Biology subjects

Santos, G.

Publications and source records attributed to Santos, G..

9 recordsLinked to original sources

bioRxiv2026

STING agonists in combination with epigenetic drugs potentiate ZNFX1-driven inflammatory necroptosis in TP53-mutated AML

TP53-mutated acute myeloid leukemia (AML) has dismal outcomes with current treatments and represents a critical unmet need. TP53-mutated AML is proposed to be susceptible to immunotherapeutic approaches but, to date, there is no established immunotherapy for this sub-group. Expression of stimulator of interferon genes (STING), a key innate immune driver that activates interferon (IFN) signaling, is decreased by epigenetic silencing or mutation in many cancers, including those with TP53 mutations. Here, we report that response to the next-generation synthetic STING agonist C92 is potentiated in AML cell lines and primary cells with TP53-mutated versus wild-type (WT) cells, representing a previously undescribed vulnerability of these leukemia cells to STING small molecule therapies. Moreover, combining treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC), significantly increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes. Cell death in TP53 KO versus WT AML is specifically dependent on innate immune zinc finger NFX1-type containing 1 (ZNFX1) and Z-DNA-binding protein 1 (ZBP1) driving increased cleavage and activation of Receptor-Interacting-Serine/Threonine-Protein Kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), suggesting mechanisms of necroptosis. Finally, C92 and DAC combination significantly reduces leukemia burden in humanized AML mouse models, accompanied by increased immune responses, including cytokines and cytotoxic T lymphocytes in the leukemia microenvironment. These results support development of clinical trial strategies combining STING agonists with DNMTis for patients with TP53-mutated AML. SummaryO_LITP53-mutated AML potentiates effects of novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, inducing increased STING activation and cytokine release C_LIO_LISTING agonists and DNMTis, synergistically increase STING activation with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes in TP53-mutated AML C_LIO_LISTING agonists induce necroptosis via a STING-ZNFX1-ZBP1-necroptosis axis in TP53-mutated AML. C_LIO_LIThis drug combination reduces leukemia burden, activates immune responses in AML models and supports translation for high-risk AML patients. C_LI Statement of Translational RelevanceThis pre-clinical study identifies a novel therapeutic vulnerability in (TP53)-mutated acute myeloid leukemia (AML), a poor prognosis subtype with a critical unmet need. Novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, induces increased STING activation and cytokine release, compared with WT TP53 in AML cell lines and primary cells, and has superior STING activity with respect to several STING agonists currently in clinical studies. Combining C92 treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) synergistically increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes, driving ZNFX1-driven inflammatory necroptotic cell death. Utilizing humanized mouse models, C92 in combination with DAC significantly reduces leukemia burden and enhances cytotoxic T-cell responses in the tumor microenvironment, supporting clinical translation for high-risk AML patients.

cancer biology↗

bioRxiv2025

Exercise Engages Coordinated Neuron-Glia Signaling to Shape Spinal Cord Plasticity

Physical activity induces systemic benefits for brain and muscle function, but how the healthy spinal cord adapts to exercise remains largely unknown. Here, we combine bulk proteomics, single-nucleus RNA sequencing, and cellular communication inference to map exercise- induced molecular adaptations in the mouse lumbar spinal cord. Endurance training elicited robust baseline remodeling, dominated by glial transcriptional changes. Acute exhaustive exercise triggered biphasic responses: widespread metabolic and synaptic gene upregulation at 6 h followed by balanced suppression at 24 h, with trained animals exhibiting enhanced amplitude and faster resolution. Cell-cell communication analysis revealed that exercise reshaped signaling networks in both magnitude and composition. While glia emerged as primary transcriptional responders, cholinergic neurons--despite minimal transcriptional changes--were central signaling hubs, engaging various pathways with astrocytes, oligodendrocyte precursor cells, and oligodendrocytes in a training-dependent and temporally restricted manner. Glial-derived communication further diversified these responses, with astrocytes, oligodendrocytes, and microglia shifting toward pathways supporting synaptic remodeling, axon guidance, and growth factor signaling while dampening inflammatory cues. Together, these findings identify neuron-glia communication as potential driver of spinal cord adaptation to exercise, suggesting pathways through which glial plasticity may serve as a key mediator linking motor activity to spinal cord resilience. Significance StatementExercise confers broad benefits for neural and motor system health, yet how the healthy spinal cord adapts to physical activity is poorly understood. Using multi-omic profiling, we show that endurance training and acute exercise elicit coordinated transcriptional and signaling responses in spinal cord glia, with cholinergic neuron-glia communication emerging as a key upstream driver. These findings identify glial plasticity and neuron-glia crosstalk as a potential mechanism of spinal cord adaptation, providing a foundation for leveraging exercise-based strategies in neurological health and disease.

