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Department of Pharmacology

 

Matchmaking at the cell surface using bispecifics to put cells on their best behavior

Pharmacology Cambridge RSS Paper feed - Thu, 06/02/2025 - 11:00

Curr Opin Biotechnol. 2025 Feb 5;92:103267. doi: 10.1016/j.copbio.2025.103267. Online ahead of print.

ABSTRACT

Intermolecular relationships at the cell surface dictate the behavior and regulatory network of cells. Such interactions often require precise spatial control for optimal response. By binding simultaneously to two different target sites, bispecific binders can bridge molecules of interest. Despite decades of bispecific development, only recently have bispecifics been engineered with programmable, tuneable geometries to replicate natural interaction geometries or achieve new responses from unnatural arrangements. This review highlights emerging methods of protein engineering and modular bioconjugation to control pairing and orientation of binders in bispecific scaffolds. We also describe novel biophysical and phenotypic assays, which reveal how bispecific geometries change cell fate. These approaches are informing design of next-generation precision therapeutics, as well as uncovering fundamental features of signal integration.

PMID:39914134 | DOI:10.1016/j.copbio.2025.103267

Multicentre retrospective study on plate osteosynthesis for non-condylar mandibular fractures in paediatric patients with deciduous, mixed, and permanent dentition: A World Oral Maxillofacial Trauma (WORMAT) project

Recent Publications - Thu, 06/02/2025 - 11:00

J Craniomaxillofac Surg. 2025 Feb 5:S1010-5182(25)00038-1. doi: 10.1016/j.jcms.2025.01.027. Online ahead of print.

ABSTRACT

Mandibular fractures are common maxillofacial injuries among children and adolescents, but treatment remains controversial. The aim of this study was to analyse the methods and outcomes of open reduction and internal fixation (ORIF) for non-condylar mandibular fractures in paediatric patients among 14 maxillofacial centres. Patients ≤16 years of age undergoing ORIF for non-condylar mandibular fractures between 2011 and 2022 were included. Age, gender, dentition stage, site and type of fracture, surgical approach, material, thickness, and number of plates, and outcome were recorded. 179 patients (mean age, 11.1 years) reported 120 single and 59 double fractures, 79% involving at least one displaced or comminuted site. Single fractures were preferentially treated with rigid osteosynthesis in all dentition groups (64%), while double fractures with non-rigid osteosynthesis in mixed and permanent dentition patients (59% and 43%) and mixed osteosynthesis in deciduous dentition patients (50%). Mean follow-up was 21 months. Surgical would infection was the most common complication (8.9%), followed by minor malocclusion (1.7%) and osteitis (1.7%). In conclusion, the centres opted for fixation patterns like those recommended for adults, favoring non-rigid or mixed osteosynthesis for double fractures. The low complication rate shows ORIF is effective and safe for non-condylar mandibular fractures in paediatric patients.

PMID:39915154 | DOI:10.1016/j.jcms.2025.01.027

Matchmaking at the cell surface using bispecifics to put cells on their best behavior

Recent Publications - Thu, 06/02/2025 - 11:00

Curr Opin Biotechnol. 2025 Feb 5;92:103267. doi: 10.1016/j.copbio.2025.103267. Online ahead of print.

ABSTRACT

Intermolecular relationships at the cell surface dictate the behavior and regulatory network of cells. Such interactions often require precise spatial control for optimal response. By binding simultaneously to two different target sites, bispecific binders can bridge molecules of interest. Despite decades of bispecific development, only recently have bispecifics been engineered with programmable, tuneable geometries to replicate natural interaction geometries or achieve new responses from unnatural arrangements. This review highlights emerging methods of protein engineering and modular bioconjugation to control pairing and orientation of binders in bispecific scaffolds. We also describe novel biophysical and phenotypic assays, which reveal how bispecific geometries change cell fate. These approaches are informing design of next-generation precision therapeutics, as well as uncovering fundamental features of signal integration.

PMID:39914134 | DOI:10.1016/j.copbio.2025.103267

Protective Factors Against e-Cigarette Use Among First Nations People Aged 16-24 in the Next Generation Youth Wellbeing Study

Recent Publications - Thu, 06/02/2025 - 11:00

Health Promot J Austr. 2025 Apr;36(2):e951. doi: 10.1002/hpja.951.

