The Artist\u27s Hand in the Digital Age

For the first ten years of my career I practiced my craft — advertising art direction — exclusively by hand. To help me in the design process itself, I hired specialists. For typography, for instance, I chose a firm I admired in Minneapolis where the typographers would hand cut the film negatives letter by letter. In those days — the 1980s — each area of design had master craftsmen. I can remember one day walking into a warehouse with thirty-foot ceilings. On the back wall I saw a large horizontal canvas. The artist was suspended from scaffolding and covered in speckled paint dots. I wasn’t in an artist’s studio looking at a masterpiece half-finished. I was admiring a billboard — a hand painted one-of-a-kind billboard. This is not to say that the old methods of working by hand were entirely idyllic. They had countless drawbacks. IT took several days to put together a layout with Pantone paper and transfer type, only to realize the color combination was wrong and the time wasted. Because processes were slow and labor-intensive, choices were limited. In the mid 1980s, design studios and creative departments started using computers. For the first time I was able to select a color scheme, click a button, and see seemingly endless options instantaneously. It wasn’t long before the skilled craftsmen of type were replaced with digitized fonts loaded directly onto hard drives. Suddenly, the idea of working type by hand became economically unfeasible. The typographers closed up shop, threw out their old tools, and went out to look for new jobs. Several years later billboards were being painted on vinyl sheets right from our electronic files. Perfect replications of the original reproduced with speed and precision saved time and manpower. The new process had replaced the billboard artists almost overnight. I saw a generation of artisans exchanged for a generation of desktop publishers. Just like the craftsmen of the past, older methods of graphic design have been cast aside finding their way uneasily into the category of fine art. And now fine art, too, may cast them aside. Recently the Dean of the Fine Arts Program at Virginia Commonwealth University has held several meetings where he discussed the elimination of older printmaking methods in order to expand digital printmaking. Computers, it seems, will not be simply content with displacing the old hand processes; they want to eliminate them. For most young designers the computer has completely replaced the hand in every stage of the design process. I’ve noticed in many cases designers aren’t problem solving outside of the computer. It isn’t even considered. Certainly, the goal and outcome of my creative project were not intended to revive antiquated hand methods, at least as they historically existed. But hopefully, I’ve created something original by combining both hand methods and modern technology. If nothing else, I want younger designers to think beyond the 20GB hard drive as the only tool in their process

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97

Abstract The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP’s potential as a novel therapeutic target

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders. [Display omitted] We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels