Biology subjects

Alonso, P.

Publications and source records attributed to Alonso, P..

5 recordsLinked to original sources

bioRxiv2026

Loss of PGC1α drives extracellular matrix remodelling in prostate cancer through CTHRC1

Despite the high curation rate of localized prostate cancer, the fraction of patients that progress to metastasis still accounts for thousands of deaths worldwide, underscoring the need to identify early molecular events that prime tumours for aggressive disease. Here, we demonstrate that loss of the metabolic transcriptional coactivator PGC1 drives early extracellular matrix (ECM) remodelling in PCa, functionally linking epithelial transcriptional programs to tumour-microenvironment interactions. Using genetically engineered mouse models, we show that combined deletion of Pten and Pgc1 induces early activation of ECM-related transcriptional programs, increased collagen deposition, and a transition towards an aligned collagen fibre architecture--hallmarks of aggressive disease--prior to metastatic dissemination. Consistently, human prostate tumours with low PGC1 expression display increased collagen deposition, supporting the clinical relevance of these findings. Restoration of PGC1 expression in prostate cancer cells suppresses cell adhesion to multiple ECM substrates, disrupts collagen organization, and impairs tumour growth in a transcription-dependent manner. Through integrative matrisome proteomics and transcriptomics, we identify the secreted glycoprotein CTHRC1 as a key downstream effector that enhances the prognostic value of PGC1 in PCa patients. Functional loss- and gain-of-function studies establish CTHRC1 expression as both necessary and sufficient to restore ECM adhesion, cytoskeletal organization, collagen architecture, and tumorigenic capacity in PGC1-expressing cells. Importantly, recombinant CTHRC1 rescues adhesion defects, indicating that its extracellular pool mediates this phenotype, whereas deglycosylation abolishes its pro-adhesive function, revealing a mechanistic requirement for glycosylation. Collectively, our findings uncover an early, cell-intrinsic ECM remodelling program driven by PGC1 loss and identify the PGC1-CTHRC1 axis as a mechanistic and clinically relevant regulator of PCa aggressiveness.

cancer biology↗

bioRxiv2026

Disrupted Higher-Order Topology in OCD Brain Networks Revealed by Hodge Laplacian - an ENIGMA Study

Brain disorders are increasingly understood as disorders of distributed brain circuits, yet functional connectivity (FC), the dominant framework for mapping them, treats the brain as a collection of pairwise relationships between regions and cannot represent pathology distributed across coordinated sets of connections. We introduce a Hodge-Laplacian topological framework that localizes higher-order "loop" (1-cycle) organization within functional connectome, maps each loop to specific edges and networks, and yields a subject-level measure of loop expression. Applied to resting-state fMRI from the ENIGMA-OCD consortium (1,024 patients and 1,028 controls across 28 sites), the framework identified 93 loop-level abnormalities in obsessive-compulsive disorder (OCD), concentrated in frontoparietal and somatomotor systems. The edges forming these loops largely showed no significant differences between groups, indicating that the abnormalities were invisible to conventional FC analysis. The frontoparietal and somatomotor loop clusters recurred across the clinical subgroups, suggesting convergence on a shared higher-order phenotype. Robustness analyses showed the loop signal reflected higher-order organization rather than an artifact of individual edges, the network backbone, or any single site. These results indicate that coordinated, multi-edge pathology exists and can be localized even when pairwise analyses fail to detect it, positioning higher-order topology as a generalizable axis for mapping circuit pathology across psychiatric and neurological disorders.

neuroscience↗

bioRxiv2023

Hippocampal and amygdala subfield volumes in obsessive-compulsive disorder differ according to medication status.

