Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor.

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound G protein (G·GDP; hereafter G) upon coupling to the β-adrenergic receptor (βAR) in atomic detail.

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting.

In conjunction with the endothelin (ET) type A (ETR) and type B (ETR) receptors, angiotensin (AT) type 1 (ATR) and type 2 (ATR) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer.

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation.

The angiotensin II (Ang II) type 1 receptor (ATR) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). ATR can also be activated by auto-antibodies (ATR-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to ATR-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary.

Expression and Characterization of Relaxin Family Peptide Receptor 1 Variants.

G-protein coupled receptors (GPCR) transduce extracellular stimuli into the cell interior and are thus centrally involved in almost all physiological-neuronal processes. This essential function and association with many diseases or pathological conditions explain why GPCRs are one of the priority targets in medical and pharmacological research, including structure determination. Despite enormous experimental efforts over the last decade, both the expression and purification of these membrane proteins remain elusive.

Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.

Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective.

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways.

Biomimetic bio-inspired biomorph sustainable? An attempt to classify and clarify biology-derived technical developments.

Over the last few decades, the systematic approach of knowledge transfer from biological concept generators to technical applications has received increasing attention, particularly because marketable bio-derived developments are often described as sustainable. The objective of this paper is to rationalize and refine the discussion about bio-derived developments also with respect to sustainability by taking descriptive, normative and emotional aspects into consideration. In the framework of supervised learning, a dataset of 70 biology-derived and technology-derived developments characterised by 9 different attributes together with their respective values and assigned to one of 17 classes was created.

A Functional Tricarboxylic Acid Cycle Operates during Growth of Bordetella pertussis on Amino Acid Mixtures as Sole Carbon Substrates.

It has been claimed that citrate synthase, aconitase and isocitrate dehydrogenase activities are non-functional in Bordetella pertussis and that this might explain why this bacterium's growth is sometimes associated with accumulation of polyhydroxybutyrate (PHB) and/or free fatty acids. However, the sequenced genome includes the entire citric acid pathway genes. Furthermore, these genes were expressed and the corresponding enzyme activities detected at high levels for the pathway when grown on a defined medium imitating the amino acid content of complex media often used for growth of this pathogenic microorganism.

Genomics of Clostridium tetani.

Genomic information about Clostridium tetani, the causative agent of the tetanus disease, is scarce. The genome of strain E88, a strain used in vaccine production, was sequenced about 10 years ago. One additional genome (strain 12124569) has recently been released.

Use of atmospheric pressure solids analysis probe time-of-flight mass spectrometry to screen for plasticisers in gaskets used in contact with foods.

Rationale: Plasticisers are used in the PVC gaskets of metal closures on glass jars and bottles used for foods and beverages. They may migrate and so contaminate the packed foodstuff. The plasticisers are present in a high proportion and are often a complex mixture of substances leading to time-consuming analytical methodologies.

Model studies of migration from paper and board into fruit and vegetables and into Tenax as a food simulant.

Four samples of paper and board (P/B) of a type used for packaging dry foods were subjected to migration tests using mushrooms, apples, potatoes and bananas, and using the polymeric powder Tenax as a food simulant. The P/B samples contained only low levels of diisopropylnaphthalene (DiPN) and diisobutyl phthalate (DiBP) and so the experiments were conducted after impregnating the P/B with added model substances. These were o-xylene, acetophenone, dodecane, benzophenone, DiPN and DiBP.

Ambiguous provenance? Experience with provenance analysis of human remains from Namibia in the Alexander Ecker collection.

The project's aim is to verify the existence of Herero and Nama skulls among the roughly 1370 skulls in the Alexander Ecker collection (AEC). Methods include historical research, which was mainly concerned with the AEC and especially Eugen Fischer during his time as curator, as well as the methods of acquisition of human remains and scientific methods to verify the identity of the relevant skulls. Scientific methods include morphological sex and age-at-death verification, morphological estimation of ancestry, morphometric analysis and the application of UV light to decipher old labels on the skull surfaces, as well as a molecular biology approach (mtDNA) and stable isotope analyses.

Analytical screening studies on irradiated food packaging.

Foods may be irradiated in their final packaging and this process may affect the composition of the packaging and in turn affect the migration of substances into food. Headspace and liquid injection GC-MS and HPLC with time-of-flight MS have been used to identify and estimate levels of radiolytic products in irradiated finished plastic packaging materials. Fifteen retail packaging materials were studied.

Methods of analysis for 2-dodecylcyclobutanone and studies to support its role as a unique marker of food irradiation.

