Biology subjects

Krishna, S.

Publications and source records attributed to Krishna, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Interplay of mechanics, growth and viral infection dynamics in a spatially expanding bacterial colony

We investigate the dynamics of the spread of the infection due to a phage- during the range expansion of an E coli colony. We find a rich panoply of spatio-temporal dynamics at large colony-level length scales, arising due to the interplay of mechanical forces, growth and viral infection dynamics at smaller cellular length scales. Strikingly, the phages "surf" the front of the growing bacterial colony by hitchhiking on E coli that are advected due to the growth of bacteria in the colony, resulting in an anisotropic spread of the phages. We identify microscopic processes - of the phage release during lysis (occurring on short millisecond timescales at length scales close to that of a single bacterium) and local nematic alignment of the rod-like E coli bacteria (occurring on timescales comparable to the bacterial growth rate and the length scales of a few bacterial cells) - that enhance the advective effects driving the hitchhiking behavior. Combining our experiments with a mathematical model, we explain the multiple spatio-temporal dynamical regimes - from the coexistence of uninfected bacteria, resistant (lysogenic) cells and phages, to fixed points where the entire population turns resistant or remains uninfected. Our work broaches a new frontier in the investigation of eco-evolutionary processes arising from the mechanical and ecological forces due to the interactions between viruses and their hosts.

biophysics↗

bioRxiv2026

Beyond codon optimality: codon pairs regulate mRNA stability dependent on translation

The coding sequence of an mRNA directs its own decay, yet how codons, codon context, and amino acids collectively regulate mRNA stability remains poorly understood. Here we use a massively parallel reporter assay to decode this regulatory layer in zebrafish embryos. We find that codon pairs and amino acid pairs regulate mRNA stability beyond the level of individual codons. This regulation depends on the identity and order of neighboring codons and their encoded amino acids in a translation-dependent manner. The relative contributions of codon and amino acid combinations to mRNA stability can be quantified using machine learning. We further found that endogenous mRNAs are regulated by codon pairs, thereby governing developmental gene regulation and biological function. This codon context-dependent decay requires deadenylation and decapping by Cnot7 and Dcp2, with Upf1 acting on long non-optimal ORFs. Together, our results redefine codon optimality as a context-dependent, pair-level code with implications for RNA biology and therapeutic mRNA design.

molecular biology↗

bioRxiv2026

Human-like meaning maps from single-prompt VLM ratings of local scene meaning

Visual attention is shaped both by low-level perceptual features and by the semantic properties of scene regions. However, compared to the salience of low-level image features, the characterization of image properties that lead to scene understanding has been more difficult. The semantic properties of scene regions have been operationalized via meaning maps, proposed by Henderson and Hayes (2017), by having human observers rate the informativeness of scene patches. However, this rating procedure is labor-intensive and limits the method's versatility. An automated alternative, the DeepMeaning model, reduces rating costs but still requires human training data from a similar class of images, limiting generalizability. Here, we tested whether instruction-following vision-language models (VLMs) can generate human-like ratings in a zero-shot manner: using the original human-rating instructions as a single prompt without any task-specific training. We obtained meaningfulness ratings from both open-weight and proprietary VLMs for scene patches across three meaning-map datasets, and compared the resulting zero-shot AI meaning maps (AIMMs) to human meaning maps and maps obtained from the DeepMeaning model. Zero-shot AIMMs closely approximate human meaning maps, and maps from the task-specific DeepMeaning model, showing that VLMs can replicate human semantic judgments without any training. Zero-shot AIMMs demonstrate utility and validity, matching human meaning maps in their ability to predict human fixations and reproducing the same pattern of relative performance against other gaze-prediction models. We provide open-source code that allows researchers to use this zero-shot approach to quickly and flexibly explore meaning maps across spatial scales, prompts, and scene categories.

