Biology subjects

Russell, S.

Publications and source records attributed to Russell, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Limb-localized induction of regeneration reshapes brain and amputation-site transcriptional states in adult Xenopus laevis

Limb regeneration requires coordinated tissue reconstruction and nervous system reintegration, yet whether regenerative induction alters brain responses to limb loss remains unclear. We analyzed transcriptomics from the paired brains and amputation sites of adult Xenopus laevis after hindlimb amputation with or without a 24 hour exposure to localized, pro-regenerative multi-drug treatment (MDT) delivered through a wearable bioreactor device. At 24 hours post treatment (24 HPT), MDT brains showed increased vascular and basement membrane transcripts and enrichment of oxidative phosphorylation and mTORC1 programs. In the limb, an exploratory integrated stress response (ISR) score increased at 11 and 24 HPT and returned to control levels by 7 days post-treatment (7 DPT), coinciding with induction of growth differentiation factor 15 (GDF15), a cytokine responsive to mitochondrial stress. We detected no corresponding increase in brain ISR score. At 7 DPT, MDT brains showed enrichment of immune, heme metabolism and biosynthetic programs, reduced synaptic transmission gene expression, and increased gdf15.L. Relative to an external uninjured reference, MDT and amputation only brains showed concordant changes, with treatment modifying selected programs. Cross-species comparative analyses identified partial overlap with an axolotl regenerative glutamatergic signature and separation from selected mammalian injury profiles. These findings reveal cross-tissue responses to regenerative induction and identify candidate mechanisms of brain body communication in biomedically engineered vertebrate limb regeneration.

neuroscience↗

bioRxiv2026

Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.

Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.

cancer biology↗

bioRxiv2026

Ultra-accurate sequencing reveals an extreme transmission bottleneck in a deep-sea clam symbiosis

Vertically transmitted symbionts experience progressive genome degradation driven by transmission bottlenecks each host generation that reduce genetic diversity and promote fixation of deleterious mutations. Direct estimates remain rare because inference requires scarce parent-offspring samples and sequencing sensitive enough to detect rare variants. Here, we investigate symbiont transmission bottlenecks in a vesicomyid clam by deeply sampling within-host endosymbiont genetic diversity using two ultra-accurate sequencing methods. Demographic modeling revealed an effective bottleneck size of approximately eight symbionts (95% CI: 1-17 genomes) per host generation. This estimate is sharply reduced relative to prior cytological estimates of bottleneck census size, with important implications for understanding the rate and dynamics of endosymbiont genome degradation.

genomics↗

bioRxiv2026

EMS Mutation and SNP Detection in Intracellular Wolbachia Genomes

Endosymbiotic bacteria such as Wolbachia pose significant challenges to genetic and molecular investigation due to their obligate intracellular lifestyle and complex growth requirements.Current understanding of their protein biology relies heavily on functional assignments inferred by homology, which may not reflect the specific roles endosymbiont proteins play within the host. This work addresses the need for robust genetic perturbation by demonstrating the successful application and detection of chemical mutagenesis in the genome of the wMel strain of Wolbachia grown within a stably infected Drosophila melanogaster JW18 cell line. To accurately detect EMS-induced mutations in a large, unsorted cell culture population, in which mutations remain at very low allele frequency, we implemented an ultra-low error rate sequencing strategy, circle sequencing. This technique enables confident detection of EMS-induced single nucleotide polymorphisms (SNPs) that would be swamped by the inherent error rates of standard next-generation sequencing. Circle sequencing library preparations successfully revealed a clear EMS mutation signal in treated cells, characterized by a significant enrichment of canonical C/G>T/A transitions. Furthermore we present a model explaining observed EMS mutation rates across the genome for different sequence contexts. These findings show that EMS-treatment can successfully leave detectable mutation signals in intracellular genomes, and offer promise for the future development of protocols to make targeted edits in Wolbachia genomes. ImportanceAs the use of intracellular symbionts for bioengineering projects grows, so does the need for foundational protocols for the genetic manipulation of intracellular genomes. Ethyl methanesulfonate (EMS), a chemical mutagen, has been a research tool for initial genomic analysis of gene function in plant and animal systems for decades and represents an established way of generating mutations for future functional testing.

genomics↗

bioRxiv2025

Wolbachia induces host cell identity changes and determines symbiotic fate in Drosophila

Host-associated bacteria influence eukaryotic cellular differentiation, but the underlying mechanisms are difficult to disentangle because of cell-type-specific tropisms and phenotypes. The association between Wolbachia pipientis and Drosophila melanogaster offers a tractable system for gaining high-resolution insight into how host and microbe gene expression interact. Using Wolbachia-infected D. melanogaster cell lines, we show that the native wMel strain alters host phenotypic, transcriptomic, and chromatin conformation states. High-throughput imaging reveals that wMel infection differentially alters host cellular phenotypes in a titer-independent manner in some cell lines. These phenotypically altered host cells exhibit differential gene expression complementary to the expression patterns observed in their wMel symbionts. Infection was also negatively associated with chromatin organization and histone modification pathways, prompting us to investigate differences in chromatin conformation between infection states. Micro-C chromatin contact data reveal that wMel infection conferred increased D. melanogaster chromatin contacts coinciding with both increased compartmentalization and derepression. The X chromosome exhibited evidence consistent with altered dosage compensation, with no downstream alteration of the X:autosome transcript ratio or X-linked histone acetylation, consistent with a dosage compensation-mediated male-killing mechanism encoded by wMel that has been suppressed in D. melanogaster. Overall, these findings suggest that the character of Wolbachia symbiosis, cooperative or antagonistic, emerges in response to the host cellular environment. Furthermore, these results demonstrate that in vitro cell lines offer promising avenues for uncovering the functional genetic basis of microbe-induced host phenotypes.

cell biology↗

bioRxiv2025

Refining the resistance-to-damage (RD) score to predict operational Insecticide-Treated Net lifespan and identify paths to innovation

BackgroundInsecticide Treated Nets (ITNs) vary greatly in their physical characteristics yet the relationship with field durability remains poorly understood. To address this, we refined the existing resistance-to-damage (RD) metric for greater predictive power in estimating operational lifespan and to identify key avenues of innovation. MethodsThe original resistance-to-damage (oRD) score was calculated by comparing four physical attributes; snag strength, bursting strength, hole enlargement resistance and abrasion resistance; against aspirational values previously determined to provide resistance to routine damage. Here, the weighting of each is improved to provide a better prediction of field life, resulting in a weighted resistance-to-damage (wRD) score. Durability data from 37 field sites (across 14 countries) involving 10,000 campaign ITNs was used to quantify the relationship between physical characteristics and field life. Bivariable linear regression models were used to assess the correlation between RD scores and ITN survival time. A Cox regression survival analysis was applied to examine the impact of the RD score on physical survival, adjusting for net care and environment variables (Risk Index), evaluating the risk of ITN failure from the time they were first hung. ResultsThe bivariate analysis, not adjusting for differences between sites, shows that the wRD was a better predictor for net lifespan than oRD (wRD r2= 0.07 oRD r2= 0.01). In the multivariate analysis, adjusting for risk index, the wRD model was able to explain more than 70% of variability in net survival (wRD r2 = 0.74). Consequently, when comparing nets with different wRD scores in the same site, a 10-point increase in wRD score was associated with a 3.9-month gain in median survival (p=0.016). Increasing wRD from 35 to 70, the range of current products, increases median field life by 13.65 months (95% CI: 3.03-24.16). An ITN product with an wRD score of 68 is associated with a median lifespan of 2.7 years. The increase in predictive power of the wRD score came primarily from increasing the weighting of the hole enlargement resistance variable, which is a strong differentiator between ITN products. In contrast, abrasion-resistance was a negligible contributor to predictive power. DiscussionThe wRD score more accurately predicts ITN survival in the field than the oRD score. These findings highlight that resistance to hole enlargement is the primary differentiating factor in predicting field life, with some products performing far better than others. Snag and bursting strength remain essential characteristics yet are similarly low compared to aspirational values across available ITN products. All ITNs WHO prequalified in 2020 perform poorly on snag strength, indicating this as a core bottleneck in achieving longer operational ITN lifespan. Consequently, resistance to snagging and hole enlargement should be keys targets for future innovation to enhance the physical durability of ITNs.

