Biology subjects

Jones, L.

Publications and source records attributed to Jones, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Structural analysis reveals high-order Nipah Virus Fusion Protein assemblies and interactions with neutralising nanobodies

Nipah virus (NiV) is a highly pathogenic emerging henipavirus for which there are no licensed vaccines or therapeutics currently available. Viral entry is mediated by the coordinated action of the attachment (NiVG) and fusion (NiVF) glycoproteins yet the organisation of NiVF on viral particles and its influence on antibody neutralisation is not completely understood. Using cryo-electron tomography of NiV pseudovirions and virus-like particles (VLPs), we directly observe inter-F contacts on viral membranes. These interactions occur frequently but are distributed stochastically, forming variably sized assemblies rather than ordered arrays, consistent with transient or low-affinity associations. We have generated single domain antibodies (termed nanobodies) to the NiVF glycoprotein that bind to an epitope at the interface between neighbouring NiVF trimers and therefore occlude the inter-NiVF contacts. We show that these nanobodies inhibit VLP cell fusion and neutralise NiV pseudoviruses in vitro, which suggests that the interaction between NiVF trimers is important for NiV virus entry. The identification of the inter-NiVF contacts on viral particles adds a previously unrecognised structural feature to the organisation of the NiV entry machinery which could be targeted to prevent viral infection.

molecular biology↗

bioRxiv2026

Nanobodies against the S2 region of the spike protein potently neutralize SARS-CoV-2 viruses and show resistance to virus escape

Entry of coronaviruses into cells is mediated by the viral spike (S) glycoproteins each consisting of S1 receptor binding and S2 membrane fusion subunits. The sequence of the S2 region is very highly conserved amongst variants of SARS-CoV-2 and compared to the S1 unit shares significant sequence identity amongst different beta-coronavirus lineages. By targeting the S2 of SARS-CoV-2 we have identified two selective and potent neutralizing nanobodies (BA.1-C2 and BA.1-D3) that bind to two different quaternary epitopes in the S2 formed by the Heptad Repeat 2 (HR2) trimer at the base of the spike protein. The HR2 sequence is identical in SARS-CoV and SARS-CoV-2 but differs in other beta-coronaviruses explaining the lack of binding to the spike proteins of MERS-CoV or HuCoV-OC43. No viral escape was observed following serial passaging of SARS-CoV-2 (JN.1) with a combination of BA.1-C2 and BA.1-D3 and the most potent of these nanobodies reduced viral load in the hamster model of COVID-19, following intranasal administration. Overall, the results show the value of nanobody technology for identifying novel neutralising epitopes in the S2 region of beta-coronaviruses with potential for the development of new selective anti-viral agents.

molecular biology↗

bioRxiv2025

Linking protein residues in literature and structure

Protein structures are crucial in understanding function, mechanism and disease-causing variants of proteins within any living cell. A number of experimental techniques are employed by researchers to determine said structure. Through structure inspection in molecular viewers combined with supporting biochemical and biophysical experiments, scientists are able to identify a proteins function, reaction mechanism and effects caused by sequence variation. These detailed findings supported by experimental results are documented and described in detail in scientific literature and by open sourcing the accompanying data. By writing a detailed report about the findings and providing evidence in additional files and complementary data formats it has become increasingly difficult for a reader, in particular a non-expert, to access the correct additional information and assess the validity of the drawn conclusion based on experimental results. It often requires a reader to resort to a number of different software packages to access the different data types. Here, we present a first-of-its-kind implementation of an artificial intelligence and text mining supported software tool that allows linking of text mentions of specific protein residues to their corresponding counterpart in the respective protein structure. An identified residue is highlighted in the publication text and upon interaction with the annotation, a molecule viewer displays the associated protein structures in the publication which contain said residue. The viewer is complemented by a display table that contains protein structure quality metrics for each occurrence of a residue. As such a reader can now explore a residue of interest they are currently assessing in a publication within its respective protein structure supported by its experimental evidence in a single view and application.

bioinformatics↗

bioRxiv2025

Liquid Lung Rest During Extracorporeal Life Support in a Porcine Model of Acute Lung Injury

