bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumors Affect the Metabolic Connectivity of the Human Brain Measured by 18F-FDG PET
Authors: Pasquini Luca , Jenabi Mehrnaz , Graham Maya , Peck Kyung K. , Schöder Heiko , Holodny Andrei I. , Krebs Simone
Published: May 2024

Purpose

18F-FDG PET captures the relationship between glucose metabolism and synaptic activity, allowing for modeling brain function through metabolic connectivity. We investigated tumor-induced modifications of brain metabolic connectivity.

Patients and Methods

Forty-three patients with left hemispheric tumors and 18F-FDG PET/MRI were retrospectively recruited. We included 37 healthy controls (HCs) from the database CERMEP-IDB-MRXFDG. We analyzed the whole brain and right versus left hemispheres connectivity in patients and HC, frontal versus temporal tumors, active tumors versus radiation necrosis, and patients with high Karnofsky performance score (KPS = 100) versus low KPS (KPS < 70). Results were compared with 2-sided t test (P < 0.05).

Results

Twenty high-grade glioma, 4 low-grade glioma, and 19 metastases were included. The patients’ whole-brain network displayed lower connectivity metrics compared with HC (P < 0.001), except assortativity and betweenness centrality (P = 0.001). The patients’ left hemispheres showed decreased similarity, and lower connectivity metrics compared with the right (P < 0.01), with the exception of betweenness centrality (P = 0.002). HC did not show significant hemispheric differences. Frontal tumors showed higher connectivity metrics (P < 0.001) than temporal tumors, but lower betweenness centrality (P = 4.5−7). Patients with high KPS showed higher distance local efficiency (P = 0.01), rich club coefficient (P = 0.0048), clustering coefficient (P = 0.00032), betweenness centrality (P = 0.008), and similarity (P = 0.0027) compared with low KPS. Patients with active tumor(s) (14/43) demonstrated significantly lower connectivity metrics compared with necroses.

Conclusions

Tumors cause reorganization of metabolic brain networks, characterized by formation of new connections and decreased centrality. Patients with frontal tumors retained a more efficient, centralized, and segregated network than patients with temporal tumors. Stronger metabolic connectivity was associated with higher KPS.
High frequency of artemisinin partial resistance mutations in the great lake region revealed through rapid pooled deep sequencing
Authors: Young Neeva Wernsman , Gashema Pierre , Giesbrecht David , Munyaneza Tharcisse , Maisha Felicien , Mwebembezi Fred , Budodo Rule , Leonetti Alec , Crudale Rebecca , Iradukunda Vincent , Bosco Ntwari Jean , Boyce Ross M. , Mandara Celine I. , Kanyankole Grace K. , Mulogo Edgar , Ishengoma Deus S. , Hangi Stan , Karema Corine , Mazarati Jean-Baptiste , Juliano Jonathan J , Bailey Jeffrey A.
Published: May 2024

In Africa, the firstPlasmodium falciparumKelch13 (K13) artemisinin partial resistance mutation 561H was first detected and validated in Rwanda. Surveillance to better define the extent of the emergence in Rwanda and neighboring countries as other mutations arise in East Africa is critical. We employ a novel scheme of liquid blood drop preservation combined with pooled sequencing to provide a cost-effective rapid assessment of resistance mutation frequencies at multiple collection sites across Rwanda and neighboring countries. Malaria-positive samples (n=5,465) were collected from 39 health facilities in Rwanda, Uganda, Tanzania, and the Democratic Republic of the Congo (DRC) between May 2022 and March 2023 and sequenced in 199 pools. In Rwanda, K13 561H and 675V were detected in 90% and 65% of sites with an average frequency of 19.0% (0-54.5%) and 5.0% (0-35.5%), respectively. In Tanzania, 561H had high frequency in multiple sites while it was absent from the DRC although 675V was seen at low frequency. Conceringly candidate mutations were observed: 441L, 449A, and 469F co-occurred with validated mutations suggesting they are arising under the same pressures. Other resistance markers associated with artemether-lumefantrine are common:P. falciparummultidrug resistance protein 1 N86 at 98.0% and 184F at 47.0% (0-94.3%) andP. falciparumchloroquine resistance transporter 76T at 14.7% (0-58.6%). Additionally, sulfadoxine-pyrimethamine-associated mutations show high frequencies.

