Human Neonatal Keratinocytes Have Very High Levels of Cellular Vitamin A-Binding Proteins

Since cellular retinol- and retinoic acid-binding proteins (CRBP and CRABP) mediate the effects of vitamin A on epidermal differentiation, the levels of these binding proteins were measured in the epidermal and dermal layers of newborn, human foreskin as well as in primary cultures of keratinocytes and fibroblasts from these layers. ligand binding assays w3ith saturating concentrations of all trans-[3H]retinol or of all trans-[11-3H]retinoic acid were used to quantitate amounts of binding proteins in cytosols prepared form these skin layers or cultured cells. The epidermal levels of CRABP and CRBP (60.9 ± 14.4 and 7.3 ± 1.7 pmol per mg cytosol protein, respectively) were markedly higher than that reported for adult epidermis but wer comparable to levels in keratinocytes cultured from neonatal foreskin epidermis (61.8 ± 7.8 and 10.7 ± 2.5, respectively). The levels of CRABP were much lower in the foreskin dermis than in the epidermis and the levels measured in the fibroblasts cultured form this dermis were consistent with the dermal levels. however, CRBP levels in cultured dermal fibroblasts were very low and could not account for the dermal CRBP levels, suggesting that another dermal cell type has high levels of CRBP

Relationship Between Gangliosides and Doubling Times in Cultured Human Brain and Brain Tumor Cells

Cells cultured in vitro from normal human white matter and 3 individual brain tumors exhibited the following population doubling times: cells from normal human white matter, 64 ± 22 h, glioblastoma multiforme, 43 ± 11 h; malignant astrocytoma, 98 ± 19 h; and anaplastic oligodendroglioma, 81 ± 24 h. Cells were seeded at subconfluent density, pulse-labelled for 24 h with the ganglioside precursor D-[1-14C]glucosamine and harvested. Radioactive patterns of extracted gangliosides showed that incorporation of label into disialoganglioside was significantly higher in the samples with longer population doubling times than in samples with shorter population doubling times. These findings suggest gangliosides may play a role in regulation of cell growth

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction