Biology subjects

Planas, J.

Publications and source records attributed to Planas, J..

8 recordsLinked to original sources

bioRxiv2026

p21(CIP1/WAF1)-mediated partial senescence supports steroidogenesis and therapy resistance in primary prostate cancer cultures

BackgroundProgression of prostate cancer to castration-resistant disease is driven by early adaptive mechanisms that remain poorly defined. Increasing evidence suggests that senescence-associated programs and intratumoral steroidogenesis may contribute to therapeutic resistance, but their functional interplay in hormone-naive disease is unclear. MethodsHormone-naive primary prostate cancer cultures (hnPCs) were established from diagnostic biopsies and characterized for proliferation, therapeutic response, senescence markers, and steroidogenic gene expression. Functional relevance of CDKN1A was assessed by knockdown experiments. Public transcriptomic datasets from ETS fusion-negative, AR signaling inhibitor-naive metastatic castration-resistant prostate cancer (mCRPC) were interrogated for clinical validation. ResultshnPCs exhibited low proliferative capacity yet intrinsic resistance to androgen deprivation therapy and docetaxel. Most cultures displayed coordinated overexpression of CDKN1A/p21CIP1 together with steroidogenic enzymes, particularly AKR1C3, alongside p16INK4a expression and SA-{beta}-galactosidase activity, consistent with a partial senescence-like state. CDKN1A depletion selectively reduced AKR1C3 expression and increased proliferation in a subset of cultures, indicating that p21 maintains specific senescence-associated features while permitting adaptive plasticity. Analysis of ETS fusion-negative, ARSI-naive mCRPC tumors revealed positive correlations between CDKN1A and steroidogenic genes, supporting the translational relevance of this program. ConclusionsThese findings identify a previously underrecognized CDKN1A-associated partial senescence program that supports steroidogenic reprogramming, survival, and early therapeutic resistance in aggressive prostate cancer. This adaptive state may predispose tumors to progression toward castration resistance and represents a potential biomarker and therapeutic vulnerability in high-risk, ETS-negative disease.

cancer biology↗

bioRxiv2024

Synthesis of geometrically realistic and watertight neuronal ultrastructure manifolds for in silico modeling

Understanding the intracellular dynamics of brain cells entails performing three-dimensional molecular simulations incorporating ultrastructural models that can capture cellular membrane geometries at nanometer scales. While there is an abundance of neuronal morphologies available online, e.g. from NeuroMorpho.Org, converting those fairly abstract point-and-diameter representations into geometrically realistic and simulation-ready, i.e. watertight, manifolds is challenging. Many neuronal mesh reconstruction methods have been proposed, however, their resulting meshes are either biologically unplausible or non-watertight. We present an effective and unconditionally robust method capable of generating geometrically realistic and watertight surface manifolds of spiny cortical neurons from their morphological descriptions. The robustness of our method is assessed based on a mixed dataset of cortical neurons with a wide variety of morphological classes. The implementation is seamlessly extended and applied to synthetic astrocytic morphologies that are also plausibly biological in detail. Resulting meshes are ultimately used to create volumetric meshes with tetrahedral domains to perform scalable in silico reaction-diffusion simulations for revealing cellular structure-function relationships. Availability and implementationOur method is implemented in NeuroMorphoVis, a neuroscience-specific open source Blender add-on, making it freely accessible for neuroscience researchers. Key pointsO_LIA plethora of neuronal morphologies is available in a point-and-diameter format, but there are no robust techniques capable of converting these morphologies into geometrically realistic models that can be used to conduct subcellular simulations. C_LIO_LIWe present a scalable method capable of synthesizing high fidelity watertight ultrastructural manifolds of complete neuronal models from their one-dimensional descriptions using the synaptic data obtained from the digitally reconstructed neuronal circuits of the Blue Brain Project. C_LIO_LIResulting manifold models comprise geometrically realistic somata and spine geometries, enabling accurate in silico experiments that can probe intricate structure-function relationships. C_LIO_LIOur method is extensible and can be seamlessly applied to other cellular structures such as astroglial morphologies and even large networks of cerebral vasculature. C_LI

neuroscience↗

bioRxiv2024

Evaluation of homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional tissue-based immunofluorescence assays

PurposeMetastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations; these biomarkers have prognostic and predictive value. Next-generation sequencing (NGS) allows for patient stratification based on these biomarkers, but widespread clinical implementation is still limited. Moreover, not all mutations in HRR genes result in functional HRR loss in the tumor. We investigated the correlation between genomic and functional loss of HRR, using NGS and an optimized RAD51 immunofluorescence (RAD51-IF) assay in mPC clinical biopsies. Experimental designObservational study including patients with stage IV prostate cancer. Biopsies from either primary tumor or metastatic biopsies underwent NGS (targeted sequencing and/or whole-exome sequencing), and RAD51-IF. Clinical data was extracted from electronic patient records. Results219 biopsies from 187 patients were acquired, including primary (151/219) and metastatic (68/219) tumor biopsies collected either in the metastatic hormone- sensitive (169/219) or castration-resistant (50/219) setting. NGS (181 biopsies from 157 patients) showed frequent genomic alterations in TP53 (40%), AR (15%), PTEN (14%), MYC (10%), BRCA2 (9%), ATM (8%) and BRCA1 (2%). Tissue for RAD51 IF was available for 206 samples; of those, 140/206 (68%) were evaluable for RAD51- IF. Based on a previously defined threshold of 10% RAD51-positive cells, 21% samples had RAD51-low results compatible with HRR deficiency (HRD). Sample matched RAD51-IF and genomics data were obtained for 128 biopsies (117 patients): RAD51-IF had a high sensitivity (68%) and specificity (85%) to identify cases with BRCA1/2 alterations. Additionally, the RAD51-IF assay was able to identify restoration of HRR function in selected cases with BRCA2 reversion mutations or BRCA1 expression. ConclusionsRAD51-IF is feasible in routine clinical samples from mPC patients and associates strongly with clinically relevant HRR gene alterations.

cancer biology↗

bioRxiv2023

Community-based Reconstruction and Simulation of a Full-scale Model of Region CA1 of Rat Hippocampus

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to reconcile information obtained from diverse experimental approaches. To address this challenge, we present a community-driven, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to address a range of scientific questions. In this article, we describe the methods used to set up simulations that reproduce and extend in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce and reconcile experimental findings. Finally, we make data, code and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This neuroscience community-driven model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

neuroscience↗

bioRxiv2023

Modeling and Simulation of Neocortical Micro- and Mesocircuitry. Part II: Physiology and Experimentation

Cortical dynamics underlie many cognitive processes and emerge from complex multi-scale interactions, which are challenging to study in vivo. Large-scale, biophysically detailed models offer a tool which can complement laboratory approaches. We present a model comprising eight somatosensory cortex subregions, 4.2 million morphological and electrically-detailed neurons, and 13.2 billion local and mid-range synapses. In silico tools enabled reproduction and extension of complex laboratory experiments under a single parameterization, providing strong validation. The model reproduced millisecond-precise stimulus-responses, stimulus-encoding under targeted optogenetic activation, and selective propagation of stimulus-evoked activity to downstream areas. The models direct correspondence with biology generated predictions about how multiscale organization shapes activity; for example, how cortical activity is shaped by high-dimensional connectivity motifs in local and mid-range connectivity, and spatial targeting rules by inhibitory subpopulations. The latter was facilitated using a rewired connectome which included specific targeting rules observed for different inhibitory neuron types in electron microscopy. The model also predicted the role of inhibitory interneuron types and different layers in stimulus encoding. Simulation tools and a large subvolume of the model are made available to enable further community-driven improvement, validation and investigation.

neuroscience↗

bioRxiv2022

Modeling and Simulation of Rat Non-Barrel Somatosensory Cortex. Part I: Modeling Anatomy

