Molecular determinants of neuropeptide-mediated activation mechanisms in tachykinin NK1 and NK2 receptors.

Substance P and neurokinin A are closely related neuropeptides belonging to the tachykinin family. Their receptors are neurokinin one receptor (NK1R) and neurokinin two receptor (NK2R), G protein-coupled receptors that transmit G and G-mediated downstream signaling. We investigate the importance of sequence differences at the bottom of the receptor orthosteric site for activity and selectivity, focusing on residues that closely interact with the C-terminal methionine of the peptide ligands.

Mechanical and Geometric Characterization of a Novel 2-Ply Vacuum-Pressed Biological Scaffold Patch Design for Posterior Mitral Valve Reconstruction.

To assess the mechanical properties of small intestinal submucosal extracellular matrix (SIS-ECM) iterations and choose the optimal version for evaluating functional geometrics after posterior mitral valve reconstruction. Four SIS-ECM versions (2- and 4-ply vacuum-pressed and lyophilized) underwent uniaxial tensile testing. A posterior mitral valve reconstruction patch was developed based on MRI scans (n = 5).

Enantiopure molecules form apparently racemic monolayers of chiral cyclic pentamers.

Ultra-high vacuum scanning tunneling microscopy (UHV-STM) was used to investigate two related molecules pulse-deposited onto Au(111) surfaces: indoline-2-carboxylic acid and proline (pyrrolidine-2-carboxylic acid). Indoline-2-carboxylic acid and proline form both dimers and -symmetric "pinwheel" pentamers. Enantiomerically pure -(-)-indoline-2-carboxylic acid and -proline were used, and the pentamer structures observed for both were chiral.

An auto-ethnographic study of co-produced health research in a patient organisation: unpacking the good, the bad, and the unspoken.

Background: In rare diseases, limited access to services and rare disease experts may force families to act as medical advocates for their child; they can volunteer to support clinician-initiated research or initiate and lead research themselves. Ketotic Hypoglycemia International (KHI) is a new, global organization for families affected by idiopathic ketotic hypoglycemia (IKH) and is run solely by volunteers. Doing research together, families and international experts in a collaborative process such as at KHI, also referred to as patient and public involvement and engagement (PPIE) or extreme citizen science, is often praised for its positive effects on the research and the stakeholders involved.

GLP-1-directed NMDA receptor antagonism for obesity treatment.

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.

Pre-existing structural control on the recent Holuhraun eruptions along the Bárðarbunga spreading center, Iceland.

The active rift zones in Iceland provide unique insight into the geodynamic processes of divergent plate boundaries. The geodynamics of Iceland are studied intensively, particularly, by geophysical methods sensitive to active and/or visible structures such as earthquake seismic and Synthetic Aperture Radar observations or aerial photographs. However, older and less active structures, that may exert a strong control on the presently active geodynamics, are often buried beneath recent volcanic or sedimentary deposits and are-due to their passive mode-overseen by the typical geophysical investigations.

Free fatty acid receptor 1 stimulates cAMP production and gut hormone secretion through Gq-mediated activation of adenylate cyclase 2.

Objective: Free fatty acid receptor 1 (FFAR1) is highly expressed in enteroendocrine cells of the small intestine and pancreatic beta cells, where FFAR1 agonists function as GLP-1 and insulin secretagogues, respectively. Most efficacious are so-called second-generation synthetic agonists such as AM5262, which, in contrast to endogenous long-chain fatty acids are able to signal through both IP/Ca and cAMP pathways. Whereas IP signaling is to be expected for the mainly Gq-coupled FFAR1, the mechanism behind FFAR1-induced cAMP accumulation remains unclear, although originally proposed to be Gs mediated.

Power and distribution of evoked gamma oscillations in brain aging and cognitive performance.

Aims: Gamma oscillations (≈25-100 Hz) are believed to play an essential role in cognition, and aberrant gamma oscillations occur in brain aging and neurodegeneration. This study examined age-related changes in visually evoked gamma oscillations at two different time points 5 years apart and tested the hypothesis that the power of gamma oscillations correlated to cognitive skills.

Methods: The cohort consists of elderly males belonging to the Metropolit 1953 Danish Male Birth Cohort (first visit, N=124; second visit, N=88) over a 5-year period from 63 to 68 years of age.

Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action.

The free fatty acid receptors FFAR1 and FFAR4 are considered promising therapeutic targets for management of metabolic and inflammatory diseases. However, there is a need for entirely novel chemical scaffolds, since many of the highly similar lipophilic chemotypes in development have been abandoned by the pharmaceutical industry, due to toxic effects on hepatocytes and β-cells. Our group has recently reported the discovery of a 1,3,5-triazine-2-amine-based compound that acts as an allosteric agonist on FFAR1.

Ketotic hypoglycemia in patients with Down syndrome.

Background: Ketotic hypoglycemia (KH) without an identifiable underlying metabolic or hormonal disease is historically named idiopathic KH. The prevalence is unknown, but idiopathic KH is considered the most frequent cause of hypoglycemia beyond the neonatal period. KH in Down syndrome (DS) has not been reported.

Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling.

