Stat3 isoforms, α and β, demonstrate distinct intracellular dynamics with prolonged nuclear retention of Stat3β mapping to its unique C-terminal end

Two isoforms of Stat3 (signal transducer and activator of transcription 3) are expressed in cells, alpha (p92) and beta (p83), both derived from a single gene by alternative mRNA splicing. The 55-residue C-terminal transactivation domain of Stat3alpha is deleted in Stat3beta and replaced by seven unique C-terminal residues (CT7) whose function remains uncertain. We subcloned the open reading frames of Stat3alpha and Stat3beta into the C terminus of green fluorescent protein (GFP). Fluorescent microscopic analysis of HEK293T cells transiently transfected with GFP-Stat3alpha or GFP-Stat3beta revealed similar kinetics and cytokine concentration dependence of nuclear accumulation; these findings were confirmed by high throughput microscope analysis of murine embryonic fibroblasts that lacked endogenous Stat3 but stably expressed either GFP-Stat3alpha or GFP-Stat3beta. However, although time to half-maximal cytoplasmic reaccumulation after cytokine withdrawal was 15 min for GFP-Stat3alpha, it was >180 min for GFP-Stat3beta. Furthermore, although the intranuclear mobility of GFP-Stat3alpha was rapid and increased with cytokine stimulation, the intranuclear mobility of GFP-Stat3beta in unstimulated cells was slower than that of GFP-Stat3alpha in unstimulated cells and was slowed further following cytokine stimulation. Deletion of the unique CT7 domain from Stat3beta eliminated prolonged nuclear retention but did not alter its intranuclear mobility. Thus, Stat3alpha and Stat3beta have distinct intracellular dynamics, with Stat3beta exhibiting prolonged nuclear retention and reduced intranuclear mobility especially following ligand stimulation. Prolonged nuclear retention, but not reduced intranuclear mobility, mapped to the CT7 domain of Stat3beta

Electrical Probing of Field-Driven Cascading Quantized Transitions of Skyrmion Cluster States in MnSi Nanowires

Magnetic skyrmions are topologically stable whirlpool-like spin textures that offer great promise as information carriers for future ultra-dense memory and logic devices1-4. To enable such applications, particular attention has been focused on the skyrmions properties in highly confined geometry such as one dimensional nanowires5-8. Hitherto it is still experimentally unclear what happens when the width of the nanowire is comparable to that of a single skyrmion. Here we report the experimental demonstration of such scheme, where magnetic field-driven skyrmion cluster (SC) states with small numbers of skyrmions were demonstrated to exist on the cross-sections of ultra-narrow single-crystal MnSi nanowires (NWs) with diameters, comparable to the skyrmion lattice constant (18 nm). In contrast to the skyrmion lattice in bulk MnSi samples, the skyrmion clusters lead to anomalous magnetoresistance (MR) behavior measured under magnetic field parallel to the NW long axis, where quantized jumps in MR are observed and directly associated with the change of the skyrmion number in the cluster, which is supported by Monte Carlo simulations. These jumps show the key difference between the clustering and crystalline states of skyrmions, and lay a solid foundation to realize skyrmion-based memory devices that the number of skyrmions can be counted via conventional electrical measurements

Finding Complex Biological Relationships in Recent PubMed Articles Using Bio-LDA

The overwhelming amount of available scholarly literature in the life sciences poses significant challenges to scientists wishing to keep up with important developments related to their research, but also provides a useful resource for the discovery of recent information concerning genes, diseases, compounds and the interactions between them. In this paper, we describe an algorithm called Bio-LDA that uses extracted biological terminology to automatically identify latent topics, and provides a variety of measures to uncover putative relations among topics and bio-terms. Relationships identified using those approaches are combined with existing data in life science datasets to provide additional insight. Three case studies demonstrate the utility of the Bio-LDA model, including association predication, association search and connectivity map generation. This combined approach offers new opportunities for knowledge discovery in many areas of biology including target identification, lead hopping and drug repurposing.Comment: 14 pages, 8 figures, 10 table

Chem2Bio2RDF: a semantic framework for linking and data mining chemogenomic and systems chemical biology data

<p>Abstract</p> <p>Background</p> <p>Recently there has been an explosion of new data sources about genes, proteins, genetic variations, chemical compounds, diseases and drugs. Integration of these data sources and the identification of patterns that go across them is of critical interest. Initiatives such as Bio2RDF and LODD have tackled the problem of linking biological data and drug data respectively using RDF. Thus far, the inclusion of chemogenomic and systems chemical biology information that crosses the domains of chemistry and biology has been very limited</p> <p>Results</p> <p>We have created a single repository called Chem2Bio2RDF by aggregating data from multiple chemogenomics repositories that is cross-linked into Bio2RDF and LODD. We have also created a linked-path generation tool to facilitate SPARQL query generation, and have created extended SPARQL functions to address specific chemical/biological search needs. We demonstrate the utility of Chem2Bio2RDF in investigating polypharmacology, identification of potential multiple pathway inhibitors, and the association of pathways with adverse drug reactions.</p> <p>Conclusions</p> <p>We have created a new semantic systems chemical biology resource, and have demonstrated its potential usefulness in specific examples of polypharmacology, multiple pathway inhibition and adverse drug reaction - pathway mapping. We have also demonstrated the usefulness of extending SPARQL with cheminformatics and bioinformatics functionality.</p

Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)

The prostate is a site of high expression of serine proteinases including members of the kallikrein-related peptidase (KLK) family, as well as other secreted and membrane-anchored serine proteinases. It has been known for some time that members of this enzyme family elicit cellular responses by acting directly on cells. More recently, it has been recognised that for serine proteinases with specificity for cleavage after arginine and lysine residues (trypsin-like or tryptic enzymes) these cellular responses are often mediated by cleavage of members of the proteinase-activated receptor (PAR) family - a four member sub-family of G protein-coupled receptors. Here, we review the expression of PARs in prostate, the ability of prostatic trypsin-like KLKs and other prostate-expressed tryptic enzymes to cleave PARs, as well as the prostate cancer-associated consequences of PAR activation. In addition, we explore the dysregulation of trypsin-like serine proteinase activity through the loss of normal inhibitory mechanisms and potential interactions between these dysregulated enzymes leading to aberrant PAR activation, intracellular signalling and cancer-promoting cellular changes

Evolution of superconductivity in isovalent Te-substituted KxFe2-ySe2 crystals

We report the evolution of superconductivity and the phase diagram of the KxFe2-ySe2-zTez (z=0-0.6) crystals grown by a simple one-step synthesis. No structural transition is observed in any crystals, while lattice parameters exhibit a systematic expansion with Te content. The Tc exhibits a gradual decrease with increasing Te content from Tconset = 32.9 K at z = 0 to Tconset = 27.9 K at z = 0.5, followed by a sudden suppression of superconductivity at z = 0.6. Upon approaching a Te concentration of 0.6, the shielding volume fraction decreases and eventually drops to zero. Simultaneously, hump positions in r-T curve shift to lower temperatures. These results suggest that isovalent substitution of Te for Se in KxFe2-ySe2 crystals suppresses the superconductivity in this system.Comment: 10 pages, 1 table, 8 figure