Biology subjects

Cook, S.

Publications and source records attributed to Cook, S..

At least 19 recordsLinked to original sources

bioRxiv2026

EASI-PASS: An accessible pipeline for linking functional imaging and mRNA profiling

We developed EASI-PASS, a reliable, high-throughput method for estimating the molecular identity of functionally characterized cells by merging live imaging with subsequent fixed-tissue imaging using conventional microscopes. Our method matches the shapes and locations of thousands of densely imaged cells between large (>1 mm2) functional images and a thick, expanded, and cleared EASI-FISH tissue volume to assess gene expression. This approach is more efficient than alignment to thin sections and recovers the molecular identity of ~78% of cells. In acute brain slice imaging from the mouse parabrachial nucleus during optogenetic stimulation of long-range spinal inputs, we observed fine-scale specificity in the molecular identity of spinorecipient neurons. In the awake mouse visual cortex, we observed distinct arousal modulation and spatial falloff in correlations within and across interneuron classes. Thus, EASI-PASS provides reliable and efficient alignment of cellular activity with molecular identity.

neuroscience↗

bioRxiv2025

Insights from U.S. beekeeper triage surveys following unusually high honey bee colony losses 2024-2025

In January of 2025, U.S. commercial beekeepers reported unusually high honey bee colony losses as they prepared colonies for almond pollination. Two industry groups launched nationwide surveys to document colony losses between June 2024 and March 2025 across all scales of beekeeping. This study analyzes these survey data to assess colony losses, estimate financial impacts, and identify correlations with beekeeper management practices and geographical locations. Unlike past surveys, commercial beekeepers experienced more severe losses than smaller-scale beekeepers during this period. Respondents, managing over half of U.S. colonies, most frequently cited Varroa mites as the cause for their losses. Varroa mites were followed by pesticides and pathogens in the case of commercial beekeepers and by queen failure and weather in the case of smaller-scale beekeepers. Although Varroa was the most frequently cited cause, losses did not significantly differ between users and non-users of amitraz, suggesting that rising amitraz resistance alone does not explain observed trends. Differences in protein and carbohydrate feeding frequencies also played a role in net losses. While colony loss rates and financial concern varied widely among respondents, commercial beekeepers understandably showed higher sensitivity to financial impacts, with concerns increasing linearly with loss severity. This study highlights the value of beekeeper surveys which, alongside direct analyses of bee samples and longitudinal studies, help identify effective management strategies and environmental risks. Such insights are crucial for addressing the leading causes of colony losses on a national scale, and ultimately aid in safeguarding honey bee health, pollination services, and agricultural production. HighlightsO_LIUnprecedented honey bee colony losses C_LIO_LIIndications of disease stress C_LIO_LIHigh economic pain for commercial beekeepers and growers C_LI

ecology↗

bioRxiv2024

A diffusion model conditioned on compound bioactivity profiles for predicting high-content images

High-content imaging (HCI) provides a rich snapshot of compound-induced phenotypic outcomes that augment our understanding of compound mechanisms in cellular systems. Generative imaging models for HCI provide a route towards anticipating the phenotypic outcomes of chemical perturbations in silico at unprecedented scale and speed. Here, we developed Profile-Diffusion (pDIFF), a generative method leveraging a latent diffusion model conditioned on in silico bioactivity profiles to predict high-content images displaying the cellular outcomes induced by compound treatment. We trained and evaluated a pDIFF model using high-content images from a Cell Painting assay profiling 3750 molecules with corresponding in silico bioactivity profiles. Using a realistic held-out set, we demonstrate that pDIFF provides improved predictions of phenotypic responses of compounds with low chemical similarity to compounds in the training set compared to generative models trained on chemical fingerprints only. In a virtual hit expansion scenario, pDIFF yielded significantly improved expansion outcomes, thus showcasing the potential of the methodology to speed up and improve the search for novel phenotypically active molecules.

bioinformatics↗

bioRxiv2024

Comparing efficiencies of population control methods for responding to foreign animal disease threats in wild pigs

