bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB1, CB2, GPR18 and GPR55 cannabinoid receptors
Authors: Glenn Nathaniel A. K. , Finlay David B. , Carruthers Emma R. , Mountjoy Kathleen G. , Walker Christopher S. , Grimsey Natasha L. 
Published: April 2023

Background and PurposeReceptor activity‐modifying proteins (RAMPs) and melanocortin receptor accessory proteins (MRAPs) modulate expression and signalling of calcitonin and melanocortin GPCRs. Interactions with other GPCRs have also been reported. The cannabinoid receptors, CB1 and CB2, and two putative cannabinoid receptors, GPR18 and GPR55, exhibit substantial intracellular expression and there are discrepancies in ligand responsiveness between studies. We investigated whether interactions with RAMPs or MRAPs could explain these phenomena.Experimental ApproachReceptors and accessory proteins were co‐expressed in HEK‐293 cells. Selected receptors were studied at basal expression levels and also with enhanced expression produced by incorporation of a preprolactin signal sequence/peptide (pplss). Cell surface and total expression of receptors and accessory proteins were quantified using immunocytochemistry. Signalling was measured using cAMP (CAMYEL) and G protein dissociation (TRUPATH Gα13) biosensors.Key ResultsMRAP2 enhanced surface and total expression of GPR18. Pplss‐GPR18 increased detection of cell surface MRAP2. MRAP1α and MRAP2 reduced GPR55 surface and total expression, correlating with reduced constitutive, but not agonist‐induced, signalling. GPR55, pplss‐CB1 and CB2 reduced detection of MRAP1α at the cell surface. Pplss‐CB1 agonist potency was reduced by MRAP2 in Gα13 but not cAMP assays, consistent with MRAP2 reducing pplss‐CB1 expression. Some cannabinoid receptors increased RAMP2 or RAMP3 total expression without influencing surface expression.Conclusions and ImplicationsMutual influences on expression and/or function for specific accessory protein‐receptor pairings raises the strong potential for physiological and disease‐relevant consequences. Sequestration and/or hetero‐oligomerisation of cannabinoid receptors with accessory proteins is a possible novel mechanism for receptor crosstalk.LINKED ARTICLESThis 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
Regulation of the pro‐inflammatory G protein‐coupled receptor GPR84
Authors: Marsango Sara , Milligan Graeme 
Published: April 2023

GPR84 is an understudied rhodopsin‐like class A G protein‐coupled receptor, which is arousing particular interest from a therapeutic perspective. Not least this reflects that gpr84 expression is significantly up‐regulated following acute inflammatory stimuli and in inflammatory diseases, and that receptor activation plays a role in regulating pro‐inflammatory responses and migration of cells of the innate immune system such as neutrophils, monocytes, macrophages and microglia. Although most physiological responses of GPR84 reflect receptor coupling to Gαi/o‐proteins, several studies indicate that agonist‐activated GPR84 can recruit arrestin adaptor proteins and this regulates receptor internalisation and desensitisation. To date, little is known on the patterns of either basal or ligand regulated GPR84 phosphorylation and how these might control these processes. Here, we consider what is known about the regulation of GPR84 signalling with a focus on how G protein receptor kinase‐mediated phosphorylation regulates arrestin protein recruitment and receptor function.LINKED ARTICLESThis article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc
Intercellular mitochondrial transfer alleviates pyroptosis in dental pulp damage
Authors: Wang Konghuai , Zhou Lu , Mao Hanqing , Liu Jiayi , Chen Zhi , Zhang Lu 
Published: April 2023