neuroscience↗

bioRxiv2026

Electrophysiological features of signals recorded from white matter

Intracranial neurophysiology studies have typically ignored signals from electrodes located in white matter (WM), assuming that their information content is artifactual or related to nearby gray matter (GM). Here, we tested the electrophysiological and functional features of signals recorded from different WM locations. Signals were recorded from 19 patients undergoing intracranial monitoring for drug-resistant epilepsy by means of stereo-electroencephalography (sEEG). Each sEEG electrode was classified into WM or GM based on the surrounding tissue. We obtained recordings from a total of 1,717 sEEG electrode contacts, 36% in WM, while the patients were in awake resting state (5 minutes). For each sEEG electrode, we employed a model-based spectral decomposition to separate periodic and aperiodic components, and we computed signal complexity metrics. For a subset of participants, we computed WM structural information from diffusion-weighted magnetic resonance imaging and we evaluated functional signals during a cognitive control task. Our results show that signals recorded from WM have different spectral features and higher complexity than GM. Complexity correlates positively with fractional anisotropy, and modulations related to behavior during the task were detected in WM. Overall, this indicates that WM signals carry information that may reflect signal propagation across WM fiber tracts.

neuroscience↗

bioRxiv2026

Single-Cell Isolation and Patient-Derived Organoid Generation Using the Pala™ Single Cell Dispenser with Cancer Cell Lines Spiked into Blood as a Circulating Tumour Cell Model: A Platform for Precision Oncology and Drug Discovery

The isolation of cancer cells and rare circulating tumour cells (CTCs) and the initiation of patient-derived organoids (PDOs) represent two critical new approach methodologies (NAMs) for advancing precision oncology and drug discovery. However, current technologies encounter significant limitations, including high system pressures that compromise cell viability, sample loss, and reliance on marker-dependent enrichment strategies. Here, we performed a technical validation of the Pala Single Cell Sorter/Dispenser (Bio-Techne) using cancer cell lines spiked into healthy donor blood as a model for CTCs, alongside cells isolated from ovarian cancer (OC) patients and cervical cancer cell lines. The platform achieved up to 80% single-cell dispensing efficiency under gentle sorting conditions (<2 psi), successfully dispensing single cancer cells, cell clusters, and cancer cells spiked into blood (mimicking CTCs). Concurrently, three-dimensional organoid structures generated from dissociated OC samples and cervical cancer cell lines showed viable growth and cluster formation within one week. Compared to literature values for fluorescence-activated cell sorting (FACS), the Pala maintained higher post-sort viability (88% vs. 55-70%) and organoid initiation efficiency (68% vs. 42%). This work establishes the Pala as a flexible tool for patient cancer cell dispensing, CTC-mimic isolation, and PDO generation within drug discovery workflows. Clinical validation using authentic patient CTCs remains necessary prior to clinical implementation.

Cancer Biology↗

bioRxiv2026

Multiscale Modeling Identifies Cardiovascular Risk from Common Chemical Exposures

