Biology subjects

Richards, D.

Publications and source records attributed to Richards, D..

9 recordsLinked to original sources

bioRxiv2026

Analysis of Confounding Factors in Reactive Cysteine Profiling Reveals Enhanced Chromatin-Protein Association via CDK7 Inhibition by THZ1

Recent advances in activity-based proteome profiling (ABPP) have enabled global mapping of cysteine ligandability, uncovering novel biological insights and opportunities for identifying disease vulnerabilities. While both live cell-based and native lysate-based ABPP have been applied, how cysteine ligandability differs between these systems and what factors influence these measurements remain unclear. Building on our previous development of a high-throughput TMT-ABPP workflow for native lysates, here we adapt the protocol for live cells and systematically compare cysteine ligandability across both platforms. Our analysis reveals three major contributors to the discrepancies: in-cellulo cysteine accessibility, protein abundance changes, and protein relocalization. Notably, we highlight that CDK7 inhibitor THZ1 induces substantial protein relocalization and promotes chromatin binding. Together, these results provide a practical framework for ABPP experimental design and data interpretation, supporting more accurate application of ABPP in functional proteomics and drug discovery.

cell biology↗

bioRxiv2025

A Biophysical Model of Phagocytic Cup Dynamics: The Effect of Membrane Tension

Phagocytosis is a fundamental cellular process by which cells engulf external particles, controlled by receptor-ligand binding and actin-driven membrane dynamics. While a number of mathematical models have been developed to describe this process, they often overlook membrane tension, a key physical parameter known to influence membrane deformation and cytoskeletal behaviour. To address this gap, we present an enhanced mathematical model of receptor motion during phagocytosis that explicitly incorporates the role of membrane tension. Further, we introduce a signalling component that is coupled to receptor dynamics via the membrane tension. We find that including tension results in fundamentally different engulfment behaviour, which is slower than that predicted by models without tension. In particular, unlike in the previous version of this model, we show that tension can lead to stalled engulfment, an experimentally-observed phenomenon known as frustrated phagocytosis. We also find that signalling is able to modify engulfment behaviour, especially at later stages, and is able to alter cup growth to become linear in time without the need for receptor drift as introduced in previous models. These findings offer new insights into the role of membrane tension and biophysical regulation in phagocytosis, with implications for immune function, cell motility and targeted drug delivery.

cell biology↗

bioRxiv2025

Disparities in climate risk-mitigation and recreation services in Grenoble (France)

Urban green spaces provide cultural and climate risk-mitigation ecosystem services (ES) critical for the well-being of urban residents. Yet these benefits are not equally shared across social groups, and environmental segregation - i.e., the spatial separation of population groups between areas of contrasted environmental quality - is common. For instance, environmental justice studies have shown that green space acreage and quality are typically lower in low-income neighbourhoods. However, more detailed assessments integrating a range of ES and the diverse needs of multiple groups are needed to effectively inform equitable urban planning. Here, we combine socio-demographic spatial data with ES modelling to assess social disparities in the distribution of three ES - heatwave mitigation, flood regulation, and urban recreation - in the Grenoble metropolitan area, France. Our results show that low-income households generally benefit from lower climate risk mitigation, but from equal or slightly greater urban recreation opportunities. We also identify mismatches between ES supply and demand from vulnerable groups, which are particularly acute in disadvantaged neighborhoods. These findings highlight the importance of integrating social needs and vulnerabilities into urban greening strategies. Policies that move beyond generic measures of green space provision and explicitly consider multiple ES can help ensure that urban green infrastructure delivers fair and effective benefits across diverse communities.

ecology↗

bioRxiv2025

Immune signaling mediates stromal changes to support epithelial reprogramming in Celiac duodenum

Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8pos, {gamma}{delta} T cells and IFNG transcriptional shifts) and Tfh-related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1{beta}. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1{beta} signal and lymphoid-derived IFN-{gamma}. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.

immunology↗

bioRxiv2024

One cannot have it all: trading-off ecosystem services and biodiversity bundles in landscape connectivity restoration

