Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle.

Background: Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system.

Methods: 41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM).

Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors.

Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [(3)H]-BBAC ((S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide).

Distinct effects of IPSU and suvorexant on mouse sleep architecture.

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305), and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R.

Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS.

From immunosuppression to immunomodulation: current principles and future strategies.

Over the last few decades, tremendous progress has been made in understanding the mechanisms of immune responses. This progress has also led to a more detailed knowledge of the processes leading to the loss of self-tolerance and the destruction of self-tissue in the case of autoimmune diseases, the effector mechanism involved in transplant allograft rejection as well as the driving factors in exacerbated inflammatory disorders. Despite this progress, the challenge still remains to selectively interfere with immune responses responsible for autoimmunity or transplant rejection while keeping an intact response to infectious agents.

Metabotropic glutamate receptors for Parkinson's disease therapy.

Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients.

Actinoplanes siamensis sp. nov., isolated from soil.

A Gram-positive filamentous bacterial strain that developed large campanulate sporangia at the ends of sporangiophores on substrate mycelium was isolated from bamboo forest soil in Thailand. According to the results of a polyphasic taxonomic study, our isolate had typical characteristics of members of the genus Actinoplanes. The 16S rRNA gene sequence analysis also indicated that strain A-T 6646(T) belonged to the genus Actinoplanes, being most closely related to Actinoplanes liguriensis DSM 43865(T) (97.

Planobispora siamensis sp. nov., isolated from soil.

A novel actinomycete strain, A-T 4600(T), which developed cylindrical sporangia containing a longitudinal pair of motile spores forming singly or in bundles on short ramifications of the aerial mycelium, was isolated from soil collected from an evergreen forest in Thailand. The cell-wall peptidoglycan contained meso-diaminopimelic acid. The whole-cell sugars contained ribose, madurose, mannose and glucose.

Towards mimicking short linear peptide motifs: identification of new mixed α,β-peptidomimetic ligands for SLAM-Associated Protein (SAP) by confocal on-bead screening.

Unlabelled: An array of chemical modifications have recently emerged, designed to improve the stability of natural peptides that inherently suffer from short in vivo half-lives, thereby preventing their use as therapeutics. The resultant peptidomimetics resemble native peptides; however, they contain synthetic elements (e.g.

Receptor-specific regulation of ERK1/2 activation by members of the "free fatty acid receptor" family.

Context: The "free fatty acid receptors" (FFARs) GPR40, GPR41, and GPR43 regulate various physiological homeostases, and are all linked to activation of extracellular signal-regulated kinases (ERK)1/2.

Objective: Investigation of coupling of FFARs to two other mitogen-activated protein kinases (MAPKs) sometimes regulated by G protein-coupled receptors (GPCRs), c-Jun N-terminal kinase (JNK) and p38MAPK, and characterization of signaling proteins involved in the regulation of FFAR-mediated ERK1/2 activation.

Methods: FFARs were recombinantly expressed, cells challenged with the respective agonist, and MAPK activation quantitatively determined using an AlphaScreen SureFire assay.

Kutzneria buriramensis sp. nov., isolated from soil, and emended description of the genus Kutzneria.

A Gram-staining-positive, filamentous bacterium, which developed large globose sporangia at the ends of long sporangiophores on aerial mycelium, was isolated from dry soil collected in a deciduous forest in Thailand. The cell-wall peptidoglycan of the novel bacterium, which was designated strain A-T 1846(T), contained meso-diaminopimelic acid and the whole-cell sugars comprised rhamnose, ribose, mannose, glucose and galactose. The predominant menaquinone was MK-9(H(4)).

Measurement and differentiation of ligand-induced calmodulin conformations by dual polarization interferometry.

In early drug discovery, knowledge about ligand-induced conformational changes and their influence on protein activity greatly aids the identification of lead candidates for medicinal chemistry efforts. Efficiently acquiring such information remains a challenge in the initial stages of lead finding. Here we investigated the application of dual polarization interferometry (DPI) as a method for the real-time characterization of low molecular weight (LMW) ligands that induce conformational changes.

Sphaerisporangium krabiense sp. nov., isolated from soil.

A Gram-staining-positive, filamentous bacterial strain, designated A-T 0308(T), was isolated from soil of a tropical mangrove forest in Thailand. Strain A-T 0308(T) developed spherical sporangia containing non-motile spores on aerial mycelium. The novel strain contained meso-diaminopimelic acid, N-acetyl-type peptidoglycan and madurose, mannose, ribose, galactose and glucose as whole-cell sugars.

Planotetraspora kaengkrachanensis sp. nov. and Planotetraspora phitsanulokensis sp. nov., isolated from soil.

