Orphan quality control shapes network dynamics and gene expression.

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex networks are established remains poorly understood. Here, we identify the E3 ligase UBR5 as a signaling hub that helps degrade unpaired subunits of multiple transcriptional regulators that act within a network centered on the c-Myc oncoprotein.

Calibration and thermal test results of prototype bolometer sensors for ITER fusion reactor.

For over 10 years, several bolometer sensors with different properties have been tested in the IBOVAC facility. The aim has been to develop a bolometer sensor that can be operated in ITER and can withstand harsh operating conditions. For this purpose, important physical properties of the sensors, i.

Screening of Chemical Libraries Using Embryos and Tadpoles for Phenotypic Drug Discovery.

Phenotypic drug discovery assesses the effect of small molecules on the phenotype of cells, tissues, or whole organisms without a priori knowledge of the target or pathway. Using vertebrate embryos instead of cell-based assays has the advantage that the screening of small molecules occurs in the context of the complex biology and physiology of the whole organism. Fish and amphibians are the only classes of vertebrates with free-living larvae amenable to high-throughput drug screening in multiwell dishes.

Functional characterization of two 20β-hydroxysteroid dehydrogenase type 2 homeologs from Xenopus laevis reveals multispecificity.

The African clawed frog, Xenopus laevis, is a versatile model for biomedical research and is largely similar to mammals in terms of organ development, anatomy, physiology, and hormonal signaling mechanisms. Steroid hormones control a variety of processes and their levels are regulated by hydroxysteroid dehydrogenases (HSDs). The subfamily of 20β-HSD type 2 enzymes currently comprises eight members from teleost fish and mammals.

Engineering Xenopus embryos for phenotypic drug discovery screening.

Many rare human inherited diseases remain untreatable despite the fact that the disease causing genes are known and adequate mouse disease models have been developed. In vivo phenotypic drug screening relies on isolating drug candidates by their ability to produce a desired therapeutic phenotype in whole organisms. Embryos of zebrafish and Xenopus frogs are abundant, small and free-living.

Stratified high-throughput screening sets enable flexible screening strategies from a single plated collection.

Customized compound picking and plating of very large corporate screening decks (many 100,000s) for high-throughput screening is generally restricted, both from a time and cost perspective. Here we present a stratified screening deck with accompanying plating design for use with very large corporate compound collections. The deck is plated as a whole, but copies for screening can be downsized flexibly and quickly on the fly, without the need for repicking of physical samples.

High-temperature scanning tunneling microscopy study of the ordering transition of an amorphous carbon layer into graphene on ruthenium(0001).

The ordering transition of an amorphous carbon layer into graphene was investigated by high-temperature scanning tunneling microscopy. A disordered C layer was prepared on a Ru(0001) surface by chemical vapor deposition of ethylene molecules at ~660 K. The carbon layer grows in the form of dendritic islands that have almost the same density as graphene.

Timing of the high-dose therapy in the area of new drugs.

The treatment approach in patients with multiple myeloma (MM) has been essentially changed with introduction of novel agents such as thalidomide, bortezomib and lenalidomide. In patients eligible for autologous stem cell transplant, combinations of novel agents with chemotherapy have been recognized as induction regimens. New induction regimens have significantly increased the rate of complete remission before and after autologous stem cell transplant with positive impact on the length of progression-free survival followed by the possibility for further improvement with the application of consolidation or use of thalidomide and lenalidomide as maintenance therapy.

DrugPred: a structure-based approach to predict protein druggability developed using an extensive nonredundant data set.

Judging if a protein is able to bind orally available molecules with high affinity, i.e. if a protein is druggable, is an important step in target assessment.

Inflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering from multiple myeloma.

Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial.

A combined ecological and epidemiologic investigation of metal exposures amongst Indigenous peoples near the Marlin Mine in Western Guatemala.