physiology↗

bioRxiv2025

Muscle Fiber- and Cell Type-Specificity of Training Adaptation in Male Mice

Skeletal muscle possesses extraordinary plasticity of structure, metabolism, and function in response to repeated contractile activity. As a syncytium embedded within a complex microenvironment, muscle relies on the coordination of distinct myonuclear populations and diverse mononucleated cell types. Here, we present a high-resolution single-nucleus RNA-sequencing atlas of 550000 skeletal muscle nuclei, capturing the longitudinal transcriptional responses of 17 distinct myonuclear and 21 mononuclear cell populations at multiple time points after one bout of exhaustive exercise in trained and sedentary mice. The transcriptional programs of these populations are further shaped by training status into divergent adaptive trajectories. A subset of oxidative myonuclei enters a delayed regenerative state post-exercise, reflecting a bifurcated response to a disproportionate metabolic load on fibers during endurance exercise. Prior training accelerates homeostatic recovery and shields oxidative nuclei from exacerbated damage signatures. In parallel, mononucleated cells emerge as the primary mediators of intercellular communication during recovery. Together, this dataset establishes that training adaptation emerges through a coordinated interplay of intrinsic adaptive programs of multicellular remodeling, and provides a foundational resource for mechanistic insights into muscle plasticity.

physiology↗

bioRxiv2025

Support for the social buffering hypothesis, especially under unpredictable precipitation regimes

Sociality is hypothesised to buffer populations against environmental stochasticity by stabilising key vital rates, yet this has rarely been tested across diverse taxa. We compiled demographic time series from 87 populations for 66 animal species spanning 12 taxonomic classes to test whether sociality promotes demographic buffering and whether this relationship depends on environmental context. Using stochastic elasticities and phylogenetically comparative analyses, we find broad support for the social buffering hypothesis: more social species exhibit lower sensitivity of population growth to vital rate variance (lower stochastic elasticity to vital rate variances, |T{sigma}|), particularly in juvenile survival and reproduction. Contrary to expectations, juvenile vital rates, but not adult survival, showed the strongest buffering patterns in social taxa, suggesting life-stage-specific social mechanisms. Furthermore, we show that social species invest more in maximising the average performance of adult survival and reproduction (higher stochastic elasticity to vital rate means, T), consistent with adaptive strategies favouring canalisation of fitness-related traits. This buffering benefit is especially relevant in highly unpredictable environments: in climates with erratic precipitation, social species have greater demographic advantages, exhibiting even lower T{sigma} values. Together, these findings provide support for the social buffering hypothesis, especially in highly stochastic environments. Social traits confer some demographic stability under moderate climatic conditions, but may become more relevant under extreme stochasticity--an insight particularly important for understanding population resilience in a rapidly changing world.

animal behavior and cognition↗

bioRxiv2023

Westwards expansion of the European catfish Silurus glanis in the Douro River (Portugal)

The current study reports the first occurrence and the spread of the European catfish Silurus glanis (Family: Siluridae) in the Portuguese section of the Douro River, suggesting a potential expansion of its distribution in Portugal either via westward dispersal across international rivers and/or human-assisted introductions into new reservoirs and drainages. European catfish has unique features (e.g., opportunistic predator, hunting, and aggregation behaviour) that make it highly suitable for establishing self-sustaining populations in new areas and likely contribute to its invasion success. The species may severely affect native prey communities and modify food web structure and ecosystem functioning. Efficient and sustainable management actions are needed to prevent further introductions in the future.

ecology↗

bioRxiv2020

Transcriptomic, proteomic and phosphoproteomic underpinnings of daily exercise performance and Zeitgeber activity of endurance training