BackgroundThe cardiovascular system is significantly affected by exogenous factors, but understanding the risks posed by pharmaceuticals and environmental chemicals is restricted due to limited data availability. New approach methodologies (NAMs) apply in vitro, in chemico, and in silico methods to characterize hazard and risk, thus offering rapid, multiscale human biology-based strategies to overcome regulatory challenges and the potential to complement or replace animal testing for understanding chemical cardiovascular effects. MethodsIn the present study, we applied a systems-based workflow using physiologically based pharmacokinetic (PBPK) models to convert bioactive concentrations from >300 high-throughput screening (HTS) assays with cardiovascular-relevant molecular and cellular targets to human equivalent administered doses (EADs) for >800 substances with widespread human exposure potential. To derive human-relevant risk predictions, the in vitro activity-derived EADs were compared with human exposure estimates and in vivo points of departure (PODs) from toxicological animal studies. For a subset of chemicals, we applied a geospatial analysis to assess the combined risks for populations across regions of the US. ResultsThe combined HTS assay data, human exposure predictions, animal study-based PODs, geospatial exposure data, and PBPK modeling identified compounds with potential cardiovascular toxicity at relevant exposure levels. Personal care product ingredients, flame retardants, herbicides, pesticides, pharmaceuticals, and byproducts of various industrial processes were noted as agents of concern preferentially targeting endothelial cell signaling, nuclear hormone receptors, and other critical cardiovascular targets. Of the 859 chemicals assessed, in vitro CV-relevant assays were more risk protective than animal studies for 96.4% of the chemicals. A set of 17 chemicals had a log10 bioactivity exposure ratio (BER) below -2, indicating estimated human exposure more than 100-fold above the in vitro-derived bioactive dose. ConclusionsThis study establishes an integrative, multiscale framework linking molecular perturbations to population-level cardiovascular risk, enabling systematic identification of potentially cardiotoxic chemicals and the communities most vulnerable to their effects. By bridging mechanistic toxicology with pharmacokinetic modeling and epidemiologic context, this approach enhances the biological relevance and translational impact of human health risk assessment. This scalable, adaptable framework supports timely, evidence-based decision-making and aligns with the growing adoption of NAMs to advance cardiovascular research and disease prevention. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABSHigh-throughput screening (HTS) assays can identify chemicals with activity at cardiovascular (CV) relevant molecular targets, but translating in vitro bioactivity concentrations into biologically meaningful human equivalent doses requires physiologically based pharmacokinetic (PBPK) modelling. The bioactivity exposure ratio (BER) provides a data-driven metric for comparing in vitro-derived equivalent administered doses against population exposure estimates, but its application to CV endpoints across a large and chemically diverse environmental chemical landscape has not been demonstrated. Geospatial mapping of CV chemical exposure risk has been demonstrated for a limited set of air pollutants but has not been extended to a broad environmental chemical landscape using human-relevant in vitro bioactivity data. What new information does this article contribute?Integrated in vitro to in vivo extrapolation (IVIVE) across 859 environmental chemicals demonstrates that cardiovascular-relevant in vitro endpoints are sensitive indicators of broader systemic toxicity, 96.4% of chemicals showed positive POD ratios, meaning in vitro CV assays flagged hazard at lower doses than non-specific animal toxicity studies despite the absence of endpoint matching. Seventeen chemicals including PFAS, brominated flame retardants, endocrine disruptors, and agricultural herbicides, had a BER below -2, indicating estimated human exposure more than 100-fold above the in vitro-derived cardiovascular bioactive dose, with convergent evidence from both in vitro and in vivo data supporting regulatory priority. County-level geospatial mapping reveals that cardiovascular chemical exposure risk is geographically heterogeneous across the United States, concentrated in industrially active regions already associated with elevated cardiovascular disease mortality, identifying specific populations for targeted environmental monitoring. SummaryThis study presents a scalable, systems-based IVIVE framework that integrates cardiovascular-relevant in vitro HTS bioactivity data with reverse dosimetry, population exposure predictions, and in vivo animal toxicity data to prioritize environmental chemicals for cardiovascular risk assessment. Applied to 859 chemicals spanning personal care products, flame retardants, pesticides, pharmaceuticals, and industrial compounds, the framework demonstrates that CV-relevant in vitro endpoints are sensitive indicators of systemic toxicity even in the absence of direct endpoint matching with in vivo studies. The BER emerges as a flexible and resource-adaptable prioritization metric, identifying 92 chemicals where estimated human exposure falls within the CV bioactive range, of which 17 represent the highest regulatory priority based on convergent evidence from both data streams. Geospatial mapping further reveals regional heterogeneity in cardiovascular chemical exposure risk concentrated in industrial areas of the central and southeastern United States. This work advances the application of new approach methodologies for cardiovascular chemical risk assessment at a time of accelerating regulatory transition toward human-relevant in vitro-based safety evaluation, providing a reproducible computational workflow directly applicable to chemical prioritization under evolving EPA and FDA regulatory frameworks.

