Feed aggregator

J Anal Methods Chem. 2025 Apr 22;2025:5522915. doi: 10.1155/jamc/5522915. eCollection 2025.

ABSTRACT

A reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed for simultaneous determination of triclabendazole (TCB) and ivermectin (IVM) in pharmaceutical dosage form. A mobile phase consisting of acetonitrile/water (50:50 v/v) with a flow rate of 1.5 mL/min was used for chromatographic separation of the mixture of TCB and IVM. The developed method was found to be linear with the correlation coefficient (r = 0.999) for TCB and IVM in the presence of suspension. The limit of quantitation (LOQ), robustness, specificity, accuracy, and precision were validated for the developed method. The peak areas of five replicates of the samples were recorded, and the acceptance rate of suspension recovery was 98%. The intraday accuracies for TCB and IVM were 98.71% and 100.79%, respectively, with a relative standard deviation (RSD) of 0.87%. The limits of detection (LOD) of TCB and IVM were 0.058 mg/mL and 0.112 μg/mL, respectively, while the LOQ of TCB and IVM were 0.178 μg/mL and 0.340 μg/mL, respectively. The method's % RSD for intra- and interday precision was deemed satisfactory. The developed method could be utilized for the determination and measurement of TCB and IVM in other samples.

PMID:40308629 | PMC:PMC12041623 | DOI:10.1155/jamc/5522915

J Public Health Res. 2025 Apr 26;14(2):22799036251330711. doi: 10.1177/22799036251330711. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Retention in care is a critical indicator of the quality of HIV care and a cornerstone for achieving epidemic control. Interruption in treatment (IIT) poses a significant threat to achieving the global 95-95-95 targets and leads to adverse health outcomes. This study assessed the effect of the national clinical mentorship program on retention in care and IIT among HIV clients in Nasarawa State, Nigeria.

METHODOLOGY: In the 47 facilities where mentors worked, every client who missed an appointment was tracked immediately. A list of potential IIT clients was generated and followed through by linking those clients to trackers who ensured they were returned to care. Mentors ensured that the process of tracking in the facilities was strengthened as part of their routine mentoring activities including facilitating the release of tracking funds. Data from the Retention and Audit Determination Tool (RADET) for patients reported between November 2021 and August 2022 were extracted and imported into an Excel template. Demographic and clinical program parameters were analyzed using descriptive statistics, bi-variate, and multivariate analysis, including Chi-square and logistic regression. The parameters in the facilities where mentorship was deployed were then compared to pre-deployment parameters.

RESULTS: This study found that a clinical mentorship program reduced the Interruption in treatment (IIT) rate from 7% to 0.5% between 2021 and 2022. Although the 25-34 age group had the highest IIT rate, it decreased from 41.6% to 33.3% after the mentorship program. Tertiary facilities still have the highest IIT rates. Non-pregnant women were more likely to continue with treatment than pregnant women. The mentorship program successfully reduced IIT rates in Nasarawa State.

CONCLUSION: Clinical mentoring can reduce IIT among HIV patients. The study found a decrease from 7% to 0.5%. Tailored mentorship programs can improve retention in HIV care and reduce IIT rates. Gender-specific barriers should be addressed, and interventions should be customized for pregnant women for better program effectiveness and health outcomes.

PMID:40296886 | PMC:PMC12035571 | DOI:10.1177/22799036251330711

Nanoscale. 2025 Apr 28. doi: 10.1039/d5nr00229j. Online ahead of print.

ABSTRACT

The experimental realization of kagome lattices that exhibit the predicted coexistence of topological states with high electron kinetics and non-dispersing quantum states remains challenging. Additionally, the robustness of these states against structural perturbations has rarely been explored. Here, we report on the formation of an analogue kagome structure via the electrostatic self-assembly of 4,7-dibromobenzo[c]-1,2,5-thiadiazole (2Br-BTD) molecules on Au(111). Local spectroscopic measurements, supported by theoretical calculations, reveal that the weak molecular coupling reshapes the topological-induced Shockley surface state of Au(111) by imposing a (7 × 7) periodicity, resulting in new band crossings. The molecular overlayer favours the opening of electron gaps at these positions manifested as sharp peaks in dI/dV spectra and electron localization in either the hexagonal or triangular sublattices of the kagome structure. To explore the robustness of these topological states, we monitored their stability under varied conditions, including different temperatures, the unaltered herringbone reconstruction of the Au(111) surface and local structural relaxation of the molecular assembly. These results demonstrate the degree of topological protection of these states, which holds potential for fundamental and applied research.

PMID:40293340 | DOI:10.1039/d5nr00229j

AJPM Focus. 2025 Mar 18;4(3):100333. doi: 10.1016/j.focus.2025.100333. eCollection 2025 Jun.

ABSTRACT

INTRODUCTION: The study of severe mental conditions has primarily remained under the purview of basic and clinical research. Although global epidemiological data indicate that immigrant groups are at higher risk of these conditions, U.S. data are lacking. Qualitative studies can be an important first step to bring attention to understudied phenomena.

METHODS: This manuscript describes strategies used to conduct semi-structured, in-depth individual interviews on experiences and perceptions of severe mental conditions among South Asian individuals with psychiatric diagnoses (n=21), family members (n=11), and clinicians (n=4) in New York City. These strategies were synthesized from the team's internal notes of adaptations during the study design and data collection, weekly debrief meetings during data analysis, and brainstorm sessions for this manuscript.

RESULTS: The main results of the study are reported elsewhere. This section focuses on lessons learned to improve immigrant participant interest and engagement, including the strengths and limitations of the healthcare setting; recruitment by a multilingual South Asian psychiatrist; interviews by non-clinical South Asian researchers selected for a variety of ages, genders, and languages; and the interview process and content.

DISCUSSION: Overall, these strategies show the feasibility of non-clinical researchers to collect high-quality data about severe mental conditions among immigrant communities, noting that the details of specific strategies and results will be particular to each immigrant community. Public health research on severe mental conditions is essential to understand and address the experiences of severe mental conditions among immigrant communities in the U.S.

PMID:40290863 | PMC:PMC12032897 | DOI:10.1016/j.focus.2025.100333

Cancer Cell Int. 2025 Apr 26;25(1):163. doi: 10.1186/s12935-025-03780-4.

ABSTRACT

Piwi-interacting RNAs (piRNAs) are small non-coding RNAs involved in transposon silencing and linked to cancer progression. However, their role in Wilms tumors (WT) remains unexplored. We conducted a thorough analysis and characterization of piRNAs in serum liquid biopsies of WT patients. Our study examined their expression patterns and functional annotations related to WT pathogenesis, as well as their clinical potential for diagnosis and monitoring. We identified 307 piRNAs expressed in WT serum samples, with 4% classified as repeat-related and 96% as non-repeat-related. The most abundant repeat-related piRNAs originated from LINEs retrotransposon, while tRNA-derived piRNAs were the most prevalent among non-repeat-related piRNAs. Furthermore, a distinct profile of 34 piRNAs showed significant differential expression in WT patients compared to healthy controls-22 downregulated and 12 upregulated. The target genes of differentially expressed piRNAs exhibited significant enrichment in biological pathways related to cytokine activity, inflammatory responses, TGF-beta signaling, p38 MAPK, and ErbB signaling. These genes are also involved in DNA damage response, DNA methylation, cell cycle regulation, as well as kidney development and function. Low expression levels of several piRNAs, especially piR-hsa-1,913,711, piR-hsa-28,190, piR-hsa-28,849, piR-hsa-28,848, and piR-hsa-28,318, showed significant diagnostic potential as non-invasive biomarkers for WT (AUC > 0.8, p < 0.05). Their expression levels also significantly correlated with adverse pathological features, including metastasis, anaplasia, and bilateral WT development. In conclusion, non-transposon-related piRNAs may serve as reliable biomarkers for WT and possess potential non-germline functions, particularly in regulating DNA methylation, cell growth, immune responses, and immune responses. Further studies are warranted to elucidate their functional significance.

PMID:40287690 | DOI:10.1186/s12935-025-03780-4

Eur Child Adolesc Psychiatry. 2025 Apr 25. doi: 10.1007/s00787-025-02722-9. Online ahead of print.

ABSTRACT

Digital mental health interventions (DMHIs) are increasingly recommended for children and young people (CYP) as a promising way to prevent and treat mental health problems. Here, we summarised and consolidated findings from existing systematic reviews to provide an overview of what is known, and which areas need further investigation. Systematic searches were conducted until January 2024 using PubMed, PsycINFO, MEDLINE, CINAHL, Scopus and Google Scholar. Records were screened against predefined criteria and quality assessed using A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) and Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Systematic Reviews. A study protocol was co-developed with key stakeholders and registered on the Open Science Framework. From 941 records, 51 systematic reviews published between 2000 and 2023 of generally moderate quality, targeting CYP 0 to 25 years, were included in our narrative summary. DMHIs were delivered in a variety of ways, including online video calls, apps and various combinations, underpinned mostly by cognitive behaviour therapy. DMHIs supported different mental health problems, but mostly symptoms of anxiety and/or depression. Although generally effective, some studies reported mixed results with limited evidence when focusing on longer-term outcomes. Other benefits of DMHIs included reduced costs and time investments for families, and increased accessibility and acceptability of support. Practitioner preparedness and unclear ethics/safety measures were identified as factors impacting engagement and potential effectiveness. The findings suggest that DMHIs can be a valuable tool for supporting CYP. However, realising the full potential of DMHIs for all CYP may require more high-quality research utilising DMHIs that are diverse in theoretical underpinnings and target audiences.

PMID:40278894 | DOI:10.1007/s00787-025-02722-9

Indian J Gastroenterol. 2025 Apr 24. doi: 10.1007/s12664-025-01780-w. Online ahead of print.

NO ABSTRACT

PMID:40272751 | DOI:10.1007/s12664-025-01780-w

J Arthroplasty. 2025 Apr 20:S0883-5403(25)00372-9. doi: 10.1016/j.arth.2025.04.035. Online ahead of print.

ABSTRACT

BACKGROUND: A better understanding of patient's a preoperative symptom state may assist in a more holistic evaluation of patients pursuing total joint arthroplasty (TJA). This study aimed to determine factors associated with preoperative Patient Acceptable Symptom State (PASS) scores in TJA patients and to determine the predictive ability of patient-reported outcome measures (PROMs) for achieving PASS preoperatively.

METHODS: All patients undergoing primary, elective TJA between January and October 2021 at a single institution and who had completed a preoperative PASS, preoperative Patient-Reported Outcome Measurement Information System (PROMIS) questionnaires, and joint-specific PROMs were eligible for inclusion. Descriptive statistics and independent samples t-tests were utilized. Receiver operating characteristic curves and area under the curve analyses were created to determine threshold values for PROMs representing PASS achievement.

RESULTS: A total of 287 total hip arthroplasty (THA) patients and 378 total knee arthroplasty (TKA) patients completed PASS preoperatively, with 12.9% of THA patients and 29.6% of TKA patients reporting acceptable symptom states. The PASS responses were associated with PROMIS Physical Function (PROMIS-PF) (P < 0.001) but not Hip Dysfunction and Osteoarthritis Score, Joint Replacement (HOOS, JR) (P = 0.073) scores in THA. The PASS responses were similarly associated with PROMIS-PF (P < 0.010) as well as Knee Injury and Osteoarthritis Outcome Score, Joint Replacement (KOOS, JR) (P = 0.030) scores in TKA. The HOOS, JR and PROMIS-PF threshold values of 55.6 and 40, respectively, only weakly predicted preoperative PASS achievement in THA. The KOOS, JR and PROMIS-PF threshold values of 52.5 and 39, respectively, only weakly predicted preoperative PASS achievement in TKA.

CONCLUSION: In patients undergoing THA or TKA, 12.9 and 29.6% of patients were satisfied with their symptoms before surgery, respectively. None of the threshold values for the assessed PROMs strongly predict PASS achievement. Given that not all patients indicated for TJA reported unacceptable health states, these findings question the validity of the PASS questionnaire preoperatively.

PMID:40262680 | DOI:10.1016/j.arth.2025.04.035

Br J Nurs. 2025 Apr 17;34(8):434-435. doi: 10.12968/bjon.2025.0097.

NO ABSTRACT

PMID:40257091 | DOI:10.12968/bjon.2025.0097

Sci Total Environ. 2025 Apr 17;978:179447. doi: 10.1016/j.scitotenv.2025.179447. Online ahead of print.