ABSTRACT

ISSUE ADDRESSED: Adolescent e-cigarette use is increasing and is associated with subsequent smoking. This study examines potential protective factors associated with not vaping among First Nations adolescents in Australia to inform community programs.

METHODS: The 'Next Generation: Youth Wellbeing Study' is a cohort study of First Nations adolescents aged 10-24 years from urban, rural and remote communities in Central Australia, Western Australia and New South Wales. Analysis of self-reported vaping from 16 to 24-year-olds, collected 2018-2020, using multi-level mixed-effects Poisson regression to estimate age-site-adjusted prevalence ratios (PRs) for never-vaping in relation to various factors.

RESULTS: Among 419 participants, 65% were female, 75% had never vaped, 49% had never smoked and 82% lived in smoke-free homes. Never vaping was more common among those who had: never-smoked (PR = 1.78, 95%CI: 1.56-2.04); never used cannabis (1.89, 1.60-2.24); non-smoking friends (1.38, 1.26-1.51); good mental health (1.15, 1.01-1.30), never diagnosed with depression (1.21, 1.01-1.46) or anxiety (1.31, 1.08-1.57); and no experiences of racism (1.21, 1.08-1.36), no negative criminal justice system experiences (1.25, 1.11-1.41), or vicarious racism through negative media (1.24, 1.10-1.39).

CONCLUSIONS: Most First Nations adolescents have never vaped, with potential protective factors being better mental health, no other substance use and fewer experiences of racism and justice system interactions. Comprehensive community adolescent prevention programs are needed to prevent vaping and protect future health, including preventing nicotine addiction and future smoking. SO WHAT?: Policies and programs must address e-cigarettes directly as well as structural factors, promoting broader adolescent wellbeing, centring culture and family in a strengths-based approach.

PMID:39912122 | DOI:10.1002/hpja.951

Predicting survival in malignant glioma using artificial intelligence

Recent Publications - Fri, 31/01/2025 - 11:00

Eur J Med Res. 2025 Jan 31;30(1):61. doi: 10.1186/s40001-025-02339-3.

ABSTRACT

Malignant gliomas, including glioblastoma, are amongst the most aggressive primary brain tumours, characterised by rapid progression and a poor prognosis. Survival analysis is an essential aspect of glioma management and research, as most studies use time-to-event outcomes to assess overall survival (OS) and progression-free survival (PFS) as key measures to evaluate patients. However, predicting survival using traditional methods such as the Kaplan-Meier estimator and the Cox Proportional Hazards (CPH) model has faced many challenges and inaccuracies. Recently, advances in artificial intelligence (AI), including machine learning (ML) and deep learning (DL), have enabled significant improvements in survival prediction for glioma patients by integrating multimodal data such as imaging, clinical parameters and molecular biomarkers. This study highlights the comparative effectiveness of imaging-based, non-imaging and combined AI models. Imaging models excel at identifying tumour-specific features through radiomics, achieving high predictive accuracy. Non-imaging approaches also excel in utilising clinical and genetic data to provide complementary insights, whilst combined methods integrate multiple data modalities and have the greatest potential for accurate survival prediction. Limitations include data heterogeneity, interpretability challenges and computational demands, particularly in resource-limited settings. Solutions such as federated learning, lightweight AI models and explainable AI frameworks are proposed to overcome these barriers. Ultimately, the integration of advanced AI techniques promises to transform glioma management by enabling personalised treatment strategies and improved prognostic accuracy.

PMID:39891313 | DOI:10.1186/s40001-025-02339-3

Ambulation Protocol for Adult Patients Receiving Extracorporeal Membrane Oxygenation: A Quality Improvement Initiative

Recent Publications - Fri, 31/01/2025 - 11:00

Crit Care Nurse. 2025 Feb 1;45(1):52-60. doi: 10.4037/ccn2025452.

ABSTRACT

BACKGROUND: For patients receiving extracorporeal membrane oxygenation, early mobility decreases mechanical ventilation time, delirium incidence, and length of intensive care unit stay and improves physical functioning. Individual centers use institutional guidelines to develop ambulation protocols. Local Problem A quality improvement initiative was used to evaluate an ambulation protocol for adult intensive care unit patients receiving extracorporeal membrane oxygenation.