pharmacology and toxicology↗

bioRxiv2026

TRACKING THE COMPOSITION AND STABILITY OF MICROBIOME ACROSS INDIAN SOCIAL HONEYBEES FORAGING IN A HOMOGENOUS RESOURCE LANDSCAPE

Microbial communities are essential for host health and ecosystem stability. However, whether host identity or shared foraging resources shapes microbiome structure among co-occurring species remains poorly understood. We studied bacterial and fungal communities of four Indian honeybee species in a mustard monoculture resource condition, integrating behavioural observation-based pollinator data with microbial co-occurrence networks derived from metabarcoding. Microbiome composition was linked to host identity rather than foraging behaviour, bee abundance, or landscape use. While core bacterial taxa were shared, relationships among bacterial cobionts, unlike those among fungal genera, remained species-specific. Microbial diversity, along with community structure and function, influenced network stability, with a highly modular microbial network of Apis cerana exhibiting more resilience to simulated perturbations. In summary, host-specific filtering shaped the microbiome more than resource homogenisation, with closely related species facing unique risks of microbial collapse, with broader implications for vulnerability to microbiome imbalance, environmental stress, and emerging infections.

ecology↗

bioRxiv2026

Lamin A/C directs nucleosome-scale chromatin remodeling to define early lineage segregation in mammals

Chromatin organization underlies gene regulation and cell fate specification, yet how nucleosome-scale chromatin structure contributes to lineage segregation during early development remains unknown. Here, we resolved chromatin ultrastructure during the first lineage decision in mouse and human, which forms the pluripotent inner cell mass (ICM) and trophectoderm (TE). To achieve this, we developed dual-tilt chromatin electron tomography (2T-ChromEMT) that allows multiscale visualization of chromatin architecture. Our analysis reveals that TE cells of both species display denser chromatin with nucleosome aggregation at the nuclear periphery. We show upregulation of the nuclear matrix protein Lamin A/C within the TE lineage across mouse, human, and opossum embryos, indicating that its regulatory role is conserved across eutherian and marsupial species. Loss of Lamin A/C reduces heterochromatin at the nuclear lamina in TE cells, reactivates pluripotency genes, and impairs mouse blastocyst expansion and human blastoid formation. These findings define the nucleosome-resolution chromatin signatures of early mammalian lineages and establish Lamin A/C-mediated chromatin organization as a conserved mechanism in the exit from pluripotency and maintenance of trophectoderm identity.

developmental biology↗

bioRxiv2025

Topology in Motion: Geometry-Driven Defect Dynamics in Social Wasp Nests

Emergence of order in social insects is exemplified by their nesting architectures. Paper wasps construct hexagonal nests that, like crystals, harbour topological defects. In a paper wasp nest, we identify transient defects that migrate by local wall reorientation and vertex addition, akin to dislocation glide. Across growth phases, non-hexagonal polygons undergo short-range transformations in form and position. The transitions resemble alternating Y-{Delta} transformation-node release and release-and-straighten events, familiar from electrical networks. Burgers circuits show that passage through intermediates does not reduce the distortion in the nest, and all transitions conserve topological charge, thereby explaining the coupling of non-hexagonal cells. These dynamics propagate defect motion only to a finite extent, after which the defect stabilizes without global reorganization or functional gain. Our findings demonstrate that social insect nest building naturally realizes dynamic topological processes, shaped by material properties, construction rules, and geometric constraints.

ecology↗

bioRxiv2025

Individuals matter: habitat factors and plant traits shape individual-level pollinator interactions in a semi-arid landscape

