Biology subjects

Gordon, S.

Publications and source records attributed to Gordon, S..

At least 19 recordsLinked to original sources

bioRxiv2026

The Aorta-Gonad-Mesonephros niche shapes the functions of yolk sac-derived macrophages involved in hematopoietic stem and progenitor cell generation ex vivo

Hematopoietic stem cells (HSCs) generated from induced pluripotent stem cells (iPSCs) offer a promising patient-specific alternative to allogeneic transplantation, yet current differentiation protocols fail to fully recapitulate in vivo HSC maturation. During mouse development, yolk sac (YS)-derived macrophages populate the aorta-gonad-mesonephros (AGM) region at the time of HSC emergence, but the mechanisms by which they support ex vivo hematopoietic stem and progenitor cell (HSPC) generation remain poorly defined. Bulk RNA sequencing revealed that mature AGM CD206 macrophages upregulate pro-inflammatory cytokines and the adhesion molecule F4/80. Using F4/80 knockout embryos, we identify a previously unreported, niche-specific role for F4/80 in restraining the frequency and colony-forming activity of HSPC subsets in the AGM, while supporting endothelial cell maintenance; this effect was absent in the YS. Lineage-tracing with a Cdh5-CreERT2;Rosa26LSL-tdTomato pulse-chase system confirmed that both CD206 and CD206- AGM cells originate from early YS-derived endothelial precursors, with no evidence of local macrophage generation within the AGM. Functional co-culture assays further demonstrated that the ability of CD206 macrophages to enhance the progenitor potential of hemogenic endothelium is AGM-specific and not an intrinsic, ontogeny-determined property, as YS macrophages failed to confer the same benefit even when paired with AGM endothelial cells, and AGM macrophages were ineffective with YS endothelium. Differential expression and NicheNet ligand-receptor interaction analyses identified a small set of AGM-restricted macrophage genes - including Mmp2, Nrep, Ccl2, and Cxcl16 - which are predicted to interact with both endothelial and cluster cells during endothelial-to-hematopoietic transition. Together, these findings establish that AGM macrophages acquire niche-specific transcriptional and functional properties upon entry into the aortic microenvironment, independent of their YS origin, and identify candidate macrophage-derived factors and a novel regulatory role for F4/80 in shaping HSPC output. These insights may guide the refinement of iPSC-based HSC differentiation protocols through the targeted, temporally controlled addition of macrophage-associated signals.

developmental biology↗

bioRxiv2026

Triploid asexual freshwater snails grow faster than sexual diploid conspecifics regardless of dietary phosphorus availability

The number of chromosome sets per nucleus is a fundamental trait, but why this number is nearly always two for multicellular eukaryotes remains unclear. Chromosomes are made of nucleic acids, which possess abundant phosphorus (P). Therefore, producing new chromosomes, as well as generating new cells and organismal growth, demands substantial phosphorus. Yet, because P is often limiting in nature, P availability could influence the prevalence of diploidy versus polyploidy. Here, we compare growth rates of diploid and triploid Potamopyrgus antipodarum, a freshwater snail, relative to P availability. Because diploid P. antipodarum are obligately sexual while obligately asexual individuals are polyploid, costs associated with sensitivity to P limitation in polyploids could also help explain the maintenance of sexual P. antipodarum. We raised juvenile diploid and triploid snails on either P-adequate or P-deficient diets and found that independent of P availability, juvenile triploid asexual snails grew faster and harbored higher P content as adults than sexual diploid conspecifics. Together, these results suggest life-history advantages of polyploidy or asexual reproduction that exacerbate rather than ameliorate the cost of sex. These outcomes suggest that P availability is unlikely to be a main driver of ploidy polymorphism or the maintenance of sex in P. antipodarum.

evolutionary biology↗

bioRxiv2026

Cholesterol Biosynthesis is a Targetable Vulnerability of CEBPA-mutant Acute Myeloid Leukemia

