Ligand binding dynamics for pre-dimerised G protein-coupled receptor homodimers: Linear models and analytical solutions

Evidence suggests that many G protein-coupled receptors (GPCRs) are bound together forming dimers. The implications of dimerisation for cellular signalling outcomes, and ultimately drug discovery and therapeutics, remain unclear. Consideration of ligand binding and signalling via receptor dimers is therefore required as an addition to classical receptor theory, which is largely built on assumptions of monomeric receptors. A key factor in developing theoretical models of dimer signalling is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. Here, we present and analyse linear models for one-ligand and two-ligand binding dynamics at homodimerised receptors, as an essential building block in the development of dimerised receptor theory. For systems at equilibrium, we compute analytical solutions for total bound labeled ligand, and derive conditions on the cooperativity factors underwhich multiphasic log-dose-response curves are expected. This could help explain data extracted from pharmacological experiments that does not fit to the standard Hill curves that are often used in this type of analysis. For the time-dependent problems, we also obtain analytical solutions. For the single-ligand case, the construction of the analytical solution is straightforward; it is bi-exponential in time, sharing a similar structure to the well known monomeric competition dynamics of Motulsky-Mahan. We suggest that this model is therefore practically usable by the pharmacologist towards developing insights into the potential dynamics and consequences of dimerised receptors

Walking on Thin Ice: Exploring Demands and Means of Coping During an Extreme Expedition

The present exploratory study was undertaken with two experienced explorers in order to examine daily events, perceived demands, coping strategies, and mood during a unique 636–675 km ‘‘double solo’’ crossing of Lake Baikal, a frozen lake in Siberia. A 59-year-old female explorer and a 49-year-old male explorer completed a daily survey and written diary during the expedition to collect situational data. Two semi-structured interviews were also completed, one within 24 hours and a second within four months of their return. These interviews sought to identify demands and coping efforts perceived as being most pertinent during their expedition. Guided by the work of Skinner et al. (2003), families of coping were organized around three human concerns (autonomy, relatedness, and competence) and two targets of coping (self or context). Findings illustrate two very different expedition experiences as evidenced by demands faced and coping strategies utilized, which influenced perceptions of workload and emotions experienced. Each explorer brought idiosyncrasies, which, when combined with different expedition experiences, bore influence on coping behaviors (focused on the self or context) and outcomes relative to the concerns of autonomy, relatedness, and competency. In discussing the findings, recommendations are offered for those preparing to undertake expeditions in extreme environments

Nucleosynthesis in Outflows from Black Hole-Neutron Star Merger Disks With Full GRν\nuRMHD

Along with binary neutron star mergers, the in-spiral and merger of a black hole and a neutron star is a predicted site of $r$-process nucleosynthesis and associated kilonovae. For the right mass ratio, very large amounts of neutron rich material may become unbound from the post-merger accretion disk. We simulate a suite of four post-merger disks with full-transport general relativistic neutrino radiation magnetohydrodynamics. We find that the outflows from these disks are very close to the threshold conditions for robust $r$-process nucleosynthesis. For these conditions, the detailed properties of the outflow determine whether a full $r$-process can or cannot occur, implying that a wide range of observable phenomena are possible. We show that on average the disk outflow lanthanide fraction is suppressed relative to the solar isotopic pattern. In combination with the dynamical ejecta, these outflows imply a kilonova with both blue and red components

Sonographic Evaluation for Endometrial Polyps

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135550/1/jum201635112381.pd

Walking on thin ice: Exploring demands and means of coping during an extreme expedition

The present exploratory study was undertaken with two experienced explorers in order to examine daily events, perceived demands, coping strategies, and mood during a unique 636-675 km ‘double solo’ crossing of Lake Baikal, a frozen lake in Siberia. A 59-year-old female explorer and a 49-year-old male explorer completed a daily survey and written diary during the expedition to collect situational data. Two semi-structured interviews were also completed, one within 24-hours and a second within four months of their return. These interviews sought to identify demands and coping efforts perceived as being most pertinent during their expedition. Guided by the work of Skinner et al. (2003), families of coping were organised around three human concerns (autonomy, relatedness, and competence) and two targets of coping (self or context). Findings illustrate two very different expedition experiences as evidenced by demands faced and coping strategies utilised, which influenced perceptions of workload and emotions experienced. Each explorer brought idiosyncrasies, which, when combined with different expedition experiences, bore influence on coping behaviours (focused on the self or context) and outcomes relative to the concerns of autonomy, relatedness, and competency. In discussing the findings, recommendations are offered for those preparing to undertake expeditions in extreme environments

The genetics of inherited cholestatic disorders in neonates and infants : evolving challenges

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.Actelion Pharmaceuticals Ltd.; the MRC Biomedical Catalyst Award; the German Federal Ministry for Education and Research (BMBF) via the Hereditary Intrahepatic Cholestasis Translational Network; NIHR Academic Clinical Fellowship.https://www.mdpi.com/journal/genesam2022Paediatrics and Child Healt