The function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, interregional connectivity. We present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, integrating whole-brain scale data while providing cellular and subcellular specificity. The model consists of 4.2 million morphologically detailed neurons, placed in a digital brain atlas. They are connected by 14.2 billion synapses, comprising local, mid-range and extrinsic connectivity. We delineated the limits of determining connectivity from neuron morphology and placement, finding that it reproduces targeting by Sst+ neurons, but requires additional specificity to reproduce targeting by PV+ and VIP+ interneurons. Globally, connectivity was characterized by local clusters tied together through hub neurons in layer 5, demonstrating how local and interegional connectivity are complicit, inseparable networks. The model is suitable for simulation-based studies, and a 211,712 neuron subvolume is made openly available to the community.

neuroscience↗

bioRxiv2019

Allosteric communications between domains modulate activity of matrix metalloprotease-1

An understanding of the structure-dynamics relationship is essential for understanding how a protein works. Prior research has shown that the activity of a protein correlates with intra-domain dynamics occurring at picosecond to millisecond timescales. However, the correlation between inter-domain dynamics and the function of a protein is poorly understood. Here we show that communications between the catalytic and hemopexin domains of matrix metalloprotease-1 (MMP1) on type-1 collagen fibrils correlate with its activity. Using single-molecule FRET (smFRET), we identified functionally relevant open conformations where the two MMP1 domains are well-separated, which were significantly absent for catalytically inactive point mutant (E219Q) of MMP1 and could be modulated by an inhibitor or an enhancer of activity. The observed relevance of open conformations resolves the debate about the roles of open and closed MMP1 structures in function. A sum of two Gaussians fitted histograms, whereas an exponential fitted autocorrelations of smFRET values. We used a two-state Poisson process to describe the dynamics and used histograms and autocorrelations of conformations to calculate the kinetic rates between the two states. All-atom and coarse-grained simulations reproduced some of the experimental features and revealed substrate-dependent MMP1 dynamics. Our results suggest that an inter-domain separation facilitates opening up the catalytic pocket so that the collagen chains come closer to the MMP1 active site. Coordination of functional conformations at different parts of MMP1 occurs via allosteric communications that can take place via interactions mediated by collagen even if the linker between the domains is absent. Modeling dynamics as a Poisson process enables connecting the picosecond timescales of molecular dynamics simulations with the millisecond timescales of single molecule measurements. Water-soluble MMP1 interacting with water-insoluble collagen fibrils poses challenges for biochemical studies that the single molecule tracking can overcome for other insoluble substrates. Inter-domain communications are likely important for multidomain proteins. Statement of SignificanceIt is often challenging to distinguish functionally important dynamics because proteins are inherently flexible. MMP1 is a model enzyme because both the catalytic and hemopexin domains are necessary to degrade triple-helical type-1 collagen, the highly proteolysis-resistant structural component of the extracellular matrix. We report, for the first time, measurements of MMP1 inter-domain dynamics on type-1 collagen fibrils. We have identified functionally relevant MMP1 conformations where the two domains are far apart. Mutations and ligands can allosterically modulate the dynamics that correlate with activity. The dynamics follow a two-state Poisson process that connects the picosecond timescales of MD simulations with the millisecond timescales of experiments. The two domains can functionally communicate via collagen even when the physical linker is absent.

biophysics↗

bioRxiv2019

The SONATA Data Format for Efficient Description of Large-Scale Network Models

Increasing availability of comprehensive experimental datasets and of high-performance computing resources are driving rapid growth in scale, complexity, and biological realism of computational models in neuroscience. To support construction and simulation, as well as sharing of such large-scale models, a broadly applicable, flexible, and high-performance data format is necessary. To address this need, we have developed the Scalable Open Network Architecture TemplAte (SONATA) data format. It is designed for memory and computational efficiency and works across multiple platforms. The format represents neuronal circuits and simulation inputs and outputs via standardized files and provides much flexibility for adding new conventions or extensions. SONATA is used in multiple modeling and visualization tools, and we also provide reference Application Programming Interfaces and model examples to catalyze further adoption. SONATA format is free and open for the community to use and build upon with the goal of enabling efficient model building, sharing, and reproducibility.

neuroscience↗