bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of chronic neuropathic pain on the self-administration of highly potent MOR agonist, fentanyl
Authors: Burgess Gwendolyn E. , Traynor John R. , Jutkiewicz Emily M. 
Published: November 2024

AbstractThere is significant overlap between chronic pain and opioid use disorder (OUD) patient populations such that approximately 50-65% of chronic pain patients have OUD. However, we understand relatively little about how chronic, long-lasting pain states alter ongoing self-administration of opioid analgesics. Thus, the goal of this study was to determine if chronic neuropathic pain altered the ongoing self-administration of fentanyl, or a non-opioid drug of abuse, cocaine. Animals were trained to self-administer fentanyl or cocaine in a multi-dose self-administration procedure composed of five 25-min components, exposing animals to multiple doses of drug per day. Operant behavior was established prior to induction of chronic pain via the spared nerve injury (SNI). Animals were allowed 72 hours of post-operative recovery and resumed self-administration on post-operative day 4. All animals dose-dependently self-administered fentanyl prior to surgery. On post-operative day 4, both sham and SNI groups showed a significant decrease in fentanyl self-administration. By post-operative day 9, fentanyl intake was no longer significantly different from pre-surgical intake. Over the course of 4 weeks of self-administration, there was an increase in intake of specifically the 10 ug/kg/inf dose of fentanyl. Cocaine self-administration was not altered at any point following either surgery. Collectively, these results suggest that SNI-induced hypersensitivity failed to alter the reinforcing effects of fentanyl, or non-opioid drug of abuse, cocaine. Future studies should evaluate the abuse potential of lower efficacy MOR agonists such as nalbuphine or buprenorphine, as small changes were observed in fentanyl-maintained behavior over time in both SNI and sham groups.Significance statementMOR agonists are excellent analgesics; however, they are not first-line treatments for chronic pain, in part due to abuse potential. This study demonstrates that small, significant rightward shifts in the fentanyl dose response curve were observed following induction ofbothsham and spared nerve injury (SNI) (chronic neuropathic pain-like) states, suggesting these changes were observed independent of pain state. These data indicate that SNI-induced neuropathic pain failed to alter the ongoing self-administration of highly potent MOR agonist, fentanyl.
Detection ofDeltacoronavirusin Environmental Fecal Samples from Seabirds in the Saint Peter and Saint Paul Archipelago, central equatorial Atlantic Ocean
Authors: Gomes Fernanda , da Silva Alexandre Freitas , Prado Tatiana , Bueno Marina Galvão , Appolinario Luciana , Flores Patrícia Soares , Resende Paola Cristina , Siqueira Marilda , Corrêa Leonardo , Brandão Martha , Reck Jose , da Luz Wallau Gabriel , Ogrzewalska Maria 
Published: November 2024

AbstractThis study investigates the presence of avian coronaviruses (CoVs), influenza A viruses (IAVs), and Avian rotaviruses (RVs) group A in seabird populations inhabiting the Saint Peter and Saint Paul Archipelago (SPSPA), an isolated and remote oceanic island situated in the equatorial region of the Atlantic Ocean. In July 2022, 95 environmental fecal samples were collected from seabird colonies and screened for the viruses by quantitative one-step real-time RT-PCR (IAVs and RVs), by the conventional pancoronavirus RT-PCR protocols and metatranscriptomics of a positive sample. Four environmental feces samples tested positive for CoVs. Avian IAVs and RVs were not detected. Phylogenetic analysis revealed CoVs closely related to avian deltacoronaviruses previously identified in waterbirds from Asia and Australia. We could not recover the CoV by metatranscriptomics but we recovered a single viral contig of an avian enterovirus. The findings contribute valuable insights into virus dynamics among seabird populations, laying the groundwork for future investigations in this field.
The Impact of the Performance-Based Financing Project: An Observational Panel Study on Health Workers’ Output in Rural Mezam, Northwest Region, Cameroon
Authors: Dingana Therence Nwana , Azibo Balgah Roland , Ndisang Daniel Agwenig , Ngasa Stewart Ndutard , Fozeu Leo Fosso 
Published: November 2024

