Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy

Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We now show that glutamine and glucose also fuel an indispensible dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of UDP-GlcNAc, a substrate for cellular glycosyltransferases. Immune activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-GlcNAc glycosyltransferase as compared to naïve cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation, via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation, and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology

Mortality in paediatric burns victims: A retrospective review from 2009 to 2012 in a single centre

Background. Childhood mortality is high in low- and middle-income countries. Burns are one of the five leading causes of childhood injury mortality in South Africa (SA). While there is an abundance of literature on burns in the developed world, there are far fewer publications dealing with childhood mortality related to burns in Africa and SA.Objective. To describe the mortality of children admitted to a dedicated paediatric burns unit, and investigate factors contributing to reducing mortality.Methods. A retrospective review was performed of patients admitted to the Johnson & Johnson Paediatric Burns Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, SA, between May 2009 and April 2012.Results. During the study period, 1 372 patients aged ≤10 years were admitted to the unit. There were 1 089 admissions to the general ward and 283 admissions to the paediatric burns intensive care unit (PBICU). The overall mortality rate was 7.9% and the rate for children admitted to the PBICU 29.3%; 90.8% of deaths occurred in children aged ≤5 years. Of children admitted with an inhalational injury, 89.5% died. No child with a burn injury >60% of total body surface area (TBSA) survived.Conclusions. Our overall mortality rate was 7.9%, and the rate declined significantly over the 3-year study period from 11.7% to 5.1%. Age ≤5 years, the presence of inhalational injury, burn injury >30% of TBSA and admission to the PBICU were significant risk factors for mortality

Organo-functionalized metal–oxide clusters: synthesis and characterization of the reduced cationic species [NaV IV 6 O 6 {(OCH 2 CH 2 ) 2 NH} 6 ] +

A new heteropolyoxovanadium compound, [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O), was synthesized and characterized by single-crystal X-ray diffraction analysis, cyclic voltammetry, FTIR and UV-vis spectroscopy, and TGA. [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O) contains the diethanolamine functionalized oxovanadium cationic cluster, [NaV(IV)6O6{(OCH2CH2)2NH}6](+). The cluster cation is composed of a fully reduced cyclic {NaV6N6O18} framework which adopts an Anderson-like structure and is comprised of a ring of six edge-sharing {VO5N} octahedra linked to a central {NaO6} unit. Two (OCH2CH2-) arms of each of the six diethanolamine ligands are incorporated into the oxometalate core. FTIR spectra are consistent with the presence of expected V=Ot stretching modes and functionalization with diethanolamine. Electrochemical and UV-vis absorption properties are consistent with two distinct MLCT processes: the characteristic V=Ot dπ-pπ interaction, and a second process occurring through the hydrogen-terminated nitrogen atoms (V-N-H) of the octahedra forming the cyclic {NaV6N6O18} core

Differential Expression of Cadherin-2 and Cadherin-4 in the Developing and Adult Zebrafish Visual System

Cadherins are homophilic cell adhesion molecules that control development of a variety of tissues and maintenance of adult structures. Although cadherins have been implicated in the development of the brain, including the visual system, in several vertebrate species, little is known of their role in zebrafish. In this study, we examined distribution of cadherin-2 (Cdh2, N-cadherin) in the visual system of developing and adult zebrafish using both immunocytochemical and in situ hybridization methods, and we compared Cdh2 distribution to that of the previously reported and closely related cadherin-4 (Cdh4, R-cadherin). As in other vertebrates, in zebrafish embryos Cdh2 was widely expressed in the early nervous system, but its expression became more restricted as development proceeded. Cdh4 was not detectable until later in development, at about the time when the first ganglion cells are generated. Cdh2 and Cdh4 were expressed in distinct regions of developing visual structures, including the lens. We hypothesize that the differential expression of these two cadherins in developing zebrafish visual structures reflects functionally different roles in the development of the vertebrate visual system

Metallation of azobenzenes by fluorine-abstraction: structure of a ruthenium complex containing nonafluoro(phenylazo)phenyl-2 C , N ′ and diphenyl-2-(η-cyclopentadienylphenyl)phosphine groups

The formation of metallated azobenzene derivatives by fluorine-abstraction reactions using nucleophilic transition metal reagents has been achieved; the structure of an ortho-metallated complex, derived from decafluoroazobenzene and also containing a Ph2P(C6H4C5H 4) ligand is described

Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection

Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population