Introduction L’insuline dégludec (IDég), une nouvelle insuline basale formant des multi-hexamères solubles après injection sous-cutanée, possède un effet hypoglycémiant ultra-long et stable. Ces ...propriétés pourraient diminuer l’hypoglycémie nocturne par rapport à ce qui est observé avec d’autres analogues de l’insuline et devraient permettre à davantage de patients d’atteindre les valeurs cibles de glycémie à jeun (GAJ) sans risque d’hypoglycémie. Patients et méthodes Cette analyse poolée a étudié la proportion de patients diabétiques de type 2 (DT2) atteignant la GAJ cible (< 5 mmol/L 90 mg/dL) sans hypoglycémie nocturne confirmée dans quatre essais randomisés en ouvert et en « treat-to-target » (titration forcée), où les patients (n = 2 380) recevaient soit l’IDég soit l’insuline glargine (IGlar) administrées ×1/j en association avec des antidiabétiques oraux, pendant 26 ou 52 semaines. L’hypoglycémie confirmée était définie par une glycémie plasmatique < 3,1 mmol/L (56 mg/dL) ou des épisodes sévères nécessitant une assistance, et l’hypoglycémie nocturne confirmée par des épisodes ayant lieu entre 00 h 01 et 05 h 59. Le critère a été analysé par un modèle de régression logistique incluant le traitement, le sexe, l’essai, le traitement antidiabétique à la sélection et la région comme facteurs fixes, et l’âge et la GAJ à l’inclusion comme covariables. Résultats La proportion de patients atteignant la GAJ cible était plus importante avec IDég comparée à IGlar (respectivement 40,9 % et 29,4 %). De plus, les patients traités par IDég présentaient moins fréquemment des épisodes d’hypoglycémie nocturne confirmée vs IGlar (respectivement 13,3 % et 16,6 %). La probabilité d’atteindre la GAJ cible sans hypoglycémie nocturne confirmée était supérieure de 82 % avec IDég comparée à IGlar : odds ratio estimé IDég/IGlar = 1,82 IC95 % 1,49 ; 2,22. Conclusion Les patients DT2 sont plus enclins à atteindre la GAJ cible sans hypoglycémie nocturne confirmée avec IDég qu’avec IGlar. Ces résultats pourraient avoir des implications importantes dans l’atteinte du contrôle glycémique en pratique clinique.
The classification of myelodysplastic syndromes is based on the morphological criteria proposed by the French-American-British (FAB) and World Health Organization (WHO) groups. Accurate enumeration ...of blast cells, although essential for diagnosis of myelodysplastic syndrome and for assignment to prognostic groups, is often difficult, due to imprecise criteria for the morphological definition of blasts and promyelocytes. An International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) of hematopathologists and hematologists expert in the field of myelodysplastic syndrome reviewed the morphological features of bone marrows from all subtypes of myelodysplastic syndrome and agreed on a set of recommendations, including recommendations for the definition and enumeration of blast cells and ring sideroblasts. It is recommended that (1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference. Clear definitions and a differential count of a sufficient number of cells is likely to improve precision in the diagnosis and classification of myelodysplastic syndrome. Recommendations should be applied in the context of the WHO classification.
The three DNA methyltransferase (DNMT)-inhibiting cytosine nucleoside analogues, azacitidine, decitabine and zebularine, which are currently studied as nonintensive therapy for myelodysplastic ...syndromes and acute myeloid leukemia (AML), differ in structure and metabolism, suggesting that they may have differential molecular activity. We investigated cellular and molecular effects of the three substances relative to cytarabine in Kasumi-1 AML blasts. Under in vitro conditions mimicking those used in clinical trials, the DNMT inhibitors inhibited proliferation and triggered apoptosis but did not induce myeloid differentiation. The DNMT inhibitors showed no interference with cell-cycle progression whereas cytarabine treatment resulted in an S-phase arrest. Quantitative methylation analysis of hypermethylated gene promoters and of genome-wide LINE1 fragments using bisulfite sequencing and MassARRAY suggested that the hypomethylating potency of decitabine was stronger than that of azacitidine; zebularine showed no hypomethylating activity. In a comparative gene expression analysis, we found that the effects of each DNMT inhibitor on gene transcription were surprisingly different, involving several genes relevant to leukemogenesis. In addition, the gene methylation and expression analyses suggested that the effects of DNMT-inhibiting cytosine nucleoside analogues on the cellular transcriptome may, in part, be unrelated to direct promoter DNA hypomethylation, as previously shown by others.
Radical discoveries? Semiconductor quantum dots (QDs) produce free radicals upon UV irradiation in aqueous solution. While CdS QDs generate superoxide and hydroxyl radicals, only the latter are ...produced from CdSe QDs. In contrast, CdSe/ZnS core/shell QDs, often applied in biolabeling applications, do not generate radicals.