RationaleIn patients with severe lung injury, extracorporeal life support can enable lung rest, but the optimal strategy is unknown. ObjectiveTo compare liquid lung rest versus standard gas rest ventilation in a porcine model of acute lung injury and extracorporeal life support. MethodsTwenty neonatal pigs with lung injury after systemic injection of oleic acid were placed on extracorporeal life support. Pigs were ventilated with standard rest settings (peak inspiratory pressure: 20 cmH2O; end expiratory pressure: 10 cmH2O; rate: 10 breaths/minute) and randomized to receive no additional therapy (gas ventilation) or 5 mL/kg perfluorooctylbromide instilled endotracheally (liquid lung rest). The study continued for 4 hours with hourly pulmonary compliance measurements. After euthanasia, lung samples were taken for histologic analysis. Inflammation was quantified via blood and lung tissue cytokines. Measurements and Main ResultsAll pigs achieved significant lung injury; static compliance decreased by a mean of 54%. After 4 hours of lung rest, static compliance was higher with liquid lung rest compared to gas ventilation (0.88{+/-}0.05 mL/kg/cmH2O versus 0.57{+/-}0.05, p<0.001). Histology revealed 2.1-fold greater airspace in dependent lung regions with liquid lung rest (p<0.001) and a reduced airspace heterogeneity index (LLR: 0.071{+/-}0.004, gas: 0.095{+/-}0.010, p=0.04), suggesting more uniform alveolar recruitment. Cytokine analysis demonstrated a 3.7-fold decrease in tissue interleukin-10 levels with liquid lung rest (p=0.02). ConclusionsLiquid lung rest improved pulmonary compliance, achieved better alveolar recruitment, and decreased tissue interleukin-10 levels compared to standard gas ventilation. This strategy may enhance lung recovery in acute lung injury requiring extracorporeal life support.

physiology↗

bioRxiv2025

Diverse epigenomic mechanisms underpin transcriptional dysregulation in Polycomb-altered acute myeloid leukemia

BackgroundPolycomb Repressive Complex 2 (PRC2) modulates chromatin accessibility and architecture to direct tissue-specific gene expression. PRC2 function is frequently altered in cancer by loss-of-function mutation or deletion, but the downstream effects on transcriptional regulation are incompletely understood. ResultsTo gain insights into these mechanisms, we performed a holistic analysis of epigenomic and transcriptional changes in an isogenic model of acute myeloid leukemia (AML) with heterozygous EZH2 deletion that mimics reduced PRC2 function in patient leukemias. PRC2-depleted cells had diverse gene expression changes, including a bias towards more immature monocyte-lineage transcriptional signatures. PRC2 depletion also correlated with marked increases in chromatin accessibility genome-wide, with 10-45% increases in ATAC-seq peaks in EZH2+/- clones. These changes were accompanied by decreased H3K27me3 and increased H3K27ac levels in CUT+RUN assays that were incompletely linked to transcriptional activity. Despite these generalised changes, 3D chromatin architecture assessed by Hi-C was largely maintained, with H3K27me3 preferentially lost in regions with low DNA-DNA contact frequency. Surprisingly, some regions gained broad H3K27me3 domains at heavily compacted chromatin. We notably saw compartmentalisation changes upstream of the transcriptionally upregulated fetal hematopoiesis gene LIN28B in EZH2+/- cells, with corresponding activation of a LIN28B-specific transcriptional program, including upregulation of the CDK6 oncogene. These results correlated with EZH2+/- cell phenotype, including decreased cellular proliferation and increased resistance to CDK6 inhibitor palbociclib. ConclusionsOur findings suggest that PRC2 depletion pleiotropically affects AML transcriptional regulation to directly impact cell phenotype and treatment responsiveness, which may partially explain the aggressive biology seen in these cases.

