👤 Oscar Mendoza

Aging is traditionally characterized by progressive structural and cognitive decline; however, increasing evidence shows that the aging brain retains a remarkable capacity for reorganization. This adaptive neuroplasticity supports cognitive resilience-defined as the ability to maintain efficient cognitive performance despite age-related neural vulnerability. To synthesize current molecular, cellular, neuroimaging, and electrophysiological neuromarkers that characterize adaptive neuroplasticity and to examine how these mechanisms contribute to cognitive resilience across aging. This narrative review integrates findings from molecular neuroscience, multimodal neuroimaging (fMRI, DTI, PET), electrophysiology (EEG, MEG, TMS), and behavioral research to outline multiscale biomarkers associated with compensatory and efficient neural reorganization in older adults. Adaptive neuroplasticity emerges from the coordinated interaction of neurotrophic signaling (BDNF, CREB, IGF-1), glial modulation (astrocytic lactate metabolism, regulated microglial activity), synaptic remodeling, and neurovascular support (VEGF, nitric oxide). Multimodal neuromarkers-including preserved frontoparietal connectivity, DMN-FPCN coupling, synaptic density (SV2A-PET), theta-gamma coherence, and LTP-like excitability-consistently correlate with resilience in executive functions, memory, and processing speed. Behavioral enrichment, physical activity, and cognitive training further enhance these biomarkers, creating a bidirectional loop between experience and neural adaptability. Adaptive neuroplasticity represents a fundamental mechanism through which older adults maintain cognitive function despite biological aging. Integrating molecular, imaging, electrophysiological, and behavioral neuromarkers provides a comprehensive framework to identify resilience trajectories and to guide personalized interventions aimed at preserving cognition. Understanding these multilevel adaptive mechanisms reframes aging not as passive decline but as a dynamic continuum of biological compensation and cognitive preservation. Show less

RNA-based therapies have emerged as a transformative approach in the management of hypercholesterolemia and coronary artery disease by directly targeting molecular pathways involved in lipid regulation. These treatments focus on silencing key genes such as PCSK9, ANGPTL3, ApoB, and Lp(a), achieving substantial reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, and other atherogenic lipoproteins. Small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) provide highly specific post-transcriptional gene suppression, while advances in chemical stabilization and GalNAc conjugation have enhanced hepatocyte delivery and prolonged therapeutic action. Approved agents such as inclisiran demonstrate sustained LDL-C reductions of approximately 50% with only two to three injections annually, improving adherence and offering an alternative for patients intolerant to statins or unable to reach lipid targets with conventional therapy. Pelacarsen and other emerging antisense therapies show promise for reducing lipoprotein(a), an independent cardiovascular risk factor, while siRNAs targeting ANGPTL3 offer prolonged lipid-lowering effects beyond those achieved with monoclonal antibodies. Despite these advantages, challenges remain. Hepatic safety concerns have halted the development of some agents, such as vupanorsen, and long-term cardiovascular outcome data for several therapies, including inclisiran, are still in development. Cost and accessibility also limit broad adoption, emphasizing the need for cost-effective strategies and long-term surveillance. Nevertheless, current evidence supports the integration of RNA-based therapies into modern lipid-lowering algorithms, particularly for high-risk patients, while ongoing research continues to refine delivery systems, enhance safety, and expand therapeutic indications. Show less

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can predispose individuals to weight regain after initial fat loss, as shown by studies indicating persistent transcriptional and chromatin changes even after fat mass reduction. Independent studies also demonstrate long-lasting metabolic shifts, such as those triggered by glucose-dependent insulinotropic polypeptide receptor (GIPR)-induced thermogenesis and sarcolipin (SLN) stabilization that also support a form of "metabolic memory" that is associated with sustained weight loss. At the neural level, rare variants in synaptic genes like Show less

Dengue virus (DENV) is a growing global public health threat. The lack of symptomatic immune-competent animal models for dengue has hindered the screening and development of effective therapeutics that can be used to control dengue virus replication and thereby control the progression to severe dengue disease. To address this, we established an infection model in neonatal C57BL/6 mice and showed that a systemic Dengue challenge leads to ataxia, seizures, paralysis, and death within 15 days. The virus was found predominantly in the eye and brain where DENV infects neurons but not astrocytes and causes extensive infiltration of macrophages and microglia activation. The response to infection included upregulation of multiple genes linked to interferons ( Show less

Upon spinal cord injury, axons attempting to regenerate need to overcome the repulsive actions of myelin-associated inhibitors, including the myelin-associated glycoprotein, Nogo-A, and the oligodendrocyte myelin glycoprotein. These inhibitors bind and signal through a neuronal receptor/co-receptor/transducer complex composed of NgR1, Lingo-1, and p75. Consequently, p75 is cleaved by alpha secretase followed by gamma-secretase, triggering downstream signaling that inhibits axonal regrowth. ADAM10 and ADAM17 are both known to function as alpha secretases in neurons. Here we show that ADAM17, and not ADAM10, is the alpha secretase that recognizes and cleaves p75, when it is a part of a 5-component neuron-myelin signaling complex comprising NgR1, Lingo-1, p75, GT1b, and a myelin inhibitor. Importantly, we demonstrate the ability of inhibitory anti-ADAM17 mAbs to abrogate the cleavage of p75 in a neuroblastoma-glioma cell line and reverse the neurite outgrowth inhibition by myelin-associated inhibitors. Show less

