Biology subjects

Le, C.

Publications and source records attributed to Le, C..

17 recordsLinked to original sources

bioRxiv2026

From silicone gel bleed chemistry to skeletal muscle and lipid alterations: clinical and in vitro evidence

Musculoskeletal symptoms are frequently reported following silicone breast implantation. However, the biological mechanisms linking implant-derived silicone exposure to skeletal muscle alterations remain poorly understood, partly because the biological effects of silicone have long been debated in the context of its biocompatibility. Here, we chemically characterized the low-molecular-weight fraction of the breast implant silicone exposome, readily released from implant gel through gel bleed, and investigated its potential biological consequences using an integrated approach combining analytical chemistry, clinical transcriptomics and histology, and controlled in vitro muscle experiments. Transcriptomic analyses of periprosthetic tissues associated with silicone implant rupture revealed unexpected myogenic and neuromuscular signatures in tissue conventionally regarded as predominantly fibrous, together with alterations in lipid metabolism and transport. These findings were supported by histological evidence of close interactions between periprosthetic tissue and skeletal muscle. Chemical analysis of the implant-gel extract detected linear siloxane L2 and cyclic siloxanes D3-D8, with tentative assignment of D9. In vitro, C2C12 cells exposed to the implant-gel extract showed up to 30% reduced viability and decreased expression of key neuromyogenic genes. Together, these findings provide convergent chemical, clinical, and experimental evidence that low-molecular-weight constituents of the breast implant silicone exposome may constitute a biologically active exposure capable of affecting skeletal muscle. The associated alterations in lipid metabolism and transport further provide a mechanistic framework for investigating the cellular handling and potential tissue distribution of hydrophobic silicone-derived species. These findings position silicone gel bleed as a biologically relevant source of chemical exposure rather than solely a material-integrity phenomenon.

bioengineering↗

bioRxiv2026

Prediction of Stimulation-Defined Eloquent Cortex Using Graph-Theoretical Connectivity from Electrocorticography During Presurgical Mapping

Background and ObjectivesElectrical stimulation mapping (ESM) is the clinical gold standard for identifying eloquent cortex during presurgical evaluation but is time-intensive, constrained by incomplete cortical sampling, and limited by patient tolerance. We investigated whether features derived from electrocorticography (ECoG), including functional connectivity measures, can provide complementary information for identifying functionally critical cortex and examined how predictive performance varies across functional domains, behavioral tasks, and data quantity. MethodsFourteen patients undergoing intracranial monitoring for epilepsy surgery performed speech production tasks while ECoG was recorded independently of stimulation mapping. Graph-theoretic functional connectivity features derived from high-gamma activity (70-150 Hz), combined with anatomical region encoding, were used to train machine learning classifiers, and predictive performance was evaluated using leave-one-subject-out validation with ESM-defined functional deficits used as ground-truth outcomes. ResultsFourteen patients were included. Performance differed across functional domains, with motor-critical electrodes identified with the highest accuracy (ROC-AUC 0.929 {+/-} 0.061; PR-AUC 0.755 {+/-} 0.191), followed by speech arrest (ROC-AUC 0.793 {+/-} 0.103; PR-AUC 0.550 {+/-} 0.196), whereas language-critical electrodes were more difficult to robustly predict (ROC-AUC 0.761 {+/-} 0.160; PR-AUC 0.385 {+/-} 0.167). Additional signal-derived features provided limited benefit beyond anatomical and connectivity features. Performance also varied across tasks and with the number of available trials, with motor prediction remaining stable across trial counts and speech arrest prediction improving with increasing trial counts up to approximately 10 trials before plateauing. In addition, evaluation at the level of stimulation pairs increased sensitivity, with only modest changes in overall performance. DiscussionGraph-theoretic connectivity analysis of ECoG provides complementary information for identifying stimulation-defined functional criticality and supports presurgical mapping. Differences in predictive performance across functional domains likely reflect underlying neuro-physiologic organization, with connectivity providing the clearest improvement for speech arrest prediction. Combined-label prediction strategies increased sensitivity at the expense of specificity, reflecting a clinically relevant tradeoff between broad detection of critical cortex and precise localization. These findings suggest that connectivity-informed approaches may help guide task selection and improve mapping efficiency while complementing electrical stimulation mapping.

