INEU

Persistent memory in network topologies following temporary stimuli

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.

Functional validation of the PSEN1 R358P and PSEN1 T119I variants in Alzheimer's Disease: an in vitro study

2025-12-23T00:00:00Z

Functional validation of the PSEN1 R358P and PSEN1 T119I variants in Alzheimer's Disease: an in vitro study García Chialva, Diego; Cifarelli, Diego; Isaja, Luciana; Apecetche, Manuela; Martínes Ojeda, Laura; Itzcovich, Tatiana; Chrem Méndez, Patricio Alexis; Sevlever, Gustavo Emilio; Scassa, Maria; Surace, Ezequiel Ignacio; Romorini, Leonardo Background Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by progressive neuronal degeneration and the accumulation of beta‐amyloid plaques (Aβ) and neurofibrillary tangles (NFT) in the brain. AD manifests in sporadic AD (sAD) and familial AD (fAD). fAD is associated with inherited genetic mutations affecting amyloid precursor protein (APP) processing, involving genes such as APP, PSEN1, and PSEN2. Method The identification of two novel PSEN1 variants, p.T119I and p.R358P in early‐onset AD patients at FLENI provided a unique opportunity to study their possible implications in fAD. Notably, the patient harboring the PSEN1 R358P variant also carried a novel SORL1 variant (Gly1536Asp). Noteworthy, genetic variants in SORL1 are now considered a major AD risk factor. To evaluate the role of these two novel PSEN1 variants in APP processing, we developed a cellular model using PSEN1 Knock‐Out (KO) HEK293T cells created through CRISPR/Cas9 technology. We assessed the Aβ 42 /Aβ 40 ratio (AD biomarker) in the supernatant of PSEN1 KO‐cells transfected with expression vectors coding for APP and either wild‐type PSEN1, the novel PSEN1 variants or PSEN1 A246E (a known pathogenic mutation). Result We observed a significant (p <0.05) increase in the Aβ 42 /Aβ 40 ratio in HEK293T cells transfected with PSEN1 A246E or PSEN1 R358P plasmids and a slight trend towards an increase in cells transfected with PSEN1 T119I vector. In the case of PSEN1 R358P‐transfected cells, the increase in the Aβ 42 /Aβ 40 ratio observed was primarily due to the decrease in Aβ 40 levels in the supernatant. Conclusion These findings suggest a potential pathogenic role for the PSEN1 R358P variant in fAD, independent of the co‐occurring SORL1 mutation.

Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies

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.

Capacity building in dementia research: insights from the World Young Leaders in Dementia

2025-12-01T00:00:00Z

Capacity building in dementia research: insights from the World Young Leaders in Dementia Morello-García, Florentina; Corvalán, Nicolás; Llibre-Guerra, Jorge; Arruabarrena, Micaela; Clarens, María Florencia; Keller, Greta; De Los Santos, Loana; Martin, María Eugenia; Schaffer Aguzzoli, Cristiano; Allegri, Ricardo Francisco; Amaral, Livia; Ardohain Cristalli, Carolina; Bellaver, Bruna; Ngozi Best, Merci; Bloomquist, Madeleine; Chen, Kevin; Surace, Ezequiel Ignacio; Wilks, Hannah; Zimmer, Eduardo; Crivelli, Lucía; Hernández, Micaela Anahí; Magrath Guimet, Nahuel Early-career researchers from low- and middle-income countries face systemic barriers to professional development and leadership growth. This article presents results from an initiative led by the World Young Leaders in Dementia (WYLD), including a leadership-focused session at the Alzheimer's Association International Conference 2024 and a global survey completed by 130 dementia researchers from 17 countries. The survey explored five capacity-building domains critical for leadership development. Over half of the survey respondents stated that scientific research in their country was not prioritized in public policy. Additionally, only 39% report holding full-time academic positions. The most cited challenges included lack of funding sources, training opportunities, and physical workspace. These findings highlight the urgent need to invest in research, training, and infrastructure to support future scientific leaders. As dementia incidence rises, prioritizing capacity building is essential to ensure global equity in research. HIGHLIGHTS: Early-career dementia researchers face major barriers, especially in LMICs. A networking session and a global survey explored capacity-building needs in dementia research. Key obstacles: lack of funding, training, workspace, and protected research time. Leadership development is a critical component of sustainable research capacity.