For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and ...heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higher-order oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.
Primary cilia are non‐motile antennae‐like structures responsible for sensing environmental changes in most mammalian cells. Ciliary signalling is largely mediated by the Sonic Hedgehog (Shh) ...pathway, which acts as a master regulator of ciliary protein transit and is essential for normal embryonic development. One particularly important player in primary cilia is the orphan G protein‐coupled receptor, GPR161. In this review, we introduce GPR161 in the context of Shh signalling and describe the unique features on its C‐terminus such as PKA phosphorylation sites and an A‐kinase anchoring protein motif, which may influence the function of the receptor, cAMP compartmentalisation and/or trafficking within primary cilia. We discuss the recent putative pairing of GPR161 and spexin‐1, highlighting the additional steps needed before GPR161 could be considered ‘deorphanised’. Finally, we speculate that the marked constitutive activity and unconventional regulation of GPR161 may indicate that the receptor may not require an endogenous ligand.
LINKED ARTICLES
This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc
Success and impact metrics in science are based on a system that perpetuates sexist and racist “rewards” by prioritizing citations and impact factors. These metrics are flawed and biased against ...already marginalized groups and fail to accurately capture the breadth of individuals’ meaningful scientific impacts. We advocate shifting this outdated value system to advance science through principles of justice, equity, diversity, and inclusion. We outline pathways for a paradigm shift in scientific values based on multidimensional mentorship and promoting mentee well-being. These actions will require collective efforts supported by academic leaders and administrators to drive essential systemic change.
Indwelling pleural catheter and talc pleurodesis are established treatments for malignant pleural effusions among patients with poor prognosis.
To determine whether indwelling pleural catheters are ...more effective than talc pleurodesis in reducing total hospitalization days in the remaining lifespan of patients with malignant pleural effusion.
This open-label, randomized clinical trial included participants recruited from 9 centers in Australia, New Zealand, Singapore, and Hong Kong between July 2012 and October 2014; they were followed up for 12 months (study end date: October 16, 2015). Patients (n = 146) with symptomatic malignant pleural effusion who had not undergone indwelling pleural catheter or pleurodesis treatment were included.
Participants were randomized (1:1) to indwelling pleural catheter (n = 74) or talc pleurodesis (n = 72), minimized by malignancy (mesothelioma vs others) and trapped lung (vs not), and stratified by region (Australia vs Asia).
The primary end point was the total number of days spent in hospital from procedure to death or to 12 months. Secondary outcomes included further pleural interventions, patient-reported breathlessness, quality-of-life measures, and adverse events.
Among the 146 patients who were randomized (median age, 70.5 years; 56.2% male), 2 withdrew before receiving the randomized intervention and were excluded. The indwelling pleural catheter group spent significantly fewer days in hospital than the pleurodesis group (median, 10.0 interquartile range IQR, 3-17 vs 12.0 IQR, 7-21 days; P = .03; Hodges-Lehmann estimate of difference, 2.92 days; 95% CI, 0.43-5.84). The reduction was mainly in effusion-related hospitalization days (median, 1.0 IQR, 1-3 day with the indwelling pleural catheter vs 4.0 (IQR, 3-6) days with pleurodesis; P < .001; Hodges-Lehmann estimate, 2.06 days; 95% CI, 1.53-2.58). Fewer patients randomized to indwelling pleural catheter required further ipsilateral invasive pleural drainages (4.1% vs 22.5%; difference, 18.4%; 95% CI, 7.7%-29.2%). There were no significant differences in improvements in breathlessness or quality of life offered by indwelling pleural catheter or talc pleurodesis. Adverse events were seen in 22 patients in the indwelling pleural catheter group (30 events) and 13 patients in the pleurodesis group (18 events).
Among patients with malignant pleural effusion, treatment with an indwelling pleural catheter vs talc pleurodesis resulted in fewer hospitalization days from treatment to death, but the magnitude of the difference is of uncertain clinical importance. These findings may help inform patient choice of management for pleural effusion.
anzctr.org.au Identifier: ACTRN12611000567921.
Background
COVID‐19 has increased pressures on caregivers, disruptions to health services and increased health concerns during COVID‐19. Reports have been made on informal carers’ increased workload ...and limited support services during the pandemic.
Aims
This study aimed to explore how informal caregivers experienced their well‐being during COVID‐19 through online discussion forums.
Materials and Methods
A reflexive thematic analysis characterised by theoretical flexibility, organic inductive coding processes and theme development was conducted on online discussion forums. The method highlighted theme reviewing which was done twice to encourage data reflection. The project was conducted on a novel topic which was a new area of research interest. Semantic coding where participants’ words were used directly in the interpretation and construction of themes was used.