Bi-allelic CEBPA mutations occur in 5-15% of acute myeloid leukemia (AML) patients. The precise molecular consequences of CEBPA mutations, especially in combination with frequently co-occurring mutations in TET2, WT1, and GATA2, remain incompletely understood. Here, we present a robust human model of CEBPA-mutant AML through gene editing of healthy bone marrow-derived hematopoietic stem cells. Loss of the CEBPA-p42 isoform expressed in healthy cells with concomitant upregulation of the leukemic CEBPA-p30 isoform resulted in a myeloproliferative phenotype. Concurrent loss-of-function mutations in TET2 or WT1 drove full leukemic transformation, while GATA2 haploinsufficiency promoted erythroid precursor accumulation without overt AML. Single-cell transcriptomics and low-input proteomics revealed enhanced myeloid output, increased interferon signaling and elevated cholesterol biosynthesis in leukemic cells. Targeting cholesterol synthesis enhanced chemosensitivity, highlighting a potential therapeutic vulnerability, particularly relevant for CEBPA-mutant patients harboring co-mutations in TET2 or WT1, which have poor outcomes. Statement of significanceInduction of CEBPA-p30 by CRISPR/Cas gene editing in healthy human BM HSCs drives overt AML in vivo. TET2 and WT1 loss accelerate leukemogenesis, while GATA2 haploinsufficiency redirects differentiation toward erythroid precursors potentially driving acute erythroid leukemia. CEBPA-p30 AML exhibits cholesterol biosynthesis dependency, revealing a therapeutic vulnerability to statins.

cancer biology↗

bioRxiv2025

Quinazolinone and Phthalazinone Inhibitors of the HDAC6/Ubiquitin Protein-Protein Interaction

Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that regulates diverse cytosolic acetylation through its two catalytic deacetylase domains and a C-terminal zinc finger ubiquitin-binding domain (ZnF-UBD). This ZnF-UBD mediates key protein-protein interactions (PPIs) that couple deacetylation and ubiquitin-dependent degradation. While most HDAC6 inhibitors target the catalytic domains, the ZnF-UBD represents an underexplored target. Here, we validate previously reported small-molecule inhibitors of the HDAC6 ZnF-UBD/ubiquitin interaction and describe novel N-alkyl moieties based on quinazolinone and phthalazinone scaffolds. Starting from known quinazolinone and phthalazinone scaffolds, a literature and modeling-guided scaffold hop revealed potential for an extended phthalazinone series. Results obtained both in fluorescence polarization (FP) and differential scanning fluorimetry (DSF) confirm this hypothesis. Additionally, late-stage diversification yields compounds with improved predicted physicochemical properties. Finally, machine-learning-based co-folding affinity predictions correlate with experimental IC{square}{square} rank order, highlighting their utility in PPI inhibitor design. These studies continue expanding the chemical space of HDAC6 ZnF-UBD inhibitors and build upon existing foundations for future therapeutic and mechanistic exploration of HDAC6- ubiquitin signaling.

biochemistry↗

bioRxiv2025

Validation of deep learning enabled software MetronMind to measure vertebral heart size and vertebral left atrial size in dogs

Vertebral heart size (VHS) and vertebral left atrial size (VLAS) are objective radiographic measurements of heart and left atrial size respectively and are associated with inter and intraobserver variability when measured by humans. Artificial intelligence (AI) tools to determine VHS and VLAS have been developed which may reduce variability and save time. Two manual methods for measuring VHS and VLAS on right and left lateral canine thoracic radiographs were compared. Measurements of VHS and VLAS made by deep learning enabled program, MetronMind, were compared to a trained observer on right and left lateral radiographs from 1058 client-owned dogs including 80 breeds with a variety of heart sizes, thoracic conformations and radiographic quality. This was a retrospective, single center, method comparison study. Pearsons correlation, Bland-Altman plots and Passing-Bablok regression were used to assess agreement. Correlation between traditional and modified manual measurements for VHS and VLAS were strong (r=0.994 and r=0.974 respectively), with minimal bias (-0.10 and 0.04 vertebrae respectively) indicating that the modified methods closely approximate traditional measurements obtained from right lateral views. MetronMind measurements of VHS and VLAS from right lateral radiographs correlated well with the human observers modified measurements (r=0.947 and r=0.811 respectively), showing small mean biases (0.08 and 0.07 vertebrae respectively). Correlation between left and right lateral radiographic measurements of VHS (0.87 and 0.91) was higher than for VLAS (0.73 and 0.64) and bias was larger for VHS (0.26 and 0.31 vertebrae) than VLAS (-0.13 and -0.10 vertebrae) for humans and MetronMind respectively. MetronMind can therefore assist veterinarians with measuring VHS and VLAS in dogs and right lateral radiographs are preferred. Future studies are needed to compare artificial intelligence derived radiographic measures with echocardiographic measures of cardiac size.