cancer biology↗

bioRxiv2025

Development of the preterm infant gut and gastric residuals microbiome

Prematurity, defined as birth before 37 completed weeks of gestation, is the leading cause of mortality in children under five and affects approximately 11% of live births globally--around 15 million infants each year. Despite advances in neonatal care, preterm infants remain at an increased risk for a range of complications. One widely used clinical practice in neonatal intensive care units (NICUs) is the monitoring of gastric residuals (GRs) to assess feeding tolerance and guide enteral nutrition. While the clinical significance of GRs is debated, their microbial composition has not been extensively studied. In this study, we performed metagenomic sequencing of 199 stool and 69 GR samples from 39 preterm infants during hospitalization to characterize their gut and stomach microbiomes. To our knowledge, this is the first study to describe the microbial landscape of GR in preterm infants. We identified 11 distinct GR clusters, often dominated by Staphylococcus, Streptococcus, and Klebsiella, with microbial diversity correlating with GR aspiration frequency. Longitudinal analysis revealed temporal colonization patterns, with early dominance of Staphylococcus epidermidis and Bradyrhizobium, and later emergence of Escherichia coli, Staphylococcus hominis, and Streptococcus thermophilus. In stool samples, 8 microbial clusters were found, frequently enriched with Enterobacteriaceae. Early samples rich in S. epidermidis were associated with higher gestational age and lower microbial richness, while Bifidobacterium breve, a beneficial gut commensal, appeared later in hospitalization. Comparative analysis showed overlap between gut and gastric microbiota, though stomach samples were more dynamic and exhibited less intra-subject similarity. Strain-level resolution revealed both subject-specific (e.g., E. coli, K. pneumoniae) and widely shared (e.g., S. epidermidis) taxa. We also identified a pathogenic Klebsiella aerogenes strain associated with bacteremia with distinct genomic features a week ahead of its first clinical isolation. These findings provide novel insights into the dynamic and niche-specific microbial colonization of preterm infants.

microbiology↗

bioRxiv2025

Active learnings impact on student course performance in STEM varies by type and intensity

We updated a recent meta-analysis of active learnings impact on student achievement in undergraduate STEM courses by following the same protocol to evaluate studies published from 2010-2017. We screened 1659 papers, coded 1294, and found 210 that met five pre-established inclusion criteria and six pre-established criteria for methodological quality. After further dropping 76 studies with no exam scores data, 134 of these studies contained data on student performance on identical or equivalent exams. We found that on average, active learnings effect size on exam scores was 0.519 {+/-} 0.049, meaning that when students are in active learning classes, they perform roughly half a standard deviation higher on an identical exam. Funnel plots and sensitivity analyses indicated that these results were not due to sampling bias. Active learning had a positive impact on student outcomes regardless of class size, course level, or STEM discipline, though there was heterogeneity in the effects. All of these results are very similar when compared to earlier meta-analyses, however increased resolution in the studies analyzed here revealed two novel results. First, student performance was significantly better in courses that employed high-intensity active learning, defined as students being on task at least two-thirds of class time, versus lower-intensities. Additionally, there was significant heterogeneity in efficacy across different types of active learning employed. These results suggest that most, if not all types of active learning are effective, and that when innovating in their classes, instructors should continually work to increase active learning intensity. We urge caution in interpreting the results on active learning types, however, and propose a preliminary framework for making more-sophisticated and reliable analyses of variation in course design. Finally, the evidence presented here for active learnings impact on student outcomes creates a strong foundation for faculty professional development and administration.

scientific communication and education↗

bioRxiv2025

A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia

Mutations activating RAS/RAF/MEK/ERK signaling are associated with poor outcome in acute myeloid leukemia (AML), but therapeutic targeting of this pathway is challenging. Here, we employ a structure-based, dynamic RAS pathway model to successfully predict RAF inhibitor (RAFi) combinations which synergistically suppress ERK signaling in RAS-mutant AML. Our in silico models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I[1/2] + Type II and Type I + Type II. Predictions were validated in vitro in AML cell lines and patient samples, with synergy verified by the Loewe Additivity model. Lifirafenib (Type II) + encorafenib (Type I[1/2]) was highly synergistic against both NRAS- and KRAS-mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to NRAS-mutants. Immunoblotting confirmed that combination efficacy correlated strongly with decreased RAS pathway activation. Leveraging the pharmacokinetic predictions of our in silico model, both combinations were then assessed in a pre-clinical NRAS-mutant AML patient-derived xenograft (PDX) model, showing significantly improved leukaemia growth delay and event-free survival compared with single agent approaches. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations. In summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against in vitro and in vivo models, thereby suggesting alternative potential therapeutic strategies for high-risk RAS-mutant AML.