ecology↗

bioRxiv2024

Horizontal transmission of functionally diverse transposons is a major source of new introns

Specialized transposable elements (TEs), introners, are one of the major drivers of intron gain in diverse eukaryotes. However, the molecular mechanism(s) and evolutionary processes driving introner propagation within and between lineages remain elusive. We analyze 8716 genomes, revealing 1093 introner families in 201 species spanning 1.7 billion years of evolution. Introners are derived from functionally diverse TEs including families of terminal-inverted-repeat DNA TEs, retrotransposons, cryptons, and helitrons as well as mobile elements with unknown molecular mechanisms. We identify eight cases where introners recently transferred between divergent host species, and show that giant viruses that integrate into genomes may facilitate introner transfer across lineages. We propose that intron gain is an inevitable consequence of TE activity in eukaryotic lineages, thereby resolving a key mystery of genome structure evolution.

genomics↗

bioRxiv2024

A Structural Proteome Screen Identifies Protein Mimicry in Host-Microbe Systems

Host-microbe systems are evolutionary niches that produce coevolved biological interactions and are a key component of global health. However, these systems have historically been a difficult field of biological research due to their experimental intractability. Impactful advances in global health will be obtained by leveraging in silico screens to identify genes involved in mediating interspecific interactions. These predictions will progress our understanding of these systems and lay the groundwork for future in vitro and in vivo experiments and bioengineering projects. A driver of host-manipulation and intracellular survival utilized by host-associated microbes is molecular mimicry, a critical mechanism that can occur at any level from DNA to protein structures. We applied protein structure prediction and alignment tools to explore host-associated bacterial structural proteomes for examples of protein structure mimicry. By leveraging the Legionella pneumophila proteome and its many known structural mimics, we developed and validated a screen that can be applied to virtually any host-microbe system to uncover signals of protein mimicry. These mimics represent candidate proteins that mediate host interactions in microbial proteomes. We successfully applied this screen to other microbes with demonstrated effects on global health, Helicobacter pylori and Wolbachia, identifying protein mimic candidates in each proteome. We discuss the roles these candidates may play in important Wolbachia-induced phenotypes and show that Wobachia infection can partially rescue the loss of one of these factors. This work demonstrates how a genome-wide screen for candidates of host-manipulation and intracellular survival offers an opportunity to identify functionally important genes in host-microbe systems.

bioinformatics↗

bioRxiv2023

A beneficial synonymous substitution in EF-Tu is contingent on genetic background

Synonymous mutations are changes to DNA sequence that occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation Elongation Factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels, as well as the polysome abundance on global transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes. ImportanceThis study explores the degree to which synonymous mutations in essential genes can influence adaptation in bacteria. An experimental system whereby an Escherichia coli strain harboring an engineered translation protein Elongation Factor-Tu (EF-Tu) was subjected to laboratory evolution. We find that a synonymous mutation acquired on the gene encoding for EF-Tu is conditionally beneficial for bacterial fitness. Our findings provide insight into the importance of the genetic background when a synonymous substitution is favored by natural selection and how such changes have the potential to impact evolution when critical cellular processes are involved.

evolutionary biology↗

bioRxiv2022

Host mixotrophy, habitat stability and recombination may all decrease geographic differentiation between symbiont populations in Western Pacific deep-sea mussels

The intra-host composition of horizontally transmitted microbial symbionts can vary across host populations due to interactive effects of host genetics, environmental and geographic factors. While adaptation to local habitat conditions can drive geographic subdivision of symbiont strains, it is unknown whether these patterns are universal and how differences in ecological characteristics among host-symbiont associations influence the genomic structure of symbiont populations. To address this question, we sequenced metagenomes of different populations of the deep-sea mussel Bathymodiolus septemdierum, which are common at Western Pacific deep-sea hydrothermal vents and show characteristic patterns of niche partitioning with sympatric gastropod symbioses. Bathymodiolus septemdierum lives in close symbiotic relationship with sulfur-oxidizing chemosynthetic bacteria but supplements its symbiotrophic diet through filter-feeding, enabling it to occupy ecological niches with less exposure to geochemical reductants. Our analyses indicate that symbiont populations associated with B. septemdierum show structuring by geographic location, but that the dominant symbiont strain is uncorrelated with vent site. These patterns are in contrast to co-occurring Alviniconcha and Ifremeria symbioses that exhibit greater symbiont nutritional dependence and occupy habitats with higher spatial variability in environmental conditions. Our results suggest that relative habitat homogeneity combined with sufficient symbiont dispersal and genomic mixing might promote persistence of similar symbiont strains across geographic locations, while mixotrophy might decrease selective pressures on the host to affiliate with locally adapted symbiont strains. Overall, these data contribute to our understanding of the potential mechanisms influencing symbiont population structure across a spectrum of marine microbial symbioses that vary in ecological niche and relative host dependency.