METHODS: Adult patients receiving extracorporeal membrane oxygenation who walked according to the protocol were compared with a historical control group of patients who walked without the protocol. Data analysis included descriptive statistics and independent t tests. Outcomes included adverse safety events, number of patients and ambulation sessions, standing and ambulation time, and distance.

RESULTS: From January to March 2021, 13 of 46 patients receiving extracorporeal membrane oxygenation (28%) walked according to the protocol. In the control group, 14 of 147 patients (10%) walked in 2019; 21 of 144 patients (15%) walked in 2020. Some characteristics of the control group (hospitalized before the COVID-19 pandemic) differed from those of the protocol group (hospitalized during the pandemic). Mean number of ambulation sessions was not significantly different between groups (protocol group, 10; control group, 9). Differences in mean standing time (protocol group, 121.23 minutes; control group, 210.80 minutes), ambulation time (protocol group, 11.77 minutes; control group, 198.70 minutes), and ambulation distance were not significant.

CONCLUSIONS: Standing time, ambulation time, and distance were not significantly different between the groups. The extracorporeal membrane oxygenation ambulation protocol demonstrated clinical significance by increasing the number of patients walking.

PMID:39889799 | DOI:10.4037/ccn2025452

Effects of Calcium Chloride Crosslinking Solution Concentration on the Long-Term Cell Viability of 16HBE14o- Human Bronchial Cells Embedded in Alginate-Based Hydrogels

Recent Publications - Fri, 24/01/2025 - 11:00

Biomimetics (Basel). 2025 Jan 10;10(1):40. doi: 10.3390/biomimetics10010040.

ABSTRACT

In this preliminary study, the long-term effects of calcium chloride crosslinking concentration on viability of 16HBE14o- human bronchial epithelial cells embedded in alginate-extracellular matrix (ECM) or alginate-methylcellulose-ECM hydrogels have been investigated. There is currently a limited understanding regarding the effects of crosslinking solution concentration on lung epithelial cells embedded in hydrogel. Furthermore, the effects of calcium chloride concentration in crosslinking solutions on other cell types have not been reported regarding whether the addition of viscosity and stiffness tuning agents such as methylcellulose will alter the responses of cells to changes in calcium chloride concentration in crosslinking solutions. While there were no significant effects of calcium chloride concentration on cell viability in alginate-ECM hydrogels, there is a decrease in cell viability in alginate-methylcellulose-ECM hydrogels crosslinked with 300 mM calcium chloride crosslinking solution. These findings have implications in the maintenance of 16HBE14o- 3D cultures with respect to the gelation of alginate with high concentrations of ionic crosslinking solution.

PMID:39851756 | DOI:10.3390/biomimetics10010040

Permanent defects in renal medullary structure and function after reversal of urinary obstruction

Recent Publications - Thu, 23/01/2025 - 11:00

JCI Insight. 2025 Jan 23:e187008. doi: 10.1172/jci.insight.187008. Online ahead of print.

ABSTRACT

Urinary obstruction causes injury to the renal medulla, impairing the ability to concentrate urine, and increasing the risk of progressive kidney disease. However, the regenerative capacity of the renal medulla after reversal of obstruction is poorly understood. To investigate this, we developed a mouse model of reversible urinary obstruction. Despite robust regeneration and complete histological recovery of the renal medulla, these mice exhibited a permanent defect in urinary concentrating capacity. However, there were lasting changes in the composition, organization, and transcriptional profiles of epithelial, endothelial, and interstitial cells. Persistent inflammatory responses were also seen in patients with renal stone disease, but there were also adaptive responses to the increasingly hypoxic environment of the renal medulla that only occurred after reversal of obstruction. These findings indicate that while partial repair occurs after reversal of urinary obstruction, there are lasting structural and functional changes across all major cellular compartments of the renal medulla. These changes reflect shared and distinct responses to different renal medullary injuries in humans and mice.

PMID:39847447 | DOI:10.1172/jci.insight.187008

Prescriptions (Rx) for Prevention: Clinical Tools for Integrating Environmental Health into Pediatric Clinical Care

Recent Publications - Thu, 23/01/2025 - 11:00

J Public Health Manag Pract. 2025 Mar-Apr 01;31(2):244-251. doi: 10.1097/PHH.0000000000002044. Epub 2024 Sep 9.