Continuous flow biocatalysis is an emerging field of industrial biotechnology that uses enzymes immobilized in flow channels for the production of value‐added chemicals. We describe the construction ...of self‐assembling all‐enzyme hydrogels that are comprised of two tetrameric enzymes. The stereoselective dehydrogenase LbADH and the cofactor‐regenerating glucose 1‐dehydrogenase GDH were genetically fused with a SpyTag or SpyCatcher domain, respectively, to generate two complementary homo‐tetrameric building blocks that polymerize under physiological conditions into porous hydrogels. Mounted in microfluidic reactors, the gels show excellent stereoselectivity with near quantitative conversion in the reduction of prochiral ketones along with high robustness under process and storage conditions. The gels function as compartment that retains intermediates thus enabling high total turnover numbers of the expensive cofactor NADP(H).
Hydrogels comprised entirely of enzymes self‐assemble under physiological conditions by covalent SpyTag/SpyCatcher interaction to porous hydrogels. Mounted in microfluidic reactors, the gels exhibit excellent stability, stereoselectivity, and cofactor retention without the need for additional carriers or membranes.
The use of living microorganisms integrated within electrochemical devices is an expanding field of research, with applications in microbial fuel cells, microbial biosensors or bioreactors. We ...describe the use of porous nanocomposite materials prepared by DNA polymerization of carbon nanotubes (CNTs) and silica nanoparticles (SiNPs) for the construction of a programmable biohybrid system containing the exoelectrogenic bacterium Shewanella oneidensis. We initially demonstrate the electrical conductivity of the CNT-containing DNA composite by employment of chronopotentiometry, electrochemical impedance spectroscopy, and cyclic voltammetry. Cultivation of Shewanella oneidensis in the conductive materials shows that the exoelectrogenic bacteria populate the matrix of the conductive composite, while nonexoelectrogenic Escherichia coli remain on its surface. Moreover, the ability to use extracellular electron transfer pathways is positively correlated with the number of cells within the conductive synthetic biofilm matrix. The Shewanella-containing composite remains stable for several days and shows electrochemical activity, indicating that the conductive backbone is capable of extracting the metabolic electrons produced by the bacteria under strictly anoxic conditions and conducting them to the anode. Programmability of this biohybrid material system is demonstrated by on-demand release and degradation induced by a short-term enzymatic stimulus. We believe that the application possibilities of such biohybrid materials could even go beyond microbial biosensors, bioreactors, and fuel cell systems.
Combining structural DNA nanotechnology with the virtually unlimited variety of enzymes offers unique opportunities for generating novel biocatalytic devices. However, the immobilization of enzymes ...is still restricted by a lack of efficient covalent coupling techniques. The rational re‐engineering of the genetically fusible SNAP‐tag linker is reported here. By replacing five amino acids that alter the electrostatic properties of the SNAP_R5 variant, up to 11‐fold increased coupling efficiency with benzylguanine‐modified oligonucleotides and DNA origami nanostructures (DON) was achieved, resulting in typical occupancy densities of 75%. The novel SNAP_R5 linker can be combined with the equally efficient Halo‐based oligonucleotide binding tag (HOB). Since both linkers exhibit neither cross‐reactivity nor non‐specific binding, they allowed orthogonal assembly of an enzyme cascade consisting of the stereoselective ketoreductase Gre2p and the cofactor‐regenerating isocitrate dehydrogenase on DON. The cascade showed approximately 1.6‐fold higher activity in a stereoselective cascade reaction than the corresponding free solubilized enzymes. The connector system presented here and the methods used to validate it represent important tools for further development of DON‐based multienzyme systems to investigate mechanistic effects of substrate channeling and compartmentalization relevant for exploitation in biosensing and catalysis.
Through rational protein engineering, an effective, genetically fusible connector for site‐selective immobilization of enzymes on DNA nanostructures is developed. Due to the greater than tenfold increase in coupling efficiency, a biocatalytic cascade reaction for the stereoselective reduction of carbonyl compounds is established by combining it with an equally efficient orthogonal connector.
Human hair dated to Late Prehistory is exceedingly rare in the Western Mediterranean. Archaeological excavations in the Bronze Age burial and cult cave of Es Càrritx, in Menorca (Balearic Islands) ...provided some human hair strands involved in a singular funerary rite. This finding offered the opportunity to explore the possible use of drug plants by Late Bronze Age people. Here we show the results of the chemical analyses of a sample of such hair using Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS). The alkaloids ephedrine, atropine and scopolamine were detected, and their concentrations estimated. These results confirm the use of different alkaloid-bearing plants by local communities of this Western Mediterranean island by the beginning of the first millennium cal BCE.
Progress in the development of protein-immobilization strategies and methods has made protein biochips increasingly accessible. The integration of these assay and analysis platforms into biomedical ...and biotechnological research has substantially expanded the repertoire of methods available for proteomics and biomarker research and for drug development. This Minireview highlights selected developments in the application of protein biochips in these fields.
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