Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance

Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation. Thereafter, erythroblasts are blocked at the orthochromatic stage, exhibiting a significant decreased level of enucleation, concomitant with an increased cell death. We demonstrate that mitochondria clearance starts at the transition from basophilic to polychromatic erythroblast, and that VDAC1 downregulation induces the mitochondrial retention. In damaged mitochondria from non-erythroid cells, VDAC1 was identified as a target for Parkin-mediated ubiquitination to recruit the phagophore. Here, we showed that VDAC1 is involved in phagophore’s membrane recruitment regulating selective mitophagy of still functional mitochondria from human erythroblasts. These findings demonstrate for the first time a crucial role for VDAC1 in human erythroblast terminal differentiation, regulating mitochondria clearance.Fil: Moras, Martina. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Hattab, Claude. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Gonzalez Menendez, Pedro. Laboratoire d’Excellence GR-Ex; Francia. Université Montpellier II; Francia. Centre National de la Recherche Scientifique; FranciaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Odontologia; ArgentinaFil: Dussiot, Michael. Universite de Paris; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Larghero, Jerome. Hôpital Saint-Louis. Unité de Thérapie cellulaire; FranciaFil: Le Van Kim, Caroline. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Kinet, Sandrina. Laboratoire d’Excellence GR-Ex; Francia. Université Montpellier II; Francia. Centre National de la Recherche Scientifique; FranciaFil: Taylor, Naomi. Laboratoire d’Excellence GR-Ex; Francia. Centre National de la Recherche Scientifique; Francia. Université Montpellier II; Francia. Center for Cancer Research; Estados UnidosFil: Lefevre, Sophie D.. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Ostuni, Mariano. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; Franci

The Spitzer Survey of the Small Magellanic Cloud: S3MC Imaging and Photometry in the Mid- and Far-Infrared Wavebands

We present the initial results from the Spitzer Survey of the Small Magellanic Cloud (S3MC), which imaged the star-forming body of the Small Magellanic Cloud (SMC) in all seven MIPS and IRAC wavebands. We find that the F_8/F_24 ratio (an estimate of PAH abundance) has large spatial variations and takes a wide range of values that are unrelated to metallicity but anticorrelated with 24 um brightness and F_24/F_70 ratio. This suggests that photodestruction is primarily responsible for the low abundance of PAHs observed in star-forming low-metallicity galaxies. We use the S3MC images to compile a photometric catalog of ~400,000 mid- and far-infrared point sources in the SMC. The sources detected at the longest wavelengths fall into four main categories: 1) bright 5.8 um sources with very faint optical counterparts and very red mid-infrared colors ([5.8]-[8.0]>1.2), which we identify as YSOs. 2) Bright mid-infrared sources with mildly red colors (0.16<[5.8]-[8.0]<0.6), identified as carbon stars. 3) Bright mid-infrared sources with neutral colors and bright optical counterparts, corresponding to oxygen-rich evolved stars. And, 4) unreddened early B stars (B3 to O9) with a large 24 um excess. This excess is reminiscent of debris disks, and is detected in only a small fraction of these stars (<5%). The majority of the brightest infrared point sources in the SMC fall into groups one to three. We use this photometric information to produce a catalog of 282 bright YSOs in the SMC with a very low level of contamination (~7%).Comment: Accepted for publication in The Astrophysical Journal. Given the draconian figure file-size limits implemented in astro-ph, readers are encouraged to download the manuscript with full quality images from http://celestial.berkeley.edu/spitzer/publications/s3mcsurvey.pd

The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients

Accumulation of Polychlorinated Biphenyls in Adipocytes: Selective Targeting to Lipid Droplets and Role of Caveolin-1

Background : Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that preferentially accumulate in lipid-rich tissues of contaminated organisms. Although the adipose tissue constitutes a major intern reservoir of PCBs and recent epidemiological studies associate PCBs to the development of obesity and its related disorders, little is known about the mechanisms involved in their uptake by the adipose tissue and their intracellular localization in fat cells

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

White Matter Development in Early Puberty: A Longitudinal Volumetric and Diffusion Tensor Imaging Twin Study

White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ∼85%), surface area (∼85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = –0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization

Large-scale association analyses identify host factors influencing human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P <5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) <P <5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis