Inhibition of Various Receptor Tyrosine Kinase (rtk) Families

Activation of cell surface growth factor receptor tyrosine kinases (RTKs) results in cellular proliferation, differentiation and survival. Humans have 58 RTKs, categorized into twenty subfamilies based on their structural properties and ligand specificity. One of the most well-studied RTKs, the epidermal growth factor receptor (EGFR), is mutated or overexpressed in many human cancers including non-small cell lung cancer and glioblastoma. Several EGFR inhibitors have been approved by the FDA, and numerous additional inhibitors are being pursued as potential cancer therapeutics. Structural studies of the EGFR tyrosine kinase domain suggest that different inhibitors bind selectively to either the active or the inactive conformation of the kinase. Contrary to this supposition, computational studies of inhibitor-stabilized EGFR conformations have suggested that erlotinib can bind equally well to either the active or inactive forms of the EGFR kinase domain. We tested this hypothesis using a mutated EGFR kinase domain that can adopt either the inactive or active kinase conformation in crystals, and determined a structure with erlotinib bound to the inactive conformation – suggesting that this inhibitor can bind either ‘state’. We also determined the crystal structure of this EGFR kinase variant bound to a novel ErbB2 inhibitor (55A) found in screens designed to select inhibitors that bind the active state. When bound to this compound, the EGFR kinase domain adopted only the active conformation, suggesting that erlotinib and 55A select different kinase ‘states’. Collaborative approaches combining biochemical, structural and cell signaling studies suggest new considerations in predicting modes of inhibitor binding in the development of therapeutic agents for cancer. Several activating mutations in the anaplastic lymphoma kinase (ALK) gene have been implicated in neuroblastoma. The small molecule tyrosine kinase inhibitor crizotinib, which inhibits ALK and Met, was recently approved by the FDA for the treatment of non-small cell lung cancer (NSCLC), and is currently in early-phase clinical testing in patients with neuroblastoma (NB). Numerous additional ALK inhibitors are also being pursued as potential therapeutics. However, more and more mutations in the ALK tyrosine kinase domain (TKD) are being found in patients with neuroblastoma. Several of these are associated with primary resistance to currently available ALK inhibitors, and several mutations in oncogenic ALK fusions have been linked to acquired crizotinib resistance. Understanding how different ALK mutations activate its kinase domain, and how they change inhibitor sensitivity, is therefore crucial for further clinical development of ALK-targeted therapeutics. We have studied the biochemical consequences of a wide variety of ALK kinase domain mutations in parallel both with studies of their transforming abilities and computational studies of their structural effects. Our first goal was to use these data to predict the effects of new clinically emerging ALK mutations on ALK’s transforming ability, signaling activity, and drug sensitivity. A second goal was to identify the most potent ALK inhibitor that has inhibitory effects on the widest possible range of ALK mutants using biochemical and cellular assays, with a view to identifying a clinical path forward. Our studies provide valuable mechanistic insight into how ALK is regulated, and also lay important groundwork for guiding more refined targeted therapy in neuroblastoma patients

Unsupervised Hyperbolic Representation Learning via Message Passing Auto-Encoders

Most of the existing literature regarding hyperbolic embedding concentrate upon supervised learning, whereas the use of unsupervised hyperbolic embedding is less well explored. In this paper, we analyze how unsupervised tasks can benefit from learned representations in hyperbolic space. To explore how well the hierarchical structure of unlabeled data can be represented in hyperbolic spaces, we design a novel hyperbolic message passing auto-encoder whose overall auto-encoding is performed in hyperbolic space. The proposed model conducts auto-encoding the networks via fully utilizing hyperbolic geometry in message passing. Through extensive quantitative and qualitative analyses, we validate the properties and benefits of the unsupervised hyperbolic representations. Codes are available at https://github.com/junhocho/HGCAE

Templated native silk smectic gels

One aspect of the present invention relates to a method of preparing a fibrous protein smectic hydrogel by way of a solvent templating process, comprising the steps of pouring an aqueous fibrous protein solution into a container comprising a solvent that is not miscible with water; sealing the container and allowing it to age at about room temperature; and collecting the resulting fibrous protein smectic hydrogel and allowing it to dry. Another aspect of the present invention relates to a method of obtaining predominantly one enantiomer from a racemic mixture, comprising the steps of pouring an aqueous fibrous protein solution into a container comprising a solvent that is not miscible with water; sealing the container and allowing it to age at about room temperature; allowing the enantiomers of racemic mixture to diffuse selectively into the smectic hydrogel in solution; removing the smectic hydrogel from the solution; rinsing predominantly one enantiomer from the surface of the smectic hydrogel; and extracting predominantly one enantiomer from the interior of the smectic hydrogel. The present invention also relates to a smectic hydrogel prepared according to an aforementioned method

CSGM Designer: a platform for designing cross-species intron-spanning genic markers linked with genome information of legumes.

BackgroundGenetic markers are tools that can facilitate molecular breeding, even in species lacking genomic resources. An important class of genetic markers is those based on orthologous genes, because they can guide hypotheses about conserved gene function, a situation that is well documented for a number of agronomic traits. For under-studied species a key bottleneck in gene-based marker development is the need to develop molecular tools (e.g., oligonucleotide primers) that reliably access genes with orthology to the genomes of well-characterized reference species.ResultsHere we report an efficient platform for the design of cross-species gene-derived markers in legumes. The automated platform, named CSGM Designer (URL: http://tgil.donga.ac.kr/CSGMdesigner), facilitates rapid and systematic design of cross-species genic markers. The underlying database is composed of genome data from five legume species whose genomes are substantially characterized. Use of CSGM is enhanced by graphical displays of query results, which we describe as "circular viewer" and "search-within-results" functions. CSGM provides a virtual PCR representation (eHT-PCR) that predicts the specificity of each primer pair simultaneously in multiple genomes. CSGM Designer output was experimentally validated for the amplification of orthologous genes using 16 genotypes representing 12 crop and model legume species, distributed among the galegoid and phaseoloid clades. Successful cross-species amplification was obtained for 85.3% of PCR primer combinations.ConclusionCSGM Designer spans the divide between well-characterized crop and model legume species and their less well-characterized relatives. The outcome is PCR primers that target highly conserved genes for polymorphism discovery, enabling functional inferences and ultimately facilitating trait-associated molecular breeding

Korean Nova Records in A.D. 1073 and A.D. 1074: R Aquarii

R Aqr is known to be a symbiotic binary system with an associated extended emission nebula, possibly produced by a historic outburst. To find the associated historic records, we searched for and compiled all 'Guest Star' and 'Peculiar Star' records in three Korean 'official' history books that cover almost two thousand years, Samguksagi, Goryeosa, Joseonwangjosillok. In addition to the record of A.D. 1073, previously noted by Li (1985), we have found in Goryeosa another candidate record of A.D. 1074, which has the same positional description as that of A.D. 1073 with an additional brightness description. We examined various aspects of the two records and conclude that they both are likely to be the records of outburst of R Aqr. This means that there were two successive outbursts in A.D. 1073 and in A.D. 1074, separated by approximately one year. Based on these records, we estimate the distance to R Aqr to be 273 pc if the expansion of the nebula has been at a constant rate. The brightness record of A.D. 1074 corresponds to the absolute magnitude at outburst of M_(outburst) = -6.2 mag. ~ -5.2 mag. at this distance. The two Korean records associated with R Aqr may provide astronomically meaningful constraints to the outburst model of R Aqr and the formative process of its nebulosity.Comment: 10 pages, 2 figures, 1 appendix. To appear in Astronomy and Astrophysic

Templated Native Silk Smectic Gels

One aspect of the present invention relates to a method of preparing a fibrous protein smectic hydrogel by way of a solvent templating process, comprising the steps of pouring an aqueous fibrous protein solution into a container comprising a solvent that is not miscible with water; sealing the container and allowing it to age at about room temperature; and collecting the resulting fibrous protein smectic hydrogel and allowing it to dry. Another aspect of the present invention relates to a method of obtaining predominantly one enantiomer from a racemic mixture, comprising the steps of pouring an aqueous fibrous protein solution into a container comprising a solvent that is not miscible with water; sealing the container and allowing it to age at about room temperature; allowing the enantiomers of racemic mixture to diffuse selectively into the smectic hydrogel in solution; removing the smectic hydrogel from the solution; rinsing predominantly one enantiomer from the surface of the smectic hydrogel; and extracting predominantly one enantiomer from the interior of the smectic hydrogel. The present invention also relates to a smectic hydrogel prepared according to an aforementioned method