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Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 µM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 µM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.
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Proteínas Portadoras , Hidroxocobalamina , Fenotipo , Deficiencia de Vitamina B 12 , Vitamina B 12 , Humanos , Hidroxocobalamina/administración & dosificación , Hidroxocobalamina/uso terapéutico , Masculino , Femenino , Deficiencia de Vitamina B 12/genética , Deficiencia de Vitamina B 12/tratamiento farmacológico , Deficiencia de Vitamina B 12/sangre , Vitamina B 12/sangre , Preescolar , Proteínas Portadoras/genética , Estudios Retrospectivos , Oxidorreductasas/genética , Niño , Ácido Metilmalónico/sangre , Homocistinuria/tratamiento farmacológico , Homocistinuria/genética , Lactante , Mutación Missense , Homocigoto , Heterocigoto , Homocisteína/sangre , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/sangre , AdultoRESUMEN
Patients with sickle cell disease (SCD) in Germany exhibit a substantial genetic diversity in the ß-globin genotype. Data collected by the national German SCD registry reflect this diversity and allowed us to analyze the phenotypes associated with different SCD genotypes. Our study focused on 90 patients with HbS/ß-thalassaemia (HbS/ß-thal) and compared these to patients with HbSS and HbSC. Patients with HbS/ß-thal were classified into three groups: HbS/ß0-thal (no HbA), HbS/ß+-thal (HbA < 14%), and HbS/ß++-thal (HbA≥14%). In comparison to HbSS, patients with HbS/ß++-thal had higher Hb-levels, lower hemolytic activity and rarely required red blood cell transfusions. HbS/ß0-thal and HbS/ß+-thal closely resembled each other and are jointly referred to as HbS/ß0/+-thal. Compared to HbSS, patients with HbS/ß0/+-thal experienced a similar frequency of vasoocclusive crises and degree of hemolysis. However, the frequency of red blood cell transfusions (0.6 vs. 0.39/year, p = .0049) and splenic sequestration crises (42.4 vs. 15.5% of patients, p = 3.799e-05) was higher in HbS/ß0/+-thal than in HbSS, but close to zero in HbS/ß++-thal. In conclusion, the level of HbA expression determines the phenotype of HbS/ß+-thal. HbS/ß-thal expressing no or little HbA is hematologically similar to HbSS, but causes a previously unknown high risk of splenic sequestration.
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Natural products exhibit interesting structural features and significant biological activities. The discovery of new bioactive molecules is a complex process that requires high-quality metabolite profiling data to properly target the isolation of compounds of interest and enable their complete structural characterization. The same metabolite profiling data can also be used to better understand chemotaxonomic links between species. This Data Descriptor details a dataset resulting from the untargeted liquid chromatography-mass spectrometry metabolite profiling of 76 natural extracts of the Celastraceae family. The spectral annotation results and related chemical and taxonomic metadata are shared, along with proposed examples of data reuse. This data can be further studied by researchers exploring the chemical diversity of natural products. This can serve as a reference sample set for deep metabolome investigation of this chemically rich plant family.
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Celastraceae , Metabolómica , Productos Biológicos/química , Celastraceae/química , Metaboloma , Extractos Vegetales/química , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Purpose: Renal replacement therapy (RRT) is used in hyperammonemia to reduce the concentration of ammonia in the blood. In the case of plasma hyperosmolarity, RRT can also rapidly decrease plasma osmolarity, which may increase cerebral edema in these patients and favor the occurrence of brain herniation. Methods: We conducted a retrospective clinical study in a tertiary care university-affiliated hospital. All patients admitted in a Pediatric Intensive Care Unit (PICU), less than 18 years old with ammonemia >150â µmol/L and who underwent RRT between January 2015 and June 2023 were included. We collected data on plasma osmolarity levels, osmolar gap and blood ammonia levels before and during RRT. Results: Eleven patients were included (10 with acute liver failure and 1 with a urea cycle disorders). Their mean age was 36.2 months. Before RRT, the median highest measured osmolarity was 320 (305-324)â mOsm/L, whereas the median calculated osmolarity was 303 (293-314)â mOsm/L, corresponding to an osmolar gap of 14â mOsm/L. Ammonia blood level over 400â µmol/L are significantly associated with higher plasma osmolarity (P-Value <0.001). In one case, a patient had a brain herniation episode after a quick osmolar drop. This episode was reversed by the administration of hyperosmolar agents and the temporary suspension of RRT. Conclusion: This study highlights the hyperosmolarity and high osmolar gap that occur in children with hyperammonemia. A careful monitoring and control of plasma osmolarity evolution may alert clinician on the risk of occurrence of neurological complication such as brain herniation.