AbstractMitochondrial transfer is emerging as a promising therapeutic strategy for tissue repair, but whether it protects against pulpitis remains unclear. Here, we show that hyperactivated nucleotide‐binding domain and leucine‐rich repeat protein3 (NLRP3) inflammasomes with pyroptotic cell death was present in pulpitis tissues, especially in the odontoblast layer, and mitochondrial oxidative stress (OS) was involved in driving this NLRP3 inflammasome‐induced pathology. Using bone marrow mesenchymal stem cells (BMSCs) as mitochondrial donor cells, we demonstrated that BMSCs could donate their mitochondria to odontoblasts via tunnelling nanotubes (TNTs) and, thus, reduce mitochondrial OS and the consequent NLRP3 inflammasome‐induced pyroptosis in odontoblasts. These protective effects of BMSCs were mostly blocked by inhibitors of the mitochondrial function or TNT formation. In terms of the mechanism of action, TNF‐α secreted from pyroptotic odontoblasts activates NF‐κB signalling in BMSCs via the paracrine pathway, thereby promoting the TNT formation in BMSCs and enhancing mitochondrial transfer efficiency. Inhibitions of NF‐κB signalling and TNF‐α secretion in BMSCs suppressed their mitochondrial donation capacity and TNT formation. Collectively, these findings demonstrated that TNT‐mediated mitochondrial transfer is a potential protective mechanism of BMSCs under stress conditions, suggesting a new therapeutic strategy of mitochondrial transfer for dental pulp repair.
Developing a mechanistic understanding of the nonlinear pharmacokinetics of letermovir and prospective drug interaction with everolimus using physiological‐based pharmacokinetic modeling
Authors: Menzel Karsten , Kuo Yuhsin , Chen Dapeng , Hartmann Georgy , Wang Ying‐Hong , Cho Carolyn R. , McCrea Jacqueline B. , Asari Kazuhiko 
Published: April 2023

AbstractLetermovir is approved for use in cytomegalovirus‐seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings. Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically‐based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)‐metabolism and by saturable hepatic uptake via organic anion‐transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose‐proportional increase in letermovir exposure is best described by a saturable OATP1B‐mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co‐administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug–drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5‐fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir.
Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID‐19 practice change
Authors: Lee Benjamin J. , Kongtim Piyanuch , Doh Jean , Griffin Shawn P. , Chan Alexandre , O'Brien Susan , Ciurea Stefan O. , Jeyakumar Deepa 
Published: April 2023

AbstractTreatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID‐19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse‐free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment‐related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS‐RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45–5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3–5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20–4.21; p = .90) at 2‐years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment‐related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.
Disentangling climate change from air pollution effects on epiphytic bryophytes
Authors: Hutsemékers Virginie , Mouton Lea , Westenbohm Hannah , Collart Flavien , Vanderpoorten Alain 
Published: April 2023

AbstractAt the interface between atmosphere and vegetation, epiphytic floras have been largely used as indicators of air quality. The recovery of epiphytes from high levels of SO2 pollution has resulted in major range changes, whose interpretation has, however, been challenged by concomitant variation in other pollutants as well as climate change. Here, we combine historical and contemporary information on epiphytic bryophyte species distributions, climatic conditions, and pollution loads since the 1980s in southern Belgium to disentangle the relative impact of climate change and air pollution on temporal shifts in species composition. The relationship between the temporal variation of species composition, climatic conditions, SO2, NO2, O3, and fine particle concentrations, was analyzed by variation partitioning. The temporal shift in species composition was such, that it was, on average, more than twice larger than the change in species composition observed today among communities scattered across the study area. The main driver, contributing to 38% of this temporal shift in species composition, was the variation of air quality. Climate change alone did not contribute to the substantial compositional shifts in epiphytic bryophyte communities in the course of the last 40 years. As a consequence of the substantial drop of N and S loads over the last decades, present‐day variations of epiphytic floras were, however, better explained by the spatial variation of climatic conditions than by extant pollution loads. The lack of any signature of recolonization delays of formerly polluted areas in the composition of modern floras suggests that epiphytic bryophytes efficiently disperse at the landscape scale. We suggest that a monitoring of epiphyte communities at 10‐year intervals would be desirable to assess the impact of raising pollution sources, and especially pesticides, whose impact on bryophytes remains poorly documented.
Re‐ensiling effects on inoculated sorghum: Intake, apparent digestibility, nitrogen balance, and animal feeding behaviour
Authors: Silva Flávia Cristina de Oliveira e , Silva Naiara Taís Alves da , Glória Joana Ribeiro da , Alves João Carlos de Freitas , Borges Ana Luiza da Costa Cruz , Gonçalves Lúcio Carlos , Rodrigues José Avelino Santos , Jayme Diogo Gonzaga 
Published: April 2023