ABSTRACT

The integration of environmental health (EH) into routine clinical care for children is in its early stages. The vision of pediatric EH is that all clinicians caring for children are aware of and able to help connect families to needed resources to reduce harmful environmental exposures and increase health-enhancing ones. Environmental exposures include air pollution, substandard housing, lead, mercury, pesticides, consumer products chemicals, drinking water contaminants, industrial facility emissions and, increasingly, climate change-related extreme weather and heat events. An identified need is to simultaneously educate clinicians while connecting families to evidence-based EH interventions. Here, we describe a multi-decadal effort to create, refine, and disseminate a clinical tool called Prescriptions (Rxs) for Prevention that responds to that identified need. These tools are modeled on a risk communication framework and use a format that support clinicians when they screen their patients for EH concerns, to then counsel on those topics, and refer to EH resources if needed. Rxs for Prevention-tailored with local resources-are now in use at more than a dozen sites in multiple regions of the U.S. supporting the promotion of healthy homes, communities, and the broader environment for children. These Rxs are reducing barriers to EH integration by educating clinicians, linking families to community resources, and strengthening clinic and community connections. On-going evaluation can help further the implementation of the Rxs for Prevention to help achieve the long-term vision of integrating EH into routine clinical care.

PMID:39847039 | DOI:10.1097/PHH.0000000000002044

Improving diagnostics and surveillance of malaria among displaced people in Africa

Recent Publications - Mon, 20/01/2025 - 11:00

Int J Equity Health. 2025 Jan 21;24(1):22. doi: 10.1186/s12939-025-02378-6.

ABSTRACT

African communities that have been forced to leave their homes experience a considerably greater susceptibility to malaria as a result of densely populated living conditions, restricted availability of healthcare, and environmental influences. Internally displaced individuals frequently live in large settlements with restricted availability to drinking water, essential sanitation, and medical services, intensifying the spread of malaria. As a result, the occurrence of malaria is significantly more common among refugees and internally displaced individuals compared to those who are not displaced. This leads to greater rates of illness and death, especially among young people. Insufficient monitoring worsens the condition, leading to delayed identification and medical intervention, and contributing to a higher incidence of severe malaria and deaths. Furthermore, these communities are faced with economic consequences that contribute to the continuation of poverty and the worsening of socio-economic inequalities. Furthermore, the psychological impact of malaria, which is marked by feelings of anxiety and uncertainty, is particularly severe in vulnerable populations such as displaced children and pregnant women, aggravating the overall burden. Hence, addressing malaria in displaced populations in Africa requires comprehensive and well-coordinated strategies. Advanced diagnostic and surveillance technologies are essential for promptly identifying and treating malaria, providing chances to monitor and control its spread effectively. Collaboration among healthcare, policy, and humanitarian sectors is crucial for implementing comprehensive solutions that incorporate enhanced diagnostics, surveillance, and socio-psychological support. Active involvement of the community, usage of Community Health Workers, and regular collection of surveillance data are crucial in increasing awareness, directing control efforts, and tackling the specific difficulties encountered by displaced groups. Moreover, the implementation of environmental management, the incorporation of health services, and the utilization of adaptable healthcare interventions are essential for reducing the effects of malaria. To mitigate the impact of malaria and improve health outcomes among displaced populations in Africa, it is crucial to focus on these specific areas.

PMID:39833862 | DOI:10.1186/s12939-025-02378-6

Direct observation of small molecule activator binding to single PR65 protein

Pharmacology Cambridge RSS Paper feed - Mon, 20/01/2025 - 11:00

NPJ Biosens. 2025;2(1):2. doi: 10.1038/s44328-024-00018-7. Epub 2025 Jan 16.

