Purine Homeostasis Is Necessary for Developmental Timing, Germline Maintenance and Muscle Integrity in Caenorhabditis elegans

International audiencePurine homeostasis is ensured through a metabolic network widely conserved from prokaryotes to humans. Purines can either be synthesized de novo, reused, or produced by interconversion of extant metabolites using the so-called recycling pathway. Although thoroughly characterized in microorganisms, such as yeast or bacteria, little is known about regulation of the purine biosynthesis network in metazoans. In humans, several diseases are linked to purine metabolism through as yet poorly understood etiologies. Particularly, the deficiency in adenylosuccinate lyase (ADSL)-an enzyme involved both in the purine de novo and recycling pathways-causes severe muscular and neuronal symptoms. In order to address the mechanisms underlying this deficiency, we established Caenorhabditis elegans as a metazoan model organism to study purine metabolism, while focusing on ADSL. We show that the purine biosynthesis network is functionally conserved in C. elegans. Moreover, adsl-1 (the gene encoding ADSL in C. elegans) is required for developmental timing, germline stem cell maintenance and muscle integrity. Importantly, these traits are not affected when solely the de novo pathway is abolished, and we present evidence that germline maintenance is linked specifically to ADSL activity in the recycling pathway. Hence, our results allow developmental and tissue specific phenotypes to be ascribed to separable steps of the purine metabolic network in an animal model

Atipical kawasaki disease with coronary aneurysm in infant

Kawasaki disease is an acute febrile disease of unknown etiology, characterized by systemic vascular inflammation involving the small and medium sized arteries, with a predilection for the coronary arteries. It represents the leading cause of acquired heart diseases in children in developed countries. Diagnosis, difficult because of the clinical characteristics of the disease with typical signs and symptoms appearing sequentially and not simultaneously, may be even more complicated in case of unusual presentation, leading to delay in recognition, particularly in infant in whom a higher incidence of coronary arteries aneurysms has been reported. A high index of suspicion of Kawasaki disease must be maintained in case of prolonged fever in these patients. Timely appropriate treatment is essential to avoid severe sequels. We report the case of a 2 months old male infant with persistent febrile episode, transferred to us from another institution, who presented on echocardiography giant aneurysms on both coronary arteries

Characterisation and classification of oligometastatic disease : a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study

A new deep branch of eurasian mtDNA macrohaplogroup M reveals additional complexity regarding the settlement of Madagascar.

BACKGROUND: Current models propose that mitochondrial DNA macrohaplogroups M and N evolved from haplogroup L3 soon after modern humans left Africa. Increasingly, however, analysis of isolated populations is filling in the details of, and in some cases challenging, aspects of this general model. RESULTS: Here, we present the first comprehensive study of three such isolated populations from Madagascar: the Mikea hunter-gatherers, the neighbouring Vezo fishermen, and the Merina central highlanders (n = 266). Complete mitochondrial DNA genome sequences reveal several unresolved lineages, and a new, deep branch of the out-of-Africa founder clade M has been identified. This new haplogroup, M23, has a limited global distribution, and is restricted to Madagascar and a limited range of African and Southwest Asian groups. CONCLUSIONS: The geographic distribution, phylogenetic placement and molecular age of M23 suggest that the colonization of Madagascar was more complex than previously thought.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Structure-Property Correlation in Sodium Borophosphate Glasses Modified with Niobium Oxide

Bulk glasses of the series (100−x)[0.4Na2O-0.2Nb2O5-0.4P2O5]-xB2O3 with x = 0–48 mol% B2O3 were prepared by slow cooling in air. Their glass transition temperature increases within the range of 0–16 mol% B2O3, but further additions of B2O3 result in its decrease. Their structure was investigated by Raman, 11B, and 31P MAS NMR spectroscopy. The relative number of BO4 units decreases with increasing B2O3 content, while the number of BO3 units increases up to 59 % at x = 48. The upfield shift of a broad resonance peak in the 31P MAS NMR spectra is ascribed to an increasing connectedness of the structural network with increasing B2O3 content. A strong Raman band at 916–929 cm−1 shows the presence of NbO6 octahedra in the structural network of these glasses. With the B2O3 addition, a decrease in DC conductivity is observed, which is attributed to the decrease in the concentration of Na+ ions

Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

Background Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could ‘rescue’ both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX. Methods We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses. Results Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, pT genotype. Conclusion Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX

Active DNA demethylation of developmental cis-regulatory regions predates vertebrate origins

DNA methylation [5-methylcytosine (5mC)] is a repressive gene-regulatory mark required for vertebrate embryogenesis. Genomic 5mC is tightly regulated through the action of DNA methyltransferases, which deposit 5mC, and ten-eleven translocation (TET) enzymes, which participate in its active removal through the formation of 5-hydroxymethylcytosine (5hmC). TET enzymes are essential for mammalian gastrulation and activation of vertebrate developmental enhancers; however, to date, a clear picture of 5hmC function, abundance, and genomic distribution in nonvertebrate lineages is lacking. By using base-resolution 5mC and 5hmC quantification during sea urchin and lancelet embryogenesis, we shed light on the roles of nonvertebrate 5hmC and TET enzymes. We find that these invertebrate deuterostomes use TET enzymes for targeted demethylation of regulatory regions associated with developmental genes and show that the complement of identified 5hmC-regulated genes is conserved to vertebrates. This work demonstrates that active 5mC removal from regulatory regions is a common feature of deuterostome embryogenesis suggestive of an unexpected deep conservation of a major gene-regulatory module