto; Abraham, Theodore P; Owens, Anjali T; Jensen, Morten K; Wojakowski, Wojciech; Seidler, Tim; Hagege, Albert; Lakdawala, Neal K; Wang, Andrew; Wheeler, Matthew T; Choudhury, Lubna; Balaratnam, Ganesh; Shah, Ashish; Fox, Shawna; Hegde, Sheila M; Olivotto, Iacopo
Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, -40.3 (32.7) mmHg; Valsalva, -55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): -562 (-1162.5, -209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.
Mending the Achilles heels of titin in cardiac and musculoskeletal disease
(2026-02-14) Martinez-Martin ,Inés; Silva-Rojas, Roberto; Alegre-Cebollada, Jorge
Titin, the largest known human protein, spans the sarcomere from Z-disk to M-line and is central to muscle elasticity, force transmission, and structural integrity. Maybe not surprisingly, accumulated evidence over the last years shows that titin, despite its titanic size, is not devoid of molecular Achilles heels that can lead to dysfunction and disease. In this review, we summarize the fundamental roles of titin in muscle mechanics, mechanosignaling, and physiology as well as in genetic and acquired disorders of cardiac and skeletal muscle. We discuss the current understanding of how mutations and posttranslational processing (dys)regulate titin, while highlighting gaps of knowledge regarding underlying molecular mechanisms. Finally, we analyze emerging experimental titin-cleavage models that are uncovering novel pathways of titin-based pathogenesis, positioning the protein not only as a central player in myocyte biomechanics but also as a determinant of pathological tissue remodeling. A main driving force in the field is to exploit the accumulated knowledge on titin to find new avenues for therapeutic intervention in cardiac and musculoskeletal disease.
A Compact Quadrupole-Orbitrap Mass Spectrometer with FAIMS Interface Improves Proteome Coverage in Short LC Gradients
(2020-04-30) Bekker-Jensen, DB; Martínez-Val, A; Steigerwald, S; Rüther, P; Fort, KL; Arrey, TN; Harder, A; Makarov, A; Olsen, J
State-of-the-art proteomics-grade mass spectrometers can measure peptide precursors and their fragments with ppm mass accuracy at sequencing speeds of tens of peptides per second with attomolar sensitivity. Here we describe a compact and robust quadrupole-orbitrap mass spectrometer equipped with a front-end High Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) Interface. The performance of the Orbitrap Exploris 480 mass spectrometer is evaluated in data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes in combination with FAIMS. We demonstrate that different compensation voltages (CVs) for FAIMS are optimal for DDA and DIA, respectively. Combining DIA with FAIMS using single CVs, the instrument surpasses 2500 peptides identified per minute. This enables quantification of >5000 proteins with short online LC gradients delivered by the Evosep One LC system allowing acquisition of 60 samples per day. The raw sensitivity of the instrument is evaluated by analyzing 5 ng of a HeLa digest from which >1000 proteins were reproducibly identified with 5 min LC gradients using DIA-FAIMS. To demonstrate the versatility of the instrument, we recorded an organ-wide map of proteome expression across 12 rat tissues quantified by tandem mass tags and label-free quantification using DIA with FAIMS to a depth of >10,000 proteins.
Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
(2021-05-04) Franciosa, G; Smits, JGA; Minuzzo, S; Martinez-Val, A; Indraccolo, S; Olsen, JV
Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution
(2021-12-07) Martinez-Val, A; Bekker-Jensen, DB; Steigerwald, S; Koenig, C; Ostergaard, O; Mehta, A; Tran, T; Sikorski, K; Torres-Vega, E; Kwasniewicz, E; Brynjólfsdóttir, SH; Frankel, LB; Kjobsted, R; Krogh, N; Lundby, A; Bekker-Jensen, S; Lund-Johansen, F; Olsen, JV
Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases
(Elsevier, 2021-04-23) Garcia-Pavia, Pablo; Rapezzi, Claudio; Adler, Yehuda; Arad, Michael; Basso, Cristina; Brucato, Antonio; Burazor, Ivana; Caforio, Alida L. P.; Damy, Thibaud; Eriksson, Urs; Fontana, Marianna; Gillmore, Julian D.; Gonzalez-Lopez, Esther; Grogan, Martha; Heymans, Stephane; Imazio, Massimo; Kindermann, Ingrid; Kristen, Arnt V.; Maurer, Mathew S.; Merlini, Giampaolo; Pantazis, Antonis; Pankuweit, Sabine; Rigopoulos, Angelos G.; Linhart, Ales
Long-lived polyclonal B-cell lines derived from midgestation mouse embryo lymphohematopoietic progenitors reconstitute adult immunodeficient mice.
(Elsevier, 2001-09-15) Martínez-M, J A; Minguet, S; Gonzalo, P; Soro, P G; de Andrés, B; Izcue, A; Marcos, M A; Gaspar, M L
Lymphohematopoietic progenitors derived from midgestation mouse embryos were established in long-term cultures with stromal cell monolayers and interleukin 7 (IL-7), giving rise to B-lineage cell lines. The initial emergence and in vitro establishment of these early embryo cell lines were highly sensitive to IL-7-mediated signals, in comparison to cell lines similarly obtained using precursors from late fetal liver (> 13 days postcoitum) and adult bone marrow. The early embryo-derived progenitors spontaneously differentiated in vitro to CD19(+)IgM(+) immature B cells in the presence of optimal concentrations of IL-7, in contrast to those progenitors obtained from late gestation and adult mice, whose differentiation only occurred in the absence of IL-7. The newly in vitro-generated B cells of the early embryo cell lines repopulated adult immunodeficient severe combined immunodeficient mice on their adoptive transfer in vivo and generated specific humoral immune responses after immunization.
The first 3 days of B-cell development in the mouse embryo.
(Elsevier, 2002-12-01) de Andrés, Belen; Gonzalo, Pilar; Minguet, Susana; Martínez-Marin, José A; Soro, Pilar G; Marcos, Miguel Angel R; Gaspar, María Luisa
B-lineage-committed cells are believed to arise in the liver of mouse embryos at 14 days after coitus (dpc). However, pre-B-specific gene transcripts and DJH gene rearrangements have been detected in earlier, midgestation embryos. We describe here a population of c-kit(+)AA4.1(+)CD19(+)Pax5(+) cells present in the aorta-gonad-mesonephros (AGM) area and in the livers of 11-dpc mouse embryos. In contrast to multipotent c-kit(+)AA4.1(+)CD19(-) hematopoietic stem cells (HSCs), these c-kit(+)AA4.1(+)CD19(+) progenitors differentiated only to B-lineage cells in vitro. We propose that mouse embryonic B lymphopoiesis starts earlier than previously thought, at 10 to 11 dpc, both in liver and extra-liver hematopoietic sites. The B-cell differentiation program is not delayed with respect to the emerging lymphohematopoiesis events in the midgestation mouse embryo (8-9 dpc).

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