evolutionary biology↗

bioRxiv2022

Isolation and Transfection of Rice Egg Cells and Zygotes for Cellular Localization

Due to the difficulty in accessing to gametes and zygotes in flowering plants, which are controlled in single cells deeply embedded in multiple tissues, little is known about how the initiation of plant embryogenesis may reflect or contrast from such systems in other eukaryotes. In this study we has developed an approach of isolation and transfection of rice egg cells and zygotes for cellular localization of rice cell cycle factors (KRP5, KRP4 and FB3), which opened a pathway to monitor protein expression in rice egg cells and zygotes at different developmental stages. The advantageous feature of isolated rice cells may serve as an ideal system for studying the molecular mechanism underlying the rice zygotic division to initiate seed formation.

cell biology↗

bioRxiv2022

In depth exploration of the alternative proteome of Drosophila melanogaster

Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.

biochemistry↗

bioRxiv2021

Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition

During T cell development, the first step in creating a unique T Cell Receptor (TCR) is the genetic recombination of the TCR{beta} chain. The quality of the newly recombined TCR{beta} is assessed at the {beta}-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of the complex events that control fate at the {beta}-selection checkpoint is not yet understood. We shed new light on fate determination during {beta}-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the {beta}-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in {beta}-selection, bookended by upregulation of the TCR co-receptors, CD28 and CD2 respectively. Within this DN3bPre stage, CD5 and Lef1 are upregulated to reflect pre-TCR signalling and their expression correlates with proliferation. During this phase, ACY1215-mediated disruption of the organisation of the {beta}-selection immunological synapse is associated with a breakdown in connectivity of expression of pre-TCR, CD5 and Lef1. Subsequent deregulation of pre-TCR-induced proliferation leads to bypass of the {beta}-selection checkpoint and subsequent failure to progress. We propose that the progressive expression of CD28, CD5 and Lef1, then CD2 reports and modulates the pre-TCR signal to orchestrate passage through the {beta}-selection checkpoint. These findings suggest a refined model of {beta}-selection in which a coordinated increase in expression of pre-TCR, CD28, CD5 and Lef1 allows for modulating TCR signalling strength, and culminates in the expression of CD2 to enable exit from the {beta}-selection checkpoint.

developmental biology↗

bioRxiv2021

Proton export drives the Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect". It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

cancer biology↗

bioRxiv2021

Drosophila nicotinic acetylcholine receptor subunits and their native interactions with insecticidal peptide toxins

Drosophila nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that represent a target for insecticides. Peptide neurotoxins are known to block nAChRs by binding to their target subunits, however, a better understanding of receptor subunit composition is needed for effective design of insecticides. To facilitate the analysis of nAChRs we used a CRISPR/Cas9 strategy to generate null alleles for all ten nAChR subunit genes in a common genetic background. We studied interactions of nAChR subunits with peptide neurotoxins by larval injections and styrene maleic acid lipid particles (SMALPs) pull-down assays. For the null alleles we determined the effects of -Bungarotoxin (-Btx) and {omega}-Hexatoxin-Hv1a (Hv1a) administration, identifying potential receptor subunits implicated in the binding of these toxins. We employed pull-down assays to confirm -Btx interactions with the D5, D6, D7 subunits. Finally, we report the localization of fluorescent tagged endogenous D6 during nervous system development. Taken together this study elucidates native Drosophila nAChR subunit interactions with insecticidal peptide toxins and provides a resource for the in vivo analysis of insect nAChRs.

neuroscience↗

bioRxiv2021

Host-symbiont population genomics provide insights into partner fidelity, transmission mode and habitat adaptation in deep-sea hydrothermal vent snails