neuroscience↗

bioRxiv2026

A Multispecies, Modality-Agnostic Scalable In Vivo Mosaic Screening Platform for Therapeutic Target Discovery

Validating therapeutic targets for complex diseases requires investigating gene functions within native tissue architectures rather than reductionist in vitro models. Here we present a modality-agnostic AAV-based in vivo high-throughput screening platform capable of delivering knockouts, gain-of-function, and synthetic miRNA knockdowns directly to cells within the diseased environment. This system scales to hundreds of perturbations and is adaptable to diverse species and organ systems. To translate high-dimensional screen data into therapeutic assessment, we established a curated analysis framework that scores single-cell transcriptomes against human disease-specific molecular signatures. This method enables quantitative ranking of targets across distinct biological domains ranging from structural fibrosis to inflammatory signaling, to narrow in on the therapeutic potential of each intervention. We applied this strategy to screen loss- and gain-of-function libraries in a murine pulmonary fibrosis model and within the spontaneously osteoarthritic joints of aged horses, identifying metabolic, antifibrotic, and immunomodulatory targets. Importantly, our analysis framework successfully predicted functional outcomes in orthogonal human ex vivo tissue models, including soluble collagen reduction in lung slices and glycosaminoglycan restoration in cartilage, thus establishing a powerful paradigm for prioritizing therapeutic targets by uniting human disease signatures with highly multiplexed in vivo functional genomics.

systems biology↗

bioRxiv2026

Neural Dynamics of Automatic Speech Production

Speech is a defining human behavior, and this ability depends critically on speech motor cortex. While the ventral precentral and postcentral gyri are classically regarded as chiefly articulatory and somatosensory regions, a growing body of literature challenges this simplification. Most prior research, however, has examined cued or structured speech production tasks, neglecting the automatic, overlearned speech commonly utilized in clinical assessment. Consequently, the neural dynamics and precise timing of cortical recruitment during automatic speech remain poorly understood. Here, we present intracranial electrocorticography (ECoG) recordings from the left perisylvian cortex in participants performing automatic speech such as counting and recitation of overlearned sequences. We investigate neural dynamics using encoding (multivariate temporal response function) and decoding (deep neural network speech synthesis) models. We show that automatic speech engages a distributed network across superior temporal, precentral, and post-central cortices, characterized by attenuated pre-articulatory activity and weaker frontal encoding. Furthermore, two complementary decoding strategies reveal that speech motor cortex represents a mixture of feedforward and feedback signals, with a subset of sites exhibiting exclusively feed-forward dynamics. These results delineate the spatiotemporal cortical organization of automatic speech and establish that the speech motor cortex supports more complex dynamics than purely feedforward control.

neuroscience↗

bioRxiv2025

Dietary glutamine supplementation alleviates age-related cardiac dysfunction by reducing elevated H3K27me3