physiology↗

bioRxiv2025

Validation of deep learning enabled web based and smartphone optimized application RadAnalyzer to measure vertebral heart size and vertebral left atrial size in dogs

BackgroundObjective radiographic measures of heart size including vertebral heart size (VHS) and vertebral left atrial size (VLAS) are associated with inter and intra-observer variability when measured by humans. Artificial intelligence (AI) tools including RadAnalyzer are available to measure VHS and VLAS. ObjectivesCompare VHS and VLAS measurements made by web based and smartphone optimized deep learning enabled program, RadAnalyzer, to a trained observer. Animals1058 client-owned dogs, across 80 breeds with a variety of heart sizes and thoracic confirmations. MethodsRetrospective, single center, method comparison study. Pearsons correlation, Bland-Altman plots and Passing-Bablok regression were used to assess agreement. ResultsRadAnalyzer measurements of VHS and VLAS correlated well with the human observers modified measurements (r=0.917 and r=0.873 respectively) and had small mean biases (0.002 and 0.007 vertebrae respectively). Conclusions and clinical importanceRadAnalyzer had clinically insignificant magnitude differences in measurement of VHS and VLAS when compared to a human observer and can therefore be used to assist veterinarians with measuring VHS and VLAS on right lateral radiographs in dogs of all sizes. Future studies comparing AI derived radiographic measures with echocardiographic measures of cardiac size are required.

physiology↗

bioRxiv2025

Targeting ALOX5/LTA4H driven granuloma caseation as a host-directed strategy for control of TB associated lung damage

Tuberculosis remains one of the major global health challenges with those previously exposed presenting persisting pulmonary dysfunction. Therefore, improved control measures are still required to prevent or reduce the TB-induced immunopathology in affected individuals. Host directed therapies that target host factors, have been suggested to improve on current treatments against TB. We previously reported a potential role for proteins which metabolize the arachidonic acids during TB immunopathogenesis. The study, therefore, sought to demonstrate the potential role of these proteins in TB-induced immunopathology. Using immune-histopathological assays, the association of macrophage driven ALOX5 signaling with severe pulmonary immunopathology during TB was demonstrated. Furthermore, using both in vitro and in vivo assays, the data demonstrated the contribution of ALOX5 signaling to TB-induced granulomatous inflammation. Interception of the signaling pathway through clinically approved pharmaceutical inhibitors, resulted in reduced lung damage during the disease. The resolution of TB-induced lung pathology further contributed to increased bactericidal activity. Taken together, our data strongly suggest a role for macrophage driven inflammation via ALOX5 signaling which can be targeted for the development of therapeutic treatment to prevent exacerbated TB-induced pulmonary immunopathology.

immunology↗

bioRxiv2024

Diminished placental Factor XIIIA1 expression associates with long term ART and preterm birth in pregnant people living with HIV.

We previously showed a link between maternal vascular malperfusion and pre-term birth (PTB) in pregnant people living with HIV (PPLH) initiating antiretroviral treatment (ART) before pregnancy, indicating poor placental vascularisation. After measuring antenatal plasma angiogenic factors to seek mechanistic insights, low levels of plasma Factor XIIIA1 (FXIIIA1) and vascular-endothelial-growth-factor (VEGF) was significantly associated with PTB at the time closest to delivery (median 34 weeks) in PPLH initiating ART before pregnancy. Knowing that FXIIIA1 is crucial for haemostasis, angiogenesis, implantation and pregnancy maintenance and that expression is found on placental macrophages (Hofbauer cells), we examined placentae at delivery from matching participants who either initiating ART before pregnancy or during gestation. Highest FXIIIA1 expression was on Hofbauer cells but was significantly lower in PTB regardless of HIV infection, but was significantly lower in PPLH in PTB from women who initiated ART before pregnancy. To test the hypothesis that antiretroviral drugs may disrupt vascularisation in the placenta, we used a human umbilical vein endothelial cell (HUVEC) matrigel angiogenesis assay. We identified that addition of pre-treated FXIIIA1-expressing MCSF-and IL-10-induced placenta-like macrophages with physiological concentrations of tenofovir, 3TC, and efavirenz resulted in significantly inhibited angiogenesis; akin to the inhibition observed with titratable concentrations of ZED1301, an inhibitor of FXIIIA1. Overall, an efavirenz-containing ART combination inhibits vasculogenesis without causing toxicity and likely does so through inhibition of a FXIIIA1-mediated-placental macrophage pathway.