ABSTRACT

The reactivation of heterotrimeric protein phosphatase 2A (PP2A) through small molecule activators is of interest to therapeutic intervention due to its dysregulation, which is linked to chronic conditions. This study focuses on the PP2A scaffold subunit PR65 and a small molecule activator, ATUX-8385, designed to bind directly to this subunit. Using a label-free single-molecule approach with nanoaperture optical tweezers (NOT), we quantify its binding, obtaining a dissociation constant of 13.6 ± 2.5 μM, consistent with ensemble fluorescence anisotropy results but challenging to achieve with other methods due to low affinity. Single-molecule NOT measurements reveal that binding increases optical scattering, indicating PR65 elongation. This interpretation is supported by all-atom molecular dynamics simulations showing PR65 adopts more extended conformations upon binding. This work highlights NOT's utility in quantifying binding kinetics and structural impact, offering insights valuable for drug discovery.

PMID:39830999 | PMC:PMC11738983 | DOI:10.1038/s44328-024-00018-7

Direct observation of small molecule activator binding to single PR65 protein

Recent Publications - Mon, 20/01/2025 - 11:00

NPJ Biosens. 2025;2(1):2. doi: 10.1038/s44328-024-00018-7. Epub 2025 Jan 16.

ABSTRACT

The reactivation of heterotrimeric protein phosphatase 2A (PP2A) through small molecule activators is of interest to therapeutic intervention due to its dysregulation, which is linked to chronic conditions. This study focuses on the PP2A scaffold subunit PR65 and a small molecule activator, ATUX-8385, designed to bind directly to this subunit. Using a label-free single-molecule approach with nanoaperture optical tweezers (NOT), we quantify its binding, obtaining a dissociation constant of 13.6 ± 2.5 μM, consistent with ensemble fluorescence anisotropy results but challenging to achieve with other methods due to low affinity. Single-molecule NOT measurements reveal that binding increases optical scattering, indicating PR65 elongation. This interpretation is supported by all-atom molecular dynamics simulations showing PR65 adopts more extended conformations upon binding. This work highlights NOT's utility in quantifying binding kinetics and structural impact, offering insights valuable for drug discovery.

PMID:39830999 | PMC:PMC11738983 | DOI:10.1038/s44328-024-00018-7

Palliative care needs and quality of life among adults with advanced chronic illnesses in low-income communities of Bangladesh

Recent Publications - Fri, 17/01/2025 - 11:00

BMC Palliat Care. 2025 Jan 18;24(1):18. doi: 10.1186/s12904-024-01643-9.

ABSTRACT

OBJECTIVES: Palliative care (PC) is an interdisciplinary approach aimed at improving the physical, psychological, and spiritual well-being of patients and families affected by life-threatening diseases. This study aimed to investigate the need for PC among critically ill patients and their quality of life (QOL) in low-income groups in Bangladesh.

METHODS: This cross-sectional study was conducted at four healthcare facilities from March to April 2023, involving 553 registered patients with advanced chronic conditions. After applying inclusion and exclusion criteria, 183 patients in the advanced stage of illness were included. We collected data on sociodemographic, comorbidities, disabilities, and the 10-item African Palliative Outcome Scale (APOS). The Supportive and Palliative Care Indicators Tool (SPICT) was used to identify individuals requiring PC. The study investigated patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 3-4, indicating significant functional impairment, and explored QOL across four domains: physical health, psychological health, social relationships, and environmental factors.

RESULTS: The mean age of the 183 patients was 53.8 (± 14.53) years, with 69.5% being female. We found that 10.3% of patients with chronic illness required PC, particularly cancer patients (87%) and those with chronic kidney disease (CKD) (53.3%). The APOS scores indicated that family anxiety (48.6%) was the most burdensome issue, followed by severe pain (15.5%), severe worry about illness (22.4%), and feelings of life being unworthy (9.4%). Patients with severe functional limitations (ECOG 3-4) were significantly more likely to need PC (58%) compared to those with moderate or no limitations (ECOG 0-2) (24%). Among those requiring PC, 70.1% rated their QOL as poor or very-poor, while only 23.8% of patients not needing PC reported similar ratings. Female patients had poorer QOL than males across all domains, and those facing financial hardships also experienced significantly lower QOL.

CONCLUSION: In Bangladesh's low-income communities, a significant proportion of patients with chronic illnesses require palliative care (PC) due to advanced conditions. The findings emphasize the importance of integrating PC early in the treatment process for cancer and CKD patients, as it can greatly improve their QOL and provide essential support for both patients and families. The results advocate for a holistic approach to PC that addresses physical, psychological, social, and environmental factors affecting patients' QOL.

