bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prompt Engineering Strategies Improve the Diagnostic Accuracy of GPT-4 Turbo in Neuroradiology Cases
Authors: Wada Akihiko , Akashi Toshiaki , Shih George , Hagiwara Akifumi , Nishizawa Mitsuo , Hayakawa Yayoi , Kikuta Junko , Shimoji Keigo , Sano Katsuhiro , Kamagata Koji , Nakanishi Atsushi , Aoki Shigeki 
Published: May 2024

AbstractBackgroundLarge language models (LLMs) like GPT-4 demonstrate promising capabilities in medical image analysis, but their practical utility is hindered by substantial misdiagnosis rates ranging from 30-50%.PurposeTo improve the diagnostic accuracy of GPT-4 Turbo in neuroradiology cases using prompt engineering strategies, thereby reducing misdiagnosis rates.Materials and MethodsWe employed 751 publicly available neuroradiology cases from the American Journal of Neuroradiology Case of the Week Archives. Prompt instructions guided GPT-4 Turbo to analyze clinical and imaging data, generating a list of five candidate diagnoses with confidence levels. Strategies included role adoption as an imaging expert, step-by-step reasoning, and confidence assessment.ResultsWithout any adjustments, the baseline accuracy of GPT-4 Turbo was 55.1% to correctly identify the top diagnosis, with a misdiagnosis rate of 29.4%. Considering the five candidates’ improved applicability, it is 70.6%. Applying a 90% confidence threshold increased the accuracy of the top diagnosis to 72.9% and the applicability of the five candidates to 85.9%, while reducing misdiagnoses to 14.1%, but limited the analysis to half of cases.ConclusionPrompt engineering strategies with confidence level thresholds demonstrated the potential to reduce misdiagnosis rates in neuroradiology cases analyzed by GPT-4 Turbo. This research paves the way for enhancing the feasibility of AI-assisted diagnostic imaging, where AI suggestions can contribute to human decision-making processes. However, the study lacks analysis of real-world clinical data. This highlights the need for further investigation in various specialties and medical modalities to optimize thresholds that balance diagnostic accuracy and practical utility.
Comparison of Different Approaches to Single Cell RNA Sequencing of Cancer Associated Fibroblasts
Authors: Kung Heng-Chung , Loycano Michael , Zheng Lei , Chen Sophia Y. , Zimmerman Jacquelyn W. 
Published: May 2024

ABSTRACTBackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis. PDAC has a high propensity for metastasis, particularly to the lungs and liver. Cancer associated fibroblasts (CAFs) represent a major stromal component of PDAC with both tumor-promoting and restraining properties. Of note, CAFs play a significant role in the creation of an immunosuppressive tumor microenvironment (TME) and the metastasis of PDAC. Studies have demonstrated functional heterogeneity among different subpopulations of CAFs, highlighting the need to identify specific subpopulations when targeting CAFs.MethodsThe orthotopic model was used for both KPC-4545 and KPC-3403 cell lines, which were derived from the primary tumors of KPC mice with liver metastases and lung metastases only, respectively. In brief, 2x106KPC cells were injected subcutaneously into the flanks of synergic female C57BI6 mice. Tumors were harvested and cut into 2-3 mm3pieces before being implanted into the pancreas of new 6–8-week-old syngeneic female C57Bl/6 mice. Murine orthotopic tumors were dissected, mechanically and enzymatically processed with Miltenyi Tumor Dissociation Kit (Miltenyi Biotec) thirteen days after tumor implantation. Samples were filtered with a 100 µm strainer, washed with T cell media, and centrifuged twice.Two different samples underwent single cell RNA-sequencing (scRNA-seq) for each cell line: an unenriched sample, which represents all cells following dissociation of the tumor, and a CAF-enriched sample. To further obtain the CAF-enriched sample, cells were then stained with CD45-AF657 (BioLegend clone 30-F11, 1:20), CD31-AF647 (BioLegend clone 390, 1:20), EPCAM-AF647 (BioLegend, clone G8.8, 1:20), and TER119-AF647 (BioLegend clone TER-119 1:20) for 30 minutes on ice. After two washes, CD45-, CD31-, EPCAM-, and TER119-negative cells, representing the CAF-enriched fraction, were obtained via cell sorting. scRNA-seq of both the unenriched and CAF-enriched fractions were performed using 10X Chromium microfluidic chips and data was analyzed using CellRanger v6.1.1, mm10 transcriptome reference, and 10X Loupe Browser.ResultsWe found that scRNA-seq of the unenriched whole tumor showed only one cluster of CAFs for both cells lines, making it difficult for studying CAF heterogeneity. Enriching for CAFs prior to scRNA-seq allowed for better capture of CAFs and provided more granularity on CAF heterogeneity for both KPC-4545 and KPC-3403.ConclusionsWhile enrichment provides more information on CAF heterogeneity, the process results in the loss of other cells within the TME. The need to capture CAF heterogeneity while studying cell-cell interaction between CAFs and other cells within the TME and identifying how distinct CAF populations respond differently to treatment warrants the use of other methods such as single-nuclear RNA-seq.
Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4
Authors: Dikovskaya Dina , Pemberton Rebecca , Taylor Matthew , Tasegian Anna , Zenevicuite Karolina , Sammler Esther M. , Howden Andrew J.M. , Alessi Dario R. , Swamy Mahima 
Published: May 2024

SummaryMutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson’s Disease (PD) and Crohn’s Disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created an EGFP-Lrrk2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 levels and activity in splenic and intestinal immune cells. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated activity but reduced LRRK2 expression. A kinase-activating PD-associated LRRK2-R1441C mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells, replicating inflammatory effects observedin vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.
Coordination and persistence of aggressive visual communication in Siamese fighting fish
Authors: Everett Claire P. , Norovich Amy L. , Burke Jessica E. , Whiteway Matthew R. , Shih Pei-Yin , Zhu Yuyang , Paninski Liam , Bendesky Andres 
Published: May 2024

ABSTRACTAnimals coordinate their behavior with each other during both cooperative and agonistic social interactions. Such coordination often adopts the form of “turn taking”, in which the interactive partners alternate the performance of a behavior. Apart from acoustic communication, how turn taking between animals is coordinated is not well understood. Furthermore, the neural substrates that regulate persistence in engaging in social interactions are poorly studied. Here, we use Siamese fighting fish (Betta splendens), to study visually-driven turn-taking aggressive behavior. Using encounters with conspecifics and with animations, we characterize the dynamic visual features of an opponent and the behavioral sequences that drive turn taking. Through a brain-wide screen of neuronal activity during coordinated and persistent aggressive behavior, followed by targeted brain lesions, we find that the caudal portion of the dorsomedial telencephalon, an amygdala-like region, promotes persistent participation in aggressive interactions, yet is not necessary for coordination. Our work highlights how dynamic visual cues shape the rhythm of social interactions at multiple timescales, and points to the pallial amygdala as a region controlling engagement in such interactions. These results suggest an evolutionarily conserved role of the vertebrate pallial amygdala in regulating the persistence of emotional states.
APOBEC3 mutagenesis drives therapy resistance in breast cancer
Authors: Gupta Avantika , Gazzo Andrea , Selenica Pier , Safonov Anton , Pareja Fresia , da Silva Edaise M. , Brown David N. , Zhu Yingjie , Patel Juber , Blanco-Heredia Juan , Stefanovska Bojana , Carpenter Michael A. , Pei Xin , Frosina Denise , Jungbluth Achim A. , Ladanyi Marc , Curigliano Giuseppe , Weigelt Britta , Riaz Nadeem , Powell Simon N. , Razavi Pedram , Harris Reuben S. , Reis-Filho Jorge S. , Marra Antonio , Chandarlapaty Sarat 
Published: May 2024

ABSTRACTAcquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer1–7, however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such asRB1loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.
Interneurons that BiTE: Harnessing the migratory capacity of cortical inhibitory interneuron precursors to treat high-grade glioma
Authors: Brosius Stephanie N. , Manley William , Harvey Kyra , Gallanaugh Jamie , Rohacek Deborah , Anderson Stewart , De Raedt Thomas 
Published: May 2024