BackgroundPlant-pollinator interactions are vital for understanding ecological processes influencing reproductive success in plant communities. While species-level pollinator interactions are important for predicting community stability, it remains equally crucial to understand individual-level interactions of keystone species in the community. This study examined the role of habitat factors and floral traits in shaping pollinator interactions at the individual plant scale of Maytenus senegalensis, a dominant native species in the semi-arid Aravalli Hills. We measured flower production, nectar sugar concentration, flower diameter, and external factors such as percentage soil moisture, distance to habitat edge, and density of co-flowering conspecifics to assess their impact on pollinator interactions and reproductive success. ResultsWe found significant variation in reproductive investment in the form of flower production and a trade-off with reward quality, where plants with higher flower production were found to have a lower nectar sugar concentration. Higher flower production negatively influenced reproductive success, suggesting the likelihood of increased within-plant visitation. Eristalinus and Apis were the dominant pollinator genera, and overall, Dipterans were found to play a critical role in maintaining the network stability. The presence of flowering conspecific plants in the neighborhood reduced the pollen deposition, suggesting competitive interactions. Moreover, individual plants were found to show some amount of specialization in their interaction niches. We predict that this could lead to further divergence of interaction niches due to pollinator-mediated competition. Any perturbation to interactions of plants with a high degree of pollinator connectance was found to disproportionately influence the network. ConclusionsOverall, our results link microhabitat (soil moisture) and neighborhood context to individual interaction niches, demonstrating that allocation trade-offs and conspecific competition jointly shape pollination and fitness. In semi-arid systems, which are undergoing considerable anthropogenic and climatic changes, our study provides insights into individual pollinator interaction niches and the role of microhabitat factors in species persistence within a community.

ecology↗

bioRxiv2025

Aperiodic neural dynamics define a novel signature of glioma-induced excitation-inhibition dysregulation

Diffuse gliomas remodel neuronal circuits with prognostic and therapeutic significance for patients. Electrophysiologic measures of cortical excitability hold promise for monitoring disease progression and evaluating therapeutic responses. The power law exponent (aperiodic slope) reflects the balance between excitatory and inhibitory activity within neuronal networks, a critical aspect of normal brain function often disrupted in neurological conditions. Despite its potential, the significance of the aperiodic slope in glioma-infiltrated tissue and its underlying cellular processes has not been fully investigated. Here, we integrate multi-modal electrophysiological analysis with transcriptomic profiling to analyze the aperiodic slope in both normal and glioma-infiltrated cortex. We determine that glioma infiltration induces a flattening of the aperiodic slope, indicating a shift toward excitation dominance that varies according to tumor subtype and correlates with impairments in semantic naming. Single-nucleus RNA sequencing revealed that cortical regions with flat aperiodic slope exhibit transcriptional programs enriched in glutamatergic signaling, membrane depolarization, and excitatory synaptic transmission. The aperiodic slope responds to pharmacologically induced changes in cortical inhibition during propofol administration, a GABAA agonist. Our results establish the aperiodic slope as a robust biomarker of glioma-associated excitation-inhibition imbalance, with potential applications in tumor classification and treatment monitoring.

cancer biology↗

bioRxiv2025

Rapid enrichment of progenitor exhausted neoantigen-specific CD8 T cells from peripheral blood

Neoantigen-reactive peripheral blood lymphocytes (NeoPBL) are tumor-specific T cells found at ultra-low frequencies in the blood. Unlike tumor-infiltrating lymphocytes (TIL), NeoPBL exist in a favorable less dysfunctional phenotypic state in vivo, but their rarity has precluded their effective use as cell therapy. Leveraging a priori knowledge of bona fide neoantigens, we combined high-intensity neoantigen stimulation with bead extraction of neoantigen peptide-pulsed target cells to enable the enrichment of NeoPBL to frequencies comparable to ex vivo cultured TIL over a 28-day period. Throughout this process, NeoPBL demonstrate specific reactivity against autologous tumor organoids and maintain memory-like features, including elevated expression of CD28 and TCF7. We additionally demonstrate that NeoPBL reactivity is polyclonal, encompassing multiple clonotypes that are detectable within in vivo TIL populations, underscoring physiological specificity for the targeted neoantigens. This streamlined process yields clinically relevant cell doses and enables identification and expansion of blood-derived neoantigen-specific TCRs. By potentially avoiding additional surgical risks and protracted delays of TIL and individualized TCR-engineered methods, the NeoPBL platform may have clinical and practical advantages. Ultimately, NeoPBL combines intrinsic cell fitness, minimal invasiveness and rapidity to potentially facilitate personalized adoptive cell therapy for cancer.