Two novel bacterial strains were isolated from tropical rain forest soil from Thailand. Strains A-T 0875(T) and A-T 1383(T) stained Gram-positive and were filamentous bacteria that developed cylindrical sporangia containing four oval- to rod-shaped spores at the ends of short sporangiophores on branched aerial mycelium. The cell-wall peptidoglycan contained meso-diaminopimelic acid, glutamic acid and alanine as cell-wall amino acids; whole-cell hydrolysates contained rhamnose, madurose, glucose, galactose and 3-O-methylmannose as whole-cell sugars.

Splicing of intron 3 of human BACE requires the flanking introns 2 and 4.

Regulation of proteolytic cleavage of the amyloid precursor protein by the aspartic protease BACE may occur by alternative splicing and the generation of enzymatically inactive forms. In fact, the presence of exonic donor and acceptor sites for intron 3 generates the two deficient variants BACE457 and BACE476. In HEK293 cells, when introns are inserted separately in the BACE cDNA, we found that whilst introns 2 and 4 are efficiently spliced out, intron 3 is not removed.

Development of a method for the high-throughput quantification of cellular proteins.

The quantification of cellular proteins is essential for the study of many different biological processes. This study describes an assay for the detection of the intracellular mutant huntingtin, the causative agent of Huntington's disease, with a method that may be generally applicable to other cellular proteins. A small recombinant protein tag that is recognized by a pair of readily available, high-affinity monoclonal antibodies was designed.

Regulation of RhoGEF proteins by G12/13-coupled receptors.

G protein-coupled receptors (GPCRs) represent a large family of seven transmembrane receptors, which communicate extracellular signals into the cellular lumen. The human genome contains 720-800 GPCRs, and their diverse signal characteristics are determined by their specific tissue and subcellular expression profiles, as well as their coupling profile to the various G protein families (G(s), G(i), G(q), G(12)). The G protein coupling pattern links GPCR activation to the specific downstream effector pathways.

mGluR5 antagonists: discovery, characterization and drug development.

Disturbances of glutamate-mediated neurotransmission have been implicated in a broad range of nervous system disorders. Numerous attempts to correct nervous system dysfunction by pharmacological intervention at glutamate receptors have been made, and some of the approaches have achieved a high level of preclinical validation. However, in a number of cases involving agents acting as blockers of the ionotropic glutamate receptors, clinical success could not be achieved, mostly because of the lack of a therapeutic window.

Cell-based assays in GPCR drug discovery.

G protein-coupled receptors (GPCRs) transmit extracellular signals into the intracellular space, and play key roles in the physiological regulation of virtually every cell and tissue. Characteristic for the GPCR superfamily of cell surface receptors are their seven transmembrane-spanning alpha-helices, an extracellular N terminus and intracellular C-terminal tail. Besides transmission of extracellular signals, their activity is modulated by cellular signals in an auto- or transregulatory fashion.

Reversible translocation of p115-RhoGEF by G(12/13)-coupled receptors.

G protein-coupled receptors (GPCRs) are important targets for medicinal agents. Four different G protein families, G(s), G(i), G(q), and G(12), engage in their linkage to activation of receptor-specific signal transduction pathways. G(12) proteins were more recently studied, and upon activation by GPCRs they mediate activation of RhoGTPase guanine nucleotide exchange factors (RhoGEFs), which in turn activate the small GTPase RhoA.

Pharmacological profile of somatostatin and cortistatin receptors.

Somatostatin (SRIF) and cortistatin (CST) are two endogenous peptides with high sequence similarities that act as hormones/neurotransmitters both in the CNS and the periphery; their genes although distinct result from gene duplication. Their receptors appear to be common, since the five known SRIF receptors (sst1-sst5) have similar subnanomolar affinity for SRIF and CST, whether the short (SRIF-14, CST-14, CST-17) or the long versions (SRIF-28, CST-29) of the peptides. Whether CST targets specific receptors not shared by SRIF, is still debated: MrgX2 has been described as a selective CST receptor, with submicromolar affinity for CST but devoid of affinity for SRIF; however the distribution of CST and MrgX2 is largely different, and there is no MrgX2 in rodents.

G12/13-dependent signaling of G-protein-coupled receptors: disease context and impact on drug discovery.

G-protein-coupled receptors (GPCRs) transmit extracellular signals across the plasma membrane via intracellular activation of heterotrimeric G proteins. The signal transduction pathways of Gs, Gi and Gq protein families are widely studied, whereas signaling properties of G12 proteins are only emerging. Many GPCRs were found to couple to G12/13 proteins in addition to coupling to one or more other types of G proteins.

Allosteric modulators for mGlu receptors.

The metabotropic glutamate receptor family comprises eight subtypes (mGlu1-8) of G-protein coupled receptors. mGlu receptors have a large extracellular domain which acts as recognition domain for the natural agonist glutamate. In contrast to the ionotropic glutamate receptors which mediate the fast excitatory neurotransmission, mGlu receptors have been shown to play a more modulatory role and have been proposed as alternative targets for pharmacological interventions.