PMID:39825369 | DOI:10.1186/s12904-024-01643-9

Coronal alignment in normal individuals and moderate scoliosis: Normative values, variation with age and comparison with sagittal alignment

Recent Publications - Fri, 17/01/2025 - 11:00

Brain Spine. 2024 Oct 11;4:103917. doi: 10.1016/j.bas.2024.103917. eCollection 2024.

ABSTRACT

INTRODUCTION: Global coronal alignment is mainly assessed by C7 plumbline and central sacral vertical line (CSVL), pelvic obliquity and shoulder alignment. A detailed analysis is mandatory when treating spinal deformity. It remains unclear to what extent mild scoliosis influences global coronal alignment.

RESEARCH QUESTION: The objective was to define a comprehensive set of coronal alignment parameters and to investigate differences between individuals without spinal deformity and with mild scoliosis. The relationship between coronal and sagittal alignment and the influence of age were studied.

METHODS: Radiographs of 236 normal individuals (Group N) and 140 patients with scoliosis <35° (Group S) were prospectively collected. Coronal parameters were femoral head distance and angle, pelvic obliquity, Maloney angle, L4 and L5 inclinations, coronal T1 pelvic angle, C7-CSVL and odontoid CSVL offset, coracoid distance and angle. Sagittal cervical, spinopelvic, thoracolumbar and global parameters were measured.

RESULTS: There was no significant difference between groups N and S for coronal parameters, except for L4 and L5 inclinations with a mean difference of 3,3° (p < 0,001). Global coronal alignment kept constant throughout age groups in N and S groups. Sagittal parameters varied with age: C2-C7 lordosis (p < 0,001), T1-T12 kyphosis (p < 0,001), pelvic incidence (p < 0,001). There was no correlation between global coronal and sagittal alignment: R-values ranging from -0.2 to 0.2.

CONCLUSION: Global coronal parameters were comparable in normal individuals and in scoliosis <35°. Coronal plane parameters were not influenced by age. Sagittal plane parameters varied significantly with age. There was no direct link between coronal et sagittal alignment.

PMID:39823062 | PMC:PMC11736157 | DOI:10.1016/j.bas.2024.103917

Single-Cell Analysis in the Mouse and Human Mammary Gland

Recent Publications - Fri, 17/01/2025 - 11:00

Adv Exp Med Biol. 2025;1464:45-73. doi: 10.1007/978-3-031-70875-6_4.

ABSTRACT

The mammary gland is a complex organ, host to a rich array of different cell types. As the only organ to complete its development in adulthood, it delicately balances both cell intrinsic and external signalling from hormones, growth factors and other stimulants. The gland can undergo vast proliferation, restructuring and functional maturation during pregnancy and undo these gross changes to a nearly identical resting state during involution. The adaptive nature of the mammary gland underpins its function but also increases its susceptibility to cancer. While already characterised at a macro scale, understanding the complexities of mammary gland morphogenesis, development and tumorigenesis requires interrogation of cellular and molecular mechanisms. As outlined below, single-cell analysis is a key approach for this, allowing us to unbiasedly explore and characterise the functions and properties of individual cells from the genome to the proteome. Here, we introduce key single-cell analysis methods and give brief introductions to their respective workflows. We then discuss the structure, cell types and development of the mammary gland from birth, puberty and through pregnancy, as well as cancer formation. Additionally, we highlight the benefits and caveats of implementing single-cell methodologies and mouse models for studying critical time points of human development and disease. Finally, we highlight some limitations and future directions of single-cell techniques. This chapter provides a starting point for users hoping to further their understanding of mammary gland development and its link to cancer as explained by single-cell analysis studies.

PMID:39821020 | DOI:10.1007/978-3-031-70875-6_4

Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology

Pharmacology Cambridge RSS Paper feed - Wed, 15/01/2025 - 11:00

J Cell Sci. 2025 Jan 1;138(1):JCS263434. doi: 10.1242/jcs.263434. Epub 2025 Jan 15.