immunology↗

bioRxiv2025

Live Cell Extrusion in Cervical Cancer - A Novel Mechanism for Cancer Progression

Extrusion during development or of transformed cells in normal epithelia has been described as a process of elimination. However, the role of extrusion in transformed epithelia is still unclear. Here, we report that in a primary tumor-derived cervical cancer cell line, SiHa, overcrowding results in the extrusion of a subset of cells. We find that the mechanism of extrusion in SiHa cells is similar to those that drive live cell extrusion in normal epithelia, suggesting the utility of this model. We propose that the subset that is extruded during overcrowding is resistant to anoikis and acquires promigratory features. We find that this population also exhibits an increase in TGF-{beta} signaling, which we show is a promigratory factor in cervical cancer cells and is a potential driver for the migratory potential observed in the extruded population. Our study shows that extrusion in cervical cancers in response to overcrowding underlies promigratory behavior of sub-populations in cervical cancer cell lines.

cancer biology↗

bioRxiv2025

Current and future relevance of marine spatial planning for the distribution of epibenthic invertebrate and fish species in a heavily used regional sea

The SNS has recently become a European hub for installations of offshore wind farms (OWF), while extensive areas have been designated as marine protected areas (MPAs). Together with the already noticeable effects of climate warming, the region transforms from an area dominated by free ranging fisheries and shipping into an industrial landscape dominated by stationary activities. To inform decision making processes around the spatial allocation of fisheries, conservation measures and licence areas for offshore renewables in the southern North Sea, we modelled the spatial distribution of 179 epibenthic invertebrate and fish species. We identify both current and future hotspots of epibenthic and demersal fish diversity and their overlap with OWFs and MPAs. Hotspots of epibenthic and fish diversity are mostly found along the English Coast, located within an extensive network of MPA and OWF sites, which may provide opportunities for conservation and fisheries alike. In the central SNS, the MPA network could be complemented by OWF, where co-use regulations with other human uses are excluded, to protect sensitive species as well as epibenthic and demersal fish communities. Scenarios for three different time periods (until 2040, 2070 & 2100) revealed that global warming might cause an increase in the probability of occurrence for more than half of the analysed demersal fish species (n = 63). The applications in our study demonstrate the relevance of comprehensive knowledge about current, near and far future distribution patterns of species and species communities to enhance the effectiveness of marine spatial planning including spatial conservation measures.

ecology↗

bioRxiv2024

Advanced Peptide Nanoparticles Enable Robust and Efficient delivery of gene editors across cell types

Efficient delivery of the CRISPR/Cas9 system and its larger derivatives, base editors, and prime editors remain a significant challenge, particularly in tissue-specific stem cells and induced pluripotent stem cells (iPSCs). This study optimized a novel family of cell-penetrating peptides, hPep, to deliver gene-editing ribonucleoproteins. The hPep-based nanoparticles enable highly efficient and biocompatible delivery of Cre recombinase, Cas9, base-, and prime editors. Using base editors, robust and nearly complete genome editing was achieved in the human cells: HEK293T (96%), iPSCs (74%), and muscle stem cells (80%). This strategy opens promising avenues for ex vivo and, potentially, in vivo applications. Incorporating silica particles enhanced the systems versatility, facilitating cargo-agnostic delivery. Notably, the nanoparticles can be synthesized quickly on a benchtop and stored as lyophilized powder without compromising functionality. This represents a significant advancement in the feasibility and scalability of gene-editing delivery technologies.

bioengineering↗

bioRxiv2024

Structural context modulates the conformational ensemble of the intrinsically disordered amino terminus of α-synuclein

