AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes.

Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF-/Y ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF-/Y thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid ß-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid ß-oxidation (e.g., palmitic acid assimilation), the AIF-/Y thymocytes retrieved the ATP levels of the AIF +/Y cells. As a consequence, it was possible to significantly reestablish AIF-/Y thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.

Semimature stage: a checkpoint in a dendritic cell maturation program that allows for functional reversion after signal-regulatory protein-alpha ligation and maturation signals.

CD47 on live cells actively engages signal-regulatory protein-alpha (SIRP-alpha) on phagocytes and delivers a negative signal that prevents their elimination. We evaluated the biological consequences of SIRP-alpha ligation on the dendritic cell (DC) response to maturation signals and the potential interplay with the IL-10/IL-10R inhibitory pathway. At first, CD47/SIRP-alpha allowed the generation of mature migratory DCs not producing IL-12, IFN-gamma-inducible protein-10, and CCL19. Rather, they secreted neutrophils attracting chemokine CXCL5 and IL-1beta, reflecting a partial block in functional DC maturation. Afterward, semimature DCs functionally regressed in an IL-10-independent fashion toward cells that retrieved the cardinal features of immature DCs: re-expression of CCR5, loss of DC-lysosome-associated membrane protein, high endocytosis, and impaired allostimulatory functions. The global gene expression profile of IL-10 and SIRP-alpha-ligated DC demonstrated two distinct molecular pathways. IL-10R and SIRP-alpha expression were reciprocally down-regulated by CD47 and IL-10, respectively. These results emphasize that the SIRP-alpha pathway might be part of the molecular machinery used by the DC to dampen or resolve an inflammatory response in an IL-10-independent manner.

Ultrasound kidney dimension and the correlation of kidney length and age, weight and height of children aged from 6 to 8 years old

Background:The dimension and function of kidney have close relationship. In the developing countries, the index on kidney dimension of children has rather fully studied. In Viet Nam, most of studies only conducted on adults. Objectives:This study aims to determine the ultrasound kidney dimension and the correlation of kidney length and age, weight and height of children aged from 6 to 8 years old. Subjects and method: The data was obtained from a prospective study on 180 normal children at age from 6 to 8 years. Each kidney was measured length, width , thickness, and parenchymal thickness, and the mean values were recorded. The relationship of kidney length with age, body weight, body height were also taken. Results: Kidney dimension was increased by age. The average ultrasound kidney dimension:+ Right kidney: At 6 years old: Boy: length: 72.8\xb14; width: 31.2\xb13 ; thickness: 33.9\xb12 ; Girl: length: 69.8\xb15; width: 30.4\xb12 ; thickness: 32.7\xb12. At 7 years old: Boy: length: 75.2\xb14; width: 31.9\xb12; thickness: 33.8\xb13; Girl: length: 75.8\xb15; width: 32.0\xb12; thickness: 32.9\xb14; + Left kidney: At 6 years old: Boy: length: 73.9\xb15; width: 33.7\xb13 ; thickness: 34.9\xb12 ; Girl: length: 71.1\xb14; width: 32.4\xb13 ; thickness: 32.4\xb16. At 7 years old: Boy: length: 77.7\xb13; width: 33.8\xb13 ; thickness:34.7\xb12; Girl: length: 76.9\xb17; width: 32.0\xb12; thickness: 33,9\xb15; The kidney length, kidney weight, kidney volume of boys were bigger than girls, and the difference was significant (p<0.05). Conclusion: The kidney length correlated strongly and positively with body weight, body height and age.