BackgroundChanges to the epigenetic landscape play an important role in cardiovascular aging, where alterations in histone modifications influence gene expression by regulating DNA accessibility and chromatin structure. Our investigation into epigenetic changes during myocardial aging revealed that the repressive epigenetic mark H3K27me3 is significantly upregulated in aged mice and humans. This increase in H3K27me3 was shown to impair cardiomyocyte autophagy and drive metabolic reprogramming, key features of myocardial aging and causatively linked to dysfunction. Notably, by alleviating this repressive mark through a modified diet, we successfully mitigated the aged myocardial phenotype. MethodsHeart tissue from young and aged mice and humans was analyzed for H3K27me3 levels using immunoblotting and immunofluorescence staining. Genes regulated by H3K27me3 were identified through CUT&RUN-Seq and RNA-Seq, while metabolites were profiled using metabolomics. In neonatal rat ventricular myocytes (NRVMs), H3K27me3 levels were elevated by siRNA-mediated knockdown of UTX. Cellular metabolism was investigated using a Seahorse analyzer in cardiomyocytes with basal or elevated H3K27me3 levels. In further human studies, we assessed how circulating glutamine levels associate with the incidence of heart failure and the association of genetic variants within the SLC1A5 region with heart disease. In aged mice, H3K27me3 levels were reduced through a modified diet, and heart function was evaluated using echocardiography. Subsequently, hearts were processed for biochemical analysis, and autophagy was assessed using electron microscopy. ResultsH3K27me3 was significantly elevated in the aged mouse and human myocardium. This observed elevation in H3K27me3 was found to be attributed to impaired glutamine metabolism, resulting from reduced expression of the glutamine transporter SLC1A5 in the aged myocardium. Furthermore, elevation in H3K27me3 was found to contribute to impaired cardiomyocyte autophagy and metabolic dysfunction. In aged mice supplemented with a high glutamine diet this attenuated myocardial H3K27me3 and improved cardiac function. Furthermore, a high-glutamine diet reversed H3K27me3-mediated impairment in cardiac autophagy in aged mice. ConclusionsReduction in SLC1A5 during aging is likely to lead to increased myocardial H3K27me3 that results in impaired autophagy and metabolic reprogramming that contribute to the aged cardiac phenotype. Our findings also suggest glutamine may improve cardiac health in the aged population by lowering H3K27me3. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIElevation in H3K27me3 during aging is likely to lead to impaired myocardial autophagy and metabolic reprogramming. C_LIO_LIReduction in SLC1A5 during aging in humans is likely to contribute to myocardial dysfunction C_LIO_LIDietary supplementation of glutamine improves cardiac function in aged mice. C_LI What are the clinical implications?O_LITargeting H3K27me3 in the aged population may to mitigate cardiovascular disease C_LIO_LIDietary glutamine supplementation offers a promising strategy to improve cardiac function during aging. C_LI

cell biology↗

bioRxiv2025

CES1 DEFICIENCY IS ASSOCIATED WITH METABOLIC REPROGRAMING AND ENDOTHELIAL DYSFUNCTION IN PULMONARY ARTERIAL HYPERTENSION

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling, driven by metabolic reprogramming, oxidative stress, and endothelial dysfunction. While BMPR2 mutations contribute to metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), their low penetrance suggests additional genetic modifiers play a role. A genetic screen of PAH PMVECs identified carboxylesterase 1 (CES1)--an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification--as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress. MethodsPAH and healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 expression was modulated in PMVECs using siRNA knockdown and plasmid overexpression. Mitochondrial and ER function were assessed via confocal microscopy and proteomics. CES1 heterozygous knockout (HET KO) and endothelial-specific knockout (ECKO) mice were exposed to normoxia or hypoxia, with lung tissues analyzed by single-cell RNA sequencing (scRNA-seq) and histopathology. ResultsCES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. Confocal imaging and metabolic studies revealed lipid droplet accumulation, reduced fatty acid oxidation, and a glycolytic shift-- phenotypes reversed by CES1 restoration. Mechanistically, CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. In vivo, CES1-deficient mice developed severe pulmonary hypertension (PH) under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways, as confirmed by lung scRNA-seq. ConclusionsCES1 is essential for pulmonary endothelial homeostasis and serves as a critical modifier of BMPR2 signaling. Given the limited efficacy of current PAH therapies in reversing endothelial dysfunction and small-vessel loss, restoring CES1 expression represents a promising therapeutic strategy.

biochemistry↗

bioRxiv2025

VN1K: a genome graph-based and function-driven multi-omics and phenomics resource for the Vietnamese population

Vietnam, the 16th most populated nation, remains profoundly underrepresented in global genomic databases. Here, we present VN1K, a first-ever comprehensive and well-curated resource of multi-omics data with a wide-range of phenotypic information of 1,011 unrelated Vietnamese individuals. High-depth short-read whole-genome sequencing data were generated for all samples along with various - omic data, including microarray, long-read whole-genome sequencing, and RNA sequencing. Using a high-sensitivity variant detection pipeline, which included a pangenome graph reference and a deep-learning framework, we identified nearly 40 million variants of which 8.5 million are novel with nearly 900 thousand short insertions/deletions and 39 thousand structural variants. Specifically, VN1K featured a first-ever whole-genome methylation profile based on long read sequencing. A genotype imputation panel was also created with the highest accuracy on the Vietnamese population. Variants with significantly different allele frequencies in the Vietnamese population compared to others were found to be functionally significant, especially in genes associated with immune diseases (HLA-B, KIR3DL3, KIR2DL1, KIR2DL4) or drug responses (CYP2C19, CYP2D6, VKORC1, CYP2B6). We were also able to map various loci related to hepatitis B virus infection as well as six disease traits, including triglyceride levels, LDL-C, serum glucose levels, HbA1c, and levels of two liver enzymes (ALT and AST). VN1K dataset is accessible via genome.vinbigdata.org, an integrated platform with both linear and graph-based genome browser for facilitating data exploration, research, and applications in precision medicine.

genomics↗

bioRxiv2024

Actin Polymerization Status Regulates Tendon Homeostasis through Myocardin-Related Transcription Factor-A

The actin cytoskeleton is a potent regulator of tenocyte homeostasis. However, the mechanisms by which actin regulates tendon homeostasis are not entirely known. This study examined the regulation of tenocyte molecule expression by actin polymerization via the globular (G-) actin-binding transcription factor, myocardin-related transcription factor-a (MRTF). We determined that decreasing the proportion of G-actin in tenocytes by treatment with TGF{beta}1 increases nuclear MRTF. These alterations in actin polymerization and MRTF localization coincided with favorable alterations to tenocyte gene expression. In contrast, latrunculin A increases the proportion of G-actin in tenocytes and reduces nuclear MRTF, causing cells to acquire a tendinosis-like phenotype. To parse out the effects of F-actin depolymerization from regulation by MRTF, we treated tenocytes with cytochalasin D. Similar to latrunculin A treatment, exposure of cells to cytochalasin D increases the proportion of G-actin in tenocytes. However, unlike latrunculin A treatment, cytochalasin D increases nuclear MRTF. Compared to latrunculin A treatment, cytochalasin D led to opposing effects on the expression of a subset of genes. The differential regulation of genes by latrunculin A and cytochalasin D suggests that actin signals through MRTF to regulate a specific subset of genes. By targeting the deactivation of MRTF through the inhibitor CCG1423, we verify that MRTF regulates Type I Collagen, Tenascin C, Scleraxis, and -smooth muscle actin in tenocytes. Actin polymerization status is a potent regulator of tenocyte homeostasis through the modulation of several downstream pathways, including MRTF. Understanding the regulation of tenocyte homeostasis by actin may lead to new therapeutic interventions against tendinopathies, such as tendinosis.

cell biology↗

bioRxiv2024

Global atlas of predicted functional domains in Legionella pneumophila Dot/Icm translocated effectors

Legionella pneumophila utilizes the Dot/Icm type IVB secretion system to deliver hundreds of effector proteins inside eukaryotic cells to ensure intracellular replication. Our understanding of the molecular functions of this largest pathogenic arsenal known to the bacterial world remains incomplete. By leveraging advancements in 3D protein structure prediction, we provide a comprehensive structural analysis of 368 L. pneumophila effectors, representing a global atlas of predicted functional domains summarized in a database (https://pathogens3d.org/legionella-pneumophila). Our analysis identified 157 types of diverse functional domains in 287 effectors, including 159 effectors with no prior functional annotations. Furthermore, we identified 35 unique domains in 30 effector models that have no similarity with experimentally structurally characterized proteins, thus, hinting at novel functionalities. Using this analysis, we demonstrate the activity of thirteen domains, including three unique folds, predicted in L. pneumophila effectors to cause growth defects in the Saccharomyces cerevisiae model system. This illustrates an emerging strategy of exploring synergies between predictions and targeted experimental approaches in elucidating novel effector activities involved in infection.

microbiology↗

bioRxiv2024

Subject-Agnostic Transformer-Based Neural Speech Decoding from Surface and Depth Electrode Signals