In August 2009 a combined epidemiological and ecological pilot study was conducted to investigate allegations of human rights abuses in the form of exposures to toxic metals experienced by mine workers and Indigenous Mam Mayan near the Marlin Mine in Guatemala. In the human study there were no differences in blood and urine metals when comparing five mine workers with eighteen non-mine workers, and there were no discernible relationships between metal exposures and self-reported health measures in any study group. On the other hand, individuals residing closest to the mine had significantly higher levels of certain metals (urinary mercury, copper, arsenic, and zinc) when compared to those living further away.

The oral histone deacetylase inhibitor LBH589 is a potential and promising therapeutic agent in multiple myeloma after at least two lines of chemotherapy including bortezomib or lenalidomide.

Background: Multiple myeloma as the second most common hematological malignancy is characterized by proliferation of monoclonal plasma cells. This entity still remains a non-curable disorder leading, amongst others, to complications as myeloma bone disease, bleeding events, kidney failure and neurological impairment. LBH589 is a histone deacetylase inhibitor with an epigenetic mechanism of action and the potential for treatment in myeloma.

Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone.

The immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with multiple myeloma (MM). Their efficacy is increased with the addition of dexamethasone, but significant rates of venous thromboembolism (VTE) are a severe side effect. Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients.

An alternative method for the evaluation of docking performance: RSR vs RMSD.

A new assessment criterion for docking poses is proposed in which experimental electron density is taken into account when evaluating the ability of docking programs to reproduce experimentally observed binding modes. Three docking programs (Gold, Glide, and Fred) were used to generate poses for a set of 88 protein-ligand complexes for which the crystal structure is known. The new criterion is based on the real space R-factor (RSR), which measures how well a group of atoms-in our case the ligand-fits the experimental electron density by comparing that density to the expected density, calculated from the model (i.

Do structurally similar ligands bind in a similar fashion?

The scope of the current work is to investigate whether structurally similar ligands bind in a similar fashion by exhaustively analyzing experimental data from the protein database (PDB). The complete PDB was searched for pairs of structurally similar ligands binding to the same biological target. The binding sites of the pairs of proteins complexing structurally similar ligands were found to differ in 83% of the cases.

From the similarity analysis of protein cavities to the functional classification of protein families using cavbase.

In this contribution, the classification of protein binding sites using the physicochemical properties exposed to their pockets is presented. We recently introduced Cavbase, a method for describing and comparing protein binding pockets on the basis of the geometrical and physicochemical properties of their active sites. Here, we present algorithmic and methodological enhancements in the Cavbase property description and in the cavity comparison step.

Inhibition of angiogenesis by non-toxic doses of temozolomide.

It is well established that certain chemotherapeutic agents have potent antiangiogenic properties which may be part of their antitumor activity. Temozolomide (TMZ) is a lipophilic methylating agent used in the therapy of malignant melanoma and other tumors. We sought to determine whether TMZ is capable of inhibiting angiogenesis or influencing endothelial function.

A new method to detect related function among proteins independent of sequence and fold homology.

A new method has been developed to detect functional relationships among proteins independent of a given sequence or fold homology. It is based on the idea that protein function is intimately related to the recognition and subsequent response to the binding of a substrate or an endogenous ligand in a well-characterized binding pocket. Thus, recognition of similar ligands, supposedly linked to similar function, requires conserved recognition features exposed in terms of common physicochemical interaction properties via the functional groups of the residues flanking a particular binding cavity.

From Structure to Function: A New Approach to Detect Functional Similarity among Proteins Independent from Sequence and Fold Homology.

Protein function is almost invariably linked with the specific recognition of substrates or endogenous ligands in particular binding pockets; proteins of related function should, therefore, share comparable recognition pockets. On the basis of this idea a new computer method has been developed to detect functional relationships among proteins, independent of a particular sequence or fold homology, in which the functionality of the residues is translated into simple physicochemical descriptors. By this method novel ligands in drug design can be suggested.

2,4,6,8-Tetracyanoazulene: A New Building Block for "Organic Metals".

Simply mixing solutions of the title compound 1 and tetrathiafulvene (TTF) in acetonitrile provides the charge-transfer complex 2. Here, 1 functions as a novel electron acceptor and is present in the complex as a radical anion. An electrical conductivity of up to 3 S cm was determined for 2 with a two-point powder measurement.