Regions of intrinsic disorder play crucial roles in biological systems, yet they often elude characterization by conventional biophysical techniques. To capture conformational distributions across different timescales, we employed a freezing approach coupled with solid-state NMR analysis. Using segmentally isotopically labeled -synuclein (-syn), we investigated the conformational preferences of the six alanines, three glycines, and a single site (L8) in the disordered amino terminus under three distinct conditions: in 8 M urea, as a frozen monomer in buffer, and within the disordered regions flanking the amyloid core. The experimental spectra varied significantly among these conditions and deviated from those of a statistical coil. In 8 M urea, monomeric -syn exhibited the most restricted conformational sampling, rarely accessing chemical shifts characteristic of -helices or {beta}-strands. In buffer, monomeric -syn showed broader conformational sampling, favoring -helical conformations and, to a lesser extent, random coil states. Notably, amino acids in the disordered regions flanking the amyloid core demonstrated the most extensive conformational sampling, with broad peaks encompassing the entire range of possible chemical shifts and a marked preference for highly extended {beta}-strand conformations. Collectively, this work demonstrates that intrinsically disordered regions exhibit distinct conformational preferences, which are influenced not only by the chemical environment but also by the conformations of adjacent protein sequences. The differences in the conformational ensembles of the disordered amino terminus may explain why the monomer and the amyloid form of -syn interact with different biomolecules inside cells.

biophysics↗

bioRxiv2024

In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils

Amyloid forms of -synuclein adopt different conformations depending on environmental conditions. Although advances in structural biology have accelerated fibril characterization, it remains unclear which conformations predominate in biological settings because current approaches typically require fibrils to be isolated from their native environments. In addition, these approaches provide limited information about flanking flexible regions. Here, using a defined polymorphic seed population and quantitative in-cell NMR, we show that propagation in intact cellular environments--but not in vitro buffer or crowded cellular lysates--reshapes the conformational ensemble of -synuclein fibrils. In vitro and in cellular lysates, both amyloid-core structure and the conformational preferences of flanking intrinsically disordered regions of the seed are faithfully propagated. In contrast, propagation inside intact cells selectively amplifies the amyloid-core conformer that is minor in vitro, increases its molecular order, and remodels conformational preferences in the flanking disordered region. These results demonstrate that cellular organization plays a decisive role in determining amyloid structure and that biologically relevant conformations cannot be inferred from purified or lysate systems alone.

biophysics↗

bioRxiv2024

Off-purpose activity of industrial and agricultural chemicals against human gut bacteria

Contamination by industrial and agricultural chemicals like pesticides are a cause of great concern due to the risk to human and environmental health. While these chemicals are often considered to have restricted activity and are labelled as such, there are concerns over a broader toxicity range. Here we report the impact of 1076 pollutants spanning diverse chemistries and indicated applications on 22 prevalent commensal gut bacteria. Our systematic investigation uncovered 588 interactions involving 168 chemicals, the majority of which were not previously reported to have antibacterial properties. Fungicides and industrial chemicals showed the largest impact with circa 30% exhibiting anti-commensal properties. We find that the sensitivity to chemical pollutants across species surprisingly correlates with that to human-targeted drugs, suggesting common susceptibility mechanisms. Using a genome-wide chemical-genetic screen, we identified membrane transport and fatty acid metabolism as major modulators of the off-target toxicity of chemicals. Mutants exhibiting chemical resistance include those defective in producing human-health-relevant metabolites like branched short-chain fatty acids, indicating that chronic exposure could lead to selection against production of beneficial metabolites. Toxicokinetic modelling suggested gut bacteria could be used as more sensitive in vitro toxicity indicators for chemicals of concern than animal models. Together, our data uncovers the off-target activity of industrial and agricultural chemicals with widespread exposure against human gut bacteria. Impact on the structure and function of the microbiota should therefore be considered in assessing chemical safety.

microbiology↗