Methods of analysis for 2-dodecylcyclobutanone (2-DCB) using gas chromatography with mass spectrometric detection (GC-MS), liquid chromatography with time-of-flight mass spectrometric detection (LC-TOF-MS) and LC with tandem MS (MS/MS) detection have been developed and optimised for maximum sensitivity to allow very low irradiation doses to be detected. The LC-MS/MS method, following derivatisation with 2,4-dinitrophenylhydrazine, was found to be the most sensitive technique and was used to determine the amount of 2-DCB formed from the model compounds palmitic acid, glyceryl tripalmitate and 1,3-dipalmitoyl-2-oleoylglycerol irradiated over a range of doses by two different irradiation sources (gamma and electron beam). The model compounds were also treated with a number of non-irradiation based processing techniques including heating in the presence and absence of oxygen, light, and redox active metal salts, in a conventional oven, microwave oven and pressure cooker.

Exposure to phthalic acid, phthalate diesters and phthalate monoesters from foodstuffs: UK total diet study results.

Phthalates are ubiquitous in the environment and thus exposure to these compounds can occur in various forms. Foods are one source of such exposure. There are only a limited number of studies that describe the levels of phthalates (diesters, monoesters and phthalic acid) in foods and assess the exposure from this source.

Determination of phthalate diesters in foods.

Methodology for the determination of 15 phthalate diesters (dimethyl phthalate, diethyl phthalate, diisopropyl phthalate, diallyl phthalate, diisobutyl phthalate, di-n-butyl phthalate, di-n-pentyl phthalate, di-n-hexyl phthalate, benzyl butyl phthalate, dicyclohexyl phthalate, di-(2-ethylhexyl) phthalate, di-n-octyl phthalate, diisononyl phthalate, diisodecyl phthalate, and di-n-decyl phthalate) is described. The method was validated in-house and its broad applicability demonstrated by the analysis of high-fat, high-carbohydrate and high-protein foodstuffs as well as combinations of all three major food constituents. Following on from the analysis of the 20 UK Total Diet Study samples, 261 foodstuffs were purchased and tested for their phthalate levels.

Demonstration of ignition radiation temperatures in indirect-drive inertial confinement fusion hohlraums.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.

Antibiotic-free selection in E. coli: new considerations for optimal design and improved production.

Background: The increasing regulatory requirements to which biological agents are subjected will have a great impact in the field of industrial protein expression and production. There is an expectation that in a near future, there may be "zero tolerance" towards antibiotic-based selection and production systems. Besides the antibiotic itself, the antibiotic resistance gene is an important consideration.

Test procedures for obtaining representative extracts suitable for reliable in vitro toxicity assessment of paper and board intended for food contact.

This paper describes the use of a suite of extraction procedures applicable to the assessment of the in vitro toxicity of paper/board samples intended for food-contact applications. The sample is extracted with ethanol, water, or exposed to modified polyphenylene oxide (Tenax) for fatty, non-fatty and dry food applications, respectively. The water extracts are directly suitable for safety assessment using in vitro bioassays.

[Specific aspects of vaccine manufacturing].

The industrial development of vaccine manufacturing expanded during the second half of the 20th century. Vaccines are medicines which target healthy people. The active principles of vaccines arise from live organisms and can be distinguished from standard pharmaceutical compounds by their extreme complexity.

Feeling present in arousing virtual reality worlds: prefrontal brain regions differentially orchestrate presence experience in adults and children.

Virtual reality (VR) is a powerful tool for simulating aspects of the real world. The success of VR is thought to depend on its ability to evoke a sense of "being there", that is, the feeling of "Presence". In view of the rapid progress in the development of increasingly more sophisticated virtual environments (VE), the importance of understanding the neural underpinnings of presence is growing.

The BIOSAFEPAPER project for in vitro toxicity assessments: preparation, detailed chemical characterisation and testing of extracts from paper and board samples.

Nineteen food contact papers and boards and one non-food contact board were extracted following test protocols developed within European Union funded project BIOSAFEPAPER. The extraction media were either hot or cold water, 95% ethanol or Tenax, according to the end use of the sample. The extractable dry matter content of the samples varied from 1200 to 11,800 mg/kg (0.

A pulmonary mass caused by Rhodococcus equi infection in a renal transplant recipient.

Background: A 62-year-old male kidney transplant recipient was admitted to hospital with a 14-day history of fever, hemoptysis and left-sided pleuritic chest pain. He had suffered malaise, weight loss, night sweats and exertional dyspnea over the previous 3 months. Imaging studies of the patient's chest revealed a noncavitated mass measuring 5 x 8 cm in the anterior segment of the left upper lobe of the lung and a left-sided pleural effusion with septa, and bacterial cultures revealed the presence of Rhodococcus equi.