bluuebunny/crossref_metadata_2025_split huggingface dataset:
ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity
Authors: Morazzo Sofia , Fernandes Soraia , Fortea Marina , Skálová Helena , Cassani Marco , Vrzalová Kamila , Kafka Filip , Vrbský Jan , Pereira de Sousa Daniel , Bosáková Veronika , Shin Jaeyoung , Fric Jan , Haase Kristina , Forte Giancarlo 
Published: June 2024

AbstractTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is associated with high cell plasticity, recurrence, and metastatic rate. During epithelial-to-mesenchymal transition (EMT), cancer cells display EMT plasticity, or partial-EMT features, which are required for breast cancer metastasis, such as collective migration. ERK3 has been implicated in promoting migration and invasion of breast cancer, but the mechanisms remain elusive. Here, we investigated ERK3 expression across patient-derived datasets of breast cancer and established its association with aggressive breast cancer phenotypes and poor clinical outcomes. Leveraging the hypothesis that ERK3 contributes to TNBC progression by supporting a partial-EMT state, we showed that ERK3 is essential in different steps of the metastatic process, especially by enabling collective migration but also by modulating cell-extracellular matrix adhesion, anchorage-independent growth, extravasation and colonization. In conclusion, our results demonstrate that ERK3 contributes to TNBC progression and potentially metastasis by promoting EMT plasticity and collective migration.
Knockdown of DJ-1 Resulted in a Coordinated Activation of the Innate Immune Antiviral Response in HEK293 Cell Line
Authors: Zohar Keren , Linial Michal 
Published: June 2024

AbstractPARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we show that cell lines vary by their antioxidation potential at basal condition. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein coding transcripts, and 4.2k non-coding RNAs relative to control cells treated with non-specific siRNAs. Among the coding genes, ∼200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with regulation of type 1 interferons (IFN) and induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated by non-specific siRNAs that were used as a negative control. Beyond the antiviral response, 114 genes were specific to KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) were associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that KD of DJ-1 diminish its protective potency against oxidative stress, rendering the cells labile and responsive to dsRNA signal by activation of a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its crucial role in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 is highly expressed in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of DJ-1 level may reduce cancer cell viability and enhance the efficacy of cancer treatments.
Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis
Authors: Iyer Mukund , Das Diganta , Baugh Aaron G. , Shah Priya , Nakamura Brooke , Sedighi Saman , Reed Max , Jang Julie , Chow Frances , Torres Evanthia Roussos , Neman Josh 
Published: June 2024

AbstractMyeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs’ contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-κB and suppress T cell proliferation, resulting in enhanced tumor growth.In vivomurine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.
Impact of Climate, Habitat and Scale on the Population Dynamics of Feral Goats on the Isle of Rùm, NW Scotland
Authors: Dunbar R.I.M. 
Published: June 2024

AbstractAlthough feral goats are an invasive species renowned for their ability to survive in degraded habitats, their capacity to occupy high latitude habitats is severely restricted. I analyse long term data on the lifehistory and demography of a feral goat population on the Isle of Rùm, NW Scotland, in relation to both longterm variation in climatic variables and within-population variation in environmental variables. While exhibiting many features characteristic of ungulate lifehistory, goats are especially sensitive to variations in thermal conditions, especially during winter. This is compounded by the fact that, at the latitude of Rùm, goats give birth in mid-winter, even though this imposes significant stress on both mother and kid. Longterm patterns in population growth rates are correlated with winter temperature and the NAO index, with little evidence for density-dependent effects (except in respect of fertility). In addition, there was evidence that the presence of a large sympatric red deer population was limiting the goats’ capacity to increase by denying them access to preferred foraging habitat. Nonetheless, their unusual sensitivity to the thermal environment implies that the goat population will increase significantly with progressive climate warming.
Onset of α5GABA-A Receptor Dependent Hippocampal Trisynaptic Circuit Dysfunction Is Associated Increased Age and Blood Pressure
Authors: Ratner Marcia H. , Wainford Richard , Farb David H. 
Published: June 2024

ABSTRACTHypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to interrogate the functional integrity of the hippocampal trisynaptic circuit (HTC), which is known to participate in memory, to determine whether age-associated increases in MAP contributes to circuitry dysfunction that may lead to mild-cognitive impairment (MCR). Ripples, and specifically sharp-wave ripple oscillations, play a role in memory replay and consolidation during awake immobility among other behaviors. These synchronous high frequency local field potentials (LFPs) in the ripple band (140 to 200 Hz) serve as an HTC level surrogate marker for circuitry function in rodents, non-human primates, and humans. Thus, we asked whether age-associated increased MAP might alter ripple dynamics. Recognizing that each patient responds in a unique way to hypertension we used a within subject design wherein each animal served as its own control in the investigative model. We surgically implanted high density silicon probe electrodes in HTC CA1 of young and aged SD males to determine whether a nootropic drug, α5IA, a negative allosteric modulator of α5 subunit containing type-A GABA receptors, could detect aberrant modulation of ripples within each subject. Here we report that acute oral administration of α5IA selectively modulated ripple amplitude, but not its duration or frequency during epochs of awake immobility. The response of peak ripple amplitude to α5IA is substantially diminished when chronic MAP exceeds 160 mmHg, corresponding to significant hypertension. The results are consistent with a model in which age-associated increases in MAP is associated with dysfunctional α5 GABA-A receptor modulation of ripple amplitude, but not duration or frequency, as a potential precision biomarker for memory dysfunction.SummaryAge-related neurogenic hypertension disrupts memory and ripple band neural circuitry function in the hippocampal trisynaptic circuit involved in memory consolidation.
The physiology of deterrence: Flicker vertigo and its application in avian management
Authors: Honda Takeshi 
Published: June 2024

AbstractHuman-bird conflicts are in a critical state, involving economic losses such as agricultural losses, bird strikes on aircraft and avian influenza. Traditional technologies leveraging bird vision and hearing often lose their effectiveness over time as birds become habituated to these stimuli. To address these challenges, our study introduces a novel countermeasure technology based on neurophysiology. The human brain reacts to flickering light, which can cause symptoms like headaches, nausea, and dizziness. In extremely rare cases, it can even lead to epilepsy. This led us to consider the possibility that similar stimuli could be applicable to birds. In our experiments conducted during the day, we used long-range flashlights. White flickering light had no effect on bird escape behavior. However, when cellophane film was attached to the flashlights to restrict the wavelength, the emitted red light induced escape behavior in birds. Additionally, employing two types of flashlights to generate flickering red+blue or red+green lights elicited escape behavior. However, the blue and green combination proved to be less effective. These results are highly similar to those found in human neurophysiology, showing that red light alone and the combination of red and blue lights have the most significant impact on the brain. By measuring the flight initiation distance (FID) of birds, we found that illuminated areas had a significantly higher FID (137m) compared to non-illuminated areas (12m). These findings suggest that applying principles of human physiology to wildlife management can offer new solutions for bird damage control.
Alzheimer’s disease as a form of in situ diabetes: A systematic review and meta-analysis of therapeutic approaches using intranasal insulin treatment
Authors: de Oliveira Andrade Luís Jesuíno , Matos de Oliveira Gabriela Correia , Matos de Oliveira Luís 
Published: June 2024

ABSTRACTIntroductionAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by the loss of memory, language, and other cognitive functions. Increasing evidence suggests that AD shares pathophysiological similarities with type 2 diabetes, leading to the concept of AD as “diabetes in situ” within the brain. Intranasal insulin (INI) for AD has emerged as a promising therapeutic approach due to its ability to directly target the brain and modulate insulin signaling pathways.ObjectiveTo evaluate the efficacy and safety of INI therapy for AD through a systematic review and meta-analysis of randomized clinical trials.MethodA comprehensive search across electronic databases, including PubMed, Web of Science, Scopus, and Embase, was conducted to identify relevant studies published up to June 2024. Studies were included if they met the following criteria: original research articles published in peer-reviewed journals; focused on humans; investigated the therapeutic effects of INI administration on cognitive impairment associated with AD or diabetes; reported quantitative data on cognitive outcomes, biomarkers, or pathological markers relevant to AD or diabetes. For studies with available data, a meta-analysis was conducted to quantitatively synthesize the effects of INI on cognitive outcomes. METAANALYSISONLINE (https://metaanalysisonline.com/), an online statistical tool, was employed to conduct the meta-analysis and generate forest plots and funnel plots.ResultsA total of 647 articles were identified through electronic database searches using predefined search terms, and eight studies met the inclusion criteria and were selected for data extraction and analysis. Based on the analysis performed using random effects model with Mantel-Haenszel method to compare the odds ratio, the overall odds ratio was 3.75 with a 95% confidence interval of 1.49 - 9.4. The test for overall effect shows a significance at p<0.05. The The I2value indicates that 85.5% of the variability among studies arises from heterogeneity rather than random chance.ConclusionWhile the data is not yet definitive enough to establish INI as a definitive treatment for AD, the accumulating evidence supporting its safety, efficacy, and reduced systemic side effects strongly suggests that INI is associated with an overall enhancement of global cognition.
Multiomics unveils extracellular vesicle-driven mechanisms of endothelial communication in human carotid atherosclerosis
Authors: Raju Sneha , Turner Mandy E , Cao Christian , Abdul-Samad Majed , Punwasi Neil , Blaser Mark C , Cahalane Rachel ME , Botts Steven R , Prajapati Kamalben , Patel Sarvatit , Wu Ruilin , Gustafson Dakota , Galant Natalie J , Fiddes Lindsey , Chemaly Melody , Hedin Ulf , Matic Ljubica , Seidman Michael , Subasri Vallijah , Singh Sasha A , Aikawa Elena , Fish Jason E , Howe Kathryn L 
Published: June 2024

