2,249 research outputs found

    Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors

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    High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with ‘high’ or ‘low’ HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice

    Identification of an anti-CRISPR protein that inhibits the CRISPR-Cas type I-B system in Clostridioides difficile

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    CRISPR-Cas systems provide prokaryotic hosts with adaptive immunity against mobile genetic elements. Many bacteriophages encode anti-CRISPR (Acr) proteins that inhibit host defense. The identification of Acr proteins is challenging due to their small size and high sequence diversity, and only a limited number has been characterized to date. In this study, we report the discovery of a novel Acr protein, AcrIB2, encoded by the φCD38-2 Clostridioides difficile phage that efficiently inhibits interference by the type I-B CRISPR-Cas system of the host and likely acts as a DNA mimic. Most C. difficile strains contain two cas operons, one encoding a full set of interference and adaptation proteins and another encoding interference proteins only. Unexpectedly, we demonstrate that only the partial operon is required for interference and is subject to inhibition by AcrIB2.This work was supported by the Institut Universitaire de France (to O.S.), the Institute for Integrative Biology of the Cell, the University Paris-Saclay, Graduate School Life Sciences and Health, and OI MICROBES funding and Vernadski fellowship (to P.M.). This work was also supported by NIH grant R01 GM10407 (to K.S.), the Russian Science Foundation grant 19-14-00323, and the Ministry of Science and Higher Education of the Russian Science Federation agreement no. 075-10-2021-114

    PRUSSIC II -- ALMA imaging of dense-gas tracers in SDP.81: Evidence for low mechanical heating and a sub-solar metallicity in a z=3.04 dusty galaxy

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    We present deep ALMA Band 3 observations of the HCN, HCO+, and HNC (4-3) emission in SDP.81, a well-studied z = 3.042 strongly lensed galaxy. These lines trace the high-density gas, which remains almost entirely unexplored in z≄\geq1 galaxies. Additionally, these dense-gas tracers are potentially powerful diagnostics of the mechanical heating of the interstellar medium. While the HCN(4-3) and HNC(4-3) lines are not detected, the HCO+(4-3) emission is clearly detected and resolved. This is the third detection of this line in a high-redshift star-forming galaxy. We find an unusually high HCO+/HCN intensity ratio of ≄\geq2.2. Based on the photodissociation region modelling, the most likely explanation for the elevated HCO+/HCN ratio is that SDP.81 has low mechanical heating - less than 10% of the total energy budget - and a sub-solar metallicity, Z=0.5 Z⊙_\odot. While such conditions might not be representative of the general population of high-redshift dusty galaxies, lower-than-solar metallicity might have a significant impact on gas masses inferred from CO observations. In addition, we report the detection of CO(0-1) absorption from the foreground lensing galaxy and CO(1-0) emission from a massive companion to the lensing galaxy, approximately 50 kpc to the southeast.Comment: A&A accepted, in press. 10 pages, 10 figure

    The bright extragalactic ALMA redshift survey (BEARS) – II. Millimetre photometry of gravitational lens candidates

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    International audienceWe present 101-and 151-GHz ALMA continuum images for 85 fields selected from Herschel observations that have 500-ÎŒm flux densities > 80 mJy and 250-500-ÎŒm colours consistent with z > 2, most of which are expected to be gravitationally lensed or hyperluminous infrared galaxies. Approximately half of the Herschel 500-ÎŒm sources were resolved into multiple ALMA sources, but 11 of the 15 brightest 500-ÎŒm Herschel sources correspond to individual ALMA sources. For the 37 fields containing either a single source with a spectroscopic redshift or two sources with the same spectroscopic redshift, we examined the colour temperatures and dust emissivity indices. The colour temperatures only vary weakly with redshift and are statistically consistent with no redshift-dependent temperature variations, which generally corresponds to results from other samples selected in far-infrared, submillimetre, or millimetre bands but not to results from samples selected in optical or near-infrared bands. The dust emissivity indices, with very few exceptions, are largely consistent with a value of 2. We also compared spectroscopic redshifts to photometric redshifts based on spectral energy distribution templates designed for infrared-bright high-redshift galaxies. While the templates systematically underestimate the redshifts by ∌15 per cent, the inclusion of ALMA data decreases the scatter in the predicted redshifts by a factor of ∌2, illustrating the potential usefulness of these millimetre data for estimating photometric redshifts

