https://repositorio.fleni.org.ar/xmlui/handle/123456789/809 2026-08-05T19:14:13Z 2026-08-05T19:14:13Z Freiberger, Rosa Nicole López, Cynthia Alicia Marcela Palma, María Belén Cevallos, Cintia Sviercz, Franco Agustin Jarmoluk, Patricio García, Marcela Nilda Quarleri, Jorge Delpino, M. Victoria https://repositorio.fleni.org.ar/xmlui/handle/123456789/1548 2026-08-03T18:23:34Z 2026-04-23T00:00:00Z

Brucella abortus Infection Promotes Mesenchymal Stem Cell Differentiation Toward Adipogenesis, Enhancing the Proinflammatory Profile Freiberger, Rosa Nicole; López, Cynthia Alicia Marcela; Palma, María Belén; Cevallos, Cintia; Sviercz, Franco Agustin; Jarmoluk, Patricio; García, Marcela Nilda; Quarleri, Jorge; Delpino, M. Victoria The most common complication of active brucellosis in humans is osteoarticular injury. In the bone marrow microenvironment, mesenchymal stem cells (MSCs) can differentiate into either adipocytes or osteoblasts, and this balance is tightly regulated because an increase in adipogenesis may negatively affect bone formation and favor bone loss. The differentiation of MSCs into adipocytes or osteoblasts is tightly regulated by mechanisms that promote cell fate toward one lineage while repressing the other. Our study demonstrated that Brucella abortus infects MSCs but does not affect the deposition of organic and mineral matrix during osteoblast differentiation. However, the infection upregulates Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression in osteoblasts, which may contribute to osteoclast activation and bone resorption. Conversely, B. abortus infection significantly influences adipocyte differentiation by modulating lipolysis, lipogenesis, and interactions between lipid droplets and mitochondria. This leads to increased cellular cholesterol levels and reduced intracellular triglycerides, accompanied by glycerol release. These changes result in more differentiated adipocytes and larger lipid droplets. Consequently, we observed increased IL-6 secretion and a higher leptin/adiponectin ratio. Importantly, these effects were independent of a functional type IV secretion system (T4SS), as purified Brucella DNA fully reproduced the adipogenic phenotype. Moreover, inhibition of TLR9-the primary sensor of bacterial DNA-significantly reduced the DNA-induced adipogenic response, demonstrating that adipocyte modulation is at least in part mediated through TLR9 signaling. In summary, B. abortus promotes MSC differentiation toward an inflammatory adipocyte phenotype. It involves a TLR-9-mediated DNA detection. It may contribute to osteoarticular injury and infection-associated bone resorption.

2026-04-23T00:00:00Z Daniels, Alisha McDade, Eric Llibre Guerra, Jorge J. Dominantly Inherited Alzheimer Network Xiong, Chengjie Perrin, Richard J. Ibañez, Laura Supnet Bell, Charlene Cruchaga, Carlos Goate, Alison M. Renton, Alan E. Benzinger, Tammie L.S. Gordon, Brian A. Hassenstab, Jason Karch, Celeste M. Levey, Allan I. Morris, John C. Buckles, Virginia Allegri, Ricardo Francisco Chrem Méndez, Patricio Alexis https://repositorio.fleni.org.ar/xmlui/handle/123456789/1538 2026-07-29T17:00:44Z 2026-02-16T00:00:00Z

15 years of longitudinal genetic, clinical, cognitive, imaging, and biochemical measures in DIAN Daniels, Alisha; McDade, Eric; Llibre Guerra, Jorge J.; Dominantly Inherited Alzheimer Network; Xiong, Chengjie; Perrin, Richard J.; Ibañez, Laura; Supnet Bell, Charlene; Cruchaga, Carlos; Goate, Alison M.; Renton, Alan E.; Benzinger, Tammie L.S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste M.; Levey, Allan I.; Morris, John C.; Buckles, Virginia; Allegri, Ricardo Francisco; Chrem Méndez, Patricio Alexis The Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs) is a longitudinal, global cohort study investigating brain aging and autosomal dominant Alzheimer's disease (ADAD), a rare monogenic form of Alzheimer's disease (AD). Established in 2008 with support from the National Institute on Aging (NIA), DIAN Obs is designed to collect comprehensive and uniform data with the aim to characterize brain biology and clinical trajectory of individuals at risk for ADAD. Mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes cause ADAD with virtually full penetrance and a predictable age at symptomatic onset. Participants, both mutation carriers and non-carriers from affected families, undergo longitudinal clinical and cognitive assessments, neurologic and physical examinations, structural and functional neuro-imaging, and amyloid and tau positron emission tomography (PET). Biospecimens include cerebrospinal fluid, plasma, serum, and whole blood for biochemical, genetic and multi-omic analyses, with brain donation upon death. This dataset enables one of the most detailed longitudinal examinations of the human brain across the continuum from presymptomatic to symptomatic AD. The extensive DIAN Obs data and biospecimen repository provides a globally accessible resource to advance understanding of AD pathophysiology, aging, and the development of preventive and therapeutic interventions.