AbstractBackground:Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque.Methods:EVs were enriched via size exclusion chromatography from human carotid endarterectomy samples dissected into paired plaque and marginal zones (symptomatic n=16, asymptomatic n=13). EV cargos were assessed via whole transcriptome miRNA sequencing and mass spectrometry-based proteomics. EV multi-omics were integrated with bulk and single cell RNA-sequencing (scRNA-seq) datasets to predict EV cellular origin and ligand-receptor interactions, and multi-modal biological network integration of EV-cargo was completed. EV functional impact was assessed with endothelial angiogenesis assays.Results:Carotid plaques contained more EVs than adjacent marginal zones, with differential enrichment for EV-miRNAs and EV-proteins in key atherogenic pathways. EV cellular origin analysis suggested that tissue EV signatures originated from endothelial cells (EC), smooth muscle cells (SMC), and immune cells. Integrated tissue vesiculomics and scRNA-seq indicated complex EV-vascular cell communication that changed with disease progression and plaque vulnerability (i.e., symptomatic disease). Plaques from symptomatic patients, but not asymptomatic patients, were characterized by increased involvement of endothelial pathways and more complex ligand-receptor interactions, relative to their marginal zones. Plaque-EVs were predicted to mediate communication with ECs. Pathway enrichment analysis delineated an endothelial signature with roles in angiogenesis and neovascularization – well-known indices of plaque instability. This was validated functionally, wherein human carotid symptomatic plaque EVs induced sprouting angiogenesis in comparison to their matched marginal zones.Conclusion:Our findings indicate that EVs may drive dynamic changes in plaques through EV- vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed angiogenic processes mediated by EVs creates new therapeutic avenues for atherosclerosis.
Analysis of live cell data with G-DNABERT supports a role for G-quadruplexes in chromatin looping
Authors: Konovalov Dmitry , Umerenkov Dmitry , Herbert Alan , Poptsova Maria 
Published: June 2024

AbstractAlternative DNA conformation formed by sequences called flipons potentially alter the readout of genetic information by directing the shape-specific assembly of complexes on DNA The biological roles of G-quadruplexes formed by motifs rich in guanosine repeats have been investigated experimentally using many different methodologies including G4-seq, G4 ChIP-seq, permanganate nuclease footprinting (KEx), KAS-seq, CUT&Tag with varying degrees of overlap between the results. Here we trained large language model DNABERT on existing data generated by KEx, a rapid chemical footprinting technique performed on live, intact cells using potassium permanganate. The snapshot of flipon state when combined with results from other in vitro methods that are performed on permeabilized cells, allows a high confidence mapping of G-flipons to proximal enhancer and promoter sequences. Using G4-DNABERT predictions,with data from ENdb, Zoonomia cCREs and single cell G4 CUT&Tag experiments, we found support for a model where G4-quadruplexes regulate gene expression through chromatin loop formation.
Breathing modulates network activity in frontal brain regions during anxiety
Authors: Dias Ana L.A. , Drieskens Davi , Belo Joseph A. , Duarte Elis H. , Laplagne Diego A. , Tort Adriano B.L. 
Published: June 2024