Symbiont specificity, both at the phylotype and strain level, can have profound consequences for host ecology and evolution. However, except for insights from a few model symbiosis systems, the degree of partner fidelity and the influence of host versus environmental factors on symbiont composition are still poorly understood. Nutritional symbioses between invertebrate animals and chemosynthetic bacteria at deep-sea hydrothermal vents are examples of relatively selective associations, where hosts affiliate only with particular, environmentally acquired phylotypes of gammaproteobacterial or campylobacterial symbionts. In hydrothermal vent snails of the sister genera Alviniconcha and Ifremeria this phylotype specificity has been shown to play a role in habitat distribution and partitioning among different holobiont species. However, it is currently unknown if fidelity goes beyond species level associations that might influence genetic structuring, connectivity and habitat adaptation of holobiont populations. We used metagenomic analyses to assess sequence variation in hosts and symbionts and identify correlations with geographic and environmental factors. Our analyses indicate that host populations are not differentiated across a ~800 km gradient, while symbiont populations are clearly structured between vent locations due to a combination of neutral and selective processes. Overall, these results suggest that host individuals flexibly associate with locally adapted strains of their specific symbiont phylotypes, which supports a long-standing but untested paradigm of the benefits of horizontal transmission. Strain flexibility in these snails likely enables host populations to exploit a range of habitat conditions, which might favor wide-spread genetic connectivity and ecological resilience unless physical dispersal barriers are present. Significance StatementSymbiont composition in horizontally transmitted symbioses is influenced by a combination of host genetics, environmental conditions and geographic barriers. Yet the relative importance of these factors and the effects of adaptive versus neutral evolutionary forces on symbiont population structure remain unknown in the majority of marine symbioses. To address these questions, we applied population genomic approaches in four species of deep-sea hydrothermal vent snails that live in obligate association with chemosynthetic bacteria. Our analyses show that host genetics plays a minor role compared to environment for symbiont strain composition despite specificity to symbiont species and corroborate a long-standing hypothesis that vent invertebrates affiliate with locally adapted symbiont strains to cope with the variable habitat conditions characterizing hydrothermal vents.

molecular biology↗

bioRxiv2021

Klarigi: Explanations for Semantic Groupings

BackgroundAnnotation of biomedical entities with ontology classes provides for formal semantic analysis and mobilisation of background knowledge in determining their relationships. To date enrichment analysis has been routinely employed to identify classes that are over-represented in annotations across sets of groups, such as biosample gene expression profiles or patient phenotypes. These approaches, however, usually consider only univariate relationships, make limited use of the semantic features of ontologies, and provide limited information and evaluation of the explanatory power of both singular and grouped candidate classes. Moreover, they do not solve the problem of deriving cohesive, characteristic, and discriminatory sets of classes for entity groups. ResultsWe have developed a new method, Klarigi, which introduces multiple scoring heuristics for identification of classes that are both compositional and discriminatory for groups of entities annotated with ontology classes. The tool includes a novel algorithm for derivation of multivariable semantic explanations for entity groups, makes use of semantic inference through live use of an ontology reasoner, and includes a classification method for identifying the discriminatory power of candidate sets. We describe the design and implementation of Klarigi, and evaluate its use in two test cases, comparing and contrasting methods and results with literature and enrichment analysis methods. ConclusionsWe demonstrate that Klarigi produces characteristic and discriminatory explanations for groups of biomedical entities in two settings. We also show that these explanations recapitulate and extend the knowledge held in existing biomedical databases and literature for several diseases. We conclude that Klarigi provides a distinct and valuable perspective on biomedical datasets when compared with traditional enrichment methods, and therefore constitutes a new method by which biomedical datasets can be explored, contributing to improved insight into semantic data.

bioinformatics↗

bioRxiv2021

A Scribble-E-cadherin complex controls daughter cell patterning by multiple mechanisms

The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate patterning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble, links E-cadherin to NuMA and Arp2/3 signalling for sequential roles in daughter positioning. First Scribble transmits cues from E-cadherin localised in retraction fibres to control orientation of the mitotic spindle. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction, generation of filopodia and subsequent cell patterning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division.

cell biology↗