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Acinetobacter enrichment shapes composition and function of the bacterial microbiota of field-grown tomato plants
No full textTomato is a staple crop and an excellent model to study host-microbiota interactions in the plant food chain. In this study, we describe a “lab-in-the-field” approach to investigate the microbiota of field-grown tomato plants. High-throughput amplicon sequencing revealed a three-microhabitat partition, phyllosphere, rhizosphere, and root interior, differentiating host-associated communities from the environmental microbiota. An individual bacterium, classified as Acinetobacter sp., emerged as a dominant member of the microbiota at the plant-soil continuum. To gain insights into the functional significance of this enrichment, we subjected rhizosphere specimens to shotgun metagenomics. Similar to the amplicon sequencing survey, a “microhabitat effect,” defined by a set of rhizosphere-enriched functions, was identified. Mobilization of mineral nutrients, as well as adaptation to salinity and polymicrobial communities, including antimicrobial resistance genes (ARGs), emerged as a functional requirement sustaining metagenomic diversification. A metagenome-assembled genome representative of Acinetobacter calcoaceticus was retrieved, and metagenomic reads associated with this species identified a functional specialization for plant-growth promotion traits, such as phosphate solubilization, siderophore production, and reactive oxygen species detoxification, which were similarly represented in a tomato genotype-independent fashion. Our results revealed that the enrichment of a beneficial bacterium capable of alleviating plant abiotic stresses appears decoupled from ARGs facilitating microbiota persistence at the root-soil interface
Score-Based Diffusion Model for Unpaired Virtual Histology Staining
No full textHematoxylin and eosin (H&E) staining visualizes histology but lacks specificity for diagnostic markers. Immunohistochemistry (IHC) staining provides protein-targeted staining but is restricted by tissue availability and antibody specificity. Virtual staining, i.e., computationally translating the H&E image to its IHC counterpart while preserving the tissue structure, is promising for efficient IHC generation. Existing virtual staining methods still face key challenges: 1) effective decomposition of staining style and tissue structure, 2) controllable staining process adaptable to diverse tissue and proteins, and 3) rigorous structural consistency modelling to handle the non-pixel-aligned nature of paired H&E and IHC images. This study proposes a mutual-information (MI)-guided score-based diffusion model for unpaired virtual staining. Specifically, we design 1) a global MI-guided energy function that disentangles the tissue structure and staining characteristics across modalities, 2) a novel timestep-customized reverse diffusion process for precise control of the staining intensity and structural reconstruction, and 3) a local MI-driven contrastive learning strategy to ensure the cellular level structural consistency between H&E-IHC images. Extensive experiments demonstrate the our superiority over state-of-the-art approaches, highlighting its biomedical potential. Codes will be open-sourced upon acceptance.</p
Mathematical descriptions of grading linked with prediction of mechanical consequences of suffusion
No full textInternal erosion is a leading cause of disfunctions and failures of earth embankments when used as water retaining structures. Internal erosion results from water flowing through the embankments, removing particles from the soils forming the embankments. It may even occur in the embankment foundations if they are made of soils. It changes a soil's particle size distribution, increases its void ratio, shifts its critical state line upwards in the compression plane and alters its stress–strain behavior. This paper presents new mathematical links and constitutive model ingredients to capture these effects. They apply to a gap-graded soil and a particular type of erosion known as suffusion. The evolution of the particle size distribution is characterised through a grading state index, defined in terms of geometrical properties which are fractal. These new ingredients are incorporated into the Severn-Trent model to simulate stress–strain responses of the soil, subjected to drained triaxial compression, having experienced different amounts of suffusion. The simulations match the experimental data well. The model and its ingredients are also used to simulate other property changes to the gap-graded soil which follow different amounts of suffusion, especially the soil's reduced strength and increased tendency for compression.</p
The Prostitution (Offences and Support) (Scotland) Bill:Opinion on consistency with international human rights law*
No full textThis opinion considers the consistency of the Prostitution (Offences and Support) (Scotland) Bill (the Bill) with international human rights law applicable in Scotland and the UK. Currently in Scotland, soliciting for prostitution is a criminal offence. The Bill seeks to repeal this offence and quash historic soliciting convictions. In parallel it would establish a new criminal offence of paying for sexual acts and a right to support for individuals exiting prostitution. Based on treaties to which the UK is a party, and associated interpretive materials, this opinion considers that:1. In criminalising the sale of sexual acts by individuals engaged in prostitution, Scottish law breaches applicable human rights treaty obligations, due to the discriminatory character of this approach of regulating prostitution with regard to women and girls. To achieve offence of soliciting under section 46 Civic Government (Scotland) Act 1982, should accordingly be repealed, and historical soliciting convictions pardoned / disregarded, as the Bill proposes.2. De-regulating both the sale and purchase of sexual acts in Scotland would be inconsistent with applicable treaty obligations, given legal duties on the UK and Scottish Governments to take all reasonable measure to eliminate discrimination and prevent violence against women, to reduce demand for trafficking and for commercial sex, and to address other human rights abuses experienced by individuals in prostitution.3. Adopting demand-side or ‘Nordic’ model legislation on prostitution in Scotland, which criminalises the purchase of sexual acts, as proposed by the Bill, does not present a risk of non-compliance with the UK’s human rights obligations. In particular, any interference with the right to privacy by legislation criminalizing the purchase of sexual acts while decriminalizing their sale and supporting exit is likely to be assessed as lawful by human rights courts or other mechanisms supervising instruments to which the UK is a party.4. Overall, the measures proposed by the Bill would both resolve a matter giving rise to a persistent breach of international human rights laws in Scotland and contribute significantly to fulfilling international human rights duties owed to women in Scotland and borne by the UK and Scottish governments
Political trust in divided societies:Who trusts whom in Northern Ireland?