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Botrytis cinerea is a necrotrophic phytopathogen able to attack more than 200 different plant species causing strong yield losses worldwide. Many synthetic fungicides have been developed to control this disease, resulting in the rise of fungicide-resistance B. cinerea strains. The aim of this study was to identify Streptomyces strains showing antagonistic activity against B. cinerea to contribute to plant protection in an environmentally friendly way. We isolated 15 Actinomycete strains from 9 different Swiss soils. The culture filtrates of three isolates showing antifungal activity inhibited spore germination and delayed mycelial growth of B. cinerea. Infection experiments showed that Arabidopsis thaliana plants were more resistant to this pathogen after leaf treatment with the Streptomyces filtrates. Bioassay-guided isolation of the active compounds revealed the presence of germicidins A and B as well as of oligomycins A, B, and E. While germicidins were mostly inactive, oligomycin B reduced the mycelial growth of B. cinerea significantly. Moreover, all three oligomycins inhibited this fungus' spore germination, suggesting that these molecules might contribute to the Streptomyces's ability to protect plants against infection by the broad host-pathogen Botrytis cinerea. IMPORTANCE: This study reports the isolation of new Streptomyces strains with strong plant-protective potential mediated by their production of specialized metabolites. Using the broad host range pathogenic fungus Botrytis cinerea, we demonstrate that the cell-free filtrate of selected Streptomyces isolates efficiently inhibits different developmental stages of the fungus, including mycelial growth and the epidemiologically relevant spore germination. Beyond in vitro experiments, the strains and their metabolites also efficiently protected plants against the disease caused by this pathogen. This work further identifies oligomycins as active compounds involved in the observed antifungal activity of the strains. This work shows that we can harness the natural ability of soil-borne microbes and of their metabolites to efficiently fight other microbes responsible for significant crop losses. This opens the way to the development of environmentally friendly health protection measures for crops of agronomical relevance, based on these newly isolated strains or their metabolic extracts containing oligomycins.
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Arabidopsis , Botrytis , Oligomicinas , Enfermedades de las Plantas , Microbiología del Suelo , Streptomyces , Botrytis/efectos de los fármacos , Botrytis/crecimiento & desarrollo , Streptomyces/clasificación , Streptomyces/genética , Streptomyces/aislamiento & purificación , Arabidopsis/microbiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Oligomicinas/farmacología , Suiza , Esporas Fúngicas/efectos de los fármacos , Esporas Fúngicas/crecimiento & desarrollo , Antifúngicos/farmacología , Micelio/efectos de los fármacos , Micelio/crecimiento & desarrolloRESUMEN
The ENPKG framework organizes large heterogeneous metabolomics data sets as a knowledge graph, offering exciting opportunities for drug discovery and chemodiversity characterization.
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Understanding the distribution of hundreds of thousands of plant metabolites across the plant kingdom presents a challenge. To address this, we curated publicly available LC-MS/MS data from 19,075 plant extracts and developed the plantMASST reference database encompassing 246 botanical families, 1,469 genera, and 2,793 species. This taxonomically focused database facilitates the exploration of plant-derived molecules using tandem mass spectrometry (MS/MS) spectra. This tool will aid in drug discovery, biosynthesis, (chemo)taxonomy, and the evolutionary ecology of herbivore interactions.