    Faint [CI](1-0) emission in z ∌\sim 3.5 radio galaxies

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    We present Atacama Large Millimeter/sub-millimeter Array (ALMA) neutral carbon, [C I](1-0), line observations that probe molecular hydrogen gas (H2_2) within seven radio galaxies at z=2.9−4.5z = 2.9 - 4.5 surrounded by extended (≳100\gtrsim100 kpc) Ly-α\alpha nebulae. We extract [C I](1-0) emission from the radio-active galactic nuclei (AGN) host galaxies whose positions are set by near-infrared detections and radio detections of the cores. Additionally, we place constraints on the galaxies' systemic redshifts via He II λ\lambda1640 lines seen with the Multi-Unit Spectroscopic Explorer (MUSE). We detect faint [C I] emission in four out of seven sources. In two of these galaxies, we discover narrow line emission of full width at half maximum â‰Č100\lesssim100 km s−1^{-1} which may trace emission from bright kpc-scale gas clouds within the ISM. In the other two [C I]-detected galaxies, line dispersions range from ∌100−600\sim100 - 600 km s−1^{-1} and may be tracing the rotational component of the cold gas. Overall, the [C I] line luminosities correspond to H2_2 masses of MH2,[CI]≃(0.5−3)×1010M⊙_{\rm H_2,[C I]} \simeq (0.5 - 3) \times 10^{10} M_\odot for the detections and MH2,[CI]<0.65×1010M⊙_{H_2,[C I]} < 0.65 \times 10^{10} M_\odot for the [C I] non-detections in three out of seven galaxies within the sample. The molecular gas masses in our sample are relatively low in comparison to previously reported measures for similar galaxies which are MH2,[CI]≃(3−4)×1010._{H_2,[C I]} \simeq (3 - 4) \times 10^{10}. Our results imply that the observed faintness in carbon emission is representative of a decline in molecular gas supply from previous star-formation epochs and/or a displacement of molecular gas from the ISM due to jet-powered outflows.Comment: 16 pages, 4 figures and 5 tables. Accepted for publication in MNRA

    Ultrasensitive PCR system for HBV DNA detection: Risk stratification for occult hepatitis B virus infection in English blood donors

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    Occult hepatitis B (HBV) infection (OBI), characterized by low viral loads, accounts for much of the risk of HBV transfusion-transmitted infection. With anticore antibodies (anti-HBc) screening introduced in England, the imperative to identify OBI donors has increased. We aimed to develop an ultra-sensitive PCR system and investigate risk factors for HBV DNA presence in blood donations. Seven extraction methods and three PCR assays were compared. The optimal system was sought to determine HBV DNA presence in anti-HBc-positive donations. Predictors of DNA positivity were subsequently investigated. Extraction from 5 mL of plasma increased sample representation and resulted in HBV DNA detection in low viral load samples (~0.5 IU/mL). Screening of 487 763 donations in 2022 identified two OBI donors and 2042 anti-HBc-positive donors, 412 of the latter with anti-HBs < 100 mIU/mL. Testing of 134 anti-HBc-positive donations utilizing the 5 mL extraction method identified two further HBV DNA-positive donations. Higher anti-HBc titer and anti-HBs negativity were significant predictors of DNA detectability in anti-HBc-positive donations. An ultrasensitive PCR assay identified potentially infectious donations increasing HBV DNA detection in anti-HBc-positive donors from 0.5% to 1.9%. Anti-HBc titers may further complement the risk stratification for DNA positivity in anti-HBc screening and minimize unnecessary donor deferral

    The gut microbiome in bullous pemphigoid: implications of the gut-skin axis for disease susceptibility

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    Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions

    Origin of Fe‐Ca‐Metasomatism in Exhumed Mantle Rocks at the MARK Area (23°N, ODP Leg 153) and Implications on the Formation of Ultramafic‐Hosted Seafloor Massive Sulfide Deposits

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    Abstract At Mid‐Ocean Ridges, hot, reduced, acidic, and metal‐rich fluids are responsible for the formation of ultramafic‐hosted seafloor massive sulfide deposits (UM‐SMSs), where mantle exhumation efficiently operates. As UM‐SMSs display great structural, mineralogical, and geochemical variabilities from site to site, a simple genetic model cannot be applied. Notably, fluid circulation and Fe‐Ca metasomatism are reported in ultramafic‐hosted hydrothermal deposits exposed in ophiolites, suggesting it might have genetic implications on the formation of mineralized systems. Similar Fe‐Ca metasomatism was reported in drilled mantle rocks at the Mid Atlantic Ridge Kane (MARK) area, offering access to the vertical dimension beneath an exhumed oceanic core complex to provide an integrative study of the nature and geometry of deep magmatic and hydrothermal processes. At MARK, mantle rocks underwent complex processes of melt‐rock and fluid‐rock interactions. Magma channeling and interactions with surrounding rocks enriched mantle silicates in Fe, Co, and Zn. There, subsequent hydrothermal alteration allowed to stabilize Fe‐rich silicates. Mineralogy and geochemistry of hydrothermal phases at MARK suggest mineral crystallization under temperatures from ∌830° down to 350°C during early mantle exhumation at a depth <6.5 km below seafloor, followed by serpentinization of the massif during progressive mantle denudation. Considering the lithological heterogeneity at (ultra)slow‐spreading ridges, metal enrichment in deep mantle rocks during melt‐rock interactions may be a widespread process. In ultramafic‐dominated environments where extensional tectonics allow fluid flows to these deep zones, fluids may leach and transport metals to the surface, accounting for metal entrapment in UM‐SMSs


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