Introductions of foreign animal diseases (FADs) into free-ranging wildlife can be difficult to control and devastating for domestic livestock trade. Combating a new FAD introduction in wildlife with an emergency response requires quickly limiting spread of the disease by intensely removing wild animals and recovering their carcasses for proper disposal. In the case of African swine fever virus (ASFv) in wild pigs (Sus scrofa), which has been spreading in many regions of the world, there is little information on the time- and cost-efficiency of methods for intensively and consistently removing wild pigs and recovering carcasses in an emergency response scenario. We compared the efficiencies of aerial operations, trapping, an experimental toxic bait, and ground shooting in northcentral Texas, USA during two months in 2023. Removing and recovering carcasses of wild pigs averaged a rate of 0.15 wild pigs/person hour and cost an average of $233.04/wild pig ($USD 2023) across all four methods. Aerial operations required the greatest initial investment but subsequently was the most time- and cost-efficient, costing an average of $7,266 to incrementally reduce the population by 10% including recovering carcasses. Aerial operations required a ground crew of [~]7 people/helicopter to recover carcasses. Costs for reducing the population of wild pigs using trapping were similar, although took 13.5 times longer to accomplish. A benefit of trapping was carcass recovery was incorporated. Toxic baiting was less efficient because carcass recovery required substantial time, and we removed very few wild pigs with ground shooting in this landscape. We recommend combining aerial and trapping methodologies to remove wild pigs and their carcasses efficiently and effectively during a FAD response. Overall, our findings can inform the preparation of resources, personnel needs, and deployment readiness for FAD responses involving wild pigs.

ecology↗

bioRxiv2024

Operational lessons learned from simulating an elimination response to a transboundary animal disease in wild animals

Transboundary animal disease (TAD) introductions can have myriad economic, ecological, and societal impacts. When TADs are introduced into wild species, rapid and intense control efforts to reduce wild animal host populations are sometimes needed to eliminate the disease and prevent endemicity and spillover to domestic animal populations. Yet, such intensive efforts are non-trivial, and the rarity of TAD introductions means that personnel rarely have direct experience with these types of operations. Thus, explicit assessments of operational challenges for these kinds of efforts can provide direction to build emergency response preparedness capacity. Here, we simulated a TAD control effort in response to initial detection of a hypothetical index case of a TAD in wild pigs (Sus scrofa) (e.g., African swine fever; ASF). We used three removal methods (aerial control, trapping, and an experimental toxic bait). Then, we conducted an after-action assessment to identify operational challenges for rapidly reducing a population of invasive wild pigs within a simulated outbreak zone. We also simulated carcass recoveries of dispatched pigs, similar to what might be conducted during a response to a TAD with carcass-based transmission (e.g., ASF virus). Here, we describe operational challenges identified during our effort, alongside technological development solutions and a priori strategy needs to improve TAD response operation outcomes.

ecology↗

bioRxiv2024

TNFR2 loss leads to decreased TOX expression in T cells without affecting TIM3 and improves responses to tumor and chronic LCMV

Exhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX and expression of TIM3. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. We reveal here that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Meanwhile, knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models.

immunology↗

bioRxiv2024

Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii (arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1{beta} release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1{beta} from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.

physiology↗

bioRxiv2023

Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentivira transduction

Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2 driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence.

cell biology↗

bioRxiv2023

Fibroblast-derived IL-11 is a driver and therapeutic target in Peutz-Jeghers syndrome polyposis

Peutz-Jeghers syndrome (PJS) is associated with early-onset and recurring gastrointestinal hamartomatous polyposis caused by hereditary inactivating mutations in the tumor suppressor gene LKB1 (STK11). Due to lack of efficient prophylactic therapies PJS patients require regular surgical interventions and have an increased risk of cancer. LKB1-deficient fibroblasts have been identified as drivers of polyposis, but a safely druggable target remains to be identified. Here we investigate tumorigenic mechanisms in PJS polyps using single-cell RNA sequencing of predisposed and tumor tissue and identified a ST2-expressing crypt top fibroblast (CTF) cluster enriched in polyps. The relevance of CTFs was supported by the fast polyposis following deletion of Lkb1 in CTFs. The transcriptional signature characterizing the ST2+ fibroblasts (ST2-CTFs) was enriched in inflammation-associated fibroblasts, and PJS polyposis was exacerbated by inflammation. Cell-cell communication analysis identified the ST2-CTF signature gene interleukin 11 (IL-11) as an upstream regulator of the ST2-CTFs, and consistently, reprogramming toward ST2 fibroblasts in vitro was dependent on IL-11. Importantly, a neutralizing IL-11 antibody efficiently reduced the tumor burden in a PJS mouse model. In summary, our results reveal ST2+ tumorigenic fibroblasts as drivers of PJS polyposis and identify IL-11 as the key mediator and a potential therapeutic target in PJS.