The PRO-CTCAE provides patient-reported data on symptomatic AEs. A summary metric-the ACS-reflecting total AE burden can be calculated by averaging AE-level composite scores at a given timepoint for each participant. This study investigated the psychometric properties and interpretability of this PRO-CTCAE ACS in patients with breast, lung, or head/neck cancers. We conducted a secondary analysis of a PRO-CTCAE validation dataset comprising 940 adults undergoing chemotherapy or radiation therapy (clinicaltrials.gov: NCT02158637). We focused on empirically recommended symptom terms for three cancer sites. Analyses included Spearman's correlations, coefficient alpha, and eigenvalues from the correlation matrices, confirmatory factor analysis (CFA), and principal component analysis (PCA). Latent profile analysis (LPA) was used to assess ACS interpretability in the lung cohort. Mean composite score inter-correlations were moderate (0.30-0.35), and coefficient alphas were high (0.81-0.91). Eigenvalue ratios and CFA supported retention of a single factor/component, with suitable model fit indices. ACS correlated highly with factor scores and the first principal component from the PCA. Reduced sets of terms produced reliable scores that closely approximated the full set scores and aligned with external criteria. LPA in the lung subgroup identified four latent classes; ACS differentiated high vs. low symptom burden groups but did not distinguish the two groups expressing distinct symptom profiles. The ACS demonstrated structural validity through adequately fitting linear factor models and effectively summarized symptomatic AE burden. However, similar ACS values may mask clinically distinct symptomatic AE profiles, underscoring the value of both summary metrics and profile-based approaches. Show less

The GramAdapt Social Contact Dataset is a curated dataset of 34 language pairs with qualitative and quantifiable data on social interaction and aspects of societal multilingualism. The language pairs were sampled globally to represent the world's linguistic diversity. The dataset can be used to interrogate the social dimensions of language contact independently or in conjunction with appropriate linguistic data. The data were collected by distributing a questionnaire to experts who have experience with either one or both of the language communities of a pair. The data represent subjective expert assessments based on choices from predetermined answers which can be quantified. Authors 1, 2 and 3 manually checked the response to identify possible misjudgments or misunderstandings. This results in a dataset containing 13,493 data points. This dataset is a first of its kind in the field of linguistics, built upon wide findings from sociolinguistics, historical linguistics, psycholinguistics, and linguistic anthropology. Show less

Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Show less

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression. Show less

Stress granules (SGs) are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge of their regulation and functional relevance is still incipient. Here, we describe a mutual-inhibition interplay between SGs and Cdc28, the budding yeast Cdk. Among Cdc28 interactors acting as negative modulators of Start, we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA of CLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdk's subjugate SG dynamics to a conserved hysteretic switch. Show less

Thyroid hormone (TH) action is essential for hepatic lipid synthesis and oxidation. Analysis of hepatocyte-specific thyroid receptor β1 (TRβ1) knockout mice confirmed a role for TH in stimulating de novo lipogenesis and fatty acid oxidation through its nuclear receptor. Specifically, TRβ1 and its principal corepressor NCoR1 in hepatocytes repressed de novo lipogenesis, whereas the TH-mediated induction of lipogenic genes depended on the transcription factor ChREBP. Mice with a hepatocyte-specific deficiency in ChREBP lost TH-mediated stimulation of the lipogenic program, which, in turn, impaired the regulation of fatty acid oxidation. TH regulated ChREBP activation and recruitment to DNA, revealing a mechanism by which TH regulates specific signaling pathways. Regulation of the lipogenic pathway by TH through ChREBP was conserved in hepatocytes derived from human induced pluripotent stem cells. These results demonstrate that TH signaling in the liver acts simultaneously to enhance both lipogenesis and fatty acid oxidation. Show less

Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell. Show less

G-quadruplexes (G4) are RNA and DNA secondary structures formed by the stacking of guanine quartets in guanine rich sequences. Quadruplex-prone motifs may be found in key genomic regions such as telomeres, ribosomal DNA, transcriptional activators and regulators or oncogene promoters. A number of proteins involved in various biological processes are able to interact with G4s. Among them, proteins dedicated to nucleic acids unwinding such as WRN, BLM, FANCJ or PIF1, can unfold G4 structures. Mutations of these helicases are linked to genome instability and to increases in cancer risks. Here, we present a high-throughput fluorescence-based reliable, inexpensive and fast assay to study G4/RHAU interaction. RHAU is an RNA helicase known as the major source of G4 resolution in HeLa cells. Our assay allows to monitor the unfolding properties of RHAU towards DNA and RNA quadruplexes in parallel and to screen for the optimal conditions for its activity. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Show less