ABSTRACTPerformance-Based Financing (PBF) has been implemented in many countries to improve healthcare access, quality, and outcomes while ensuring the efficient and equitable allocation of resources within the healthcare system. However, very little effort is visible in assessing its real impacts. This study evaluates the impact of the PBF project on health workers’ output and healthcare quality in the Mezam division in the North West region of Cameroon between 2012 and 2022. Specifically, the study aims to understand health workers’ perceptions of the PBF project, analyze the effect of PBF on health workers’ output, and examine the impact of PBF on healthcare quality. A structured questionnaire was used to generate panel data among healthcare workers in six beneficiary health districts in the study site. The perception scores were estimated based on the Net Promoter Score (NPS) methodology and variability tested using ANOVA. Health workers’ output and performance indicators were analyzed using the chi-square test, assessing the relation between PBF introduction and changes in health workers’ output, while healthcare quality metrics were analyzed using the Mann-Whitney U test to compare healthcare quality before and after PBF implementation. The results showed that health workers’ perceptions varied but were generally positive, with a Net Promoter Score (NPS) of approximately 48.25. PBF significantly boosted health workers’ output (p = 0.002) and healthcare quality (p < 0.05). It can be concluded that the PBF project in the Mezam division had positive effects on workers’ output and healthcare quality. Given the positive impacts, the study recommends scaling up PBF initiatives in Cameroon and other African countries with precarious health systems. Our study demonstrates the relevance of impact assessments in providing evidence for making informed decisions on efficient resource allocation in the health sector.
Evaluation of an artificial intelligence model for opportunistic calculation of Agatston score on non-gated computed tomography of the chest
Authors: McKinney Suzannah E , Mercaldo Sarah F , Chin John K , Ghatak Ankita , Halle Madeleine A , Hedgire Sandeep S , Meyersohn Nandini M , Ghoshhajra Brian , Dreyer Keith J , Kalra Mannudeep , Bizzo Bernardo C , Hillis James M 
Published: November 2024

AbstractImportanceThe Agatston score is a measure of cardiovascular disease traditionally calculated on cardiac gated computed tomography (CT) of the chest. Cardiac gated CT is resource-intensive, can be hard to access, and involves extra radiation exposure. Artificial intelligence (AI) can be used to opportunistically calculate Agatston score on non-gated CTs performed for other indications.ObjectiveThis study compared the accuracy of an AI model (Riverain Technologies ClearRead CT CAC) at calculating Agatston scores on non-gated CTs to both consensus radiologist interpretations on the same CTs and Agatston scores from paired cardiac gated CTs.DesignA retrospective standalone performance assessment was conducted on a dataset of non-contrast CT chest cases acquired between January 2022 and December 2023.SettingThe study was conducted at five hospitals in the United States.ParticipantsThe cohort included non-gated CTs from 491 patients. It was enriched to ensure a representation of disease severity by selecting approximately two-thirds of patients using the originally reported Agatston score on a paired cardiac gated CT within the study timeframe.Main Outcome(s) and Measure(s)The study compared the agreement of Agatston categories (0, 1-99, 100-399 and ≥400) between the AI model and ground truth radiologists or original radiology reports using the quadratic weighted Kappa coefficient.Exposure(s)Each non-gated CT case was interpreted independently by three radiologists to establish consensus interpretations. Each CT was then interpreted by the AI model. The Agatston scores for paired cardiac gated CTs were obtained from original radiology reports.ResultsThe agreement between the AI model and ground truth radiologists was 0.959 (95% CI: 0.943-0.975). This result was broadly consistent across sex, age group, race, ethnicity and CT scanner manufacturer subgroups. The agreement between the AI model and paired cardiac gated CT was 0.906 (95% CI: 0.882-0.927).Conclusions and RelevanceThe assessed AI model accurately calculated Agatston scores on non-gated CTs and produced similar scores to paired cardiac gated CTs. Its use could broaden screening for atherosclerotic cardiovascular disease, enabling opportunistic screening on CTs captured for other indications.
RNA Polymerase II subunits overexpressions induce genome instability and deregulate transcription
Authors: Sadurni Martina Muste , Jones Megan Louise , Pavlou Lucas , Radi Mohamed , Kompocholi Smaragda , Passaretti Paolo , Gambus Agnieszka , Gregersen Lea H. , Saponaro Marco 
Published: November 2024