Overall,K13mutations are rapidly expanding in the region further endangering control efforts with the potential of engendering partner drug resistance.
Serum cytokine and inflammatory markers in individuals with heroin use disorder: potential biomarkers for diagnosis and disease severity
Authors: Butelman Eduardo R. , Huang Yuefeng , Cathomas Flurin , Gaudreault Pierre-Olivier , Roussos Panos , Russo Scott J. , Goldstein Rita Z. , Alia-Klein Nelly
Published: May 2024

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially as a multi-target biomarker. We used a validated proximity extension assay for relative quantification of 92 cytokines and inflammatory proteins in serum of iHUD on medication assisted therapy (MAT; n=21), versus HC (n=24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison correction (p=0.05). This included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, and PC1 scores were iHUD>HC (p<0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC=91.7% (p<0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, which included demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, and provides a multi-target “cytokine biomarker score” for potential diagnostic purposes, and examination of disease severity.
Inflammation Proteomic Profiling of Psychosis in Young Adults: findings from the ALSPAC birth cohort
Authors: Tsang Ruby S. M. , Timpson Nicholas J. , Khandaker Golam M.
Published: May 2024

Psychotic disorder is associated with altered levels of various inflammatory markers in blood, but existing studies have typically focused on a few selected biomarkers, have not examined specific symptom domains notably negative symptoms, and are based on individuals with established/chronic illness. Based on data from young people aged 24 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort, we have examined the associations of 67 plasma immune/inflammatory proteins assayed using the Olink Target 96 Inflammation panel with psychotic disorder, positive (any psychotic experiences and definite psychotic experiences) and negative symptoms, using linear models with empirical Bayes estimation. The analyses included between 2641 and 2854 individuals. After adjustment for age, sex, body mass index and smoking and correction for multiple testing, upregulation of CDCP1 and IL-6 were consistently associated with positive symptoms and psychotic disorder, while psychotic disorder was additionally associated with upregulation of MMP-10. Negative symptoms were associated with upregulation of the highest number of proteins (n=11), including cytokines, chemokines and growth factors which partly overlap with proteins associated with positive symptoms or psychotic disorder (CDCP1, IL-6 and MMP-10). Our findings highlight associations of inflammatory proteins involved in immune regulation, immune cell activation/migration, blood-brain barrier disruption, and extracellular matrix abnormalities with psychosis or psychotic symptoms in young people, consistent with a role of inflammation and immune dysfunction in the pathogenesis of psychotic disorders.
The Effectiveness of Using a Clinical Support Tool in Managing Adolescents with Non-Traumatic Knee Pain (MAP-Knee): protocol for a cluster-randomised superiority trial with delayed intervention and embedded realist evaluation
Authors: Riel Henrik , Johansen Simon Kristoffer , Andersen Erika Maria , Bruun Malene Kjær , Bruun Niels Henrik , Djurtoft Chris , Doessing Simon , Heyckendorff-Diebold Tina , Hölmich Per , Jensen Martin Bach , Kaalund Søren , Kaldau Niels-Christian , Oehlenschlaeger Tommy Frisgaard , Overgaard Charlotte , Rahbek Ole , Rasmussen Dorthe Brøndum , Schaarup Susanne Olesen , Sørensen Thomas , Thomsen Louise Lund Holm , Rathleff Michael Skovdal
Published: May 2024

Background

Knee pain affects one in three adolescents, which makes it one of the most common pain sites. Guideline recommendations about the clinical selection of patients likely to benefit from interventions are unclear, which leads to treatment heterogeneity and the potential of wasted resources among adolescents with a good prognosis. In contrast, adolescents with a poorer prognosis may not receive sufficient care. A newly developed clinical decision-support tool (The MAP-Knee Tool) intends to support clinicians in engaging with patients and adjusting the clinicians’ evidence-based practices to accommodate patient preferences and treatment needs via a shared decision-making process. The aims of this trial are 1) to investigate the effectiveness of using a clinical decision-support tool (The MAP-Knee Tool) compared with usual care in adolescents with non-traumatic knee pain in reducing pain measured by KOOS-Child Pain after 12 weeks and 2) to investigate how the intervention worked, for whom, why and under which circumstances applying realist evaluation methodology.