AbstractGlioblastoma has a poor prognosis with limited therapeutic options. To date, almost all therapeutic agents that showed promise inin vitroassays, preclinical trials, or even in early clinical trials have failed to make a substantial impact on the survival of patients with high-grade glioma. One major obstacle for small molecules, therapeutic proteins, or immune cells remains the blood brain barrier, which often prevents the efficient delivery of agents to the tumor. To address this delivery issue, we developed a cellular vector where implanted modified post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs) migrate to high-grade glioma by chemoattraction to locally secrete a therapeutic protein. The inhibitory interneurons of the cerebral cortex originate predominantly in the ventral/subcortical portion of the telencephalic neural tube. During fetal brain development, MCIP migration is guided over long distances by chemorepulsant and chemoattractant factors. Remarkably, several MCIP chemoattractant factors are also secreted by high-grade gliomas. Indeed, ourin vitroandin vivodata show that MCIPs robustly migrate to the majority of glioblastoma cell lines evaluated. As a proof of principle, we modified the MCIPs to secrete bispecific T-cell engagers (BiTEs), linking the EGFR tumor antigen to CD3 on T-cells to create an adaptor molecule that induces an anti-tumor response of resident and supplied T-cells by bridging a tumor antigen and the T-cell receptor. We find that implanted BITE-secreting MCIPs significantly extended survival of mice injected with high-grade glioma. Therefore, we conclude that the use of MCIPs as a delivery vector for therapeutic agents could revolutionize the way we treat glioblastoma, as they allow for the local delivery of therapeutic agents in high concentrations, bypassing the need for these agents to cross the blood brain barrier while reducing the risk for systemic toxicities outside of the brain.
Partial FAM19A5 Deficiency in Mice Leads to Disrupted Spine Maturation, Hyperactivity, and an Altered Fear Response
Authors: Shahapal Anu , Park Sumi , Yoo Sangjin , Hwang Jong-Ik , Seong Jae Young 
Published: May 2024

ABSTRACTThe FAM19A5polypeptide, encoded by the TAFA5gene, is evolutionarily conserved among vertebral species. This protein is predominantly expressed in the brain, highlighting its crucial role in the central nervous system. Here, we investigated the potential roles of FAM19A5in brain development and behavior using a FAM19A5-LacZ KI mouse model. This model exhibited a partial reduction in the FAM19A5protein level. FAM19A5-LacZ KI mice displayed no significant alterations in gross brain structure but alterations in dendritic spine distribution, with a bias toward immature forms. These mice also had lower body weights. Behavioral tests revealed that compared with their wild-type littermates, FAM19A5-LacZ KI mice displayed hyperactivity and a delayed innate fear response. These findings suggest that FAM19A5plays a role in regulating spine formation and maintenance, thereby contributing to neural connectivity and behavior.
Nature exposure induces hypoalgesia by acting on nociception-related neural processing
Authors: Steininger Maximilian O. , White Mathew P. , Lengersdorff Lukas , Zhang Lei , Smalley Alexander J. , Kühn Simone , Lamm Claus 
Published: May 2024

AbstractNature exposure has numerous psychological benefits, and previous findings suggest that exposure to nature reduces self-reported acute pain. Given the multi-faceted and subjective quality of pain and methodological limitations of prior research, it is unclear whether the evidence indicates genuine hypoalgesia or results from domain-general effects and subjective reporting biases. This preregistered functional neuroimaging study aimed to identify how nature exposure modulates nociception-related and domain-general brain responses to acute pain. We compared the self-reported and neural responses of healthy neurotypical participants (N = 49) receiving painful electrical shocks while exposed to virtual nature or to closely matched urban and indoor control settings. Replicating existing behavioral evidence, pain was reported to be lower during exposure to the natural compared to the urban or indoor control settings. Crucially, machine-learning-based multi-voxel signatures of pain demonstrated that this subjective hypoalgesia was associated with reductions in nociception-related rather than domain-general cognitive-emotional neural pain processing. Preregistered region-of-interest analyses corroborated these results, highlighting reduced activation of areas connected to lower-level somatosensory aspects of pain processing (such as the thalamus, secondary somatosensory cortex, and posterior insula). These findings demonstrate that nature exposure results in genuine hypoalgesia and that neural changes in lower-level nociceptive pain processing predominantly underpin this effect. This advances our understanding of how nature may be used as a non-pharmacological pain treatment. That this hypoalgesia was achieved with brief and easy-to-administer virtual nature exposure has important practical implications and opens novel avenues for research on the precise mechanisms by which nature impacts our mind and brain.
From electrophysiology to drink: Adolescent alcohol consumption predicted by differences in functional connectivity and neuroanatomy
Authors: del Cerro-León Alberto , Antón-Toro Luis Fernando , Shpakivska-Bilan Danylyna , Uceta Marcos , Santos-Mayo Alejandro , Cuesta Pablo , Bruña Ricardo , García-Moreno Luis M , Maestú Fernando 
Published: May 2024

