CHD7 and Runx1 interaction provides a braking mechanism for hematopoietic differentiation.

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.Bloodwise, CRUK, MRC, Wellcome Trust, NIH, Leukemia and Lymphoma Societ

Stable gold nanoflowers modified by zwitterionic sulfhydryl sulfobetaine for enhanced antitumor effiecieny

Gold nanoflowers are flower-like gold nanoparticles with high photothermal conversion efficiency. Unfortunately, many gold nanoflowers have complicated synthesis methods using toxicity molecules and lack colloidal stability. In this work, in order to improve the long-term colloidal stability of existing gold nanoflowers, sulfhydryl sulfobetaine (SB-SH) was modified on the surface of gold nanoflowers by S-Au bonds to produce SB-SH stabilized gold nanoflowers (SB-SH@AuNFs). SB-SH@AuNFs did not generate any precipitation within 24 h and had a high photothermal conversion efficiency at 38.9%. In addition, the relative cell viability of A549 cells was only 11% with 0.193 mM SB-SH@AuNFs under laser irradiation. More importantly, SB-SH@AuNFs had the best antitumor effect in vivo under 808 nm laser irradiation. Thus, stable SB-SH@AuNFs with high photothermal conversion efficient were synthesized by using zwitterionic molecules. The modification of gold nanoflowers using zwitterionic molecules here is a new method to improve the antitumor efficiency of noble metal photothermal agents

Mechanical response and data-driven fatigue model of interlayer soils in track-bed considering multi-factor coupling effect

International audienc

Complete mitochondrial genome sequences of sea slug Melanochlamys sp. (Cephalaspidae: Aglajidae)

One complete mitochondrial genome (mitogenomes) was determined for Melanochlamys sp. (Cephalaspidae: Aglajidae). The mitochondrial genome size was 13,795 bp. The sequence contains two ribosomal RNA genes (rrnL and rrnS), 20 tRNA genes, and 12 protein-coding genes (PCGs). The A + T content of the complete mitochondrial genome sequence was 68.2%. The base composition showed a tendency of high AT. The resulted maximum-likelihood (ML) tree of Opisthobranchia supported that genetic differences between Melanochlamys sp. with other species of Cephalaspidae, so that there is a well-defined separation of clades

Development of a Novel BAFF Responsive Cell Line Suitable for Detecting Bioactive BAFF and Neutralizing Antibodies against BAFF-Pathway Inhibiting Therapeutics

BAFF has a critical role in B-cell survival, maturation and function, which makes its pathway a prime therapeutic target for various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjögren’s syndrome. A cell-based assay that measures the functional activity of BAFF is required for many high throughput purposes, such as lead target screening and BAFF quantification. We report here the development of a sensitive BAFF responsive cell line via stable transfection of the BAFFR-TNFR1 hybrid receptor into monkey kidney epithelial COS-1 cells. The cellular response to BAFF can be detected by measuring the secretion of IL-8. This BAFF bioassay is not only reproducible and sensitive, but also responsive to a wide concentration range of BAFF stimulation in sera from various species. This cell line is useful in the development of sensitive bioassays to measure the levels of bioactive BAFF, inhibition of BAFF and neutralizing antibodies against any BAFF pathway-mediated therapeutic proteins

Müller glia are a major cellular source of survival signals for retinal neurons in diabetes

To dissect the role of vascular endothelial growth factor receptor-2 (VEGFR2) in Muller cells and its effect on neuroprotection in diabetic retinopathy (DR), we disrupted VEGFR2 in mouse Muller glia and determined its effect on Muller cell survival, neuronal integrity, and trophic factor production in diabetic retinas. Diabetes was induced with streptozotocin. Retinal function was measured with electroretinography. Miller cell and neuronal densities were assessed with morphometric and immunohistochemical analyses. Loss of VEGFR2 caused a gradual reduction in Muller goal density, which reached to a significant level 10 months after the onset of diabetes. This observation was accompanied by an age-dependent decrease of scotopic and photopic electroretinography amplitudes and accelerated loss of rod and cone photoreceptors, ganglion cell layer cells, and inner nuclear layer neurons and by a significant reduction of retinal glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Our results suggest that VEGFR2-mediated Muller cell survival is required for the viability of retinal neurons in diabetes. The genetically altered mice established in this study can be used as a diabetic animal model of nontoxin-induced Muller cell ablation, which will be useful for exploring the cellular mechanisms of neuronal alteration in DR

Expression of GFRα1 receptor splicing variants with different biochemical properties is modulated during kidney development

International audienc

Glial cell line-Derived Neurotrophic Factor differentially stimulates Ret mutants associated with the Multiple Endocrine Neoplasia type 2 syndromes and Hirschsprung’s disease

Ret is a receptor tyrosine kinase involved in several neoplastic and developmental diseases affecting the thyroid gland and tissues of neuroectodermal origin. Different ret mutations are associated with different disease phenotypes. Gain-of-function of ret is caused by gene rearrangements in thyroid papillary carcinomas and by point mutations in multiple endocrine neoplasia (MEN) type 2A syndrome (MEN2A), in familial medullary thyroid carcinoma (FMTC), and in the more severe MEN2B syndrome. Conversely, Hirschsprung’s disease (HSCR) is associated with loss of function of ret. Recently, it has been shown that glial cell line-derived neurotrophic factor (GDNF), by binding to the accessory molecule GDNFR-a, acts as a functional ligand of Ret and stimulates its tyrosine kinase and biological activity. To ascertain whether the biological effects of ret mutations are modulated by GDNF, we have investigated the responsiveness to GDNF of ret mutants in cell lines coexpressing GDNFR-a and MEN2A-, MEN2B-, FMTC-, or HSCR-associated ret mutants. Here, we show that triggering of GDNF affected only ret/MEN2B, i.e. it stimulated ret/MEN2B mitogenic and kinase activities, as well as its ability to phosphorylate Shc, a bona fide Ret substrate. In contrast, ret mutants associated with MEN2A or FMTC (carrying Cys634 or Cys620 mutations) were unresponsive to GDNF. HSCR mutations, by affecting either the extracellular or the intracellular Ret domain, impaired responsiveness to GDNF. These data suggest that the phenotype of human diseases caused by ret mutations can be differentially influenced by GDN