Biology subjects

Sanchez, I.

Publications and source records attributed to Sanchez, I..

6 recordsLinked to original sources

bioRxiv2025

HDL-associated phosphatidylserine blunts myeloid activation and protects from atherosclerosis

Background and aimsLipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe-/- mice. MethodsHuman lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. ResultsIn humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro, this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulations potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. ConclusionsCollectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.

immunology↗

bioRxiv2025

HIF-1α and HIF-2α transcription factors differentially regulate lung alveolar macrophage function

Alveolar Macrophages (AMs) reside in the alveoli, where oxygen pressure is high, therefore maintaining an active degradation of hypoxia-inducible transcription factors (HIF) mediated by the Von Hippel-Lindau protein (pVHL) ubiquitin ligase complex. We previously found that Vhl-deficient AMs not sensing high oxygen pressure are immature and functionally impaired. Here we investigated the specific roles of HIF-1 and HIF-2 isoforms in the regulation of AM functions. With this aim, we combined deletion of Vhl with single or double deletion of Hif1a and/or Hif2a in AMs under the control of the CD11c promoter using a Cre-Lox system. Our work demonstrates that in Vhl-deficient macrophages, both HIF-1 and HIF-2 contribute to AM defective self-renewal, while HIF-2 plays a central role in regulating the impaired AM maturation associated with pVHL loss. HIF-1 promotes a glycolytic shift in alveolar macrophages, while HIF-2 hinders lipid oxidation and surfactant clearance. Thus, HIF-2 raises as a selective critical factor restraining the therapeutic potential of AMs to degrade surfactant excess in mice that have developed pulmonary alveolar proteinosis (PAP). Overall, regulation of both HIF-1 and HIF-2 isoforms is required for an optimal AM function, highlighting HIF-2 as a potential pharmacological target for secondary PAP.

physiology↗

bioRxiv2025

The tubulin poly-glutamylase complex, TPGC, is required for phosphatidyl inositol homeostasis and cilium assembly and maintenance

The tubulin poly-glutamylase complex (TPGC) is comprised of TTLL1 and at least five associated proteins that promote the addition of glutamate residues to tubulin tails of microtubules. Despite its discovery two decades ago, the enzyme has been refractory to characterization owing to its complex multimeric nature and the inability to detect poly-glutamylase activity after assembling the six-subunit complex. We now show that TPGC is the key enzyme driving centriolar and ciliary poly-glutamylation. We identified two novel TPGC subunits, TBC1D19 and KIAA1841, and showed that both components play an essential role in the assembly of the eight-subunit holo-enzyme. Remarkably, we were able to reconstitute the activity of TPGC with all eight subunits. TBC1D19 and KIAA1841 were essential for assembly and activity, and loss of TBC1D19 strongly compromised multiple tubulin modifications, including axonemal poly-glutamylation. TBC1D19 loss abolished transport of Arl13b and other ciliary membrane proteins, abrogating primary cilium assembly. Structural modeling revealed an essential role for TBC1D19 and KIAA1841 in complex assembly, microtubule binding, and preferential poly-glutamylation of -tubulin. We found that TBC1D19 loss abrogated the ciliary localization of phosphatidyl inositol phosphatase, INPP5E, triggering cilium instability. Ciliogenesis in TBC1D19 null cells could be restored through inhibition of a specific phosphatidyl inositol phosphate (PIP) kinase, PIP5K1c, suggesting that TBC1D19 is required to instigate and maintain PIP homeostasis during ciliogenesis. Collectively, our data show that TPGC is a multi-functional enzyme essential for cilium assembly and maintenance.

cell biology↗

bioRxiv2021

On the generalizability of diffusion MRI signal representations across acquisition parameters, sequences and tissue types: chronicles of the MEMENTO challenge.