AbstractAlcohol consumption during adolescence has been associated with neuroanatomical abnormalities and the appearance of future disorders. However, the latest advances in this field point to the existence of risk profiles which may lead to some individuals into an early consumption. To date, some studies have established predictive models of consumption based on sociodemographic, behavioural, and anatomical-functional variables using MRI. However, the neuroimaging variables employed are usually restricted to local and hemodynamic phenomena. Given the potential of connectome approaches, and the high temporal dynamics of electrophysiology, we decided to explore the relationship between future alcohol consumption and electrophysiological connectivity measured by MEG in a cohort of 83 individuals aged 14 to 16. We calculated predictive models throughout multiple linear regressions based on behavioural, anatomical, and functional connectivity variables. As a result, we found a positive correlation between alcohol consumption and the functional connectivity in frontal, parietal, and frontoparietal connections. Also, we identified negative relationships of alcohol consumption with neuroanatomical variables. Finally, the linear regression analysis determined the importance of anatomical and functional variables in the prediction of alcohol consumption but failed to find associations with impulsivity, sensation-seeking, and executive function scales. As conclusion, the predictive traits obtained in these models were closely associated with changes occurring during neurodevelopment, suggesting the existence of different paths in neurodevelopment that have the potential to influence adolescents’ relationship with alcohol consumption.Significance statementTo understand the onset of heavy drinking habits and develop prevention strategies, we need to characterize predisposition profiles at early ages. This longitudinal work provides important evidence by showing how adolescents at risk for engaging in alcohol behaviors showed resting-state functional connectivity and grey matter differences years before. The combination of these metrics allows us to establish predictive models of future alcohol episodes. In addition, differences in functional connectivity showed a positive relationship with behavioral variables such as lower executive functions and higher on the sensation-seeking. These predisposition phenotypes may rely on divergent neurodevelopmental pathways and deeper neurobiological abnormalities, such as dysfunctions of inhibitory neurotransmission and/or a genetic background of vulnerability.
Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
Authors: Pugh Kira , Jones Rhys DO , Powathil Gibin , Hamis Sara 
Published: May 2024

AbstractThe interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings.
Synaptic enrichment and dynamic regulation of the two opposing dopamine receptors within the same neurons
Authors: Hiramatsu Shun , Saito Kokoro , Kondo Shu , Katow Hidetaka , Yamagata Nobuhiro , Wu Chun-Fang , Tanimoto Hiromu 
Published: May 2024

AbstractDopamine can play opposing physiological roles depending on the receptor subtype. In the fruit flyDrosophila melanogaster,Dop1R1andDop2Rencode the D1- and D2-like receptors, respectively, and are reported to oppositely regulate intracellular cAMP levels. Here, we profiled the expression and subcellular localization of endogenous Dop1R1 and Dop2R in specific cell types in the mushroom body circuit. For cell-type-specific visualization of endogenous proteins, we employed reconstitution of split-GFP tagged to the receptor proteins. We detected dopamine receptors at both presynaptic and postsynaptic sites in multiple cell types. Quantitative analysis revealed enrichment of both receptors at the presynaptic sites, with Dop2R showing a greater degree of localization than Dop1R1. The presynaptic localization of Dop1R1 and Dop2R in dopamine neurons suggests dual feedback regulation as autoreceptors. Furthermore, we discovered a starvation-dependent, bidirectional modulation of the presynaptic receptor expression in the PAM and PPL1 clusters, two distinct subsets of dopamine neurons, suggesting regulation of appetitive behaviors. Our results highlight the significance of the co-expression of the two opposing dopamine receptors in the spatial and conditional regulation of dopamine responses in neurons.
Identification of a specific granular marker of zebrafish eosinophils enables development of new tools for their study
Authors: Herbert Miriam , Goosmann Christian , Brinkmann Volker , Dimmler Christiane , Cronan Mark R. 
Published: May 2024

AbstractEosinophils control many aspects of the vertebrate innate immune response. They contribute to homeostasis, inflammatory conditions and defense against pathogens, yet, their function in disease often remains enigmatic. The zebrafish has emerged as a useful model organism for human diseases but tools to study eosinophils in this model are severely limited. Here, we characterize a new and highly specific marker for eosinophils in zebrafish and report a new transgenic reporter line to visualize eosinophilsin vivo. In addition, we created a polyclonal antibody that allows the identification of eosinophilsex vivo. These new tools expand the toolkit to study eosinophils in the zebrafish model. Using our tools, we have been able to identify the likely ortholog of eosinophil major basic protein, a critical mediator of eosinophil function, in zebrafish. These advances will allow for the investigation of eosinophil biology in the zebrafish model organism, allowing researchers to identify the contribution of eosinophils to the many diseases that are modeled within zebrafish and also shed light on the evolution of eosinophils within vertebrates.