The numerical stroop effect in primary school children: a comparison of low, normal, and high achievers.

Sixty-six primary school children were selected, of which 21 scored low on a standardized math achievement test, 23 were normal, and 22 high achievers. In a numerical Stroop experiment, children were asked to make numerical and physical size comparisons on digit pairs. The effects of congruity and numerical distance were determined.

Fragment-based lead discovery: screening and optimizing fragments for thermolysin inhibition.

Fragment-based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment-based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well-studied enzyme and serves as a model system for other proteases.

[Meniscal degeneration score and NITEGE expression : immunohistochemical detection of NITEGE in advanced meniscal degeneration].

Background: Meniscal degeneration (MD) is a structural change of fibrous cartilage that is common in orthopaedic diagnostics and relevant for health insurance matters. So far, there has been neither a standardised scoring system nor an immunohistochemical marker for MD.

Material And Method: In this retrospective trial, the meniscal tissue of 60 patients was assessed immunohistochemically for NITEGE (G1 fragment of the proteoglycan aggrecan) expression.

Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry.

Additivity of functional group contributions to protein-ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce.

Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216.

Correlation of clinical and immunological data in a metastatic melanoma patient with heterogeneous tumor responses to ipilimumab therapy.

Melanoma patients treated with anti-CTLA-4 have shown a range of anti-tumor responses. In this report, we describe the response of a single patient to anti-CTLA-4, with individual lesions disappearing, others stabilizing, and others progressing. These responses can be viewed as a clear manifestation of cancer immunoediting and its three phases of elimination, equilibrium and escape, with each tumor in this patient being at a discrete stage in the process.

How to replace the residual solvation shell of polar active site residues to achieve nanomolar inhibition of tRNA-guanine transglycosylase.

In a computational and structural study, we investigated a series of 4-substituted lin-benzoguanines that are potent inhibitors of tRNA-guanine transglycosylase (TGT), a putative target for the treatment of shigellosis. At first glance, it appears self-evident that the placement of a positively charged ligand functional group between the carboxylate groups of two adjacent aspartate residues in the glycosylase catalytic center leads to enhanced ligand binding. The concomitant displacement of water molecules that partially solvate the aspartates prior to ligand binding appears to result as a consequence of this.

Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen.

Using dendritic cells (DCs) electroporated with whole RNA isolated from blasts of a patient with acute myeloid leukemia (AML), we were able to generate leukemia-specific cytotoxic T lymphocytes (CTLs) capable of recognizing the leucemic cells. To identify T-cell epitopes mediating lysis of malignant cells, peptides were eluted from the patient's blasts and analyzed by mass spectrometry (LC/MS)-based peptide sequencing. Using this approach, an HLA-A24-binding peptide derived from Bax inhibitor-1 (BI-1), a regulator of apoptosis pathways, was identified as an epitope recognized by the generated CTLs.

Think twice: understanding the high potency of bis(phenyl)methane inhibitors of thrombin.

Successful design of potent and selective protein inhibitors, in terms of structure-based drug design, strongly relies on the correct understanding of the molecular features determining the ligand binding to the target protein. We present a case study of serine protease inhibitors with a bis(phenyl)methane moiety binding into the S3 pocket. These inhibitors bind with remarkable potency to the active site of thrombin, the blood coagulation factor IIa.

Interaction of an extended series of N-substituted di(2-picolyl)amine derivatives with copper(II). Synthetic, structural, magnetic and solution studies.

The interaction of Cu(II) with the following secondary N-substituted derivatives of di(2-picolyl)amine () are reported: N-cyclohexylmethyl-di(2-picolyl)amine (), N-benzyl-di(2-picolyl)amine (), N-(4-pyridylmethyl)-di(2-picolyl)amine (), N-(4-carboxymethylbenzyl)-di(2-picolyl)amine (), N-(9-anthracen-8-ylmethyl)-di(2-picolyl)amine (), 1,3-bis[di(2-picolyl)aminomethyl]benzene (), 1,4-bis[di(2-picolyl)aminomethyl]benzene () and 2,4,6-tris[di(2-picolyl)amino]triazine (). The solid complexes [Cu()(micro-Cl)](2)(PF(6))(2), [Cu()(micro-Cl)](2)(PF(6))(2).0.

More than a simple lipophilic contact: a detailed thermodynamic analysis of nonbasic residues in the s1 pocket of thrombin.

The field of medicinal chemistry aims to design and optimize small molecule leads into drug candidates that may positively interfere with pathological disease situations in humans or combat the growth of infective pathogens. From the plethora of crystal structures of protein-inhibitor complexes we have learned how molecules recognize each other geometrically, but we still have rather superficial understanding of why they bind to each other. This contribution surveys a series of 26 thrombin inhibitors with small systematic structural differences to elucidate the rationale for their widely deviating binding affinity from 185 microM to 4 nM as recorded by enzyme kinetic measurements.

Different behavioral and eye movement patterns of dyslexic readers with and without attentional deficits during single word reading.

