Biology subjects

Henriques, A.

Publications and source records attributed to Henriques, A..

6 recordsLinked to original sources

bioRxiv2026

Delayed onset and heterogeneous collective organization characterize twitching motility in Acinetobacter baumannii

Type IV pili (T4P) mediate twitching motility and contribute to surface colonization, biofilm formation, and host interactions in Acinetobacter baumannii. However, the prevalence, dynamics, and diversity of twitching motility across A. baumannii populations remain poorly understood. Here, we compared twitching motility in a collection of 35 A. baumannii strains originating from clinical, environmental, and animal sources, using Pseudomonas aeruginosa PAO1 as a reference. Standardization of assay conditions revealed a strong influence of agar composition on twitching motility, with Eiken agar supporting the most robust surface translocation. Under these conditions, 14 of 35 A. baumannii isolates exhibited detectable twitching motility. Time-lapse microscopy revealed major differences between A. baumannii and P. aeruginosa. Whereas PAO1 initiated twitching within minutes after inoculation and formed characteristic multicellular rafts, motile A. baumannii strains displayed a prolonged non-motile phase before movement initiation and exhibited distinct patterns of collective organization. Two major expansion phenotypes were identified, termed Homogeneous Front (HF) and Raft-Like Front (RLF), together with Early-Onset Motility (EOM) and Delayed-Onset Motility (DOM) subgroups. Quantitative analyses further revealed substantial variation in speed, directional persistence, and migration dynamics among strains. Because a majority of isolates were non-motile, we investigated the contribution of the minor pilin FimT. Although deletion of fimT abolished twitching motility and specific substitutions modulated motility efficiency, sequence variation in FimT alone could not account for the observed phenotypic diversity. Collectively, these findings reveal extensive heterogeneity in T4P-mediated surface motility in A. baumannii and identify delayed twitching activation and distinct collective migration strategies as key features of surface colonization in this species. HighlightsO_LIPopulation analysis reveals extensive twitching diversity in A. baumannii C_LIO_LIDelayed motility onset distinguishes A. baumannii from P. aeruginosa C_LIO_LIHomogeneous and raft-like fronts define distinct migration strategies C_LIO_LIFimT contributes to motility but not all non-motile phenotypes C_LI

microbiology↗

bioRxiv2024

HYL001, a new potent TGFβ signaling inhibitor that is efficacious against microsatellite stable CRC metastasis in combination with immune checkpoint therapy in mice

Blockade of the TGF{beta} signalling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has known little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGF{beta} receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favourable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumours at doses where galunisertib is ineffective. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/593510v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1909963org.highwire.dtl.DTLVardef@4644d2org.highwire.dtl.DTLVardef@1506d80org.highwire.dtl.DTLVardef@14504b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

A Mechanism Underpinning the Bioenergetic Metabolism-Regulating Function of Gold Nanocatalysts

Bioenergetic deficits, such as mitochondrial impairments and dysfunction in glucose metabolism, have been identified as significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the bioenergetic metabolism-regulating function of a suspension of gold (Au) nanocrystals, referred to as CNM-Au8(R), that are synthesized electrochemically in the absence of any surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and preservation of neurite networks across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic co-factor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized, dehydrogenated counterpart (NAD+), which triggers an increase in energy production in the form of adenosine triphosphate (ATP). Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. CNM-Au8 functions as an NADH-dehydrogenase-mimicking nanozyme that effectively regulates intracellular bioenergetic metabolism. We further utilize photoexcited charge carriers and photothermal transduction, which can be generated through optical excitations of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, as unique leverages to modulate reaction kinetics. Benefiting from their bio-compatibility, blood-brain barrier penetrance, tunable optical properties, and enzyme-mimicking functions, CNM-Au8 nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Profound lipid dysregulation in mutant TDP-43 mice is ameliorated by the glucocerebrosidase 2 inhibitor ambroxol

The importance of dyslipidemia in amyotrophic lateral sclerosis (ALS) patients is increasingly recognised as a potential key mechanism driving disease onset, progression and survival. Evidence in familial ALS models suggests that lipid composition is significantly affected, however clinically relevant models have yet to be investigated. Using a powerful lipidomic approach, we uncover significant dysregulation of glycosphingolipid (GSL) metabolism in both the spinal cord and skeletal muscles of transgenic TDP-43Q331K mice. Treatment with the selective glucocerebrosidase 2 (GBA2) inhibitor ambroxol at symptom onset significantly improved motor and gait functions in TDP-43Q331K mice. Ambroxol treatment preserved motor neurons and neuromuscular junctions which was associated with modulation of GSL metabolism. Our study establishes significant lipid dysregulation in a clinically relevant model of ALS. Importantly, we show positive therapeutic outcomes in a mouse model of TDP-43 proteinopathy, suggesting that ambroxol may be a promising candidate to treat underlying dyslipidemia and symptoms of ALS.

neuroscience↗

bioRxiv2021

Col6a1+/CD201+ telocytes regulate intestinal morphogenesis and homeostasis

Intestinal mesenchymal cells encompass multiple subsets, whose origins, functions, and pathophysiological importance are still not clear. Here, we used the Col6a1Cre mouse, which targets telocytes and perivascular cells that can be further distinguished by the combination of the CD201, PDGFR and SMA markers. Developmental studies revealed that the Col6a1Cre mouse also targets mesenchymal aggregates that are crucial for intestinal morphogenesis and patterning, suggesting an ontogenic relationship between them and homeostatic telocytes. Cell depletion experiments in adulthood showed that Col6a1+/CD201+ mesenchymal cells regulate homeostatic enteroendocrine cell differentiation and epithelial proliferation. During acute colitis, they expressed an inflammatory and extracellular matrix remodeling gene signature, but they also retained their properties and topology. Notably, both in homeostasis and tissue regeneration, they were dispensable for normal organ architecture, while CD34+ mesenchymal cells expanded, localised at the top of the crypts and showed increased expression of villous-associated morphogenetic factors, providing thus evidence for the plasticity potential of distinct mesenchymal populations in the intestine. Our results provide a comprehensive analysis of the identities, origin, and functional significance of distinct mesenchymal populations in the intestine.

cell biology↗

bioRxiv2020

A Single-Cell Tumor Immune Atlas for Precision Oncology

The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system for a harmonized interpretation. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying striking spatial immune cell patterns in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immuno-therapy.

cancer biology↗