No full textPolitical trust is essential for peace in divided societies. In postaccord Northern Ireland (NI), past research has identified differences in political trust among the Catholic and Protestant communities. The present research explored which political institutions are trusted, and by whom, in the NI context. Drawing on the Northern Ireland Life and Times 2022 survey data (n = 968; 373 males, 595 females, aged 18 and over, 537 Protestant, 431 Catholic), principal component analyses identified two factors (with 62.85% cumulative variance explained), one factor trusted mainly by Catholics, which includes the European Union and the Alliance Party, and the other factor trusted mainly by Protestants, which includes the U.K. government (at Westminster) and the NI Executive. This differentiation suggests that political events such as Brexit and the suspension of the NI Assembly have impacted political trust differently in each community. Findings highlight the complexity of political trust and how ostensibly neutral political institutions are perceived in divided societies
The secondary bile acid, lithocholic acid, inhibits cystic fibrosis transmembrane conductance regulator expression and activity in colonic epithelial cells
Get PDFClassically known for their roles in facilitating lipid digestion and absorption, bile acids are now also appreciated as enterocrine hormones that modulate many aspects of intestinal physiology. We have previously shown lithocholic acid (LCA), a secondary bile acid, to be protective against colonic inflammation. Here, we investigated whether LCA also regulates colonic epithelial fluid and electrolyte transport. T84 cell monolayers were mounted in Ussing chambers for measurements of transepithelial Cl− secretion. CFTR mRNA and protein expression were analyzed by qRT-PCR and Western blotting in T84 cells and human-derived colonic organoids. CFTR promoter activity was assessed using a luciferase promoter/reporter assay in HEK293 cells. Pretreatment of T84 cells with LCA inhibited Cl− secretory responses to the cAMP-dependent agonist, forskolin (FSK), with maximal effects occurring at a concentration of 10 µM after 24 h of treatment. Under these conditions, LCA also inhibited responses to the Ca2+-dependent secretagogues, thapsigargin, and histamine. In nystatin-permeabilized T84 monolayers, LCA reduced FSK-stimulated apical Cl− conductances, an effect that correlated with reduced CFTR Cl− channel expression. Although LCA activated both farnesoid X receptor (FXR) and vitamin D receptor (VDR), its effects on CFTR expression and Cl− conductances were mimicked only by an FXR agonist, GW4064, and not by a VDR agonist, calcitriol. Finally, LCA inhibited CFTR promoter activity in HEK3 cells, but only when FXR was expressed. LCA, at physiologically relevant concentrations, chronically inhibits colonic epithelial Cl− secretion, likely via FXR-induced downregulation of CFTR. These data broaden our knowledge of the regulatory roles of LCA in the colon and highlight its potential as a therapeutic target for intestinal disorders.NEW & NOTEWORTHY This study reveals a previously unrecognized role for lithocholic acid (LCA) in chronically suppressing colonic epithelial chloride secretion. We demonstrate a genomic mechanism of action for LCA that is likely mediated by FXR-induced downregulation of CFTR expression and function. These findings highlight LCA as a key modulator of intestinal fluid and electrolyte transport and underline the therapeutic potential of targeting bile acids and their receptors for the treatment of diarrheal diseases
Roles of cytokines in modulating Trypanosoma brucei rhodesiense infection outcomes in vervet monkeys
Get PDFIntroduction: Human African trypanosomiasis (HAT), caused by Trypanosoma brucei rhodesiense, is categorized as acute due to rapid disease progression but presents varying clinical outcomes. Although the mechanisms underpinning differential clinical progression are poorly understood, both host and parasite factors are implicated. Therefore, we sought to elucidate roles of primate host factors in mediating varying T. b. rhodesiense infection outcomes.Methods: Here, we assessed the roles of selected host cytokines in disease progression using a tsetse-mediated infection in a non-human primate (NHP) vervet monkey model that closely mimics HAT and natural infection. We quantified eight cytokines, including TNF-α, IFN-γ, IL-10, IL-6, IL-12, and IL-1β, as well as the brain injury biomarker S100b and clinical data, and compared acute and chronic infections. In addition,Results: Monkeys infected with KETRI 3801 and KETRI 3928 had mean survival times of 28 and 95 days, respectively. In both infected groups, cytokine levels were significantly higher than those in uninfected controls (p < 0.05). IL-12, IL-6, and IL-1β cytokines were significantly elevated (p < 0.05) from early-stage disease to the onset of late-stage disease. IL-1β, IL-6, IL-12, and IL-10 are implicated in pro- and counter inflammatory responses. In addition, cerebrospinal fluid parasite and white blood cell levels were higher in KETRI 3801 infections compared with KETRI 3928 infections.Discussion: We conclude that cytokines play roles in modulating disease progression and severity in an NHP model of HAT, which is important for understanding varying infection outcomes