AbstractThis study aimed to determine whether using inoculants and re‐ensiling in sorghum silages affect the intake and feeding behaviour, apparent digestibility, digestible energy, and nitrogen balance of sheep in maintenance. Half the sorghum was inoculated on the day of harvest, and the other half received the same inoculation volume but with water. Sorghum was ensiled in 100 experimental metal drum silos of 200 L covered with plastic: 50 silos with inoculants and 50 without them. After 56 days, 25 drums with inoculants and 25 without were exposed to air for 48 h. The other silos remained closed. The treatments were arranged in a 2 × 2 factorial scheme with inoculation and re‐ensiling. The sheep received the silages after 211 days of ensiling and 155 days of re‐ensiling to determine the intake, apparent digestibility, and feeding behaviour of animals. The experimental design was a simultaneous double 4 × 4 Latin square. The re‐ensiling process increased silage pH, N‐NH3.TN−1, butyric acid, and propionic acid. The inoculant increased propionic acid in ensiled and re‐ensiled silages. Lactic acid concentration presented a statistical interaction with the inoculated and ensiled silage, 58% higher than the other treatment averages. The ADFap digestibility showed a complex interaction, in which the control ensiled and the inoculated and re‐ensiled silages were about 35% lower than the inoculated ensiled silage. The Nbal:Nint ratio (g.g−1) in the inoculated and re‐ensiled silage had lower nitrogen retention than intake compared with the other treatments. These results indicate that exposing inoculated silages to air does not compromise their use in sheep feeding.
Evaluating the effects of a multicomponent support service for people recently diagnosed with dementia and their carers: A qualitative study
Authors: Ling Jonathan , McCabe Karen , Crosland Ann , Kane Laura , Eberhardt Judith 
Published: April 2023

AbstractIntroductionAlthough prior research has provided an understanding of the needs of people living with dementia (PLWD) and their carers, less is known about how tailored multicomponent interventions impact their lives. This study explored the effect of providing ongoing support to people who had been recently diagnosed with dementia and to their carers.MethodsWe conducted interviews with a convenience sample of key stakeholders: 11 interviews with people who had dementia and their familial carers (n = 14) and six interviews with staff and other practitioners involved with the service (n = 13). Inductive thematic analysis was performed on the data.ResultsFour themes were developed: the service as a source of respite, peer support, activities as facilitators of emotional wellbeing, and social support. The service was well‐respected, credible, and trusted and was highly valued by practitioners, clients, and carers. It had a clear role in supporting PLWD and their carers. Peer support provided through the service contributed to greatly reducing self‐reported carer burden.ConclusionRecommendations arising from this study include offering holistic services to PLWD and their carers, developing activities for men, raising awareness of services among practitioners working with PLWD, and improving partnerships between services and agencies working with older people.Patient or Public ContributionService users were consulted on the themes generated from the data and were asked to provide feedback to help guide the interpretation of the data and ensure this reflected their views and experiences.
Is job quality better or worse? Insights from quiz data collected before and after the pandemic
Authors: Davies Rhys , Felstead Alan 
Published: April 2023

AbstractThis article is based on data collected from almost 100,000 individuals who completed the www.howgoodismyjob.com quiz either side of the pandemic. The results show that overall non‐pecuniary job quality has improved, differences between occupations have shrunk and the growth of remote working is a factor behind these trends.
Sustaining complementor engagement in digital platform ecosystems: Antecedents, behaviours and engagement trajectories
Authors: Engert Martin , Evers Julia , Hein Andreas , Krcmar Helmut 
Published: April 2023

AbstractDigital platform ecosystems increasingly dominate the enterprise software domain, and the persistence of platforms depends on the sustained engagement of complementors. However, there is a limited understanding of its antecedents, complementors' evaluation of antecedents and the manifestations and dynamic changes of complementors' engagement. Therefore, we investigate complementors' engagement within platform ecosystems over time. We draw on actor and stakeholder engagement from service research to conceptualise complementor engagement (CE) and create an integrated empirical understanding of CE and its dynamics in digital platform ecosystems. Our embedded case study builds on 30 interviews with complementors in Anubis and Osiris enterprise software platform ecosystems. Inductive data analysis reveals five CE antecedents: platform resources and rules, platform value proposition, platform agents, customer needs and other complementors' value propositions. The antecedents are associated with three CE behaviours: generating, networking and synchronising. Further analysis of CE over time resulted in 26 different sequences representing stable and changing engagement trajectories, the latter comprising selective, growing and abating engagement as subcategories. We show how complementors' evaluations of antecedents lead to behaviour changes, providing a novel perspective on the dynamics underlying CE. Finally, we link complementors' evaluation outcomes to their (dis)satisfaction, contributing to the discussion on what drives and impedes CE. The findings implicate the debate on dynamic platform governance and inform platform owners about using cooperative and competitive approaches in the short and long term.
Strong bounds and exact solutions to the minimum broadcast time problem
Authors: Ivanova Marika , Haugland Dag , Tvedt Bård Hennning 
Published: April 2023