Methods

This trial is a cluster-randomised superiority trial with a delayed intervention and a realist evaluation. Six hospital departments start with a usual care period of 4 months before randomly crossing over to using the intervention (The MAP-Knee Tool) after 4, 6, or 8 months, respectively. We will recruit 290 adolescents suffering from non-traumatic knee pain diagnoses who are followed for one year, with the change in KOOS-Child Pain after 12 weeks considered the primary endpoint. Secondary outcomes include 1) Global Rating of Change, 2) EQ-5D-Youth, 3) Anterior Knee Pain Youth, 4) the International Physical Activity Questionnaire short version, and 5) sports participation. The realist evaluation will utilise a prospective, qualitative approach for collecting data needed to develop and test a program theory and identify context-mechanism-outcome configurations essential for understanding how outcomes are achieved within specific contexts.

Discussion

This trial focuses on how the initial clinical encounter can be improved to meet the support and management needs of adolescents with chronic knee pain seeking treatment for knee pain in secondary care and investigates how the intervention worked, for whom, why and under which circumstances.

Trial registration

Clinicaltrials.gov(NCT05791513). Prospectively registered on March 30th, 2023.
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

Background

Large 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%.

Purpose

To improve the diagnostic accuracy of GPT-4 Turbo in neuroradiology cases using prompt engineering strategies, thereby reducing misdiagnosis rates.

Materials and Methods

We 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.

Results

Without 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.

Conclusion

Prompt 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

Background

Pancreatic 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.

Methods

The 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.

Results

We 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.

Conclusions

While 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

Mutations 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

Animals 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

Acquired 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

Glioblastoma 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

The 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

Nature 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

Alcohol 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 statement

To 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

The 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

Dopamine 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

Eosinophils 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.
R-loops acted on by RNase H1 are a determinant of chromosome length-associated DNA replication timing and genome stability inLeishmania
Authors: Damasceno Jeziel D. , Briggs Emma M. , Krasilnikova Marija , Marques Catarina A. , Lapsley Craig , McCulloch Richard
Published: May 2024

Genomes in eukaryotes normally undergo DNA replication in a choreographed temporal order, resulting in early and late replicating chromosome compartments.Leishmania, a human protozoan parasite, displays an unconventional DNA replication program in which the timing of DNA replication completion is chromosome size-dependent: larger chromosomes complete replication later then smaller ones. Here we show that both R-loops and RNase H1, a ribonuclease that resolves RNA-DNA hybrids, accumulate inLeishmania majorchromosomes in a pattern that reflects their replication timing. Furthermore, we demonstrate that such differential organisation of R-loops, RNase H1 and DNA replication timing across the parasite’s chromosomes correlates with size-dependent differences in chromatin accessibility, G quadruplex distribution and sequence content. Using conditional gene excision, we show that loss of RNase H1 leads to transient growth perturbation and permanently abrogates the differences in DNA replication timing across chromosomes, as well as altering levels of aneuploidy and increasing chromosome instability in a size-dependent manner. This work provides a link between R-loop homeostasis and DNA replication timing in a eukaryotic parasite and demonstrates that orchestration of DNA replication dictates levels of genome plasticity inLeishmania.
Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex
Authors: Hudetz Anthony G
Published: May 2024

Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate the state-dependent effective connectivity of neurons in rat visual cortex in vivo. Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Microstimulation caused early (<10ms) increase followed by prolonged (11-100ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. The number of motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. The results illuminate the impact of anesthesia on functional integrity of local circuits affecting the state of consciousness.
The Noisy Encoding of Disparity Model Predicts Perception of the McGurk Effect in Native Japanese Speakers
Authors: Magnotti John F. , Lado Anastasia , Beauchamp Michael S.
Published: May 2024

The McGurk effect is an illusion that demonstrates the influence of information from the face of the talker on the perception of auditory speech. The diversity of human languages has prompted many intercultural studies of the effect, including in native Japanese speakers. Studies of large samples of native English speakers have shown that the McGurk effect is characterized by high variability, both in the susceptibility of different individuals to the illusion and in the frequency with which different experimental stimuli induce the illusion. The noisy encoding of disparity (NED) model of the McGurk effect uses Bayesian principles to account for this variability by separately estimating the susceptibility and sensory noise for each individual and the strength of each stimulus. To test whether the NED model could account for McGurk perception in a non-Western culture, we applied it to data collected from 80 native Japanese-speaking participants. Fifteen different McGurk stimuli were presented, along with audiovisual congruent stimuli. The McGurk effect was highly variable across stimuli and participants, with the percentage of illusory fusion responses ranging from 3% to 78% across stimuli and from 0% to 91% across participants. Despite this variability, the NED model accurately predicted perception, predicting fusion rates for individual stimuli with 2.1% error and for individual participants with 2.4% error. Stimuli containing the unvoiced pa/ka pairing evoked more fusion responses than the voiced ba/ga pairing. Model estimates of sensory noise was correlated with participant age, with greater sensory noise in older participants. The NED model of the McGurk effect offers a principled way to account for individual and stimulus differences when examining the McGurk effect within and across cultures.
Analysis of Hippocampal Synaptic Function in a Rodent Model of Early Life Stress
Authors: Wilkinson Matthew P , Robinson Emma S J , Mellor Jack R
Published: May 2024

Background

Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function.

Methods

Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones.

Results

MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol.

Conclusions

The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.
A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology
Authors: Sutton Nate , Gutiérrez-Guzmán Blanca , Dannenberg Holger , Ascoli Giorgio A.
Published: May 2024

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties fromHippocampome.orgto study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal was to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters fromHippocampome.org. The software is released as open source to enable broad community reuse and encourage novel applications.
Alterations of PINK1-PRKN signaling in mice during normal aging
Authors: Baninameh Zahra , Watzlawik Jens O. , Hou Xu , Richardson Tyrique , Kurchaba Nicholas W. , Yan Tingxiang , Di Florio Damian N. , Fairweather DeLisa , Kang Lu , Nguyen Justin H. , Kanekiyo Takahisa , Dickson Dennis W. , Noda Sachiko , Sato Shigeto , Hattori Nobutaka , Goldberg Matthew S. , Ganley Ian G. , Stauch Kelly L. , Fiesel Fabienne C. , Springer Wolfdieter
Published: May 2024

The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studiedin vitroupon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagyin vivois less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessmentin vivo,setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.
Avian Influenza Virus Infections in Felines: A Systematic Review of Two Decades of Literature
Authors: Coleman Kristen K. , Bemis Ian G.
Published: May 2024

As an avian influenza virus (AIV) panzootic is underway, the threat of a human pandemic is emerging. Infections among mammalian species in frequent contact with humans should be closely monitored. One mammalian family, the Felidae, is of particular concern. Domestic cats are susceptible to AIV infection and provide a potential pathway for zoonotic spillover to humans. Here, we provide a systematic review of the scientific literature to describe the epidemiology and global distribution of AIV infections in felines reported from 2004 – 2024. We identified 607 AIV infections in felines, including 302 associated deaths, comprising 18 countries and 12 felid species. We observed a drastic flux in the number of AIV infections among domestic cats in 2023 and 2024, commensurate with the emergence of H5N1 clade 2.3.4.4b. We estimate that this phenomenon is underreported in the scientific literature and argue that increased surveillance among domestic cats is urgently needed.