cancer biology↗

bioRxiv2023

What is Known, Unknown, and Needed to be Known about Damage Caused by Wild Pigs

Damage assessments provide evidence for initiating and evaluating management programs that protect natural resources and human livelihoods against invasive species. Wild pigs (Sus scrofa) cause extensive damage in their native and non-native ranges, but the extent of current damage and efficacy of management of the damage (i.e., population control of wild pigs, exclusion fencing, etc.) remains poorly described. We conducted a systematic review of physical damage caused by wild pigs to summarize what is known and identify knowledge gaps for damage assessment. Wild pig damage assessments have been overwhelmingly qualitative (84% of studies) and measured differently across studies, which prevents the determination of typical damage amounts to a particular resource and comparison across studies. Key priorities going forward are to standardize damage assessments quantitatively and measure population density (or index of such) of wild pigs concurrently with damage assessments to determine the relationship between damage and population levels. We provide a framework for inferring damage in new areas and assessing the benefits of management - to evaluate and optimize landscape-scale management programs. Overall, we recommend future studies strive for: 1) report the amount of damages in a standardized fashion (e.g., area damaged/area surveyed), 2) evaluate and report the amount of damage relative to the density of wild pigs, and 3) when reporting economic costs of damages incurred and management actions, describe the economic valuation method used along with the year of reference for the valuation. Capturing these elements are necessary steps to predict the benefits of management for an area with particular profile of resources and wild pig density, even in areas where damage assessments are not available. Meeting these criteria with allow for more generalizable results that can inform managers across the nearly global distribution of wild pigs

ecology↗

bioRxiv2023

Generation of Super-resolution Images from Barcode-based Spatial Transcriptomics Using Deep Image Prior

Spatial transcriptomics (ST) has revolutionized the field of biology by providing a powerful tool for analyzing gene expression in situ. However, current ST methods, particularly barcode-based methods, have limitations in reconstructing high-resolution images from barcodes sparsely distributed in slides. Here, we present SuperST, a novel algorithm that enables the reconstruction of dense matrices from low-resolution ST libraries. SuperST based on deep image prior reconstructs spatial gene expression patterns as image matrices. SuperST allows gene expression mapping to better reflect immunofluorescence (IF) images. Compared with previous methods, SuperST generated output images that more closely resembled IF images for given gene expression maps. Additionally, SuperST overcomes the limitations inherent in IF images, highlighting its potential applications in the realm of spatial biology. By providing a more detailed understanding of gene expression in situ, SuperST has the potential to contribute to comprehensively understanding biology from various tissues.

bioinformatics↗

bioRxiv2023

IAMSAM : Image-based Analysis of Molecular signatures using the Segment-Anything Model

Spatial transcriptomics is a cutting-edge technique that combines gene expression data with spatial information, allowing researchers to study gene expression patterns within tissue architecture. Here, we present IAMSAM, a user-friendly web-based tool for analyzing spatial transcriptomics data focusing on morphological features. IAMSAM accurately segments tissue images using the Segment-anything model, allowing for the semi-automatic selection of regions of interest based on morphological signatures. Furthermore, IAMSAM provides downstream analysis, such as identifying differentially expressed genes, enrichment analysis, and cell type prediction within the selected regions. With its simple interface, IAMSAM empowers researchers to explore and interpret heterogeneous tissues in a streamlined manner.

bioinformatics↗

bioRxiv2023

Temperature and food chain length, but not latitude, explain region-specific kelp forest responses to an unprecedented heatwave

Kelp forests are among the most abundant coastal marine habitats but are vulnerable to the impacts of climate change. Between 2014 and 2016, an unprecedented heatwave and associated changes in trophic dynamics threatened kelp forests across the Northeast Pacific, with impacts documented from Mexico to Alaska. However, responses have varied substantially and remain poorly characterized across large stretches of coast, especially British Columbia (B.C.), which represents a significant percentage of the range of floating kelp species in the Northeast Pacific. Here, we explore variation in floating kelp (Macrocystis, Nereocystis) persistence pre- and post-heatwave across a >675 km latitudinal gradient, asking whether B.C. kelp forests are of conservation concern. We assembled and analyzed available quantitative kelp data, comparing snapshots of kelp extent before (1994 - 2007) and after (2018 - 2021) the heatwave in 11 regions spanning a range of temperature and sea otter-occupancy statuses, and contextualizing these with time series analyses, where available (n = 7 regions). We provide strong evidence that kelp forests have declined in many regions but with evidence of refugia at both local and regional scales. Kelp forest persistence was negatively correlated with summer sea temperatures in southern B.C., where temperatures varied by ~6{degrees}C across sites, at times exceeding species thermal tolerances. Kelp dynamics in northern regions appeared instead to be modulated by top-down control by urchins and sea otters. Our results demonstrate that B.C.s kelp forest have been substantially reduced in recent years but that regional and local-scale factors influence the resilience of forests to large-scale perturbations.

ecology↗

bioRxiv2022

Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate.

Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). The paracrine effects of cell-based treatments of MI might modulate these interactions and impact cardiac repair. The immunomodulatory capacity of the therapeutic cells is therefore of interest and could be modulated by the use of biomaterials. We first showed that bone marrow cells (BMC) associated with fibrin could treat MI. Then, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation. MethodsIn vivo, two weeks post-MI, rats were treated with epicardial implantation of BMC and fibrin or sham-operated. High-resolution echocardiography was performed to evaluate the heart function and structure changes after 4 weeeks. Histology and immunostaining were performed on harvested hearts. In vitro, BMC were first primed with fibrin. Second, non-polarized macrophages were differentiated toward either pro-inflammatory or anti-inflammatory phenotypes and stimulated with the conditioned medium of fibrin-primed BMC (F-BMC). Proteomic, cytokine levels quantification, and RT-PCR were performed. EdU incorporation and real-time cell analysis assessed cell proliferation. ResultsThe epicardial implantation of fibrin and BMC reduced the loss of cardiac function induced by MI, increased wall thickness and prevented the fibrotic scar expansion. After 4 and 12 weeks, the infarct content of CD68+ and CD206+ was similar in control and treated animals. In vitro, we showed that fibrin profoundly influenced the gene expression and the secretome of BMC, simultaneously upregulating both pro- and anti-inflammatory mediators. Furthermore, the conditioned medium from F-BMC significantly increased the proliferation of macrophages in a subsets dependent manner and modulated their gene expression and cytokines secretion. For instance, F-BMC significantly downregulated the expression of Nos2, Il6 and Ccl2/Mcp1 while Arg1, Tgfb and IL10 were upregulated. Interestingly, macrophages educated by F-BMC increased cardiomyoblast proliferation. In conclusion, our study provides evidence that BMC/fibrin-based treatment lowered the infarct extent and improved cardiac function. The macrophage content was unmodified when measured at a chronic stage. Nevertheless, acutely and in vitro, the F-BMC secretome promotes an anti-inflammatory response that stimulates cardiac cell growth. Finally, our study emphases the acute impact of F-BMC educated macrophages on cardiac cell fate.

physiology↗

bioRxiv2021

Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

BackgroundAlcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide with limited treatment options. Interleukin-11 (IL-11) is a pro-fibrotic, pro-inflammatory cytokine with increasingly recognized toxicities in parenchymal and epithelial cells. AimThe aim of this study was to explore the prognostic value of IL-11 serum levels in patients suffering from AH and cirrhosis of various etiology and to understand the role of IL-11 in experimental ALD. MethodsIL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort including 186 patients. Ethanol-fed wildtype mice were treated with a neutralizing murine IL-11 receptor-antibody (anit-IL11RA) and thereafter examined for severity signs and markers of ALD. ResultsHuman IL-11 serum concentration and liver tissue expression increased with severity of liver disease and were most pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 picograms/milliliter was a MELD independent risk factor for transplant-free liver disease survival in patients with compensated and decompensated cirrhosis. Findings were confirmed in an independent cohort. In mice, severity of alcohol-induced liver inflammation was positively correlated to enhanced hepatic IL-11 expression. Pretreatment with a neutralizing anti-IL11RA inhibited hepatic inflammation and mice were protected from ethanol-induced liver injury. In comparison to IgG-control, ethanol-fed mice treated with anti-IL11RA showed decreased steatosis, hepatic neutrophil infiltration, and expression of pro-inflammatory cytokines. ConclusionIL-11 plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signaling might be a therapeutic option in human ALD, particularly AH.

immunology↗

bioRxiv2020

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

BackgroundAccurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. MethodsWe present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets. ResultsCardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant variant classification. ConclusionsWe demonstrate that a disease-specific variant pathogenicity prediction tool outperforms state-of-the-art genome-wide tools for the classification of rare missense variants of uncertain significance for inherited cardiac conditions. To facilitate evaluation of CardioBoost, we provide pre-computed pathogenicity scores for all possible rare missense variants in genes associated with cardiomyopathies and arrhythmias (https://www.cardiodb.org/cardioboost/). Our results also highlight the need to develop and evaluate variant classification tools focused on specific diseases and clinical application contexts. Our proposed model for assessing variants in known disease genes, and the use of application-specific evaluations, is broadly applicable to improve variant interpretation across a wide range of Mendelian diseases.

genetics↗

bioRxiv2020

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

BackgroundFamily history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. MethodsWe analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. ResultsThe frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant (p=0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group. The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. ConclusionOur findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.

genomics↗

bioRxiv2019

Interleukin 11 expression causes murine inflammatory bowel disease

Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohns disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.

pathology↗