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microbeMASST, a taxonomically informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbe-derived metabolites and relative producers without a priori knowledge will vastly enhance the understanding of microorganisms' role in ecology and human health.
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Metabolómica , Espectrometría de Masas en Tándem , Humanos , Metabolómica/métodos , Bases de Datos FactualesRESUMEN
The Streptomyces genus is known to produce many specialized metabolites of value for medicine, but the potential of these metabolites in agronomy remains largely unexplored. In this study, we investigated three phylogenetically closely related Streptomyces strains (B5, B91, and B135) isolated from three distinct soil samples in Sudan. Despite belonging to the same species, these strains exhibited different ranges of Phytophthora infestans inhibition. The objective of this work was to identify the active compound(s) responsible for the inhibition of P. infestans and of other plant pathogens by comparing the genomes and metabolomes of the three strains which showed distinct activity patterns: B5 was the strongest inhibitor of oomycetes, B5 and B91 both inhibited most fungi and B135 was the only strain showing antibacterial activity. Our comparative genomic and metabolomic analysis identified borrelidin as the bioactive compound underlying B5's strong anti-oomycete activity and highlighted a few other metabolites as putative candidates underlying the strains' antifungal and antibacterial activities. This study illustrates the power of comparative genomics and metabolomics on phylogenetically closely related strains of differing activities to highlight bioactive compounds that could contribute to new sustainable crop protection strategies.
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Streptomyces , Streptomyces/metabolismo , Antifúngicos/metabolismo , Genómica , Hongos/metabolismo , Antibacterianos/farmacología , Antibacterianos/metabolismoRESUMEN
Introduction: In contrast to the dynamics observed in plant/pathogen interactions, endophytic fungi have the capacity to establish enduring associations within their hosts, leading to the development of a mutually beneficial relationship that relies on specialized chemical interactions. Research indicates that the presence of endophytic fungi has the ability to significantly modify the chemical makeup of the host organism. Our hypothesis proposes the existence of a reciprocal exchange of chemical signals between plants and fungi, facilitated by specialized chemical processes that could potentially manifest within the tissues of the host. This research aimed to precisely quantify the portion of the cumulative fungal endophytic community's metabolome detectable within host leaves, and tentatively evaluate its relevance to the host-endophyte interplay. The understory palm Astrocaryum sciophilum (Miq.) Pulle was used as a interesting host plant because of its notable resilience and prolonged life cycle, in a tropical ecosystem. Method: Using advanced metabolome characterization, including UHPLC-HRMS/MS and molecular networking, the study explored enriched metabolomes of both host leaves and 15 endophytic fungi. The intention was to capture a metabolomic "snapshot" of both host and endophytic community, to achieve a thorough and detailed analysis. Results and discussion: This approach yielded an extended MS-based molecular network, integrating diverse metadata for identifying host- and endophyte-derived metabolites. The exploration of such data (>24000 features in positive ionization mode) enabled effective metabolome comparison, yielding insights into cultivable endophyte chemodiversity and occurrence of common metabolites between the holobiont and its fungal communities. Surprisingly, a minor subset of features overlapped between host leaf and fungal samples despite significant plant metabolome enrichment. This indicated that fungal metabolic signatures produced in vitro remain sparingly detectable in the leaf. Several classes of primary metabolites were possibly shared. Specific fungal metabolites and/or compounds of their chemical classes were only occasionally discernible in the leaf, highlighting endophytes partial contribution to the overall holobiont metabolome. To our knowledge, the metabolomic study of a plant host and its microbiome has rarely been performed in such a comprehensive manner. The general analytical strategy proposed in this paper seems well-adapted for any study in the field of microbial- or microbiome-related MS and can be applied to most host-microbe interactions.