immunology↗

bioRxiv2024

Breastmilk IgG engages the neonatal immune system to instruct host-microbiota mutualism

Maternal antibodies fundamentally regulate infant immunity to the developing gut microbiota, yet the mechanisms underlying this process remain elusive. Here, we show that maternal IgG, ingested in the first week of life, functions to restrain microbiota-dependent adaptive immune responses and reduce offspring susceptibility to intestinal inflammation weeks later, following weaning. To exert these functions, efficient binding of IgG to gut bacterial antigens and engagement of Fc and complement dependent effector functions in offspring was required. These discoveries reveal a novel mechanism wherein maternal IgG engages the offspring immune system to calibrate responses to gut microbes. This mode of maternal immune instruction may provide adaptability to developmental shifts in microbiota necessary for establishing host-microbiota mutualism and limiting susceptibility to inflammatory disease. One sentence abstractIngestion of maternal IgG during a discrete postnatal window calibrates neonatal immunity to the gut microbiota.

immunology↗

bioRxiv2024

The synaptonemal complex assembles between meiotic chromosomes by wetting

AbstractDuring meiosis, the parental chromosomes are drawn together to enable exchange of genetic information. Chromosomes are aligned through the assembly of a conserved interface, the synaptonemal complex, composed of a central region that forms between two parallel chromosomal backbones called axes. Here we identify the axis-central region interface in C. elegans, containing a conserved positive patch on the axis component HIM-3 and the C-terminus of the central region protein SYP-5. Crucially, the canonical ultrastructure of the synaptonemal complex is altered upon weakening this interface. We developed a thermodynamic model that recapitulates our experimental observations, indicating that the liquid-like central region can assemble by wetting the axes without active energy consumption. More broadly, our data show that condensation drives tightly regulated nuclear reorganization during sexual reproduction.

cell biology↗

bioRxiv2024

A STAT3 Degrader Demonstrates Pre-clinical Efficacy in Venetoclax resistant Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to have poor prognosis despite recent therapeutic advances. Venetoclax (Ven), a BCL2-inhibitor has shown a high response rate in AML; however, relapse is invariable due to mitochondrial dysregulation that includes upregulation of the antiapoptotic protein MCL1, a central mechanism of Ven resistance (Ven-res). We have previously demonstrated that the transcription factor STAT3 is upregulated in AML hematopoietic stem and progenitor cells (HSPCs) and can be effectively targeted to induce apoptosis of these aberrant cells. We now show that overexpression of STAT3 alone is sufficient to initiate a strong AML phenotype in a transgenic murine model. Phospho-proteomic data from Ven treated AML patients show a strong correlation of high total STAT3 and phospho-STAT3 [both p-STAT3(Y705) and p-STAT3(S727)] expression with worse survival and reduced remission duration. Additionally, significant upregulation of STAT3 was observed in Ven-res cell lines, in vivo models and primary patient samples. A novel and specific degrader of STAT3 demonstrated targeted reduction of total STAT3 and resulting inhibition of its active p-STAT3(Y705) and p-STAT3(S727) forms. Treatment with the STAT3 degrader induced apoptosis in parental and Ven-res AML cell lines and decreased mitochondrial depolarisation, and thereby dependency on MCL1 in Ven-res AML cell line, as observed by BH3 profiling assay. STAT3 degrader treatment also enhanced differentiation of myeloid and erythroid colonies in Ven-res peripheral blood mononuclear cells (PBMNCs). Upregulation of p-STAT3(S727) was also associated with pronounced mitochondrial structural and functional dysfunction in Ven-res cell lines, that were restored by STAT3 degradation. Treatment with a clinical-stage STAT3 degrader, KT-333 resulted in a significant reduction in STAT3 and MCL1 protein levels within two weeks of treatment in a cell derived xenograft model of Ven-res AML. Additionally, this treatment significant improvement in the survival of a Ven-res patient-derived xenograft in-vivo study. Degradation of STAT3 resulting in downregulation of MCL1 and improvements in global mitochondrial dysfunction suggests a novel mechanism of overcoming Ven-res in AML. Statement of PurposeFive-year survival from AML is dismal at 30%. Our prior research demonstrated STAT3 over-expression in AML HSPCs to be associated with inferior survival. We now explore STAT3 over-expression in Ven-res AML, explain STAT3 mediated mitochondrial perturbations and describe a novel therapeutic strategy, STAT3 degradation to overcome Ven-res.

cancer biology↗

bioRxiv2024

Loss of the scavenger receptor MARCO results in uncontrolled vomocytosis of fungi from macrophages.