AbstractGiven a graph and a subset of its nodes, referred to as source nodes, the minimum broadcast time problem asks for the minimum number of steps in which a signal can be transmitted from the sources to all other nodes in the graph. In each step, the sources and the nodes that already have received the signal can forward it to at most one of their neighbour nodes. The problem has previously been proved to be NP‐hard. In the current work, we develop a compact integer programming model for the problem. We also devise procedures for computing lower bounds on the minimum number of steps required, along with methods for constructing near‐optimal solutions. Computational experiments demonstrate that in a wide range of instances, in particular instances with sufficiently dense graphs, the lower and upper bounds under study collapse. In instances where this is not the case, the integer programming model proves strong capabilities in closing the remaining gap and proves to be considerably more efficient than previously studied models.
Pressure‐driven phase transition and energy conversion in ferroelectrics: Principles, materials, and applications
Authors: Xie Meng , Nie Hengchang , Liu Zhen , Lu Teng , Liu Yun , Wang Genshui 
Published: April 2023

AbstractThe pressure‐driven explosive energy‐conversion (EEC) effect of ferroelectric (FE) materials has been extensively studied in scientific research and high‐tech applications owing to its high pulse‐power output capability. The fundamental principle of this effect is pressure‐driven phase transition and depolarization in FE materials, accompanied by discharging behavior from the charge release upon pressure loading. Pb(Zr,Ti)O3has been an excellent example of a materials exhibiting these properties. However, recent investigations have been focused on developing other lead‐based or lead‐free materials with a higher energy‐storage ability and better temperature stability. In this article, we review the recent progress achieved in the past decades on different types of lead‐based and lead‐free ceramics, single crystals, and multilayer films, based on their unique pressure‐driven phase transition and energy‐conversion properties. Their pulse power discharging performance under actual shock‐wave compression is also summarized, followed by a detailed discussion of the failure mechanism under shock‐wave compression. Finally, several issues and perspectives are proposed for future investigation in this area. All these not only assist in the design of new materials for high‐performance EEC but are also helpful for the practical application of these promising materials in pulse‐power technologies.
Exemplar typicality in interventions to reduce public stigma against people with mental illness
Authors: Maunder Rachel D. , White Fiona A. 
Published: April 2023

AbstractA large number of studies support the effectiveness of interventions aimed at reducing public stigma, which has numerous deleterious effects on the lives of people with mental illness. Missing from research literature, however, is an examination of intervention characteristics which may enhance their effectiveness. Drawing from the broader literature concerned with changing perceptions of social outgroups, the present research program explores the role of exemplar typicality—the degree to which the characteristics of outgroup members who participants read about or interact with adhere to stereotypes about their group. Scholars have arrived at divergent conclusions regarding the level of typicality that is the most beneficial, prompting experimentation into this issue. In three studies concerned with stigma against people with mental illness, participants read about (n = 262) or had contact with (E‐contact, n = 248; imagined contact, n = 506) a typical, moderately atypical, or extremely atypical exemplar. Overall, the results suggested typical exemplars to be detrimental or less effective, while atypical exemplars appeared to produce lower public stigma. But there were inconsistent findings regarding the difference between the moderately and extremely atypical exemplars. These results call for intergroup contact scholars to reexamine the claim that typical exemplars are ideal, given their potential to aggravate biases toward some vulnerable social groups. The findings also suggest that organizations implementing prevalent interventions such as contact and personal narratives to reduce mental health stigma should carefully attend to the characteristics of the outgroup exemplars involved.