Results
In the theme ‘Locked in or locked away’ caregivers worried about continuing care at home, due to limited freedom and worries of hiring help during a pandemic. Some expressed worries about visitation rights and grief of not being present with a loved one if they would reside in a care home. The theme ‘Nothing left to give’ suggested that COVID‐19 exasperated caregivers’ loneliness, social isolation and increased responsibilities and challenges with other roles. Bitterness, resentment and anger were felt towards lack of social support and workload. Theme ‘Celebrating a virtual way of life’ described how caregivers used online forums when other support services were disrupted.
Discussion
We discuss the role of informal caregiver that was described as all‐encompassing during COVID‐19. We highlight the importance of advanced planning for care home transitions and the use of online forums as a form of support. We suggest further exploration into informal caregivers’ role balancing.
Conclusion
COVID‐19 seemed to affect informal caregivers negatively, but they reframed their situations and sought online support. With COVID‐19‐related restrictions and increased workload, COVID‐19 added an all‐or‐nothing aspect to care home transition decisions.
During HIV type-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, altered iron balance correlates with morbidity. The liver-produced hormone hepcidin dictates systemic iron ...homeostasis. We measured hepcidin, iron parameters, cytokines, and inflammatory markers in three cohorts: plasma donors who developed acute HIV-1, HBV, or HCV viremia during the course of donations; HIV-1–positive individuals progressing from early to chronic infection; and chronically HIV-1–infected individuals (receiving antiretroviral therapy or untreated). Hepcidin increased and plasma iron decreased during acute HIV-1 infection, as viremia was initially detected. In patients transitioning from early to chronic HIV-1 infection, hepcidin in the first 60 d of infection positively correlated with the later plasma viral load set-point. Hepcidin remained elevated in individuals with untreated chronic HIV-1 infection and in subjects on ART. In contrast to HIV-1, there was no evidence of hepcidin up-regulation or hypoferremia during the primary viremic phases of HCV or HBV infection; serum iron marginally increased during acute HBV infection. In conclusion, hepcidin induction is part of the pathogenically important systemic inflammatory cascade triggered during HIV-1 infection and may contribute to the establishment and maintenance of viral set-point, which is a strong predictor of progression to AIDS and death. However, distinct patterns of hepcidin and iron regulation occur during different viral infections that have particular tissue tropisms and elicit different systemic inflammatory responses. The hypoferremia of acute infection is therefore a pathogen-specific, not universal, phenomenon.
Identification of G protein-coupled receptors that are activated by free fatty acids has led to considerable interest in their pharmacology and function because of the wide range of normal physiology ...and disease states in which fatty acids have been implicated. Free fatty acid receptor (FFA) 1 is activated by medium- to long-chain fatty acids and is expressed in the insulin-producing beta-cells of the pancreas. Activation of FFA1 has been proposed to mediate fatty acid augmentation of glucose-stimulated insulin secretion although it is unclear whether the known long-term detrimental effects of beta-cell exposure to high levels of fatty acids are also mediated through this receptor. The related receptors FFA2 and FFA3 are both activated by short-chain fatty acids although they have key differences in the signaling pathways they activate and tissue expression pattern. The aim of this review is to provide a comprehensive overview of the current understanding of the pharmacology and physiological role of these fatty acid receptors.
Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan ...GPCRs are the endothelin B receptor-like proteins, GPR37 ET(B)R-LP, Pael-R and GPR37L1 ET(B)R-LP-2. Originally identified through searches for homologs of endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson's disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored.
The diversity–invasibility hypothesis and ecological theory predict that high-diversity communities should be less easily invaded than species-poor communities, but empirical evidence does not ...consistently support this prediction. While fine-scale experiments tend to yield the predicted negative association between diversity and invasibility, broad-scale observational surveys generally report a positive correlation. This conflicting pattern between experiments and observational studies is referred to as the invasion paradox and is thought to arise because different processes control species composition at different spatial scales. Here, we test empirically the extent to which the strength and direction of published diversity–invasibility relationships depend on spatial scale and on the metrics used to measure invasibility. Using a meta-analytic framework, we explicitly separate the two components of spatial scale: grain and extent, by focusing on fine-grain studies that vary in extent. We find evidence of multiple drivers of the paradox. When we consider only fine-grain studies, we still observe conflicting patterns between experiments and observational studies. In contrast, when we examine studies that are conducted at both a fine grain and fine extent, there is broad overlap in effect sizes between experiments and observation, suggesting that comparing studies with similar extents resolves the paradox at local scales. However, we uncover systematic differences in the metrics used to measure invasibility between experiments, which use predominantly invader performance, and observational studies, which use mainly invader richness. When we consider studies with the same metric (i.e., invader performance), the contrasting associations between study types also disappear. It is not possible, at present, to fully disentangle the effect of spatial extent and metric on the paradox because both variables are systematically associated in different directions with study type. There is therefore an urgent need to conduct experiments and observational studies that incorporate the full range of variability in spatial extent and invasibility metric.
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