Vomocytosis, also known as nonlytic exocytosis, is a process whereby fully phagocytosed microbes are expelled from phagocytes without discernible damage to either the phagocyte or microbe. Although this phenomenon was first described in the opportunistic fungal pathogen Cryptococcus neoformans in 2006, to date, mechanistic studies have been hampered by an inability to reliably stimulate or inhibit vomocytosis. Here we present the fortuitous discovery that macrophages lacking the scavenger receptor MAcrophage Receptor with COllagenous domain (MARCO), exhibit near-total vomocytosis of internalised cryptococci within a few hours of infection. Our findings suggest that MARCOs role in modulating vomocytosis is independent of its role as a phagocytic receptor and instead may be driven by variation in cytoskeletal arrangement between wildtype and MARCO-deficient macrophages.

immunology↗

bioRxiv2023

Characterization of the Pristionchus pacificus epigenetic toolkit reveals the evolutionary loss of the histone methyltransferase complex PRC2

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation - or lack thereof - of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the "epigenetic toolkit" available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with C. elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to enable reverse-genetic experiments related to plasticity, and in doing so have described the first loss of PRC2 in a multicellular organism.

genetics↗

bioRxiv2023

MARCO in alveolar macrophages negatively regulates Ace expression and aldosterone production

Aldosterone is a potent cholesterol-derived steroid hormone that plays a major role in controlling blood pressure via regulation of blood volume. The release of aldosterone is typically controlled by the renin-angiotensin aldosterone system, situated in the adrenal glands, kidneys, and lungs. Here, we reveal that the class A scavenger receptor MARCO, expressed on alveolar macrophages, negatively regulates aldosterone production and suppresses angiotensin converting enzyme (Ace) expression in the lungs of male mice. Collectively, our findings point to alveolar macrophages as additional players in the renin-angiotensin-aldosterone system and introduce a novel example of interplay between the immune and endocrine systems.

immunology↗

bioRxiv2023

Distinct adrenal gland macrophages regulate corticosteroid production

The adrenal glands are hormone secreting glands that sit on top of the kidneys. Adrenal glands produce glucocorticoids, mineralocorticoids, and catecholamines, and are therefore critical regulators of the stress response, the immune response, metabolism, and blood pressure. Despite being identified for more that 30 years, our understanding of adrenal macrophages remains incomplete. In numerous other tissues, macrophages carry out a plethora of physiological and homeostatic roles in addition to their classical immune functions. The aim of this study was to characterise the macrophage compartment of the adrenal gland and assess its contribution to adrenal function. Using an in vivo approach, we herein describe two morphologically and spatially distinct subsets of adrenal macrophages - dendritic-like macrophages that are present throughout the gland in young and old mice, and "foamy" lipid-laden macrophages that accumulate in the murine adrenal cortex in an age and diet-dependent manner. Furthermore, we present data showing that these foamy-like macrophages accumulate cholesterol and thereby regulate adrenal hormonal output, at steady state and in the context of obesity. We hereby provide novel insights into the physiological roles of macrophages in the adrenal gland and the mechanisms by which adrenal hormone production is regulated.

immunology↗

bioRxiv2023

Essential role of proline synthesis and the one-carbon metabolism pathways for systemic virulence of Streptococcus pneumoniae

Previous virulence screens have indicated potential roles during Streptococcus pneumoniae infection for the one-carbon metabolism pathway component Fhs and proline synthesis mediated by ProABC. To define how these metabolic pathways affect S. pneumoniae virulence we have investigated phenotypes and transcription profiles of {Delta}fhs and {Delta}proABC strain mutants. S. pneumoniae capsular serotype 6B BHN418 {Delta}fhs and {Delta}proABC mutant strains were markedly reduced virulence in mouse models of systemic infection and pneumonia, but were still able to colonise the nasopharynx. Although the {Delta}fhs and {Delta}proABC mutant strains grew normally in complete media, both mutant strains had markedly impaired growth in chemically defined medium, human serum and human CSF. The {Delta}proABC strain also had impaired growth under conditions of osmotic and oxidative stress. When transferred to the serotype 2 D39 S. pneumoniae strain background, the {Delta}fhs mutation replicated the virulence and growth in serum phenotype of the BHN418 mutation. In contrast, the D39 {Delta}proABC mutant could cause septicaemia and grow in human serum, indicating the role of this genetic locus during virulence is strain-specific. In human sera the {Delta}fhs and {Delta}proABC mutants both had major derangements in global gene transcription affecting multiple but different metabolic pathways, identifying the corresponding S. pneumoniae metabolic functions affected by these genes under infection-related conditions. Our data demonstrate an essential role for the S. pneumoniae one- carbon metabolism and a strain-conditional role for proline biosynthesis for growth in physiological fluids and therefore systemic infection, and further demonstrate the vital importance of bacterial metabolism for disease pathogenesis. ImportanceRapid adaptation to grow within the physiological conditions found in the host environment is an essential but poorly understood virulence requirement for systemic pathogens such as Streptococcus pneumoniae. We have now demonstrated an essential role for the one-carbon metabolism pathway and a conditional role depending on strain background for proline biosynthesis for S. pneumoniae growth in serum or CSF and therefore for systemic virulence. RNAseq data demonstrated that loss of one carbon metabolism or proline biosynthesis both have profound but differing effects on S. pneumoniae metabolism in human serum, identifying the metabolic processes dependent on each pathway during systemic infection. These data provide a more detailed understanding of the adaptations required by systemic bacterial pathogens in order to cause infection, and demonstrate that the requirement for some of these adaptations vary between strains from the same species and could therefore underpin strain variations in virulence potential.

microbiology↗

bioRxiv2023

Reciprocal regulation of TLR4, TLR3 and Macrophage Scavenger Receptor 1 regulates nonopsonic phagocytosis of the fungal pathogen Cryptococcus neoformans.

The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognized and phagocytosed by macrophages. Here we investigate the role of TLR4 in the nonopsonic phagocytosis of C. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of nonopsonized cryptococci. The increased phagocytosis observed in Tlr4-/- cells was dampened by pre-treatment of macrophages with either a TLR3 inhibitor or oxidised-LDL, a known ligand of scavenger receptors. The scavenger receptor, macrophage scavenger receptor 1 (MSR1) (also known as SR-A1 or CD204) was upregulated in Tlr4-/- macrophages and there was a 75% decrease in phagocytosis of nonopsonized cryptococci by Msr1-/- macrophages. Furthermore, immunofluorescence imaging revealed colocalization of MSR1 and internalised cryptococci. Together, these results identify MSR1 as a key receptor for the phagocytosis of nonopsonized C. neoformans and demonstrate TLR4/MSR1 crosstalk in the phagocytosis of C. neoformans.

microbiology↗

bioRxiv2021

Tracking the Ancestry of Known and 'Ghost' Homeologous Subgenomes in Model Grass Brachypodium Polyploids

Unraveling the evolution of plant polyploids is a challenge when their diploid progenitor species are extinct or unknown or when their progenitor genome sequences are unavailable. The subgenome identification methods cannot adequately retrieve the homeologous genomes that are present in the allopolyploids if they do not take into account the potential existence of unknown progenitors. We addressed this challenge in the widely distributed dysploid grass genus Brachypodium, which is a model genus for temperate cereals and biofuel grasses. We used a transcriptome-based phylogeny and newly designed subgenome detection algorithms coupled with a comparative chromosome barcoding analysis. Our phylogenomic subgenome detection pipeline was validated in Triticum allopolyploids, which have known progenitor genomes, and was used to infer the identities of three extant and four ghost subgenomes in six Brachypodium polyploids (B. mexicanum, B. boissieri, B. retusum, B. phoenicoides, B. rupestre and B. hybridum), of which five contain undescribed homeologous subgenomes. The existence of the seven Brachypodium progenitor genomes in the polyploids was confirmed by their karyotypic barcode profiles. Our results demonstrate that our subgenome detection method is able to uncover the ancestral genomic components of both allo- and autopolyploids.

plant biology↗