Deoxyguanosine kinase deficiency: natural history and liver transplant outcome

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype–phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Synthèse de pharmacophores par cycloaddition [3+2] à partir de carbohydrates

Le travail décrit dans ce manuscrit s'inscrit dans un cadre général de développer une méthodologie propice à la synthèse asymétrique de nouvelles familles de molécules pharmacologiques potentielles. L'étape-clef dans cette approche est la cycloaddition dipolaire-1,3, une réaction avec un fort potentiel, puisque des nouvelles liaisons et des centres asymétriques sont générés en une étape. Aisément accessibles, relativement peu onéreux et possédant de nombreux centres chiraux, les carbohydrates ont été utilisés comme précurseurs de cette réaction. Après une étude bibliographique de la cycloaddition [3+2] appliquée aux sucres, nous décrivons la synthèse régio- et stéréosélective d'isoxazolidines, analogues de la Mésembrine, dans des conditions thermiques classiques puis sous champ micro-ondes. Enfin, dans une seconde partie, nous développons la synthèse de systèmes pyranopyrrolidiniques bicycliques obtenus avec de bons rendements et d'excellentes régio- et stéréosélectivités.We describe herein the development of a novel methodology propitious to the asymmetric synthesis of new families of molecules with potential pharmacological interest. Our strategy involves the 1,3-dipolar cycloaddition reaction as key step: indeed, this reaction allows the creation of new bonds and asymmetric centres in a single step. Easily accessible and inexpensive unsaturated sugars are employed as precursors in this reaction, taking advantage of the existing chiral centres. We describe the regio- and stereoselective synthesis of isoxazolidines, a class of molecules of structural analogy with Sceletium alkaloids such Mesembrine. The use of microwaves in the context of the [3+2] cycloaddition reaction using carbohydrates was also explored. The major improvements are reduced time of reaction and higher yields due to reduced side products. Finally, we describe the synthesis of pyranopyrrolidinic bicyclic systems obtained in good yields and high regio- and stereoselectivity.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Reducing the diffraction artifacts while implementing a phase function on a spatial light modulator

International audienceSpatial light modulators are often used to implement phase modulation. Since they are pixelated, the phase function is usually approximated by a regularly sampled piecewise constant function, and the periodicity of the pixel sampling generates annoying diffraction peaks. We theoretically investigate two pixelation techniques: the isophase method and a new nonperiodic method derived from the Voronoi tessellation technique.We show that, for a suitable choice of parameters, the diffraction peaks disappear and are replaced by a smoothly varying halo. We illustrate the potential of these two techniques for implementing a lens function and wavefront correction

Minimization of diffraction peaks of spatial light modulators using Voronoi diagrams

13 pagesInternational audienceIt is possible to reduce the diffraction peaks of a Spatial Light Modulator (SLM) by breaking the periodicity of the pixels shape. We propose a theoretical investigation of a SLM that would be based on a Voronoi diagram, obtained by deforming a regular grid, and show that for a specific deformation parameter the diffraction peaks disappear and are replaced with a speckle-like diffraction halo. We also develop a simple model to determine the shape and the level of this halo

Réalisation d'un composant optique transparent à structure cellulaire

Un composant optique transparent à structure cellulaire comprend un réseau de parois (106) qui forme un ensemble de cellules (104) juxtaposées parallèlement à une surface du composant. Pour réaliser ... ... un tel composant, on détermine d'abord un ensemble irrégulier de points (101, 105) dans la surface du composant, chaque point étant destiné à former un centre d'une des cellules. Ensuite, on détermine une position et une orientation de chaque paroi, de sorte que l'ensemble des cellules forme une partition de Voronoï de la surface du composant. Le composant présente alors un niveau de transparence qui est compatible avec une utilisation optique ou ophtalmique