ObjectiveThis study investigates speech decoding from neural signals captured by intracranial electrodes. Most prior works can only work with electrodes on a 2D grid (i.e., Electrocorticographic or ECoG array) and data from a single patient. We aim to design a deep-learning model architecture that can accommodate both surface (ECoG) and depth (stereotactic EEG or sEEG) electrodes. The architecture should allow training on data from multiple participants with large variability in electrode placements and the trained model should perform well on participants unseen during training. ApproachWe propose a novel transformer-based model architecture named SwinTW that can work with arbitrarily positioned electrodes by leveraging their 3D locations on the cortex rather than their positions on a 2D grid. We train subject-specific models using data from a single participant and multi-patient models exploiting data from multiple participants. Main ResultsThe subject-specific models using only low-density 8x8 ECoG data achieved high decoding Pearson Correlation Coefficient with ground truth spectrogram (PCC=0.817), over N=43 participants, outperforming our prior convolutional ResNet model and the 3D Swin transformer model. Incorporating additional strip, depth, and grid electrodes available in each participant (N=39) led to further improvement (PCC=0.838). For participants with only sEEG electrodes (N=9), subject-specific models still enjoy comparable performance with an average PCC=0.798. The multi-subject models achieved high performance on unseen participants, with an average PCC=0.765 in leave-one-out cross-validation. SignificanceThe proposed SwinTW decoder enables future speech neuropros-theses to utilize any electrode placement that is clinically optimal or feasible for a particular participant, including using only depth electrodes, which are more routinely implanted in chronic neurosurgical procedures. Importantly, the generalizability of the multi-patient models suggests that such a model can be applied to new patients that do not have paired acoustic and neural data, providing an advance in neuroprostheses for people with speech disability, where acoustic-neural training data is not feasible.

neuroscience↗

bioRxiv2023

Deep Phenotyping of Sleep in Drosophila

Animal behavior depends on internal state. While subtle movements can signify significant changes in internal state, computational methods for analyzing these "microbehaviors" are lacking. Here, we present FlyVISTA, a machine-learning platform to characterize microbehaviors in freely-moving flies, which we use to perform deep phenotyping of sleep. This platform comprises a high-resolution closed-loop video imaging system, coupled with a deep-learning network to annotate 35 body parts, and a computational pipeline to extract behaviors from high-dimensional data. FlyVISTA reveals the distinct spatiotemporal dynamics of sleep-associated microbehaviors in flies. We further show that stimulation of dorsal fan-shaped body neurons induces micromovements, not sleep, whereas activating R5 ring neurons triggers rhythmic proboscis extension followed by persistent sleep. Importantly, we identify a novel microbehavior ("haltere switch") exclusively seen during quiescence that indicates a deeper sleep stage. These findings enable the rigorous analysis of sleep in Drosophila and set the stage for computational analyses of microbehaviors.

neuroscience↗

bioRxiv2023

Evolutionary fingerprints of EMT in pancreatic cancers

Mesenchymal plasticity has been extensively described in advanced and metastatic epithelial cancers; however, its functional role in malignant progression, metastatic dissemination and therapy response is controversial. More importantly, the role of epithelial mesenchymal transition (EMT) and cell plasticity in tumor heterogeneity, clonal selection and clonal evolution is poorly understood. Functionally, our work clarifies the contribution of EMT to malignant progression and metastasis in pancreatic cancer. We leveraged ad hoc somatic mosaic genome engineering, lineage tracing and ablation technologies and dynamic genetic reporters to trace and ablate tumor-specific lineages along the phenotypic spectrum of epithelial to mesenchymal plasticity. The experimental evidences clarify the essential contribution of mesenchymal lineages to pancreatic cancer evolution and metastatic dissemination. Spatial genomic analysis combined with single cell transcriptomic and epigenomic profiling of epithelial and mesenchymal lineages reveals that EMT promotes with the emergence of chromosomal instability (CIN). Specifically tumor lineages with mesenchymal features display highly conserved patterns of genomic evolution including complex structural genomic rearrangements and chromotriptic events. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross species analysis of pancreatic and other human epithelial cancers. Mechanistically, we discovered that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, which in turn results in delayed mitosis and catastrophic cell division. Therefore, EMT favors the emergence of high-fitness tumor cells, strongly supporting the concept of a cell-state, lineage-restricted patterns of evolution, where cancer cell sub-clonal speciation is propagated to progenies only through restricted functional compartments. Restraining those evolutionary routes through genetic ablation of clones capable of mesenchymal plasticity and extinction of the derived lineages completely abrogates the malignant potential of one of the most aggressive form of human cancer.

cancer biology↗

bioRxiv2023

Rigosertib promotes anti-tumor immunity via autophagic degradation of PD-L1 in colorectal cancer cells

Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment remains elusive. In our experiments, compared with immunodeficient mouse model, increased tumor growth arrest and robust anti-tumor immunity were observed in RGS-treated colorectal cancer (CRC) xenograft tumors in immunocompetent mice. Intriguingly, RGS markedly down-regulated programmed cell death ligand 1 (PD-L1) expression in both vivo and in vitro. Meanwhile, RGS increased autophagic vacuole number in CRC cells as seen by transmission electron microscopy and immunofluorescence. Moreover, increased LC3-II level and tandem- mRFP- GFP- LC3 labeled vacuole accumulation demonstrated RGS-induced autophagic flux. Mechanistically, it is the activation of AMP-activated protein kinase-UNC-51-like kinase 1 (AMPK-ULK1) axis, rather than the canonical mTOR signaling pathway, that plays a pivotal role in RGS-induced autophagy. AMPK-ULK1 dependent autophagy inhibition, by either short interfering RNA or chemical inhibitors, blocked RGS-induced PD-L1 degradation. Finally, RGS exhibited synergistic anti-tumor activity with cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody in the CRC xenograft model. Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.

cancer biology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2021

Impact of Human Serum Proteins on Susceptibility of Acinetobacter baumannii to Cefiderocol: role of iron transport

Cefiderocol is a siderophore antibiotic that co-opts iron transporters to facilitate cell entry. We show that genes related to iron uptake systems and resistance to {beta}-lactams in Acinetobacter baumannii have altered expression levels in the presence of human serum, human serum albumin, or human pleural fluid. Cefiderocol MICs are also raised in the presence of the mentioned fluids. Clinical response in A. baumannii infections may be related to the interplay of these human factors.

microbiology↗

bioRxiv2021

Interplay between meropenem and human serum albumin on expression of carbapenem resistance genes and natural competence in Acinetobacter baumannii

Acinetobacter baumannii A118, a mostly susceptible strain, and AB5075, carbapenem-resistant, were cultured in L broth or L broth with different supplements: 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5 % HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation in A. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus associated genes. The combination meropenem plus 3.5% HSA produced a synergistic augmentation in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumannii AMA16 blaNDM-1 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may produce stronger cellular stress, the A. baumannii responds increasing the levels of expression of genes involved in natural competence. This process may favor the acquisition of foreign DNA and accelerate evolution. ImportanceAcinetobacter baumannii causes a variety of nosocomial- and community-infections that are usually resistant to multiple antimicrobial agents. As new strains acquire more resistance genes, these infections become harder to treat, and mortality can reach up to 39%. The high genomic plasticity exhibited by A. baumannii must be the consequence of numerous mechanisms that include acquiring foreign DNA and recombination. Here, we describe the ability of A. baumannii to induce competence genes when exposed to environments that resemble those found in the human body during untreated infection or after administration of carbapenems. In this latter scenario expression of genes related to resistance also modify their expression levels such that resistance is increased. The contributions of this article are two-pronged. First, when A. baumannii is exposed to substances present during infection, it responds, augmenting the ability to capture DNA and accelerate evolution. Second, in those conditions, the bacterium also modifies the expression of resistance genes to increase its resistance levels. In summary, recognition of substances that are naturally (HSA) or artificially (treatment with carbapenems) induces A. baumannii to defend, enhancing resistance and increasing the chances of acquiring new resistance mechanisms.

microbiology↗

bioRxiv2021

ePlant in 2021: New Species, Viewers, Data Sets, and Widgets

ePlant was introduced in 2017 for exploring large Arabidopsis thaliana data sets from the kilometre to nanometre scales. In the past four years we have used the ePlant framework to develop ePlants for 15 agronomically-important species: maize, poplar, tomato, Camelina sativa, soybean, potato, barley, Medicago truncatula, eucalyptus, rice, willow, sunflower, Cannabis sativa, wheat and sugarcane. We also updated the interface to improve performance and accessibility, and added two new views to the Arabidopsis ePlant - the Navigator and Pathways viewers. The former shows phylogenetic relationships between homologs in other species and their expression pattern similarities, with links to view data for those genes in the respective ePlants. The latter shows Plant Reactome metabolic reactions. We also describe new Arabidopsis data sets including single cell RNA-seq data from roots, and how to embed ePlant eFP expression pictographs into any web page.

bioinformatics↗