Succinate functions both as a classical TCA cycle metabolite and an extracellular metabolic stress signal sensed by the mainly Gi-coupled succinate receptor SUCNR1. In the present study, we characterize and compare effects and signaling pathways activated by succinate and both classes of non-metabolite SUCNR1 agonists. By use of specific receptor and pathway inhibitors, rescue in G-protein-depleted cells and monitoring of receptor G protein activation by BRET, we identify Gq rather than Gi signaling to be responsible for SUCNR1-mediated effects on basic transcriptional regulation.

Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International.

Background: Idiopathic Ketotic hypoglycemia (IKH) is a diagnosis of exclusion. Although considered as the most frequent cause of hypoglycemia in childhood, little progress has been made to advance the understanding of IKH since the medical term was coined in 1964. We aimed to review the literature on ketotic hypoglycemia (KH) and introduce a novel patient organization, Ketotic Hypoglycemia International (KHI).

Graphene oxide transport and retention in biochar media.

This study explores the use of biochar (BC), an inexpensive filtration media, for removing graphene oxide (GO) contaminants from the aquatic subsurface environments. Mass balance approaches and column dissection tests were used to analyze the retention behavior of GO in a series of model fixed-bed columns as a function of ionic strength (IS) and flowrate. The column based on the biochar media (BC) displayed 3.

Mapping empirical experiences of Tom Kitwood's framework of person-centred care for persons with dementia in institutional settings. A scoping review.

Introduction: Tom Kitwood's theoretical framework of person-centred care is extensively and internationally referred to in healthcare services. However, despite the broad use of Kitwood's approach in clinical practice, the research examining experiences with the approach has not been mapped.

Aim: To map the available literature on current empirical experiences in clinical practice of Kitwood's approach to person-centred care for people with dementia, living in institutional settings in primary health care.

Case Reports of Pre-clinical Replication Studies in Metabolism and Diabetes.

Recent articles have highlighted the lack of reproducibility of data from scientific publications. Here we would argue that a better way to describe and also tackle this matter is to use the term "lack of robustness," since it points toward potential solutions. Presenting several case reports, we highlight examples with common underlying issues from Novo Nordisk's experience: animal model variability, reagent quality, and inter-lab variability.

Motor Imagery based Brain Computer Interface Paradigm for Upper Limb Stroke Rehabilitation.

Motor Imagery (MI) based Brain Computer Interface (BCI) systems have shown potential to serve as a tool for neurorehabilitation for post stroke patients to complement the standard therapy. The aim of this study was to develop an MI based BCI system that could potentially be used in neurorehabilitation of hand motor function in stroke patients. Two co-adaptive, three-class MI based BCI systems for realtime processing were developed and compared using the publicly available data from the BCI Competition III Dataset V as well as our own data.

Systems Signatures Reveal Unique Remission-path of Type 2 Diabetes Following Roux-en-Y Gastric Bypass Surgery.

Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB.

Stable Inks Containing Upconverting Nanoparticles Based on an Oil-in-Water Nanoemulsion.

An oil-in-water nanoemulsion capable of dispersing upconverting nanoparticles (UCNPs) for 7 months was investigated. Negative staining transmission electron microscopy shows that the UCNPs reside in the oil phase of the nanoemulsion. Dynamic light scattering measurements indicate that the majority of the oil volume is contained in droplets less than 1 μm in diameter.

Non-intuitive clustering of 9,10-phenanthrenequinone on Au(111).

The direct injection of a 9,10-phenanthrenequinone in tetrahydrofuran solution on a Au(111) substrate in high vacuum results in the formation of metastable clusters with a non-intuitive structure. Metastable, rectangular tetramers of this molecule form in which the net molecular dipoles all orient toward the center of the cluster. This structure does not allow for additional hydrogen bonding and thus the origin of its metastability is not clear.

Hansen solubility parameters of surfactant-capped silver nanoparticles for ink and printing technologies.

Optimal ink formulations, inclusive of nanoparticles, are often limited to matching the nanoparticle's capping agent or surface degree of polarity to the solvent of choice. Rather than relying on this single attribute, nanoparticle dispersibility was optimized by identifying the Hansen solubility parameters (HSPs) of decanoic-acid-capped 5 nm silver nanoparticles (AgNPs) by broad spectrum dispersion testing and a more specific binary solvent gradient dispersion method. From the HSPs, solvents were chosen to disperse poly(methyl methacrylate) (PMMA) and nanoparticles, give uniform evaporation profiles, and yield a phase-separated microstructure of nanoparticles on PMMA via film formation by solvent evaporation.

Partial remission definition: validation based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish children with new-onset type 1 diabetes.

Objective: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c).

Subjects And Methods: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes (T1D).

Disease progression among 446 children with newly diagnosed type 1 diabetes located in Scandinavia, Europe, and North America during the last 27 yr.

Objective: To clarify whether the rate of decline in stimulated C-peptide (SCP) from 2 to 15 months after diagnosis has changed over an interval of 27 yr.

Research Design And Methods: The rate of decline in SCP levels at 1, 2, 3, 6, 9, 12, and 15 months after diagnosis was compared in four paediatric cohorts from Scandinavian and European countries including 446 children with new onset type 1 diabetes (T1D, 1982-2004). Findings were evaluated against 78 children (2004-2009) from the TrialNet studies.