Diffusion MRI (dMRI) has become an invaluable tool to assess the microstructural organization of brain tissue. Depending on the specific acquisition settings, the dMRI signal encodes specific properties of the underlying diffusion process. In the last two decades, several signal representations have been proposed to fit the dMRI signal and decode such properties. Most methods, however, are tested and developed on a limited amount of data, and their applicability to other acquisition schemes remains unknown. With this work, we aimed to shed light on the generalizability of existing dMRI signal representations to different diffusion encoding parameters and brain tissue types. To this end, we organized a community challenge - named MEMENTO, making available the same datasets for fair comparisons across algorithms and techniques. We considered two state-of-the-art diffusion datasets, including single-diffusion-encoding (SDE) spin-echo data from a human brain with over 3820 unique diffusion weightings (the MASSIVE dataset), and double (oscillating) diffusion encoding data (DDE/DODE) of a mouse brain including over 2520 unique data points. A subset of the data sampled in 5 different voxels was openly distributed, and the challenge participants were asked to predict the remaining part of the data. After one year, eight participant teams submitted a total of 80 signal fits. For each submission, we evaluated the mean squared error, the variance of the prediction error and the Bayesian information criteria. Most predictions predicted either multi-shell SDE data (37%) or DODE data (22%), followed by cartesian SDE data (19%) and DDE (18%). Most submissions predicted the signals measured with SDE remarkably well, with the exception of low and very strong diffusion weightings. The prediction of DDE and DODE data seemed more challenging, likely because none of the submissions explicitly accounted for diffusion time and frequency. Next to the choice of the model, decisions on fit procedure and hyperparameters play a major role in the prediction performance, highlighting the importance of optimizing and reporting such choices. This work is a community effort to highlight strength and limitations of the field at representing dMRI acquired with trending encoding schemes, gaining insights into how different models generalize to different tissue types and fiber configurations over a large range of diffusion encodings.

neuroscience↗

bioRxiv2019

Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

The IL17A inhibitor secukinumab is efficacious for the treatment of psoriasis. In order to define its mechanism of action, it is important to understand its impact on psoriatic whole skin tissue as well as specific skin-resident immune cell populations such as T lymphocytes. In this study, we treated 15 moderate-to-severe plaque psoriasis patients with secukinumab and characterized the longitudinal transcriptomic changes of whole lesional skin tissue and cutaneous CD4+ T effector cells (Teffs), CD4+ T regulatory cells (Tregs), and CD8+ T effector cells during 12 weeks of treatment. Secukinumab was clinically effective, with 100%, 47%, and 27% of patients in the study achieving PASI75, PASI90, and PASI100 by week 12, respectively. At baseline prior to treatment, we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than Teffs, supporting the importance of IL-17-secreting CD8+ T cells (Tc17) compared to IL-17-secreting CD4+ T cells (Th17) cells in the pathogenesis of psoriasis. Although secukinumab targets only IL17A, we observed rapid reduction of IL17A, IL17F, IL23A, IL23R, and IFNG expression in lesional skin as soon as 2 weeks after initiation of treatment and normalization of expression by week 12. Secukinumab treatment resulted in resolution of 89-97% of psoriasis-associated expression differences in both bulk tissue and T cell subsets by week 12 of treatment. Overall, secukinumab appears to rapidly reverse many of the molecular hallmarks of psoriasis.

genomics↗

bioRxiv2018

Relief from nitrogen starvation entails quick unexpected down-regulation of glycolytic/lipid metabolism genes in enological Saccharomyces cerevisiae

Nitrogen composition of the grape must has an impact on yeast growth and fermentation kinetics as well as on the organoleptic properties of the final product. In some technological processes, such as white wine/rose winemaking, the yeast-assimilable nitrogen content is sometimes insufficient to cover yeast requirements, which can lead to slow or sluggish fermentations. Growth is nevertheless quickly restored upon relief from nutrient starvation, e.g. through the addition of ammonium nitrogen, allowing fermentation completion. The aim of this study was to determine how nitrogen repletion affected the transcriptional response of a Saccharomyces cerevisiae wine yeast strain, in particular within the first hour after nitrogen addition. We found almost 4800 genes induced or repressed, sometimes within minutes after nutrient changes. Some of these responses to nitrogen depended on the TOR pathway, which controls positively ribosomal protein genes, amino acid and purine biosynthesis or amino acid permease genes and negatively stress-response genes, and genes related to the retrograde response (RTG) specific to the tricarboxylic acid (TCA) cycle and nitrogen catabolite repression (NCR). Some unexpected transcriptional responses concerned all the glycolytic genes, the starch and glucose metabolism and citrate cycle-related genes that were down-regulated, as well as genes from the lipid metabolism.

microbiology↗