IntroAlthough it has been suggested that the hippocampus and amygdala (HA) are involved in the neurobiology of obsessive-compulsive disorder (OCD), volumetric findings have been inconsistent. Furthermore, the HA consist of heterogenous anatomic units with specific functions and cytoarchitecture, and little work has been undertaken on the volumetry of these subfields in OCD. MethodsT1-weighted images from 381 patients with OCD and 338 healthy controls (HCs) from the OCD Brain Imaging Consortium were segmented to produce twelve hippocampal subfields and nine amygdala subfields using FreeSurfer 6.0. We assessed between-group differences in subfield volume using a mixed-effects model adjusted for age, quadratic effects of age, sex, site, and whole HA volume. Given evidence of confounding effects of clinical characteristics on brain volumes in OCD, we also performed subgroup analyses to examine subfield volume in relation to comorbid anxiety and depression, medication status, and symptom severity. ResultsPatients with OCD and HCs did not significantly differ in HA subfield volume. However, medicated patients with OCD had significantly smaller hippocampal dentate gyrus (pFDR=0.042, d=-0.26) and molecular layer (pFDR=0.042, d=-0.29) and larger lateral (pFDR=0.049, d=0.23) and basal (pFDR=0.049, d=0.25) amygdala subfields than HCs. Unmedicated patients had significantly smaller hippocampal CA1 (pFDR=0.016, d=-0.28) than HCs. No association was detected between any subfield volume and OCD severity. ConclusionDifferences in HA subfields between OCD and HCs are dependent on medication status, in line with previous work on other brain volumetric alterations in OCD. This emphasizes the importance of considering psychotropic medication in neuroimaging studies of OCD.

neuroscience↗

bioRxiv2021

Expression patterns of Plasmodium falciparum clonally variant genes at the onset of a blood infection in non-immune humans

Clonally variant genes (CVGs) play fundamental roles in the adaptation of Plasmodium falciparum parasites to the fluctuating conditions of the human host. However, their expression patterns under the natural conditions of the blood circulation have been characterized in detail only for a few specific gene families. Here we provide a detailed characterization of the complete P. falciparum transcriptome across the full intraerythrocytic development cycle (IDC) at the onset of a blood infection in non-immune human volunteers. We found that the vast majority of transcriptional differences between parasites obtained from the volunteers and the parental parasite line maintained in culture occur in CVGs. Specifically, we observed a major increase in the transcript levels of most members of the pfmc-2tm and gbp families and of specific genes of other families, in addition to previously reported changes in var and clag3 genes expression. Large transcriptional differences correlate with changes in the distribution of heterochromatin, confirming their epigenetic nature. The analysis of parasites collected at different time points along the infection indicates that when parasites pass through transmission stages, the epigenetic memory at CVG loci is lost, resulting in a reset of their expression state and reestablishment of new epigenetic patterns. ImportanceThe ability of malaria parasites to adapt to changes in the human blood environment, where they produce long term infection associated with clinical symptoms, is fundamental for their survival. Clonally variant genes, regulated at the epigenetic level, play a major role in this adaptive process, as changes in the expression of these genes result in antigenic and functional alterations that enable immune evasion and provide phenotypic plasticity. However, the way these genes are expressed under the natural conditions of the human circulation or how their expression is affected by passage through transmission stages is not well understood. Here we provide a comprehensive characterization of the expression patterns of these genes at the onset of human blood infections, which reveals major differences with in vitro cultured parasites and also distinctive alterations between different families of clonally variant genes. We also show that epigenetic patterns are erased and reestablished during transmission stages.

microbiology↗

bioRxiv2020

Biomarkers to distinguish bacterial from viral pediatric clinical pneumonia in a malaria endemic setting

BACKGROUNDDifferentiating the etiology of acute febrile respiratory illness in children is a challenge in low-income, malaria-endemic settings because the main pathogens responsible (viruses, bacteria, and malaria parasites) overlap in clinical presentation and frequently occur together as mixed infections. The critical task is to rapidly identify bacterial pneumonia to enable appropriate antibiotic treatment, ideally at point of care. Current diagnostic tests are insufficient and there is a need for the discovery and development of new tools. Here we report the identification of a unique biomarker signature that can be identified in blood samples. METHODSBlood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based high dynamic range assay to quantify [~]1200 proteins. For discovery of new biomarkers, we identified a training set of patient samples in which the underlying etiology of the pneumonia was established as bacterial, viral or malaria. Proteins whose abundances varied significantly between patients with verified etiologies (FDR<0.01) formed the basis for predictive diagnostic models that were created using machine learning techniques (Random Forest, Elastic Net). These models were validated on a dedicated test set of samples. RESULTS219 proteins had significantly different abundances between bacterial and viral infections, and 151 differed between bacterial infections and a mixed pool of viral and malaria infections. Predictive diagnostic models achieved >90% sensitivity and >80% specificity, regardless of whether one or two pathogen classes were present. Bacterial pneumonia was strongly associated with markers of neutrophil activity, in particular neutrophil degranulation. Degranulation markers included HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. CONCLUSIONBlood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia.

genomics↗