Applications and Implementation of Nucleosomal Supergroove Binders for Biochemical Study

Nucleosomes are molecular spools composed of an octameric core of histones that binds and wraps ~147 base pairs (bp) of DNA into a tight superhelical coil. They are the fundamental structural unit of all eukaryotic chromosomes, and consequently, many nuclear proteins possess binding motifs specific for nucleosomal recognition. Notable nucleosome-specific binding sites include the acidic patch on the nucleosomal surface, as well as histone tail residues for post-translational modification (PTM). The winding of DNA around the histone octamer also produces another recognition motif called a &lsquo;supergroove&rsquo;. This motif aligns major and minor grooves that are ~80 bp apart on linear DNA into quasi-continuous supergrooves spanning two gyres of the DNA superhelix. Recently, it has been shown that some transcription factors (TFs) may prefer binding nucleosomal DNA in a transgyre fashion, signifying that the nucleosomal supergroove could potentially serve as an important molecular recognition platform. Each supergroove is composed of 10-12 bp of solvent-accessible DNA compared to 5-6 consecutive bp of a single gyre. Therefore, the alignment of DNA sequences from adjacent gyres essentially magnifies the degree of specificity with which a supergroove-binding ligand can complex with a nucleosome. Since such a ligand would effectively cross-brace both DNA gyres, this immediately suggests a nucleosome-stabilizing function for supergroove binders. This study focuses on the implementation of pyrrole-imidazole polyamides (PIPs) as supergroove binders as well as the viability of an alternative, zinc-finger-based solution. The results provide novel insight for the development of reagents that can serve as sequence-specific chaperones for structural/mechanistic studies of nucleosomal systems.</p

Heterologous Expression of ATG8c from Soybean Confers Tolerance to Nitrogen Deficiency and Increases Yield in Arabidopsis

Nitrogen is an essential element for plant growth and yield. Improving Nitrogen Use Efficiency (NUE) of crops could potentially reduce the application of chemical fertilizer and alleviate environmental damage. To identify new NUE genes is therefore an important task in molecular breeding. Macroautophagy (autophagy) is an intracellular process in which damaged or obsolete cytoplasmic components are encapsulated in double membraned vesicles termed autophagosomes, then delivered to the vacuole for degradation and nutrient recycling. One of the core components of autophagosome formation, ATG8, has been shown to directly mediate autophagosome expansion, and the transcript of which is highly inducible upon starvation. Therefore, we postulated that certain homologs of Saccharomyces cerevisiae ATG8 (ScATG8) from crop species could have potential for NUE crop breeding. A soybean (Glycine max, cv. Zhonghuang-13) ATG8, GmATG8c, was selected from the 11 family members based on transcript analysis upon nitrogen deprivation. GmATG8c could partially complement the yeast atg8 mutant. Constitutive expression of GmATG8c in soybean callus cells not only enhanced nitrogen starvation tolerance of the cells but accelerated the growth of the calli. Transgenic Arabidopsis over-expressing GmATG8c performed better under extended nitrogen and carbon starvation conditions. Meanwhile, under optimum growth conditions, the transgenic plants grew faster, bolted earlier, produced larger primary and axillary inflorescences, eventually produced more seeds than the wild-type. In average, the yield was improved by 12.9%. We conclude that GmATG8c may serve as an excellent candidate for breeding crops with enhanced NUE and better yield

Diverse Applications of Nanomedicine

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic. \ua9 2017 American Chemical Society

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist