Biology subjects

Wang, L. M.

Publications and source records attributed to Wang, L. M..

12 recordsLinked to original sources

bioRxiv2026

Investigating the Dynamic Relationship Between Anxiety and Spatial Memory Using Autonomous Ecological Momentary Assessment

Anxiety has been extensively studied in relation to memory, yet its dynamic association with spatial episodic memory in naturalistic clinical settings remains largely unexplored. We developed an anxiety-spatial-memory EMA protocol (asm-EMA) and deployed it in 30 epilepsy patients undergoing inpatient EEG monitoring, delivering combined momentary anxiety ratings and a validated spatial memory task pseudo-randomly every 90-150 minutes across multiple days. Subject-level asm-EMA means and session-to-session variability both correlated significantly with standard neuropsychological assessments, supporting the clinical validity of our design. Elevated within-person STAI-6 was selectively associated with faster retrieval responses, yet spatial memory accuracy was independent of all three anxiety measures, suggesting a shift in response strategy rather than memory impairment. Within-day anxiety showed short-term carryover between consecutive sessions, with little persistence beyond the next session. The asm-EMA protocol provides a feasible, autonomous framework for capturing moment-to-moment anxiety-memory dynamics in naturalistic settings.

neuroscience↗

bioRxiv2024

Dysbiosis-associated gut bacterium Ruminococcus gnavus varies at the strain level in ability to utilize key mucin component sialic acid

Ruminococcus gnavus is a prevalent human gut commensal bacterium with known roles in intestinal mucus degradation, including by catabolism of the terminal mucin sugar sialic acid. While R. gnavus is not considered a pathogen, overabundance of this species is correlated with Inflammatory Bowel Disease (IBD), and its sialic acid metabolism may play a role in the dysbiotic state. Interestingly, liberation of mucin-bound sialic acid by R. gnavus yields the distinct product of 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), in contrast to other known mucin-degrading bacteria, which generate Neu5Ac. This prompted us to look for 2,7-anhydro-Neu5Ac metabolism proteins in the genomes of 77 R. gnavus clinical isolates. We found that 2,7-anhydro-Neu5Ac metabolism is sporadically distributed in this species with respect to phylogeny and strain origin. We measured sialic acid-dependent growth of 12 sequenced isolates, finding that the presence of 2,7-anhydro-Neu5Ac catabolism proteins was predictive of growth on this substrate. Our analysis also uncovered "partial" 2,7-anhydro-Neu5Ac catabolism pathways in two R. gnavus strains, which we determined constitute the canonical Neu5Ac catabolism pathway, previously unreported in this species. These results reveal a notable diversity of sialic acid catabolism across the R. gnavus species, an essential consideration for further investigations into the importance of this metabolism in mucin degradation and in roles of R. gnavus in IBD and other gut dysbioses.

microbiology↗

bioRxiv2024

GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche via stromal remodelling

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we used a disease-positioned mouse, and human tissue, to explore the consequences of pathological Bone Morphogenetic Protein (BMP) signalling dysregulation on epithelial- mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist GREM1, resulted in ectopic crypt formation with lineage tracing demonstrating the presence of Lgr5(-) stem/progenitor cells. Isolated epithelial cell Grem1 expression had no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with a novel anti-Grem1 antibody abrogated the polyposis phenotype, and triangulation of specific pathway inhibitors defined a pathological sequence of events, with wnt-ligand dependent ectopic stem cell niches formed through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function. One Sentence SummaryPathological epithelial GREM1 expression induces therapeutically reversible ectopic stem cell niches through stromal remodelling

cancer biology↗

bioRxiv2023

SCD inhibition eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients outcome. These features should be ideally present in many patients independently of mutational background. Here we identify de novo fatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML models in vitro and in vivo. We use the novel clinical grade SCD inhibitor SSI-4 to show that SCD inhibition induces AML cell death via pleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. SSI-4 efficacy is enhanced by driving FA biosynthesis in vitro while stroma confers protective effects that extend to in vivo models. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential. One Sentence SummarySCD inhibition is toxic to AML cells with high rates of fatty acid desaturation and in combination with chemotherapy prolongs survival in murine AML models.

cancer biology↗

bioRxiv2023

Automated model discovery for muscle using constitutive recurrent neural networks

The stiffness of soft biological tissues not only depends on the applied deformation, but also on the deformation rate. To model this type of behavior, traditional approaches select a specific time-dependent constitutive model and fit its parameters to experimental data. Instead, a new trend now suggests a machine-learning based approach that simultaneously discovers both the best model and best parameters to explain given data. Recent studies have shown that feed-forward constitutive neural networks can robustly discover constitutive models and parameters for hyperelastic materials. However, feed-forward architectures fail to capture the history dependence of viscoelastic soft tissues. Here we combine a feed-forward constitutive neural network for the hyperelastic response and a recurrent neural network for the viscous response inspired by the theory of quasi-linear viscoelasticity. Our novel rheologically-informed network architecture discovers the time-independent initial stress using the feed-forward network and the time-dependent relaxation using the recurrent network. We train and test our combined network using unconfined compression relaxation experiments of passive skeletal muscle and compare our discovered model to a neo Hookean standard linear solid and to a vanilla recurrent neural network with no mechanics knowledge. We demonstrate that, for limited experimental data, our new constitutive recurrent neural network discovers models and parameters that satisfy basic physical principles and generalize well to unseen data. We discover a Mooney-Rivlin type two-term initial stored energy function that is linear in the first invariant I1 and quadratic in the second invariant I2 with stiffness parameters of 0.60kPa and 0.55kPa. We also discover a Prony-series type relaxation function with time constants of 0.362s, 2.54s, and 52.0s with coefficients of 0.89, 0.05, and 0.03. Our newly discovered model outperforms both the neo Hookean standard linear solid and the vanilla recurrent neural network in terms of prediction accuracy on unseen data. Our results suggest that constitutive recurrent neural networks can autonomously discover both model and parameters that best explain experimental data of soft viscoelastic tissues. Our source code, data, and examples are available at https://github.com/LivingMatterLab.

bioengineering↗

bioRxiv2022

Conserved basal lamina proteins, laminin and nidogen, are repurposed to organize mechanosensory complexes responsible for touch sensation.

The sense of touch is conferred by the conjoint function of somatosensory neurons and skin cells. These cells meet across a gap filled by a basal lamina, an ancient structure found in metazoans. Using Caenorhabditis elegans, we show that membrane-matrix complexes containing laminin, nidogen, and the MEC-4 mechano-electrical transduction channel reside at this interface and are instrumental for proper touch sensation. These complexes fail to coalesce in touch-insensitive extracellular matrix mutants and in dissociated neurons. MEC-4, but not laminin or nidogen, is destabilized by point mutations in the C-terminal Kunitz domain of the extracellular matrix component, MEC-1. Thus, neuron-epithelial cell interfaces are instrumental in mechanosensory complex assembly and function. Loss of nidogen reduces the density of mechanoreceptor complexes and the amplitude of the touch-evoked currents they carry. These findings imply that somatosensory neurons secrete proteins that actively repurpose the basal lamina to generate special-purpose mechanosensory complexes responsible for vibrotactile sensing.

cell biology↗

bioRxiv2021

Colorectal cancer risk in bowel adenomas based on lifestyle exposures, tissue preconditioning and DNA methylation

BackgroundColorectal cancer (CRC) is associated with patient demographics, lifestyle exposures and molecular alterations. However, it is not possible to determine which adenomas will progress to CRC, as ethically it is unacceptable to leave and follow adenomas. We hypothesised that certain lifestyle exposures at high levels could precondition exposed bowel tissue by changing and aging it, increasing the risks of deleterious DNA methylation and genetic alterations. We used a novel study design comparing adenomas with concurrent CRC (thus more likely exposed to deleterious lifestyle effects) to single adenomas in bowels with no history of CRC; we called these high (HR) and low-risk (LR) adenomas respectively. MethodsWe carried out a discovery and replication epigenome-wide association study (EWAS) on 106 HR and 111 LR adenomas, profiled with MethylationEPIC BeadChips. In order, to identify differentially methylated positions (DMP), regions (DMR), and DNAm (DNAmethylation) lifestyle exposures and risks, with adjustment for confounders, and gene ontology (GO) and pathway enrichment. Then, two open-source gene expression omnibus (GEO) validation datasets (52, 57 and 49, 48 HR and LR normal bowel tissues respectively) were analysed for these DNAm lifestyle exposures and risks, with adjustment for confounders. ResultsOur EWAS found 5 Bonferroni significant DMPs with absolute delta betas [≥] 5%, and 14 significant DMRs with absolute mean DMR delta betas [≥] 5%, replicated in the GPX7, RGS3 and TMEM135 cancer-associated genes. DNAm high alcohol exposures were strongly associated with increased risk of HR adenomas (odds ratio (OR) per standard deviation (SD) = 2.16 (95% confidence interval (CI) 1.55 - 3.09, p-value = 9.7 x 10-6)). In the validation datasets, DNAm high alcohol (ORperSD = 2.12 (95% CI 1.35 - 3.55, p-value = 2.0 x 10-3) and ORperSD = 1.79 (95% CI 1.14 - 2.96, p-value = 1.7 x 10-2)), and high body mass index (BMI) exposures (ORperSD = 1.72 (95% CI 1.13 - 2.73, p-value = 1.5 x 10-2)) were associated with increased risk of HR normal bowel tissues. ConclusionsHigh alcohol and BMI exposures may precondition normal bowel tissues and adenomas for increased risk of DNA methylation alterations associated with CRC progression. The DNAm exposure signatures and our newly identified genes may be useful epigenetic biomarkers for CRC prevention.

cancer biology↗

bioRxiv2021

BMP pathway antagonism by Grem1 regulates epithelial cell fate in intestinal regeneration

In the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrine Bmp4 expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMPs role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist, Grem1, from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, following Grem1 deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1 respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.