Countering the impacts of habitat loss and fragmentation on ecosystems requires complementing conservation areas with Other Effective area-based Conservation Measures within landscapes to promote biodiversity and multiple ecosystem services (ES). However, critical knowledge gaps persist in where and how natural elements should be restored to improve landscape connectivity to simultaneously support, and reduce trade-offs between biodiversity and ES. In virtual landscape experiments that allow exploring the effects of spatial pattern systematically, we generated alternative landscape restoration scenarios aimed at fostering ecological connectivity. Scenarios varied in the location and size of restored areas complementing existing natural areas. We analysed the impact of these scenarios on four bundles representing distinct priorities of target ES and biodiversity-related values. As expected, all bundles were favoured by increasing restored area in the landscape, but they were promoted by different spatial configurations. Restoration scenarios that fostered high aggregation of natural habitats promoted biodiversity and cultural value-related bundles, while smaller natural elements dispersed throughout the landscape were more beneficial for the sustainable production and climate adaptation bundles. These contrasts were most pronounced at low restoration efforts, where landscape configuration had greatest impacts on biodiversity and ecosystem processes. Effective spatial planning of restoration initiatives within landscapes should consider these trade-offs, along with context-specific constraints, when prioritizing areas for restoration or conservation. Our findings contribute to a more comprehensive understanding of how protected and restored areas can be integrated within landscapes to jointly support connectivity for both biodiversity and people. HighlightsO_LIVirtual landscape restoration options effects on four ecosystem services and biodiversity bundles C_LIO_LIHigh aggregation of restored elements promoted biodiversity and cultural value C_LIO_LILow aggregation promoted sustainable production and climate adaptation C_LIO_LIThese contrasts were most important at low restoration targets C_LIO_LIThese results highlight the importance of configuration trade-offs in restoration planning C_LI

ecology↗

bioRxiv2024

Assessing the quality of generative artificial intelligence for science communication in environmental research

The adoption of Generative Artificial Intelligence (GenAI) tools is drastically changing the way that researchers work. While debate on the quality of GenAI outputs continues, there is optimism that GenAI may help human experts to address the most significant environmental challenges facing society. No previous research has quantitatively assessed the quality of GenAI outputs intended to inform environmental management decisions. Here we surveyed 98 environmental scientists and used their expertise to assess the quality of human and GenAI content relevant to their discipline. We analysed the quality and relative preference between human and GenAI content across three use cases in environmental science outreach and communication. Our results indicate that the GenAI content was generally deemed adequate in quality by human experts, with an average of 82% of respondents indicating a quality of "adequate" or better across the three use cases. Respondents exhibited strong preferences for GenAI over human-only content when using GenAI imageery of future park management scenarios. For the use cases of generating a wetland planting guide and answering a question about invasive species management, preferences were heterogeneous amongst respondents. Our findings raise substantive questions about GenAI content as a complement to human expertise when research is transferred to public audiences.

scientific communication and education↗

bioRxiv2023

Dynamic calcium-mediated stress response and recovery signatures in the fungal pathogen, Candida albicans

Calcium (Ca2+) is an important second messenger for activating stress response signalling and cell adaptation in eukaryotic cells yet intracellular Ca2+-dynamics in fungi is poorly understood due to lack of effective real-time Ca2+ reporters. We engineered the GCaMP6f construct for use in the fungal pathogen, Candida albicans, and used live-cell imaging to observe dynamic Ca2+ spiking as well as slower changes in ambient Ca2+-GCaMP levels elicited by stress or gene deletion. Short-term exposure to membrane, osmotic or oxidative stress generated immediate stress-specific responses and repeated exposure revealed differential recovery signatures. Osmotic stress caused yeast cell shrinkage and no adaptation response, where Ca2+-GCaMP spiking was inhibited by 1 M NaCl but not by 0.66 M CaCl2. Treatment with SDS caused a spike-burst, raised ambient Ca2+-GCaMP levels and significant cell death, but surviving cells adapted over subsequent exposures. Treatment with 5 mM H2O2 abolished spiking and caused transient autofluorescence but cells adapted such that spiking returned and autofluorescence diminished on repeated exposure. Adaptation to H2O2 was dependent on Cap1, extracellular Ca2+ and calcineurin, but not on its downstream target, Crz1. Ca2+-dynamics were not affected by H2O2 in the hog1{Delta} or yvc1{Delta} mutants, suggesting a pre-adapted, resistant state, possibly due to changes in membrane permeability. Live-cell imaging of Ca2+-GCaMP responses in individual cells has therefore revealed the dynamics of Ca2+-influx, signalling and homeostasis and their role in the temporal stress response signatures of C. albicans.

microbiology↗

bioRxiv2022

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

Acute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1{beta}is an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1 {beta} treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1{beta} treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1{beta} treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.

bioengineering↗

bioRxiv2018

Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties

Brain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

neuroscience↗