Biology subjects

Blanco, L.

Publications and source records attributed to Blanco, L..

5 recordsLinked to original sources

bioRxiv2026

From Splicing to Survival: Understanding the Molecular Basis of Prognostic Differences in advanced Small Intestine Neuroendocrine Tumors

Small intestine neuroendocrine tumors (SI-NETs) represent a challenging neoplasm due to their high rate of metastasis and the limited availability of effective therapies. Recent evidence has unveiled altered splicing as an influential player in tumor progression, linked to patient prognosis, which provides a powerful source of novel biomarkers and therapeutic targets in cancer. Here, we conducted a comprehensive analysis regarding the possible connection of the spliceosomic landscape of metastatic SI-NETs with patient survival. Initial analyses revealed a distinctive pattern of splicing events between the two conditions, short (< 5 years, n = 17 patients), vs. long survival ([≥] 5 years, n = 26 patients), with strong discrimination capacity. Furthermore, numerous key splicing events were associated with relevant clinical parameters in SI-NETs. The observed impairments in spliceosomic parameters led us to interrogate the integrity of the splicing machinery. This revealed striking changes in the expression of a high proportion of core spliceosome components and splicing factors between short vs. longsurvival groups, suggesting a possible mechanistic link with the distinct profile of splicing events observed. Among them, CPSF2, a core component of the CPSF complex, stands out as its higher expression is associated with worse survival and vascular and perineural invasion. Interestingly, the shifts potentially generated by this factor supported a possible role in tumor plasticity oriented to higher tumor aggressiveness and treatment resistance. In sum, this study offers the first detailed snapshot of the status of the spliceosomic landscape in SI-NETs and its molecular linkage to patient survival, thus offering a new window towards identification of novel candidate biomarkers and/or therapeutic targets.

cancer biology↗

bioRxiv2025

Dysregulation of U12-Type Splicing in Lupus Neutrophils

ObjectiveNeutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and post-transcriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing. MethodsLDGs and normal-density neutrophils (NDGs) were isolated from SLE patients and healthy controls (HCs). CYBA (P22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes. ResultsCYBA expression was reduced in SLE LDGs (n=11) compared to SLE NDGs and HCs (n=6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n=7 SLE, n=12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad downregulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-- including exon skipping and mutually exclusive exon use--in genes such as GBP5, MAEA and STX10. These abnormalities were validated in an independent long-read RNA-seq dataset from SLE PBMCs. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles. ConclusionImpaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.

immunology↗

bioRxiv2025

High-intensity interval exercise affects explicit sequential motor consolidation with both physical and mental practice

High-intensity interval exercise (HIIE) is known to enhance motor consolidation following physical practice (PP), but its effects on sequential motor learning (SML) through PP or motor imagery (MI) remain unclear. We examined whether HIIE modulates SML consolidation in 48 participants who learned an explicit SML task through PP or MI. Performance was assessed before and after acquisition, after HIIE or rest, and at 24 hours and 7 days. Both PP and MI improved performance, with greater gains for PP (p = 0.042), and both induced intracortical disinhibition (p = 0.03). HIIE increased BDNF (p = 0.044) and lactate levels (p < 0.001), markers typically linked to neuroplasticity, yet unexpectedly impaired SML at early (p < 0.01) and late consolidation (p < 0.05), without affecting excitability. These findings challenge the presumed coupling between exercise-induced biomarkers and behavioral gains, suggesting that HIIE may hinder consolidation when explicit components of motor learning are involved. Significance StatementHIIE is increasingly proposed as a tool to boost neuroplasticity and enhance motor learning. However, whether its benefits extend to all forms of learning remains unclear. Here, we show that both physical and motor imagery practice improve SML and induce intracortical disinhibition, a neurophysiological signature of plasticity. Surprisingly, HIIE impaired SML consolidation at both early and late stages, despite increases in BDNF and lactate, biomarkers typically linked to learning facilitation. This deterioration was observed across both practice modalities and is likely driven by the explicit, cognitively demanding nature of the task. These findings challenge the generalizability of HIIEs beneficial effects and highlight the need to align exercise-based interventions with the specific cognitive-motor demands of the learning task. Such insights are critical for optimizing motor learning strategies in both athletic training and neurorehabilitation.

neuroscience↗

bioRxiv2020

A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol

Replication forks often stall at damaged DNA. Resumption of DNA synthesis can occur by replacement of the replicative DNA polymerase with specialized, error-prone translesion DNA polymerases (TLS), that have higher tolerance for damaged substrates. Several of these polymerases (Pol{lambda}, Pol{eta} and PrimPol) are stimulated in DNA synthesis through interaction with PolDIP2, however the mechanism of this PolDIP2-dependent stimulation is still unclear. Here we show that PrimPol uses a flexible loop to interact with the C-terminal ApaG-like domain of PolDIP2, and that this contact is essential for PrimPols enhanced processivity. PolDIP2 increases PrimPols primer-template and dNTP binding affinity, which concomitantly enhances PrimPols nucleotide incorporation efficiency. This activity is dependent on a unique arginine cluster in PolDIP2 and could be essential for PrimPol to function in vivo, since the polymerase activity of PrimPol alone is very limited. This mechanism, where the affinity for dNTPs gets increased by PolDIP2 binding, could be common to all other PolDIP2-interacting TLS polymerases, i.e. Pol{lambda}, Pol{eta}, Pol{zeta} and REV1, and might be critical for their in vivo function of tolerating DNA lesions at physiological nucleotide concentrations.

biochemistry↗

bioRxiv2020

PrimPol primase mediates replication traverse of DNA interstrand crosslinks

Interstrand crosslinks (ICLs) are DNA lesions frequently induced by chemotherapy that interfere with essential processes such as replication and transcription. ICL repair may be initiated by the convergence of two replication forks at the crosslink, which results in a termination-like DNA structure recognized and processed by the Fanconi Anemia (FA) pathway. An alternative possibility to generate a suitable substrate for ICL repair involves "ICL traverse", a DNA damage tolerance mechanism in which a single fork arriving at the ICL can skip the lesion and restart DNA synthesis from a downstream point. This reaction requires FANCM translocase, the BLM/TOP3A/RMI1-2 (BTR) complex and other factors. Here we report that PrimPol, the second primase-polymerase identified in mammalian cells after Pol/Primase, interacts with BTR and participates in the ICL traverse reaction. A functional complementation assay reveals that the primase activity of PrimPol is required, confirming the need for re-priming events during ICL traverse. Genetic ablation of PRIMPOL strongly impaired this tolerance mechanism, making cells more dependent on fork convergence to initiate ICL repair. PRIMPOL KO cells and mice display hypersensitivity to ICL-inducing drugs, opening the possibility of targeting PrimPol activity to enhance the efficacy of chemotherapy based on DNA crosslinking agents.

molecular biology↗