Recent progress toward understanding the molecular biology of von Recklinghausen neurofibromatosis

The gene for von Recklinghausen neurofibromatosis (NF1) was recently identified by positional cloning and found to code for a large, ubiquitously expressed protein. This protein has both structural and functional similarity to a family of proteins with guanosine triphosphatase–activating properties, involved in the regulation of the protooncogene ras . One of the postulated functions of the NF1 gene product may relate to its ability to regulate ras -mediated cell proliferation. Selective pharmacotherapy directed at downregulating ras may be of benefit to patients with NF1.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50350/1/410310515_ftp.pd

The meson spectrum in large-N QCD

We present lattice results on the meson spectrum and decay constants in large-N QCD. The results are obtained in the quenched approximation for N = 2,3,4,5,6,7 and 17 and extrapolated to N = ∞. Xth Quark Confinement and the Hadron Spectrum

Progeria: Translational insights from cell biology

Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a “poster child” for how basic cell biology can be translated to the clinic

Discovery of active enhancers through bidirectional expression of short transcripts

Abstract Background Long-range regulatory elements, such as enhancers, exert substantial control over tissue-specific gene expression patterns. Genome-wide discovery of functional enhancers in different cell types is important for our understanding of genome function as well as human disease etiology. Results In this study, we developed an in silico approach to model the previously reported phenomenon of transcriptional pausing, accompanied by divergent transcription, at active promoters. We then used this model for large-scale prediction of non-promoter-associated bidirectional expression of short transcripts. Our predictions were significantly enriched for DNase hypersensitive sites, histone H3 lysine 27 acetylation (H3K27ac), and other chromatin marks associated with active rather than poised or repressed enhancers. We also detected modest bidirectional expression at binding sites of the CCCTC-factor (CTCF) genome-wide, particularly those that overlap H3K27ac. Conclusions Our findings indicate that the signature of bidirectional expression of short transcripts, learned from promoter-proximal transcriptional pausing, can be used to predict active long-range regulatory elements genome-wide, likely due in part to specific association of RNA polymerase with enhancer regions

Atropos: specific, sensitive, and speedy trimming of sequencing reads

A key step in the transformation of raw sequencing reads into biological insights is the trimming of adapter sequences and low-quality bases. Read trimming has been shown to increase the quality and reliability while decreasing the computational requirements of downstream analyses. Many read trimming software tools are available; however, no tool simultaneously provides the accuracy, computational efficiency, and feature set required to handle the types and volumes of data generated in modern sequencing-based experiments. Here we introduce Atropos and show that it trims reads with high sensitivity and specificity while maintaining leading-edge speed. Compared to other state-of-the-art read trimming tools, Atropos achieves significant increases in trimming accuracy while remaining competitive in execution times. Furthermore, Atropos maintains high accuracy even when trimming data with elevated rates of sequencing errors. The accuracy, high performance, and broad feature set offered by Atropos makes it an appropriate choice for the pre-processing of Illumina, ABI SOLiD, and other current-generation short-read sequencing datasets. Atropos is open source and free software written in Python (3.3+) and available at https://github.com/jdidion/atropos

Transfection of primary human skin fibroblasts by electroporation

Primary human skin fibroblasts are an accessible source of phenotypically and karyotypically normal human cells, but are difficult to transfect with exogenous DNA. Here we demonstrate that both transient expression and stable transformation can be carried out by the method of electroporation. Highly efficient transient chloramphenicol acetyltransferase expression was shown after transfection with plasmid pRSVCAT. Stable transformation of human skin fibroblasts to G418 resistance was obtained after electroporation with neo-containing plasmids at an efficiency of approximately 1.4 x 10-5/[mu]g DNA. The ability to easily transfect these cells with exogenous DNA may have important applications in the study of human genetic diseases and cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27179/1/0000177.pd

A Pair of Compact Red Galaxies at Redshift 2.38, Immersed in a 100 kpc Scale Ly-alpha Nebula

We present Hubble Space Telescope (HST) and ground-based observations of a pair of galaxies at redshift 2.38, which are collectively known as 2142-4420 B1 (Francis et al. 1996). The two galaxies are both luminous extremely red objects (EROs), separated by 0.8 arcsec. They are embedded within a 100 kpc scale diffuse Ly-alpha nebula (or blob) of luminosity ~10^44 erg/s. The radial profiles and colors of both red objects are most naturally explained if they are young elliptical galaxies: the most distant yet found. It is not, however, possible to rule out a model in which they are abnormally compact, extremely dusty starbursting disk galaxies. If they are elliptical galaxies, their stellar populations have inferred masses of ~10^11 solar masses and ages of ~7x10^8 years. Both galaxies have color gradients: their centers are significantly bluer than their outer regions. The surface brightness of both galaxies is roughly an order of magnitude greater than would be predicted by the Kormendy relation. A chain of diffuse star formation extending 1 arcsec from the galaxies may be evidence that they are interacting or merging. The Ly-alpha nebula surrounding the galaxies shows apparent velocity substructure of amplitude ~ 700 km/s. We propose that the Ly-alpha emission from this nebula may be produced by fast shocks, powered either by a galactic superwind or by the release of gravitational potential energy.Comment: 33 pages, 9 figures, ApJ in press (to appear in Jun 10 issue

A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

BACKGROUND: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. RESULTS: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. CONCLUSION: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system