AbstractIndependently of the pathways or circuits deregulated in cancer cells, these present altered transcription patterns, often also direct consequence of deregulation of transcription factors. In this sense, also the RNA Polymerase complexes responsible for transcription can be affected in cancers. We find that upregulations of RNA Polymerase II subunits, especially the largest ones, correlates with poor cancer patients’ outcome across a range of tumor types, presenting increased genome instability. Overexpressing the subunits RPB1, RPB3 and RPB4 in cells we find that these induce DNA damage. However, the mechanisms behind this increased genome instability are specific for each subunit, linked to the unique transcription alterations generated by the subunit overexpression. Importantly, we find significant overlap between the genes with more DNA damage in our cell line models and those more affected in cancers with subunit upregulation, indicating that upregulations could be responsible for some of the phenotypes present in these patients.
Design of allosteric modulators that change GPCR G protein subtype selectivity
Authors: Moore Madelyn N. , Person Kelsey L. , Alwin Abigail , Krusemark Campbell , Foster Noah , Ray Caroline , Inoue Asuka , Jackson Michael R. , Sheedlo Michael J. , Barak Lawrence S. , Fernandez de Velasco Ezequiel Marron , Olson Steven H. , Slosky Lauren M. 
Published: November 2024

ABSTRACTG protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G protein binding determinants on NTSR1, promoting association with select G protein subtypes for which an alternative, shallow-binding conformation is energetically favorable. Minor modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein subtype selectivity profiles. Selectivity profiles are probe-independent, conserved across species, and translate to differences inin vivoactivity. These studies demonstrate that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor-transducer interface and, as this pocket is broadly conserved, present a strategy for pathway-selective drug discovery applicable to the diverse GPCR superfamily.
Defining the parameters for sorting of different RNA cargo into Extracellular vesicles
Authors: Abdelgawad Ahmed , Huang Yiyao , Gololobova Olesia , Yu Yanbao , Witwer Kenneth W. , Parashar Vijay , Batish Mona 
Published: November 2024

AbstractExtracellular vesicles (EVs) are small particles that are released by cells and mediate cell-cell communication by transferring bioactive molecules. RNA cargo of EVs, including coding and non-coding RNAs, can change the behavior of recipient cells, affecting processes like gene expression, proliferation, and apoptosis. Circular RNAs (CircRNA) are a newly appreciated class of regulatory RNAs that are stable, resistant to degradation and have been shown to be enriched in EVs. They play key roles in gene regulation and are also emerging as promising biomarkers for disease diagnosis. While microRNAs (miRNAs) are the most well studied RNA cargo of EVs, very little is known about the mechanisms of enrichment of circRNAs as well as long linear RNAs. Here, we take a comprehensive genome-wide approach to investigate the role of GC%, size, exon count, structuredness and coding potential, in the sorting and enrichment of circular and long linear RNAs into EVs. We found that size and structuredness had a significant role in enriching RNAs into EVs which was consistent across all classes of RNAs. Furthermore, we found that structuredness could explain the relative enrichment of circRNAs over their linear counterparts. These results were validated on existing public databases of circular and linear RNAs in EVs. By identifying and analyzing these factors, we aim to better understand the complex mechanisms behind EV-mediated RNA transfer and its impact on cell communication in both health and disease. This mechanistic understanding of RNA enrichment in EVs is crucial for engineering EVs with selective RNA cargo.
Green Elegance T2T: An upgraded telomere-to-telomere genome assembly and annotation of looseleaf lettuce (Lactuca sativavar.crispa)
Authors: Zhang Bin , Liu Xue , Ding Haifeng , Yang Yesheng , Tang Jinfu , Li Dayong 
Published: November 2024