cancer biology↗

bioRxiv2025

Stress-dependent activation of PQM-1 orchestrates a second-wave proteostasis response for organismal survival

Stress responses are controlled by specialized stress-responsive proteostasis transcription factors that rapidly upregulate protein quality components to re-establish protein homeostasis and safeguard survival. Here we show that the zinc finger transcription factor PQM-1 is crucial for stress survival in response to thermal and oxidative challenges. We provide mechanistic insight into the regulation of PQM-1 during stress that depends on ILS-DAF-16 signaling, as well as phosphorylation on threonine residue 268 that is located within a conserved AKT motif. Our data show that in reproductively mature adults and during well-fed conditions, PQM-1 induction requires DAF-16 and occurs during the recovery period post heat shock. Moreover, PQM-1 co-localizes with DAF-16 in the nucleus during the stress recovery phase. This regulatory dependency on DAF-16 is bypassed under dietary restriction, allowing PQM-1 to promote stress resilience independent of the ILS pathway. During both conditions, PQM-1 is crucial for the upregulation of cytosolic and endoplasmic reticulum stress response genes required for organismal recovery and stress resilience. Our transcriptional and bioinformatic analysis reveals that PQM-1 regulates a distinct set of target genes during the stress recovery phase, suggesting that PQM-1 may be involved in vital secondary wave stress response. Thus, our findings uncover a previously unrecognized mechanism of stress-dependent PQM-1 activation that integrates multiple environmental cues to ensure proteostasis and organismal survival.

genetics↗

bioRxiv2025

PARP inhibitors elicit distinct transcriptional programs in homologous recombination competent castration-resistant prostate cancer

Prostate cancer (PCa) is the second most lethal cancer in men in the United States. African American (AA) men have twice the incidence and death rate from the disease than European American (EA) men. Early-stage PCa is treated with hormone deprivation therapy, although patients frequently experience relapse. Advanced stage PCa is associated with increased expression and activity of the DNA damage/repair pathway enzyme, poly (ADP-ribose) polymerase 1 (PARP1). Furthermore, PARP1 inhibitors are FDA-approved for the treatment of advanced PCa tumors that carry mutations in components of a specific DNA damage/repair pathway termed homologous recombination repair (HRR). However, PARPi also provide benefit in model systems without HRR incompetencies. A number of different PARPi have now been developed, tested and approved for use in PCa. These inhibitors utilize multiple biochemical mechanisms of action and exhibit distinct potencies and toxicity profiles. While there is emerging evidence of differences in DNA damage/repair pathway enzyme expression between EA and AA men, PARP1 itself has not been fully explored in the context of race. This study hypothesized that 1) AA and EA PCa may respond differently to PARPi and 2) different PARPi may differentially impact the transcriptome, irrespective of HRR status. To test these hypotheses, PCa patient samples from a racially diverse cohort were examined to define race-based differences in PARP activity/expression. Additionally, biologically relevant doses of five clinically relevant PARPi were established across multiple PCa lines carrying different genetic backgrounds, HRR status, and hormone therapy sensitivities. Collectively, these findings demonstrate a link between racial background and PARP1 expression/activity and define a core transcriptional response that lies downstream of all five PARPi, while simultaneously defining transcriptional programs unique to each inhibitor. These findings broaden our understanding of the effector pathways downstream of individual PARPi and provide a compelling rationale for a broader exploration of the impact of race on the response to PARPi. They may also help refine personalized recommendations for use of specific PARPi.

cancer biology↗

bioRxiv2025

APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence

Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.

immunology↗

bioRxiv2024

Harmonising digitised herbarium data to enhance biodiversity knowledge: creating an updated checklist for the flora of Greenland.

