Thyssencole7545

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.This study evaluated the shielding effect of a newly developed dose-reduction fiber (DRF) made from barium sulfate, in terms of radiation doses delivered to patients' radiosensitive organs and operator during C-arm fluoroscopy and its impact on the quality of images. A C-arm fluoroscopy unit was placed beside a whole-body phantom. Radiophotoluminescent glass dosimeters were attached to the back and front of the whole-body phantom at 20 cm intervals. Radiation doses were measured without DRF and with it applied to the back (position 1), front (position 2) or both sides (position 3) of the phantom. To investigate the impact of DRF on the quality of fluoroscopic images, step-wedge and modulation transfer function phantoms were used. The absorbed radiation doses to the back of the phantom significantly decreased by 25.3-88.8% after applying DRF to positions 1 and 3. The absorbed radiation doses to the front of the phantom significantly decreased by 55.3-93.6% after applying DRF to positions 2 and 3. The contrast resolution values for each adjacent step area fell in the range 0.0119-0.0209, 0.0128-0.0271, 0.0135-0.0339 and 0.0152-0.0339 without and with DRF applied to positions 1, 2 and 3, respectively. The investigated DRF effectively reduces absorbed radiation doses to patients and operators without decreasing the quality of C-arm fluoroscopic images. Therefore, routine clinical use of the DRF is recommended during the use of C-arm fluoroscopy.Exome sequencing has identified the glyceronephosphate O-acyltransferase (GNPAT) gene as a genetic modifier of iron overload in hereditary hemochromatosis (HH). Subjects with HFE (Homeostatic Iron Regulator) p.C282Y mutations and the GNPAT p.D519G variant had more iron loading compared with subjects without the GNPAT variant. In response to an oral iron challenge, women with GNPAT polymorphisms loaded more iron as compared with women without polymorphisms, reinforcing a role for GNPAT in iron homeostasis. The aim of the present study was to develop and characterize an animal model of disease to further our understanding of genetic modifiers, and in particular the role of GNPAT in iron homeostasis. We generated an Hfe/Gnpat mouse model reminiscent of the patients previously studied and studied these mice for up to 26 weeks. We also examined the effect of dietary iron loading on mice with reduced Gnpat expression. learn more Gnpat heterozygosity in Hfe knockout mice does not play a role in systemic iron homeostasis; Gnpat+/- mice fed a high-iron diet, however, had lower hepatic hepcidin (HAMP) mRNA expression, whereas they have significantly higher serum iron levels and transferrin saturation compared with wildtype (WT) littermates on a similar diet. These results reinforce an independent role of GNPAT in systemic iron homeostasis, reproducing in an animal model, the observations in women with GNPAT polymorphisms subjected to an iron tolerance test.CXCL8, a member of CXC chemokines, was constitutively expressed in many types of human cancers, and its overexpression has been shown to play a critical role in promoting tumorigenesis. The purpose of the present study was to determine CXCL8 expression in a commercial human liver tissue microarray, and elucidate the effects and underlying mechanisms by which CXCL8 is involved in the malignant progression of human liver cancer. Our data showed that high level expression of CXCL8 in tissues with liver cancer was identified as compared with non-cancer tissues, and its up-regulation was closely associated with clinical stage and tumor infiltration. In vitro, exogenous CXCL8 at concentrations of 10, 20 or 40 ng/ml obviously stimulated the proliferation abilities of HepG2 cells. Coupled with this, 10, 20 or 40 ng/ml of exogenous CXCL8 also triggered a significant elevation in HepG2 cells migration. Additionally, overexpression of CXCL8 in HepG2 cells also resulted in increased cell proliferation and migration capacities. Finally, Western blotting analysis showed that overexpression of CXCL8 increased the expression of ERK, p-ERK and survivin, decreased the expression of caspase-3 and BAX at protein level.In the immune system, T lymphocytes undergo rapid clonal expansion upon pathogen infection. Following pathogen clearance, most of proliferated T cells will be eliminated by the apoptosis pathway to keep the balance of immune cells. FASLG, by interacting with its cognate receptor FAS, plays a major role in controlling the T cell death. FASLG is a type II transmembrane protein, with its C-terminal extracellular domain responsible for interacting with FAS. The N-terminal cytosolic region, despite short and intrinsically disordered, plays critical roles on the protein stability and transportation. The correct localization, either on the plasma membrane or secreted with exosome, or shed into the extracellular region after protease cleavage, has a great impact on the proper function of FASLG. Following synthesis, FASLG is transported by intracellular vesicle transportation system to the final destination. In this report, ALG2, a molecule identified in the T cell apoptosis and shown to be involved in vesicle trafficking previously, was found to interact with FASLG and regulate FASLG transportation.