AbstractLettuce (Lactuca sativaL.), a globally important vegetable crop, is cultivated in various horticultural varieties. Looseleaf lettuce is one of the main varieties that are consumed. Here, we report a telomere-to-telomere (T2T) genome assembly of looseleaf lettuce (L. sativavar.crispacv. Green Elegance). By combining the sequencing data of previously reported Green Elegance v1.2, the 42.20 Gb clean ultra-long reads produced by Oxford Nanopore Technology were used to close the gaps and upgrade the genome assembly. After filling 11 gaps in Green Elegance v1.2, the final gapless telomere-to-telomere genome assembly is 2.58 Gb in length with a contig N50 of 282.47 Mb, containing nine centromeres and 18 telomeres. The genome contained 41,375 protein-coding genes, of which 99.10% were functionally annotated. This T2T genome of looseleaf lettuce will be valuable for the identification of genetic variation and the advancement of lettuce breeding.
Broca’s area responsible for speech production is regulated by lung functions
Authors: Cao Siyu , Zhuang Wenwen , Hu Yuqian , Qiu Shijun , Tan Li-Hai 
Published: November 2024

SUMMARYFor more than one and a half centuries, Broca’s area, specifically, the pars opercularis and pars triangularis in the left inferior frontal gyrus, has been known to be crucial for human speech production. However, it remains unanswered why this region is recruited for speaking. Speech production involves not only conceptualization and motor planning, but also respiration that provides the airflow necessary for creating sounds. Thus, the role of Broca’s area in speech may be shaped by the functionality and the related brain regions associated with lungs. To test this hypothesis, we recruited the patients suffering from chronic obstructive pulmonary disease (COPD) and required them to speak out words while scanning their brains with functional and quantitative magnetic resonance imaging (fMRI and qMRI). We observed that COPD patients exhibited altered cortical responses in left inferior prefrontal cortex and other regions during speech tasks, with abnormal activation in cortical sites associated with breathing. In addition, using the qMRI to generate longitudinal relaxation time (T1) maps as an index of brain microstructural changes including dendritic maturation and myelination, we discovered that the patients showed significantly higher T1values than the control group in Broca’s area, suggesting reduced myelination and impaired microstructural integrity. Crucially, the data indicated that more severe dyspnea was associated with less well-developed microstructure in Broca’s area and its weaker activation. Our study has demonstrated for the first time that lungs may function to shape Broca’s area as the speaking center, and this is consistent with the recent work of a lung–brain axis.
Unveiling the functional heterogeneity of endogenous tissue extracellular vesicles in skeletal muscle through multi-omics
Authors: Wang Yizhuo , Lou Peng , Zhou Xiyue , Xie Yijing , Zhang Yimeng , Liu Shuyun , Li Lan , Lu Yanrong , Wan Meihua , Cheng Jingqiu , Liu Jingping 
Published: November 2024