A Novel Class of Orally Bioavailable Phenylglycine–Benzoxaborole Conjugates with Antimalarial Activity and Potentially Novel Mechanism of Action
Get PDFA new class of benzoxaboroles with a phenylglycine appendage was found to display in vitro blood stage activity against the human malaria parasite Plasmodium falciparum (Pf). Structure–activity relationship studies of the starting hit compound 3 resulted in compounds active against PfNF54 drug-sensitive and PfK1 drug-resistant strains with an in vitro antiplasmodium IC50 < 0.4 μM, selectivity over mammalian cell-lines (selectivity index > 47) and high aqueous solubility (160 to >200 μM). Selected compounds showed good in vitro metabolic stability when incubated with human, rat, and mouse liver microsomes and showed no cross-resistance against barcoded mutant lines. Two frontrunner compounds, 6 and 7, were dosed orally at 50 mg·kg–1 using a standard quadrupole dosing regimen in a P. berghei mouse infection model and showed encouraging in vivo efficacy. This work identifies a promising new class of phenylglycine-based benzoxaboroles, which warrants further medicinal chemistry optimization.</p
Fluorographene-derived colloidal dispersions for donepezil delivery:From chemical synthesis to engineering of drug carriers
Get PDFFluorinated graphene oxide (FGO) colloidal dispersions have recently emerged as promising drug delivery systems. In this study, graphene acid (GA) and its partially fluorinated counterpart (FGA) were synthesized and characterized comprehensively. Both GA and FGA formed stable colloidal dispersions in phosphate-buffered saline (PBS, 1 mg/mL) after sonication, with particle size and surface charge strongly influenced by surface chemistry and interparticle interactions. Biocompatibility tests indicated that neither GA nor FGA exhibits cytotoxicity, as high cell viability remained across all tested concentrations. Donepezil (Don) was chosen as a model Active Pharmaceutical Ingredient (API) in order to evaluate the drug-loading capacity of FGA. Simple mixing of FGA with Don resulted in efficient drug loading, while molecular dynamic and quantum-chemical studies provided molecular-level insight into FGA-donepezil interactions. Overall, these findings demonstrate that FGA is a biocompatible nanocarrier with potential added value for pharmaceutical applications.</p
Untargeted metabolomics for triaging of cytochrome b inhibitors during Chagas’ disease drug discovery
No full textChagas’ disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a potentially fatal condition for which new treatments are urgently needed. Due to the lack of validated drug targets, phenotypic screening followed by target deconvolution is the dominant approach in Chagas’ disease drug discovery. However, as most phenotypic screening hits act through a small number of promiscuous targets, implementation of counter-screening methodology for these targets as early as possible in the workflow is essential to enable prioritisation of compounds with novel Modes of Action (MoA). Here, we demonstrate that untargeted metabolomic profiling using liquid chromatography mass spectrometry (LC-MS) can reliably identify compounds that act through one of the most common targets, cytochrome b. Treatment of epimastigote form T. cruzi in culture with cytochrome b inhibitors resulted in rapid and pronounced perturbation of the metabolome. We identified a signature of 79 metabolites that were differentially expressed by at least 2-fold (p < 0.05). Unsupervised multivariate analysis using these features allowed clear separation of cytochrome b inhibitors from compounds acting through other MoA, and through disruption of oxidative phosphorylation by other mechanisms. Flexibility was observed in this cytochrome b signature between experiments, and depending on the compounds used, suggesting that this approach could be readily implemented in other laboratories. Triage of cytochrome b inhibitors early in the Chagas’ disease drug discovery workflow using untargeted metabolomics will aid in prioritisation of medicinal chemistry resources towards compounds acting through novel mechanisms
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