International efforts to digitise herbarium specimens provide the building blocks for a global digital herbarium. However, taxonomic changes and errors can result in inconsistencies when amalgamating specimen metadata, that compromise the assignment of occurrence records to correct taxa, and the subsequent interpretation of patterns in biodiversity. We present a novel workflow to mass-curate digital specimens. By employing existing digital taxonomic backbones, we aggregate specimen names by their accepted name and flag remaining cases for manual review. We then validate names using site-specific floras, balancing automation with taxonomic expert-based curation. Applying our workflow to the vascular plants of Greenland, we harmonised 175,266 digitised herbarium specimens and observations from 92 data providers from the Global Biodiversity Information Facility (GBIF). The harmonised metacollection for the Greenland flora contains 780 plant species. Our workflow increases the number of species known from Greenland compared to other currently available species checklists and increases the mean number of occurrences per species by 42.6. Our workflow illustrates the integration required in order to create a global, universally accessible digital herbarium, and shows how previous obstacles to database curation can be overcome through a combination of automation and expert curation. From the specific perspective of the Greenland flora, our approach arrives at a new checklist of taxa, a new curated metacollection of occurrence data, and revised estimates of plant richness. The list of taxa and their prevalence allow a new basis for biodiversity assessment and conservation planning. Societal Impact StatementDigitising plant collections has allowed for data to be aggregated across multiple collections, forming a single harmonised resource of unprecedented scale. This resource is only accurate once the database names are assigned to one accepted name per species. We established a semi-automated workflow for processing plant name data, leveraging taxonomic backbones and employing taxonomic expertise at key stages. Applying our workflow to the flora of Greenland, we developed a curated checklist of 780 species, capturing greater species richness than previously published, while also curating 175,266 plant records. Our findings redefine our knowledge of Greenlandic plant diversity, while harmonising a vast digital collection for further research.

ecology↗

bioRxiv2024

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

Huntingtons disease (HD), due to expansion of a CAG repeat in HTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

genetics↗

bioRxiv2024

Differential maturation of the brain networks required for the sensory, emotional and cognitive aspects of pain in human newborns

Pain is multidimensional and complex, including sensory-discriminative, affective- motivational, and cognitive-evaluative components. While the concept of pain is learned through life experience, it is not known when and how the brain networks that are required to encode these different dimensions of pain develop. Using the two largest databases of human brain magnetic resonance (MR) images in the world - the developing Human Connectome Project and the Human Connectome Project - we have mapped the development of the neural pathways required for pain perception in the human brain in infants from <32 weeks to 42 weeks postmenstrual age (n = 372), compared to adults (n = 98). Partial correlation analysis of 15 mins resting BOLD signal between all possible pairwise combinations of 12 pain-related regions of interest showed that overall functional connectivity is significantly weaker in 32- week infants compared to adults. However, over the following weeks, significantly different developmental patterns of connectivity emerge in sensory-discriminative, affective- motivational, and cognitive-evaluative pain networks. The first subnetwork to reach adult levels in strength and proportion of connections is the sensory-discriminative subnetwork (34- 36 weeks PMA), followed by the affective-motivational subnetwork (36-38 weeks PMA), while the cognitive-evaluative subnetwork has still not reached adult levels at 42 weeks. This study reveals a previously unknown pattern of postnatal development of connectome subnetworks necessary for mature pain processing. The brain networks that form the infrastructure to encode different components of pain experience, change rapidly in the equivalent of the last gestational trimester but are still immature at the time of normal birth. Newborn neural pathways required for mature pain processing in the brain are incomplete in newborns compared to adults, particularly with respect to the emotional and evaluative aspects of pain. This data suggests that pain-related networks may have distinct periods of vulnerability to untimely noxious procedures during hospitalization, particularly in preterm infants.