ABSTRACT

The invasion of foreign species into ecosystems is a growing human-induced problem. Global warming is expected to magnify the problem by facilitating invasions and amplifying the ecological impact of invaders. We investigated if rising water temperature influences the impact of an invading shrimp Palaemon elegans on the reproductive success of a native fish, the threespine stickleback Gasterosteus aculeatus. Using a 2 × 2 factorial design, we found the shrimp to reduce the probability that stickleback males built a nest, defended it against a perceived intruder, courted females and gained matings. This reduced the number of offspring they produced, independently of temperature. Males lost more weight in the presence of the shrimp, which indicates that the shrimp can reduce the number of breeding cycles that males can complete. Thus, the shrimp has both direct negative effects and the potential for indirect delayed effects. The impact of the shrimp on stickleback reproduction overrode that of warming, most likely because the stickleback has adapted to temperature fluctuations in shallow coastal waters, but not to a high abundance of the non-native shrimp. Interestingly, the shrimp did not reduce egg hatching success, which indicates that the stickleback overestimates the risk posed by the invader. Refraining from reproduction in the presence of shrimp may have been an adaptive strategy in the past, but not in the current environment where shrimp-free habitats may no longer be found. Thus, the past reaction norm - to avoid nesting in the presence of shrimp - may have become an 'evolutionary trap'. These results emphasise the immediate threat that invading species can pose, which can be larger than the impact of warming, and stresses the importance of controlling their invasions.

PMID:40250225 | DOI:10.1016/j.scitotenv.2025.179447

Transpl Int. 2025 Apr 2;38:14268. doi: 10.3389/ti.2025.14268. eCollection 2025.

ABSTRACT

Normothermic machine perfusion (NMP) provides opportunity for viability assessment of donated kidneys. Diminished microvascular perfusion, despite adequate total blood flow, is a key pathophysiology in ischaemia-mediated acute kidney injury. Contrast-enhanced ultrasound (CEUS) could allow objective assessment of microvascular perfusion during renal NMP. Blood-based NMP was performed on porcine kidneys (circulatory death model) and human kidneys declined for transplant (preclinical). CEUS was performed with a contrast bolus into the NMP circuit arterial limb. Microvascular perfusion quality was quantified and z-score normalisation allowed combination of metrics and regions into an overall "CEUS-score." In porcine kidneys, inferior microvascular perfusion of cortex and medulla correlated with increased urinary NGAL (Neutrophil gelatinase-associated lipocalin) and histological DNA-fragmentation (a hallmark of apoptosis). In human kidneys, CEUS-score at 2 h was correlated with histological DNA-fragmentation (r = -0.937; P = 0.019) and predicted urinary NGAL at 24 h of NMP (r = -0.925; P = 0.024). Total renal flow was not correlated with these outcomes. An open-source web application (stingle.shinyapps.io/Time_intensity_analysis) and R package ("tican") were developed for quantitative time-intensity curve analysis. CEUS allows objective point-of-care microvascular perfusion assessment during NMP. As 2-hour CEUS-score predicts NGAL at 24 h, CEUS warrants future clinical investigation as a potential tool to assess kidney quality in assessment and reconditioning centres.

PMID:40242325 | PMC:PMC11999844 | DOI:10.3389/ti.2025.14268

Infect Dis Ther. 2025 Apr 14. doi: 10.1007/s40121-025-01151-0. Online ahead of print.

ABSTRACT

INTRODUCTION: The 20-valent pneumococcal conjugate vaccine (PCV20) was licensed for prevention of pneumococcal disease in infants and children on the basis of immunogenicity compared with PCV13. We aimed to evaluate PCV20 immunogenicity compared with PCV10 (Synflorix; PhiD-CV) because both vaccines demonstrated lower immunogenicity than PCV13. Nevertheless, PCV10 was highly effective against vaccine-serotype pneumococcal disease in post-licensure studies. Since no study has directly compared PCV20 versus PCV10, we conducted an indirect comparison.

METHODS: We conducted indirect comparisons for PCV20 versus PCV10 using data from published randomized control trials that directly compared these vaccines with PCV13 in 3 + 1 or 2 + 1 schedules. Serotype-specific immunoglobulin (Ig)G concentrations and opsonophagocytic activity (OPA) were assessed post-booster dose and post-primary series. First, geometric mean ratios (GMRs) were obtained for shared serotypes for each direct comparison against PCV13; we conducted a meta-analysis to generate pooled GMRs if data from multiple trials were available. Next, we indirectly compared relative GMRs of PCV20 versus PCV10 using PCV13 as the common comparator. In this descriptive analysis, GMRs > 1 favored PCV20 and GMR < 1 favored PCV10.

RESULTS: Meta-analyses of PCV10 versus PCV13 data found that PCV10 was less immunogenic for most of the ten shared serotypes. When indirectly compared via PCV13, the relative immunogenicity of PCV20 versus PCV10 varied by serotype. Overall, IgG responses for the ten shared serotypes were similar for both 3 + 1 and 2 + 1 schedules, both post-primary series and post-booster dose. GMRs for both IgG and OPA were close to the line of equivalence, or spread between favoring PCV20 or PCV10.

CONCLUSIONS: The comparable immunogenicity of PCV20 versus PCV10 in 2 + 1 and 3 + 1 schedules suggests that PCV20 will have similar effectiveness for the ten serotypes included in both vaccines, including for direct protection during infancy and toddler age, while also expanding serotype coverage. Effectiveness for PCV20 needs to be confirmed in post-marketing studies.

PMID:40227558 | DOI:10.1007/s40121-025-01151-0

J Can Assoc Gastroenterol. 2025 Jan 23;8(2):63-70. doi: 10.1093/jcag/gwae061. eCollection 2025 Apr.

ABSTRACT

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is performed using anaesthesia or conscious sedation, though the effectiveness, adverse events (AEs), and tolerability of each approach remain unclear. Thus, we compared these approaches prospectively.

METHODS: We performed a multi-centre prospective cohort study including patients with native papillae undergoing ERCP for biliary indications between 2018 and 2023. The primary outcome was sedation-related AEs, defined as sustained hypoxaemia or hypotension, unplanned mask ventilation or intubation, vasopressor or reversal agent use, cardiorespiratory arrest, or death. Secondary outcomes included other AEs, technical success measures, and patient-reported tolerability using a validated scale. Multivariable logistic regression was performed in addition to propensity score-matched analyses.

RESULTS: At 8 centres, a total of 3174 first-time biliary ERCPs were performed, 433 (13.6%) employing anaesthesia. Nine sedation-related AEs occurred with conscious sedation (0.3%), while 2 (0.5%) occurred with anaesthesia (odds ratio, OR, 0.35, 0.07-2.37). Only 25 (0.9%) conscious sedation-supported ERCPs were aborted due to the inability to appropriately sedate patients. There were no significant differences in other AE rates, cannulation success, time, or attempts, use of pre-cut or needle-knife access methods, or inadvertent pancreatic duct cannulation. Odds of significant patient-reported intra-procedural awareness and discomfort were both higher with conscious sedation (ORs 16.19, 4.81-54.53, and 21.25, 4.44-101.61, respectively). Propensity score-matched analyses yielded no differences in any outcome compared with primary analyses.

CONCLUSIONS: Routine biliary ERCP is equally safe and effective with conscious sedation (vs anaesthesia). Given regional resource limitations, conscious sedation is justified as a primary option for routine biliary ERCP.

PMID:40224576 | PMC:PMC11991873 | DOI:10.1093/jcag/gwae061

Orthop Traumatol Surg Res. 2025 Apr 10:104244. doi: 10.1016/j.otsr.2025.104244. Online ahead of print.

ABSTRACT

BACKGROUND: Despite being one of the main drivers of patients' satisfaction, the cosmetic appearance after posterior spinal fusion for adolescent idiopathic scoliosis (AIS) has not yet been thoroughly investigated. This study evaluated the self-perceived cosmetic outcomes following posterior spinal fusion in patients with AIS using the SRS-22 and Trunk Appearance Perception Scale (TAPS).

HYPOTHESIS: It is possible to highlight outcome differences before and after surgery, and to determine correlations between these self-image assessments and radiographic as well as implant-related parameters.

PATIENTS AND METHODS: A multicenter retrospective analysis on data prospectively collected between February 2011 and November 2021. AIS patients requiring surgery and with a 1-year follow-up were included. Pre- and postoperative radiographic data, including Cobb angle, clavicle angle, pelvic and sacral obliquity, and thoracic kyphosis, were compared with patient-reported outcomes. Statistical analyses evaluated correlations between self-image subdomains and surgical outcomes.

RESULTS: Data from 123 patients were available (101 females, 22 males). Considerable improvements in cosmetic self-perception were observed postoperatively, with both TAPS and SRS-22 r scores increasing one year after surgery. Coronal parameters such as major Cobb angle and clavicle angle were the primary drivers of preoperative self-image perception. In particular, the Cobb angle increased from 41.06 ± 33.29 ° in patients who did not perceive a back deformity to 65.86 ± 12.46 ° in patients who perceived a severe deformity (p = 0.009). Similarly, the clavicle angle increased from 0.31 ± 0.53 ° to 2.8 ± 2.49 ° (p = 0.02). Postoperative cosmetic appearance was correlated to implant density and thoracic kyphosis (T2-T5). Implant density decreased from 1.65 ± 0.3 to 1.47 ± 0.13 in patients with no perceived deformation and slight deformation of the back, respectively (p = 0.03); and from 1.65 ± 0.27 to 1.51 ± 0.15 in patients with no perceived deformation and slight deformation of the front, respectively (p = 0.04). The T2 - T5 kyphosis increased from 17.25 ± 9.36 ° to 38.72 ° (p = 0.05) in patients with poorer forward bending perception, and decreased from 26.61 ° to 19.9 ± 10.15 ° (p = 0.04) in patients with better cosmetic appearance in the SRS Q6.

DISCUSSION: Posterior fusion significantly enhances self-perceived trunk appearance in AIS patients. The coronal alignment has a more marked influence on preoperative cosmetic appearance, whereas postoperative sagittal alignment and implant density play a more critical roles in the postoperative self-image assessment.

LEVEL OF EVIDENCE: III.

PMID:40220785 | DOI:10.1016/j.otsr.2025.104244

Front Pharmacol. 2025 Mar 27;16:1367991. doi: 10.3389/fphar.2025.1367991. eCollection 2025.

ABSTRACT

INTRODUCTION: The β2-adrenoceptor (β2AR) is a class A G protein-coupled receptor (GPCR). It is therapeutically relevant in asthma and chronic obstructive pulmonary disease (COPD), where β2AR agonists relieve bronchoconstriction. The β2AR is a prototypical GPCR for structural and biophysical studies. However, the molecular basis of agonist efficacy at the β2AR is not understood. We hypothesised that the kinetics of GPCR-G protein interactions could play a role in determining ligand efficacy. By studying a range of agonists with varying efficacy, we examined the relationship between ligand-induced mini-Gs binding to the β2AR and ligand efficacy, along with the ability of individual ligands to activate the G protein in cells.

METHODS: We used NanoBRET technology to measure ligand-induced binding of purified Venus-mini-Gs to β2AR-nLuc in membrane preparations under both equilibrium and kinetic conditions. In addition, we examined the ability of these β2AR agonists to activate the heterotrimeric Gs protein, measured using the Gs-CASE protein biosensor in living cells. This assay detects a reduction in NanoBRET between the nano-luciferase (nLuc) donor on the Gα subunit and Venus acceptor on the Gγ upon Gs protein activation.

RESULTS: The 12 β2AR agonists under study revealed a broad range of ligand potency and efficacy values in the cellular Gs-CASE assays. Kinetic characterisation of mini-Gs binding to the agonist β2AR complex revealed a strong correlation between ligand efficacy values (Emax) and mini-Gs affinity (K d) and its association rate (k on). In contrast, there was no correlation between ligand efficacy and reported ligand dissociation rates (or residence times).

CONCLUSION: The association rate (k on) of the G protein to the agonist β2AR complex is directly correlated with ligand efficacy. These data support a model in which higher-efficacy agonists induce the β2AR to adopt a conformation that is more likely to recruit G protein. Conversely, these data did not support the role of agonist binding kinetics in determining the molecular basis of efficacy.

PMID:40213684 | PMC:PMC11983327 | DOI:10.3389/fphar.2025.1367991

Front Pharmacol. 2025 Mar 27;16:1367991. doi: 10.3389/fphar.2025.1367991. eCollection 2025.

ABSTRACT

INTRODUCTION: The β2-adrenoceptor (β2AR) is a class A G protein-coupled receptor (GPCR). It is therapeutically relevant in asthma and chronic obstructive pulmonary disease (COPD), where β2AR agonists relieve bronchoconstriction. The β2AR is a prototypical GPCR for structural and biophysical studies. However, the molecular basis of agonist efficacy at the β2AR is not understood. We hypothesised that the kinetics of GPCR-G protein interactions could play a role in determining ligand efficacy. By studying a range of agonists with varying efficacy, we examined the relationship between ligand-induced mini-Gs binding to the β2AR and ligand efficacy, along with the ability of individual ligands to activate the G protein in cells.

METHODS: We used NanoBRET technology to measure ligand-induced binding of purified Venus-mini-Gs to β2AR-nLuc in membrane preparations under both equilibrium and kinetic conditions. In addition, we examined the ability of these β2AR agonists to activate the heterotrimeric Gs protein, measured using the Gs-CASE protein biosensor in living cells. This assay detects a reduction in NanoBRET between the nano-luciferase (nLuc) donor on the Gα subunit and Venus acceptor on the Gγ upon Gs protein activation.

RESULTS: The 12 β2AR agonists under study revealed a broad range of ligand potency and efficacy values in the cellular Gs-CASE assays. Kinetic characterisation of mini-Gs binding to the agonist β2AR complex revealed a strong correlation between ligand efficacy values (Emax) and mini-Gs affinity (K d) and its association rate (k on). In contrast, there was no correlation between ligand efficacy and reported ligand dissociation rates (or residence times).

CONCLUSION: The association rate (k on) of the G protein to the agonist β2AR complex is directly correlated with ligand efficacy. These data support a model in which higher-efficacy agonists induce the β2AR to adopt a conformation that is more likely to recruit G protein. Conversely, these data did not support the role of agonist binding kinetics in determining the molecular basis of efficacy.

PMID:40213684 | PMC:PMC11983327 | DOI:10.3389/fphar.2025.1367991

Ann Med Surg (Lond). 2025 Mar 27;87(4):2049-2058. doi: 10.1097/MS9.0000000000003052. eCollection 2025 Apr.

ABSTRACT

Global neurosurgery has witnessed transformative developments in advocacy and policy aimed at overcoming the barriers that hinder equitable access to neurosurgical care. This paper reveals the stark disparities faced by low- and middle-income countries (LMICs) with an annual burden of 5 million affected individuals. Despite these challenges, the emergence of global neurosurgery stands as a beacon of hope, aspiring to deliver timely, safe, and affordable neurosurgical care. Advocacy and policy play pivotal roles in this endeavour, exemplified by initiatives, like National Surgical, Obstetrics, and Anesthesia Plans (NSOAPs) and Global Neurosurgery Initiatives (GNI), addressing accessibility, training, and disparities. Collaborations between diverse entities and interdisciplinary approaches gain prominence, fostering comprehensive advocacy and policy frameworks. A resolute commitment to equity is discernible, propelling policies toward universal access to neurosurgical care. However, crucial challenges, such as limited resources, awareness gaps, complex political landscapes, data deficiencies, and insufficient international collaborations, must be addressed to see the full potential of these initiatives. While challenges persist, progress is evident through collaborative efforts, technological advancements, and evolving policy landscapes, promising a trajectory toward accessible, safe, and affordable neurosurgical care for all.

PMID:40212174 | PMC:PMC11981366 | DOI:10.1097/MS9.0000000000003052

Int J Biol Macromol. 2025 Apr 8:142976. doi: 10.1016/j.ijbiomac.2025.142976. Online ahead of print.

ABSTRACT

Blend nanocomposites of chitosan (CS) and polyvinyl alcohol (PVA), reinforced with varying concentrations of nanocurcumin (NC), were synthesized using a simple green method. The impact of NC on the optical, structural, and morphological characteristics of the blend nanocomposite films was evaluated through different analytical techniques, including FT-IR, XRD, UV-Vis spectroscopy, scanning electron microscopy, TGA, universal testing machine and electrical measurements. The distinctive peaks observed in the FT-IR and XRD analysis confirmed the successful incorporation of NC into the PVA/CS (PC) blend matrix. UV spectroscopy revealed that absorption increased with nanoparticle concentration, with the 9 wt% sample showing the highest intensity, which correlates with its low optical bandgap energy. SEM analysis showed that nanoparticles influenced the surface morphology of the PC matrix, with the most uniform particle distribution observed in the 9 wt% sample. Increasing NC content improved the thermal stability of the PC films. The nanocomposite with 9 wt% NC exhibited a significant improvement in tensile strength, increasing by 35 % compared to neat PC, along with an excellent Young's modulus. The temperature-dependent dielectric constant, AC conductivity, and impedance were analyzed across different NC loadings. The maximum conductivity and dielectric constant were found in the 9 wt% nanocomposites. The superior tensile strength, Young's modulus, thermal stability, conductivity, dielectric constant, and optical properties of the PC blend nanocomposites highlight their potential for use in eco-friendly, flexible optoelectronic devices.

PMID:40210076 | DOI:10.1016/j.ijbiomac.2025.142976

Bioinformatics. 2025 Apr 10:btaf158. doi: 10.1093/bioinformatics/btaf158. Online ahead of print.

ABSTRACT

MOTIVATION: Several methods have been developed for trajectory inference in single cell studies. However, identifying relevant lineages among several celltypes and interpreting the results of downstream analysis remains a challenging task that requires deep understanding of various celltype transitions and progression patterns. Therefore, there is a need for methods that can aid researchers in the analysis and interpretation of such trajectories.

RESULTS: We developed PyEvoCell, a dashboard for trajectory interpretation and analysis that is augmented by large language model (LLM) capabilities. PyEvoCell applies the LLM to the outputs of trajectory inference methods such as Monocle3, to suggest biologically relevant lineages. Once a lineage is defined, users can conduct differential expression and functional analyses which are also interpreted by the LLM. Finally, any hypothesis or claim derived from the analysis can be validated using the veracity filter, a feature enabled by the LLM, to confirm or reject claims by providing relevant PubMed citations.

AVAILABILITY: The software is available at https://github.com/Sanofi-Public/PyEvoCell. It contains installation instructions, user manual, demo datasets, as well as license conditions (including limitation to non-commercial uses only). https://doi.org/10.5281/zenodo.15114803.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:40209077 | DOI:10.1093/bioinformatics/btaf158

J Am Chem Soc. 2025 Apr 10. doi: 10.1021/jacs.4c13473. Online ahead of print.

ABSTRACT

Parkinson's disease (PD) is linked to the aggregation of the intrinsically disordered protein α-synuclein (aSyn), but the precise triggers and mechanisms driving this process remain unclear. Local environmental factors, such as ion concentrations, can influence aSyn's conformational ensemble and its tendency to aggregate. In this study, we explore how physiologically relevant ions, mainly Ca2+ and Na+, affect aSyn aggregation, monomer structural dynamics, and fibril polymorphism. ThT fluorescence assays show that all ions speed up aggregation, with Ca2+ having the strongest effect. Using heteronuclear single quantum correlation nuclear magnetic resonance (1H-15N HSQC NMR) spectroscopy, we validate that Ca2+ binds at the C-terminus while Na+ interacts nonspecifically across the sequence. Small-angle neutron scattering (SANS) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) show that Na+ leads to more extended aSyn structures, while Ca2+ results in moderate extension. Molecular dynamics (MD) simulations support this, showing Na+ increases extension between the NAC region and C-terminus, whereas Ca2+ biases the ensemble toward a moderately elongated structure. MD also shows that Ca2+ increases water persistence times in the hydration shell, indicating that aSyn aggregation propensity is due to a combination of conformational bias of the monomer and solvent mobility. Atomic force microscopy (AFM) points toward the formation of distinct fibril polymorphs under different ionic conditions, suggesting ion-induced monomer changes contribute to the diversity of fibril structures. These findings underscore the pivotal influence of the local ionic milieu in shaping the structure and aggregation propensity of aSyn, offering insights into the molecular underpinnings of PD and potential therapeutic strategies targeting aSyn dynamics.

PMID:40207671 | DOI:10.1021/jacs.4c13473