ABSTRACT

G protein-coupled receptor (GPCR) signalling pathways underlie numerous physiological processes, are implicated in many diseases and are major targets for therapeutics. There are more than 800 GPCRs, which together transduce a vast array of extracellular stimuli into a variety of intracellular signals via heterotrimeric G protein activation and multiple downstream effectors. A key challenge in cell biology research and the pharmaceutical industry is developing tools that enable the quantitative investigation of GPCR signalling pathways to gain mechanistic insights into the varied cellular functions and pharmacology of GPCRs. Recent progress in this area has been rapid and extensive. In this Review, we provide a critical overview of these new, state-of-the-art approaches to investigate GPCR signalling pathways. These include novel sensors, Förster or bioluminescence resonance energy transfer assays, libraries of tagged G proteins and transcriptional reporters. These approaches enable improved quantitative studies of different stages of GPCR signalling, including GPCR activation, G protein activation, second messenger (cAMP and Ca2+) signalling, β-arrestin recruitment and the internalisation and intracellular trafficking of GPCRs.

PMID:39810711 | DOI:10.1242/jcs.263434

Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology

Recent Publications - Wed, 15/01/2025 - 11:00

J Cell Sci. 2025 Jan 1;138(1):JCS263434. doi: 10.1242/jcs.263434. Epub 2025 Jan 15.

ABSTRACT

G protein-coupled receptor (GPCR) signalling pathways underlie numerous physiological processes, are implicated in many diseases and are major targets for therapeutics. There are more than 800 GPCRs, which together transduce a vast array of extracellular stimuli into a variety of intracellular signals via heterotrimeric G protein activation and multiple downstream effectors. A key challenge in cell biology research and the pharmaceutical industry is developing tools that enable the quantitative investigation of GPCR signalling pathways to gain mechanistic insights into the varied cellular functions and pharmacology of GPCRs. Recent progress in this area has been rapid and extensive. In this Review, we provide a critical overview of these new, state-of-the-art approaches to investigate GPCR signalling pathways. These include novel sensors, Förster or bioluminescence resonance energy transfer assays, libraries of tagged G proteins and transcriptional reporters. These approaches enable improved quantitative studies of different stages of GPCR signalling, including GPCR activation, G protein activation, second messenger (cAMP and Ca2+) signalling, β-arrestin recruitment and the internalisation and intracellular trafficking of GPCRs.

PMID:39810711 | DOI:10.1242/jcs.263434

Characterization of Individuals Achieving Type 2 Diabetes Remission in Real-World Settings: Bridging Clinical Evidence and Patient Experiences

Recent Publications - Tue, 14/01/2025 - 11:00

Appl Physiol Nutr Metab. 2025 Jan 14. doi: 10.1139/apnm-2024-0316. Online ahead of print.

ABSTRACT

The objectives of the study were to: 1) Describe characteristics and lifestyle factors of individuals who have achieved type 2 diabetes (T2D) remission (sub-diabetes glucose levels without glucose-lowering medications for ≥3 months) through changes to diet and exercise behaviour in real-world settings; 2) Investigate continuous glucose monitoring (CGM) profiles of these individuals and explore how dietary pattern may influence glucose regulation metrics. This cross-sectional study recruited individuals living with T2D who achieved remission via changes to diet or exercise behaviours. Various questionnaires were used to assess overall health and participants wore a blinded CGM for 14 days to assess glucose profiles and filled out three-day food records. A total of 21 adults (57 ± 8 years of age) who were recently diagnosed with T2D (4±3 years) with a A1c of 5.7±0.4% volunteered to participate. Participants achieved remission through various means (e.g., combination of diet and exercise/physical activity) and self-reported following different diets, including 52% following a low-carbohydrate or very low-carbohydrate diet, 14% following a "ketovore/carnivore" diet, 10% using a meal replacement diet, 5% following Weight Watcher's diet, and 19% no defined dietary pattern. The 24-hour average CGM glucose value was 5.0 [4.8-5.6] mmol/L (median [IQR]) with 92 [85-97]% of time spent in range (between 4.0-9.9 mmol/). 24-hour average CGM glucose (r=0.692; P=0.001), as well as A1c (r=0.470; P=0.049), were correlated with the daily percentage of energy intake from carbohydrate. Remission of T2D appears achievable through various means, including adoption of different dietary approaches and a more active lifestyle underpinning the importance of a patient-centred care.

PMID:39808777 | DOI:10.1139/apnm-2024-0316