AbstractAnxiety elicits various physiological responses, including changes in respiratory rate and neuronal activity within specific brain regions such as the medial prefrontal cortex (mPFC). Previous research suggests that the olfactory bulb (OB) modulates the mPFC through respiration-coupled neuronal oscillations (RCOs), which have been linked to fear-related freezing behavior. Nevertheless, the impact of breathing on frontal brain networks during other negative emotional responses, such as anxiety-related states characterized by higher breathing rates, remains unclear. To address this, we subjected rats to the elevated plus maze (EPM) paradigm while simultaneously recording respiration and local field potentials in the OB and mPFC. Our findings demonstrate distinct respiratory patterns during EPM exploration: slower breathing frequencies prevailed in the closed arms, whereas faster frequencies were observed in the open arms, independent of locomotor activity, indicating that anxiety-like states are associated with increased respiratory rates. Additionally, we identified RCOs at different frequencies, mirroring the bimodal distribution of respiratory frequencies. RCOs exhibited higher power during open arm exploration, when they showed greater coherence with breathing at faster frequencies. Furthermore, we confirmed that nasal respiration drives RCOs in frontal brain regions, and found a stronger effect during faster breathing. Interestingly, we observed that the frequency of prefrontal gamma oscillations modulated by respiration increased with heightened anxiety levels and breathing frequency. Overall, our study provides evidence for a significant influence of breathing on prefrontal cortex networks during anxious states, shedding light on the complex interplay between respiratory physiology and emotional processing.Significance StatementUnderstanding how breathing influences brain activity during anxious states could pave the way for novel therapeutic interventions targeting respiratory control to alleviate anxiety symptoms. Our study uncovers a crucial link between respiratory patterns and anxiety-related neural activity in the brain. By investigating the interplay between breathing, neuronal oscillations, and emotional states, we reveal that anxiety induces distinct respiratory patterns, with higher breathing rates correlating with anxious behavior. Importantly, we demonstrate that respiration drives oscillatory activity in the prefrontal cortex, and this effect is potentiated during the fast breathing associated with anxiety. Furthermore, the breathing cycle modulates the emergence of prefrontal gamma oscillations differentially across anxiety levels. This discovery sheds new light on the intricate relationship between respiratory physiology and emotional processing.
ACtnnb1enhancer transcriptionally regulates Wnt signaling dosage to balance homeostasis and tumorigenesis of intestinal epithelia
Authors: Hua Xiaojiao , Zhao Chen , Tian Jianbo , Wang Junbao , Miao Xiaoping , Zheng Gen , Wu Min , Ye Mei , Liu Ying , Zhou Yan 
Published: June 2024

AbstractThe β-catenin-dependent canonical Wnt signaling is pivotal in organ development, tissue homeostasis, and cancer. Here we identified an upstream enhancer ofCtnnb1– the coding gene for β-catenin, named ieCtnnb1 (intestinalenhancer ofCtnnb1), which is crucial for intestinal homeostasis. ieCtnnb1 is predominantly active in the base of small intestinal crypts and throughout the epithelia of large intestine. Knockout of ieCtnnb1 led to a reduction inCtnnb1transcription, compromising the canonical Wnt signaling in intestinal crypts. Single-cell sequencing revealed that ieCtnnb1 knockout altered epithelial compositions and potentially compromised functions of small intestinal crypts. While deletion of ieCtnnb1 hampered epithelial turnovers in physiologic conditions, it prevented occurrence and progression of Wnt/β-catenin-driven colorectal cancers. Human ieCTNNB1 drove reporter gene expression in a pattern highly similar to mouse ieCtnnb1. ieCTNNB1 contains a single-nucleotide polymorphism associated withCTNNB1expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues was stronger than that in adjacent normal tissues. HNF4αand phosphorylated CREB1 were identified as key trans-factors binding to ieCTNNB1 and regulatingCTNNB1transcription. Together, these findings unveil an enhancer-dependent mechanism controlling the dosage of Wnt signaling and homeostasis in intestinal epithelia.
Muscle Moment Arm–Joint Angle Relations in the Hip, Knee, and Ankle: A Visualization of Datasets
Authors: Chen Ziyu , Franklin David W. 
Published: June 2024

AbstractMuscle moment arm is a property that associates muscle force with joint moment and is crucial to biomechanical analysis. In musculoskeletal sim-ulations, the accuracy of moment arm is as important as that of muscle force, and moment arm calibration requires data from anatomical measure-ments. Nonetheless, such data are elusive, and the complex relation between moment arm and joint angle can be unclear. Using common techniques in systematic review, we collected a total of 300 moment arm datasets from literature and visualized the muscle moment arm–joint angle relations in the hip, knee, and angle. The findings contribute to the understanding and anal-ysis of musculoskeletal mechanics, as well as providing reference regarding the experimental design for future moment arm measurements.