Timed physical activity might potentiate the health benefits of training. The underlying signaling events triggered by exercise at different times of the day are, however, poorly understood. Here, we found that time-dependent variations in maximal treadmill exercise capacity of naive mice were associated with energy stores, mostly hepatic glycogen levels. Importantly, running at different times of the day resulted in a vastly different activation of signaling pathways, e.g., related to stress response, vesicular trafficking, repair, and regeneration. Second, voluntary wheel running at the opposite phase of the dark, feeding period surprisingly revealed minimal Zeitgeber (i.e., synchronizing) activity of training. This integrated study provides important insights into the circadian regulation of endurance performance and the control of the circadian clock by exercise. These results are of high importance to understand circadian aspects of training design in athletes and the application of chrono-exercise-based interventions in patients. HighlightsO_LIMaximal endurance performance is greater in the early morning C_LIO_LITimed exercise differentially alters the muscle transcriptome and (phospho)-proteome C_LIO_LIMorning exercise triggers energy provisioning and tissue regeneration C_LIO_LIEvening exercise activates stress-related and catabolic pathways C_LIO_LITraining exerts poor Zeitgeber activity on the muscle and liver clocks C_LI

physiology↗

bioRxiv2018

PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1 overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor (ERR)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1. As a result, PGC-1 prevents tubular aggregate formation and fiber apoptosis in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1 in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1 exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1 on muscle function and overall health span in aging.\n\nStatement of significanceThe loss of muscle function in aging results in a massive impairment in life quality, e.g. by reducing motor function, strength, endurance, the ability to perform daily tasks or social interactions. Unfortunately, the mechanistic aspects underlying age-related muscle disorders remain poorly understood and treatments improving the disease are extremely limited. We now show that PGC-1, a transcriptional coactivator, is a key regulator of mitochondrial calcium homeostasis, cellular stress and death, all of which are linked to muscle aging and dysfunction. As a result, inhibition of the age-related decline in muscle PGC-1 considerably reduces aging of muscle and constitutes a promising target to prevent and treat the deterioration of muscle function in the elderly.\n\nAbbreviationsBNIP3, BCL2/Adenovirus E1B 19kDa interacting protein 3; Cpt1b, carnitine palmitoyltransferase 1B; CSQ1, calsequestrin 1; Drp1, dynamin-related protein 1; ER stress, endoplasmic reticulum stress; ERR, estrogen-related receptor ; Fis1, fission 1; GRP75, Glucose-Regulated Protein 75; IGFBP5, insulin like growth factor binding protein 5; IP3, inositol 1,4,5-trisphosphate; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; Letm1, leucine zipper and EF-hand containing transmembrane protein 1; MAMs, mitochondria-associated ER membranes; Mcad, medium-chain acyl-CoA dehydrogenase; Opa1, optic atrophy 1; OXPHOS, oxidative phosphorylation; PGC-1, peroxisome proliferator-activated receptor {gamma} coactivator 1; pH2AX, phospho-H2A Histone Family Member X; ppRB, phospho-preproretinoblastoma-associated protein; Puma, BCL2 Binding Component 3; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; TA, tibialis anterior; TBP, TATA binding protein; TPG, thapsigargin; Ucp3, uncoupling protein 3; VDAC, voltage-dependent anion channel; XBP1, X-Box Binding Protein 1; Xiap, X-linked inhibitor of apoptosis protein

cell biology↗

bioRxiv2018

FPtool a software tool to obtain in silico genotype-phenotype signatures and fingerprints based on massive model simulations

Fptool is an intuitive tool that provides to the user a preliminary fingerprint of the behaviour simulated by a mathematical model of a biochemical network when comparing two biological scenarios defined by the user. Here we present the tool and we applied to an already published mathematical model of lung legionella infection. The fingerprint obtained correlates with the results obtained in the original article. This tool is optimal for the users that would like to obtain a fast and preliminary view of the qualitative behaviour of a mathematical model before deciding for more elaborate analyses.

systems biology↗

bioRxiv2017

A Mathematical model to predict Trichodesmiun spp. bloom during a sewage burst

A modified version of the Monod equation is proposed to understand the bloom emergence of Trichodesmiun spp. in presence of sewage outburst. The mathematical model predicts that the bacterial population does not affect the bloom growth. Also, the quotient between the bacteria during the sewage outburst and before is proposed to be equal to the quotient between the influx of limiting resources during burst and the influx before the burst.

systems biology↗