neuroscience↗

bioRxiv2023

Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval

Long QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions. LQTS represents a significant clinical challenge due to its complex genetic underpinning and propensity for fatal arrhythmias. In this study, we generated induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMCs) of six patients with extreme polygenic scores for short and long corrected QT intervals. iPSC lines were rigorously validated for genomic integrity through karyotyping and targeted mutation analysis specific to a lengthened or shortened QT interval. Pluripotency was confirmed by expression of key markers TRA 1-60, TRA 1-81, SOX2, OCT4, NANOG, and REX1 via quantitative PCR and immunofluorescence. Subsequent cardiac induction successfully generated cardiomyocytes that were further characterized. This patient-specific approach will enable us to better understand variable expressivity and penetrance of LQTS. Rigorously validated iPSC lines serve as a vital resource for elucidating the molecular mechanisms underlying LQTS. Our study provides a robust and clinically relevant resource to facilitate our understanding the genetic and cellular complexity of LQTS.

genetics↗

bioRxiv2023

Loss of Polycomb Repressive Complex 2 function causes asparaginase resistance in T-acute lymphoblastic leukemia through decreased WNT pathway activity

Loss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor prognosis and treatment resistance in T-acute lymphoblastic leukemia (T-ALL). We leveraged clinical mutational and transcriptional data to identify a functional link between PRC2 alterations and changes in WNT signaling pathway activity in leukemia cells. Computational integration of transcriptomic, proteomic and phosphoproteomic data from an isogenic T-ALL cellular model revealed reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in cells lacking core PRC2 factor EZH2. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels that bolstered leukemia cell asparagine reserves. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a novel and clinically tractable means to tackle induction treatment failure in high-risk T-ALL.

cancer biology↗

bioRxiv2023

A Highly Efficient Aorta-Gonad-Mesonephros-Like Definitive Hemogenic Endothelium From Human Pluripotent Stem Cells

Summary/AbstractHuman pluripotent stem cells are a tremendous tool to model early human development and disease including their use in the in vitro generation of blood cell fates. Hematopoietic progenitors and stem cells are the primary source of blood and the immune system from early development to adulthood and arise through successive waves of hemogenic mesoderm either in the yolk sac or embryo proper. Researchers have long sought a tractable human model for observing and distinguishing these waves of hematopoiesis in the dish for human developmental and disease modeling. Here we report a high-efficiency method for differentiating human pluripotent stem cells into an aorta-gonad-mesonephros-like definitive hemogenic mesoderm capable of giving rise to definitive hematopoietic progenitor and stem cells. The hematopoietic progenitor and stem cells exhibit robust multilineage in vitro colony forming potential. Gene expression analysis and single cell sequencing strongly support the developmental timing and notion that the pluripotent stem cell derived hematopoietic stem and progenitors are strikingly like bone fide hematopoietic stem cells. The hematopoietic progenitors can be subsequently differentiated into polarized macrophage and T-cells in vitro. Minimal silencing was observed upon differentiation of the pluripotent stem cells to hematopoietic lineages when conducting gene editing. Finally, upon engraftment into immunodeficient animals the hematopoietic progenitors and stem cells differentiate into multiple lineages including B-cells, T-cells, NK-cells, and monocytes.

developmental biology↗

bioRxiv2023

Cancer drug sensitivity prediction from routine histology images

Drug sensitivity prediction models can aid in personalising cancer therapy, biomarker discovery, and drug design. Such models require survival data from randomized controlled trials which can be time consuming and expensive. In this proof-of-concept study, we demonstrate for the first time that deep learning can link histological patterns in whole slide images (WSIs) of Haematoxylin & Eosin (H&E) stained breast cancer sections with drug sensitivities inferred from cell lines. We employ patient-wise drug sensitivities imputed from gene expression based mapping of drug effects on cancer cell lines to train a deep learning model that predicts sensitivity to multiple drugs from WSIs. We show that it is possible to use routine WSIs to predict the drug sensitivity profile of a cancer patient for a number of approved and experimental drugs. We also show that the proposed approach can identify cellular and histological patterns associated with drug sensitivity profiles of cancer patients. HighlightsO_LIPredicting drug sensitivity from routine histology images and cell lines C_LIO_LIDiscovery of histology image patterns linked to drug sensitivity C_LIO_LIA novel deep learning pipeline for analysing drug sensitivity profiles C_LI

cancer biology↗