2026-02-16T00:00:00Z Sevlever, Federico Waisman, Ariel Miriuka, Santiago Ventura, Alejandra C. https://repositorio.fleni.org.ar/xmlui/handle/123456789/1498 2026-05-27T13:56:09Z 2025-11-21T00:00:00Z

Persistent memory in network topologies following temporary stimuli Sevlever, Federico; Waisman, Ariel; Miriuka, Santiago; Ventura, Alejandra C. Molecular memory in signaling and gene regulatory networks shapes how cells respond to transient inputs. Here, we present a mathematical framework to quantify memory as changes in system state after temporary stimulation. Using computational models, we show that circuits with positive feedback loops, particularly those enabling bistability, sustain long-term memory, while certain negative feedbacks can erase it. We further identify minimal network motifs that reliably confer memory, revealing symmetry between activating and inactivating mechanisms. In addition, oscillatory circuits can encode memory even without positive feedback, storing information in the phase of their oscillations. Applying this approach to mouse embryonic stem cells exposed to transient differentiation cues, we find that different genes display distinct degrees of memory retention, with some reflecting partial reversion and others indicating commitment to differentiation. This framework provides a unified way to compare memory across systems and highlights how circuit architecture influences information storage in biology.

2025-11-21T00:00:00Z Castañeda, Sheila Amín, Guadalupe Freiberger, María Inés Zabalegui, Federico Renes, Sol Fernández Gamba, Ágata Rosa, Alberto Luis Cejas, Claudia Patricia Pastor Rueda, José Manuel Waisman, Ariel Ferreiro, Diego Sevlever, Gustavo Emilio Miriuka, Santiago Moro, Lucía Natalia https://repositorio.fleni.org.ar/xmlui/handle/123456789/1492 2026-05-19T14:39:14Z 2025-12-31T00:00:00Z

Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies Castañeda, Sheila; Amín, Guadalupe; Freiberger, María Inés; Zabalegui, Federico; Renes, Sol; Fernández Gamba, Ágata; Rosa, Alberto Luis; Cejas, Claudia Patricia; Pastor Rueda, José Manuel; Waisman, Ariel; Ferreiro, Diego; Sevlever, Gustavo Emilio; Miriuka, Santiago; Moro, Lucía Natalia Background: Desmin (DES) is a major intermediate filament protein involved in the structural integrity and function of striated muscles. Pathogenic mutations in DES are predominantly missense variants, causing isolated cardiomyopathy and combinations of myopathy and cardiomyopathy. In-frame insertions are very rare and usually classified as variants of uncertain significance or likely pathogenic due to limited predictive and/or experimental evidence. Methods: This study describes a novel heterozygous in-frame insertion in exon 6 of DES (RefSeq NM_001927.4:c.1059_1061dup) identified in an Argentine family with myofibrillar myopathy (MFM). This mutation results in the duplication of a glutamic acid residue at position 353 (NP_001918.3:p.(Glu353dup)), in the 2B subdomain of the central rod domain. Clinical, computational and functional analyses were performed to study the pathogenicity of this variant. Results: Clinically, the index patient exhibited hallmark MFM features, including progressive muscle weakness, atrophy and fatty muscle replacement. In silico analyses of molecular dynamics revealed that p.Glu353dup alters DES dimer assembly by stabilising an aberrant coiled-coil conformation, a mechanism not previously proposed for DES mutations. Functional studies in HEK293T cells and C2C12 myocytes suggested that the p.Glu353dup variant induces aberrant DES aggregation, confirming its detrimental effect on filament organisation. Conclusion: These findings are consistent with the idea that p.Glu353dup is a pathogenic variant, supported by clinical studies, in silico protein modelling and functional evidence, highlighting the impact of in-frame insertions on DES filament homeostasis. By providing computational and experimental evidence, this study expands our understanding of desminopathies and offers new perspectives for pathogenicity assessment of uncertain DES variants.

2025-12-31T00:00:00Z