The oxygen sensitive ␣-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1␣ by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1␣ mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1␣ mRNA levels and HIF-1␣ promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1␣ mRNA and HIF-1␣ promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-B (NFB) nuclear translocation and activity. In line, expression of the NFB subunits p50 and p65 enhanced HIF-1␣ mRNA levels, whereas blocking of NFB by an inhibitor of nuclear factor-B attenuated HIF-1␣ mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFB site within the HIF-1␣ promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFB subunits to the HIF-1␣ promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1␣ mRNA expression via the PI3K/AKT pathway and activation of NFB.

Key Points Healthy human BM is enriched for PC lacking CD19 that express a prosurvival and distinctly mature phenotype. CD19− PC resist mobilization into blood during immune responses after vaccination as well as B-cell depletion with rituximab.

No abstract

Rubinstein-Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation. The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date. Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated. We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS ("moderate or incomplete RSTS", detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H. We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS. Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.

Current evidence supports the use of the ASES, SST, or OSS. We recommend the SST for longitudinal studies or clinical trials, the Dutch Shoulder Disability Questionnaire for clinical practice to minimize administration burden, and the ASES or OSS to discriminate among patients' or groups' evaluations at one point of time.

Data availability RNA-seq data and ribosomal profiling data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE106858. Mass spectrometry data that support the findings of this study have been deposited in figshare.com under the title of this manuscript (A MYC/GCN2/eIF2a negative feedback loop limits protein synthesis to prevent MYC dependent apoptosis in colorectal cancer) by the author Werner Schmitz (

The evolutionarily conserved proteins REI1-LIKE (REIL1) and REIL2 have four conserved zinc finger domains and are Arabidopsis thaliana homologs of the cytosolic 60S ribosomal maturation factor Rei1p (for Required for isotropic bud growth1 protein) from yeast (Saccharomyces cerevisiae) and its paralog Reh1p (for REI1 homologue1 protein). The yeast and A. thaliana paralogs result from independent gene duplications. The A. thaliana REIL paralogs are required specifically in the cold (10°C) but not for growth at optimal temperature (20°C). A reil1-1 reil2-1 double mutant is arrested at 10°C prior to the emergence of the first rosette leaf. Two allelic reil2 mutants, reil2-1 and reil2-2, form small spoon-shaped leaves at 10°C. This phenomenon reverts after emergence of the inflorescence in the cold or upon shift to 20°C. Except for a slightly delayed germination, a reil1-1 mutant shows no further growth phenotype under the currently investigated conditions. A comparative analysis demonstrates conserved coexpression of orthologous genes from yeast and A. thaliana that are coregulated with yeast rei1 or with A. thaliana REIL2, respectively. The conserved correlations point to a role of A. thaliana REIL proteins in the maturation of the eukaryotic ribosomal 60S subunit. We support this conclusion by heterologous complementation of the cold-induced growth defect of the yeast Drei1 deletion.

Schmidt et al. show that loss of the membrane-bound metalloprotease ADAM17 led to impaired intestinal cancer development in the murine APCmin/+ model, which also depended on IL-6 trans-signaling via the soluble IL-6R and could be blocked by the specific IL-6 trans-signaling inhibitor sgp130Fc.