Comorbidity of learning disabilities is a very common phenomenon which is intensively studied in genetics, neuropsychology, prevalence studies and causal deficit research. In studies on the behavioral manifestation of learning disabilities, however, comorbidity is often neglected. In the present study, we systematically examined the reading behavior of German-speaking children with dyslexia, of children with attentional problems, of children with comorbid dyslexia and attentional problems and of normally developing children by measuring their reading accuracy, naming latencies and eye movement patterns during single word reading.

[Estimation of population genetic parameters and breeding values for elbow dysplasia in Rottweilers].

We analysed scores of elbow dysplasia following the IEWG protocol from the official screening programme of the Allgemeiner Deutscher Rottweiler Club (ADRK). The data set included X-rays from 5100 Rottweiler dogs born between 1995 and 2004. Out of these 5,100 dogs, 46.

Crystal structure analysis and in silico pKa calculations suggest strong pKa shifts of ligands as driving force for high-affinity binding to TGT.

A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNA(Asn,Asp,His,Tyr) against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested.

Immunotherapy in renal cell carcinoma.

Treatment of metastatic renal cell cancer is still challenging due to its resistance to conventional therapies, such as radiotherapy or chemotherapy. Immunotherapeutic approaches with IL-2 and/or IFN-alpha have become standard regimens in treating metastatic renal cell cancer. Furthermore, molecularly targeted therapies, such as VEGF-pathway inhibition or use of mammalian target of rapamycin inhibitors, have demonstrated promising results and might become even more important in the following years.

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells.

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation.

Matrilysin (MMP-7) is a novel broadly expressed tumor antigen recognized by antigen-specific T cells.

Purpose: A prerequisite for the development of vaccination strategies is the identification and characterization of relevant tumor-associated antigen. Using microarray and reverse transcription-PCR analysis, we found matrix metalloproteinase (MMP)-7 to be extensively up-regulated in renal cell carcinomas and expressed in a broad variety of malignant cells. MMP-7 can promote cancer invasion and angiogenesis by proteolytic cleavage of extracellular matrix and basement membrane proteins, thus making it a promising target in the context of immunotherapies.

Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors.

Due to the important role that aspartic proteases play in many patho-physiological processes, they have intensively been targeted by modern drug development. However, up to now, only for two family members, renin and HIV protease, approved drugs are available. Inhibitor development, mostly guided by mimicking the natural peptide substrates, resulted in very potent inhibitors for several targets, but the pharmacokinetic properties of these compounds were often not optimal.

Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors.

HIV protease is a well-established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of the most studied and best characterized proteins. Although the protease exhibits high flexibility, all approved drugs target virtually the same protein conformation.

Structural and kinetic analysis of pyrrolidine-based inhibitors of the drug-resistant Ile84Val mutant of HIV-1 protease.

Human immunodeficiency virus (HIV) protease is a well-established drug target in HIV chemotherapy. However, continuously increasing resistance towards approved drugs inevitably requires the development of new inhibitors preferably showing no susceptibility against resistant HIV protease strains. Recently, symmetric pyrrolidine-3,4-bis-N-benzyl-sulfonamides have been developed as a new class of HIV-1 protease inhibitors.

Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.

Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket.

Structure-guided design of C2-symmetric HIV-1 protease inhibitors based on a pyrrolidine scaffold.

Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process.

Deeply inverted electron-hole recombination in a luminescent antibody-stilbene complex.

The blue-emissive antibody EP2-19G2 that has been elicited against trans-stilbene has unprecedented ability to produce bright luminescence and has been used as a biosensor in various applications. We show that the prolonged luminescence is not stilbene fluorescence. Instead, the emissive species is a charge-transfer excited complex of an anionic stilbene and a cationic, parallel pi-stacked tryptophan.

Generation of antigen-specific CTL responses using RGS1 mRNA transfected dendritic cells.

Advances in tumor immunology and Identification of tumor-associated antigens (TAAs) provide a basis for the development of novel immunotherapies to treat malignant diseases. In order to identify novel TAAs, we performed comparative microarray analysis of (heterogeneous) tissues and found regulator of G protein-signaling 1 (RGS1) extensively up-regulated in renal cell carcinoma (RCC) tissues. To examine the possible function of this molecule as a novel, broadly applicable TAA, synthetic full-length RGS1-mRNA was synthesized for the transfection of monocyte-derived dendritic cells (DCs).

Glutamate versus glutamine exchange swaps substrate selectivity in tRNA-guanine transglycosylase: insight into the regulation of substrate selectivity by kinetic and crystallographic studies.

Bacterial tRNA-guanine transglycosylase (Tgt) catalyses the exchange of guanine in the wobble position of particular tRNAs by the modified base preQ(1). In vitro, however, the enzyme is also able to insert the immediate biosynthetic precursor, preQ(0), into those tRNAs. This substrate promiscuity is based on a peptide switch in the active site, gated by the general acid/base Glu235.