cell biology↗

bioRxiv2020

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, the loss and gain of whole and part chromosomes, is near-ubiquitous in cancer genomes and likely defines cancer cell biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterised. Here we perform longitudinal genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that represent distinct stages of tumour evolution through metastasis and treatment. Adenomas typically had few copy number alterations (CNAs) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual CRC glands from the same tumour typically had very similar karyotypes, despite evidence of ongoing instability at the cell level in patient tumours, cell lines and organoids. CNAs in metastatic lesions sampled from liver and other organs, after chemotherapy or targeted therapies, and in late recurrences were typically similar to the primary tumour. Mathematical modelling and statistical inference indicated that these data are consistent with the action of negative selection on CNAs that traps cancer cell genomes on a fitness peak defined by the specific pattern of chromosomal aberrations. These data suggest that the initial progression of colorectal cancer requires the traversal of a rugged fitness landscape and subsequent CNA evolution, including metastatic dissemination and therapeutic resistance, is constrained by negative selection.

cancer biology↗

bioRxiv2019

A CRISPR Knockout Screen Identifies Foxf1 as a Suppressor of Colorectal Cancer Metastasis That Acts Through Reduced mTOR Signalling

IntroductionA greater understanding of molecular mechanisms underlying metastasis is necessary for development of new strategies to prevent and treat cancer.\n\nMethodsWe performed a genome-wide CRISPR/Cas9 knockout screen in MC38 colorectal cancer (CRC) cells transplanted orthotopically into mice to identify genes that promote metastasis. We undertook focussed molecular analyses to identify mechanisms underlying metastasis.\n\nResultsThe screen identified several gene knockouts over-represented in lung metastases, including Dptor (mTOR signalling) and Foxf1 (gastrointestinal tumour predisposition). We validate that loss of Foxf1 promotes metastasis, increased Foxf1 expression restrained cellular migration in-vitro and human CRC metastases express lower Foxf1 than paired primary tumours. Analysis of gene expression changes downstream of Foxf1 identified increased mTOR signalling as a possible mechanism of metastasis caused by Foxf1 loss, consistent with Dptor identification. We confirmed this mechanism demonstrating that mTOR inhibitor sirolimus reduced lung metastasis burden in xenografts.\n\nConclusionMesenchymal Foxf1 plays a major role in intestinal development. We have shown for the first time, through an unbiased genetic screen, that reduced epithelial Foxf1 results in raised mTOR signalling and metastasis.\n\nAuthorship statementLennard Lee-study concept and design, acquisition of data, analysis, interpretation of data, drafting of the manuscript, statistical analysis and obtained funding. Connor Woolley-acquisition of data, analysis and interpretation of data. Thomas Starkey-acquisition of data, analysis, interpretation of data, drafting of the manuscript. Luke Freeman-Mills-interpretation of data. Andrew Bassett-technical and material support. Fanny Fanchini-technical support. Lai Mun Wang-acquisition of data and study supervision. Annabelle Lewis-study supervision. Roland Arnold-analysis, interpretation of data, statistical analysis. Ian Tomlinson-study supervision and critical revision of the manuscript.\n\nConflict of InterestThe authors whose names are listed above declare that they have no conflict of interest.

cancer biology↗

bioRxiv2019

Mechanical stress compromises multicomponent efflux complexes in bacteria

Physical forces have long been recognized for their effects on the growth, morphology, locomotion, and survival of eukaryotic organisms1. Recently, mechanical forces have been shown to regulate processes in bacteria, including cell division2, motility3, virulence4, biofilm initiation5,6, and cell shape7,8, although it remains unclear how mechanical forces in the cell envelope lead to changes in molecular processes. In Gram-negative bacteria, multicomponent protein complexes that form rigid links across the cell envelope directly experience physical forces and mechanical stresses applied to the cell. Here we manipulate tensile and shear mechanical stress in the bacterial cell envelope and use single-molecule tracking to show that shear (but not tensile) stress within the cell envelope promotes disassembly of the tripartite efflux complex CusCBA, a system used by E. coli to resist copper and silver toxicity, thereby making bacteria more susceptible to metal toxicity. These findings provide the first demonstration that mechanical forces, such as those generated during colony overcrowding or bacterial motility through submicron pores, can inhibit the contact and function of multicomponent complexes in bacteria. As multicomponent, trans-envelope efflux complexes in bacteria are involved in many processes including antibiotic resistance9, cell division10, and translocation of outer membrane components11, our findings suggest that the mechanical environment may regulate multiple processes required for bacterial growth and survival.

biophysics↗

bioRxiv2018

Single cell RNA-seq reveals profound transcriptional similarity between Barretts esophagus and esophageal glands

Barretts esophagus is a precursor of esophageal adenocarcinoma. In this common condition, squamous epithelium in the esophagus is replaced by columnar epithelium in response to acid reflux. Barretts esophagus is highly heterogeneous and its relationships to normal tissues are unclear. We investigated the cellular complexity of Barretts esophagus and the upper gastrointestinal tract using RNA-sequencing of 2895 single cells from multiple biopsies from four patients with Barretts esophagus and two patients without esophageal pathology. We found that uncharacterised cell populations in Barretts esophagus, marked by LEFTY1 and OLFM4, exhibit a profound transcriptional overlap with a subset of esophageal cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barretts esophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.

genetics↗