Biology subjects

Herrera, F.

Publications and source records attributed to Herrera, F..

8 recordsLinked to original sources

bioRxiv2025

Decrease in dose per fraction impairs the FLASH sparing effect in murine intestine model

PurposeFLASH radiotherapy (FLASH) can ease radiation-induced normal tissue toxicities; however, its benefit in clinically relevant fractionation protocols remains insufficiently explored. This study investigated the FLASH sparing effect under two fractionated regimens using a murine model of acute gastrointestinal toxicity. Methods and MaterialsTumor-free C57BL/6 mice received abdominal irradiation with either conventional radiotherapy (CONV) or FLASH using a 9 MeV electron beam. Three dose delivery protocols were assessed: single-fraction delivery, two equal fractions over two consecutive days, and ten equal daily fractions over two weeks. Dose escalation was performed within each protocol, while overall survival was used to monitor normal tissue sparing. The FLASH dose modifying factor (FDMF) was derived from normal tissue toxicity probability (NTCP) curves to quantify the relative protective effect of FLASH. ResultsThe single-fraction irradiation demonstrated a significant FLASH sparing effect, with an FDMF of 1.14. In contrast, this protective effect was diminished in the fractionated protocols, with the two-fraction regimen yielding an FDMF of 1.03, while the ten-fraction regimen showed no measurable sparing (FDMF = 1.00). ConclusionsIn an acute responding model of radiation-induced abdominal toxicity, the FLASH sparing effect was substantially reduced with a two-fraction regimen and completely absent with a ten-fraction regimen. These findings suggest that the benefit of FLASH may be limited at lower doses per fraction and highlight the need for further studies in other clinically relevant models to better define the boundaries of its therapeutic applicability. HighlightsO_LIFLASH-RT spares mice intestine from acute toxicity for single-dose delivery. C_LIO_LIFLASH effect declines in mice intestine with more fractions and less dose/fraction. C_LIO_LIFLASH sparing in mice intestine is lost with ten equal fractions over two weeks. C_LI

cancer biology↗

bioRxiv2024

Subcellular, biochemical and biophysical alterations in two glial cell models of ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a developmental and degenerative disorder caused by loss-of-function mutations in the gene that codifies for the sacsin chaperone. Sacsin was initially described as a neuronal protein but is found in various cell types, including astroglial, microglial, kidney, and skin cell lines. We and others have shown that virtually all cell and animal models of ARSACS show disruption of intermediate filament (IF) cytoskeleton and organelle distribution. This article extends previous observations from our lab on the C6 astroglial-like model and describes the development and characterization of a new human microglial cell model based on HMC3 cells. HMC3 cells knocked out for sacsin show similar alterations to C6 astroglial-like cells: aberrant distribution of IF network and organelles, downregulation of developmental transcription factors STAT3 and Smad1, and alterations in autophagy machinery and markers of intracellular stress, resulting in morphological changes. Our results extend previous observations suggesting a possible role for glial cells in ARSACS and provide new tools to understand the glial-specific mechanisms involved in this pathology.

biochemistry↗

bioRxiv2024

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

developmental biology↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2021

Sentinel2GlobalLULC: A deep-learning-ready Sentinel-2 RGB image dataset for global land use/cover mapping

Land-Use and Land-Cover (LULC) mapping is relevant for many applications, from Earth system and climate modelling to territorial and urban planning. Global LULC products are continuously developing as remote sensing data and methods grow. However, there is still low consistency among LULC products due to low accuracy for some regions and LULC types. Here, we introduce Sentinel2GlobalLULC, a Sentinel-2 RGB image dataset, built from the consensus of 15 global LULC maps available in Google Earth Engine. Sentinel2GlobalLULC v1.1 contains 195572 RGB images organized into 29 global LULC mapping classes. Each image is a tile that has 224 x 224 pixels at 10 x 10 m spatial resolution and was built as a cloud-free composite from all Sentinel-2 images acquired between June 2015 and October 2020. Metadata includes a unique LULC type annotation per image, together with level of consensus, reverse geo-referencing, and global human modification index. Sentinel2GlobalLULC is optimized for the state-of-the-art Deep Learning models to provide a new gate towards building precise and robust global or regional LULC maps.

ecology↗

bioRxiv2019

Asymmetric post-translational modifications regulate the intracellular distribution of unstimulated STAT3 dimers

Signal Transducer and Activator of Transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus-STAT3 bimolecular fluorescence complementation (BiFC) assay that allows the visualization and study of STAT3 dimerization and protein-protein interactions in living cells. Inactivating mutations on residues susceptible to post-translational modifications (K49R, K140R, K685R, Y705F and S727A) did not alter the basal dimerization of unstimulated STAT3, but changed significantly the intracellular distribution of STAT3 dimers. Surprisingly, the distribution of specific asymmetric STAT3 dimers (i.e. the STAT3 molecules carry different mutations) was different from symmetric dimers. Our results indicate that asymmetric post-translational modifications on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. This set of Venus-STAT3 BiFC constructs provides yet unexplored means to advance our understanding of STAT3 behavior and function in cancer and beyond.

cell biology↗

bioRxiv2018

Automatic whale counting in satellite images with deep learning

Despite their interest and threat status, the number of whales in worlds oceans remains highly uncertain. Whales detection is normally carried out from costly sighting surveys, acoustic surveys or through high-resolution orthoimages. Since deep convolutional neural networks (CNNs) achieve great performance in object-recognition in images, here we propose a robust and generalizable CNN-based system for automatically detecting and counting whales from space based on open data and tools. A test of the system on Google Earth images in ten global whale-watching hotspots achieved a performance (F1-measure) of 84% in detecting and 97% in counting 80 whales. Applying this cost-effective method worldwide could facilitate the assessment of whale populations to guide conservation actions. Free and global access to high-resolution imagery for conservation purposes would boost this process.

ecology↗

bioRxiv2017

Protein Phosphatase 1 Regulates Huntingtin Exon 1 Aggregation And Toxicity

Huntingtons disease (HD) is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregation and toxicity in human cells and Drosophila neurons. We used bimolecular fluorescence complementation (BiFC) to show that expression of single phosphomimic mutations completely abolished HTTex1 aggregation in human cells. In Drosophila, Mimicking phosphorylation at T3 decreased HTTex1 aggregation both in larvae and adult flies. Interestingly, pharmacological or genetic inhibition of protein phosphatase 1 (PP1) prevented HTTex1 aggregation in both human cells and Drosophila while increasing neurotoxicity in flies. Our findings suggest that PP1 modulates HTTex1 aggregation by regulating phosphorylation on T3. In summary, our study suggests that modulation of HTTex1 single phosphorylation events by PP1 could constitute an efficient and direct molecular target for therapeutic interventions in HD.

neuroscience↗