AbstractExtracellular vesicles (EVs) have emerged as promising tools for the development of disease biomarkers and therapeutics because they can transfer various bioactive cargos between cellsin vivo. A better understanding of the heterogeneous properties of EVsin vivomay provide insights into their biological roles and clinical translation potential. As a proof-of-concept, we report that different EV subpopulations from skeletal muscle tissues have distinct composition signatures and diverse biological effects on recipient cells. Multiple cell types (e.g., myoblasts and endothelial cells (ECs)) can contribute to the pool of muscle tissue-derived EVs, and large EVs (L-EVs) are enriched with proteins related to metabolic regulation, whereas small EVs (S-EVs) are enriched with original muscle cell-specific proteins related to muscle function regulation. Compared with L-EVs, S-EVs exhibited abundant surface proteins and higher cell uptake rates. Moreover, L-EVs and S-EVs can induce diverse changes in global gene expression, metabolic patterns and some cellular behaviors (e.g., proliferation and differentiation) in recipient cells. These results suggest that different EV subpopulations might control tissue hemostasis in a coordinated manner and suggest the importance of reconsidering their favorable role in future applications (e.g., S-EVs for biomarker discovery and L-EVs for metabolic intervention). This study highlights the functional heterogeneity of tissue-derived EVsin vivo, and the selection of an ideal EV subset on the basis of its specific biological properties may be a promising strategy for developing more precise biomarkers or tailored EV therapies for regenerative medicine.Graphic abstractSignificanceExtracellular vesicles (EVs) are emerging as important tools for diagnostics, therapeutics, and prognostics in various diseases. Understanding the inherent heterogeneity of EVs is crucial, as distinct subpopulations function differently. While extensive research focuses on EVs derived from cell supernatants, endogenous tissue EVs can more accurately reflect the pathophysiological characteristics of their originating cells. Here, we propose different tissue-EV subpopulations coordinately regulate tissue homeostasis. Small EVs with tissue-specific signatures show promise for biomarker development, while large EVs with metabolic signatures are suitable for metabolic interventions. Additionally, small EVs with enhanced surface proteins are ideal for targeted delivery. This work highlights the importance of selecting tissue-EV subpopulations based on their unique properties for developing precise biomarkers and tailored therapies in regenerative medicine.
Mechano-sensing role of oncogenic lncRNA NEAT1 on soft vs. stiff substrates and its implications for glioblastoma progression
Authors: Ghosh Arpita , Soundharya R. , Jolly Mohit Kumar , Majumder Abhijit 
Published: November 2024

AbstractLong non-coding RNAs (lncRNAs) have gained increasing recognition as key regulators of cancer biology, overturning their earlier classification as non-functional genomic elements. Among them, NEAT1 (Nuclear-Enriched Abundant Transcript 1) has emerged as a prominent oncogenic lncRNA involved in multiple solid tumors, including liver, prostate, and gastric cancers, as well as gliomas. Although the role of NEAT1 in cancer has been extensively studied, most of these investigations have focused on biochemical factors, leaving the mechano-sensitivity of NEAT1 to mechanical alterations in the tumor microenvironment (TME) largely unexplored. As tumors progress, the TME undergoes significant mechanical changes, particularly extracellular matrix (ECM) stiffening, which modulates cellular behavior through mechano-transduction pathways. While much research has focused on how these mechanical cues influence protein-coding gene expression, their impact on lncRNAs such as NEAT1 remains understudied. This study aims to address this gap by investigating the mechano-sensitivity of NEAT1 in glioblastoma (GBM) cells cultured on polyacrylamide (PAA) gels that mimic the brain’s physiological stiffness (0.5 kPa) versus conventional, stiff tissue culture plastic (TCP). NEAT1 expression, quantified using qRT-PCR, revealed a significant increase on softer, brain-mimicking substrates compared to stiffer TCP. Overexpression of NEAT1 in brain-mimicking stiffness also showed higher expression levels of cancer progression markers, quantified by qRT-PCR. To further explore NEAT1’s role in oncogenesis due to its mechano-sensing capabilities, siRNA-mediated downregulation of NEAT1 in GBM cells cultured on soft PAA gels was performed to reduce NEAT1 levels to those comparable to TCP. The results showed reduced cancer aggressiveness, characterized by decreased expression of invasion, stemness, and epithelial-mesenchymal transition (EMT) markers, further supported by migration and invasion assays. These findings highlight NEAT1 as a mechanosensitive regulator in response to substrate stiffness, underscoring its role in tumor progression.