bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepFocus: A Transnasal Approach for Optimized Deep Brain Stimulation of Reward Circuit Nodes
Authors: Guo Yuxin , Forssell Mats , Kusyk Dorian M. , Jain Vishal , Swink Isaac , Corcoran Owen , Lee Yuhyun , Goswami Chaitanya , Whiting Alexander C. , Cheng Boyle C. , Grover Pulkit 
Published: October 2024

AbstractObjectiveTranscranial electrical stimulation (TES) is an effective technique to modulate brain activity and treat diseases. However, TES is primarily used to stimulate superficial brain regions and is unable to reach deeper targets. The spread of injected currents in the head is affected by volume conduction and the additional spreading of currents as they move through head layers with different conductivities, as is discussed in [1]. In this paper, we introduce DeepFocus, a technique aimed at stimulating deep brain structures in the brain’s “reward circuit” (e.g. the orbitofrontal cortex, Brodmann area 25, amygdala, etc.).ApproachTo accomplish this, DeepFocus utilizes transnasal electrode placement (under the cribriform plate and within the sphenoid sinus) in addition to electrodes placed on the scalp, and optimizes current injection patterns across these electrodes. To quantify the benefit of DeepFocus, we develop the DeepROAST simulation and optimization platform. DeepROAST simulates the effect of complex skull-base bones’ geometries on the electric fields generated by DeepFocus configurations using realistic head models.It also uses optimization methods to search for focal and efficient current injection patterns, which we use in our simulation and cadaver studies.Main ResultsIn simulations, optimized DeepFocus patterns created larger and more focal fields in several regions of interest than scalp-only electrodes. In cadaver studies, DeepFocus patterns created large fields at the medial orbitofrontal cortex (OFC) with magnitudes comparable to stimulation studies, and, in conjunction with established cortical stimulation thresholds, suggest that the field intensity is sufficient to create neural response, e.g. at the OFC.SignificanceThis minimally invasive stimulation technique can enable more efficient and less risky targeting of deep brain structures to treat multiple neural conditions.
Beyond the CTCT: Remote Structural Changes After VIM-MRgFUS in Essential Tremor
Authors: Krauß Jonas , Upadhyay Neeraj , Purrer Veronika , Borger Valeri , Daamen Marcel , Maurer Angelika , Schmeel Carsten , Radbruch Alexander , Wüllner Ullrich , Boecker Henning 
Published: October 2024

AbstractIntroductionEssential tremor (ET) is a progressive disorder characterized by altered network connectivity between the cerebellum, thalamus, and cortical regions. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) of the ventral intermediate nucleus (VIM) is an effective, minimally invasive treatment for ET. Increasing clinical use in ET facilitates research on structural changes after thalamic lesions.MethodsForty-six patients with medication-resistant ET underwent unilateral VIM-MRgFUS. Voxel-based morphometry was applied to investigate Gray Matter Volume (GMV) changes over a time span of 6 months in the whole brain and the thalamus in particular to investigate local and distant effects.ResultsClinically, contralateral tremor significantly decreased by 68 % at 6 months following MRgFUS. In addition to local changes in thalamic nuclei (VIM, ventral lateral posterior, centromedian thalamus and pulvinar), VBM revealed remote GMV decreases in the ipsilesional insula and the anterior cingulate cortex as well as the contralesional middle occipital gyrus. Increased GMV was found in both temporal gyri. There was no significant correlation between regional GMV declines and tremor improvement. However, temporal volume increases were associated with improved motor-related functional abilities and quality of life outcomes.ConclusionOur findings implicate distributed structural changes following unilateral VIM-MRgFUS. Structural losses could reflect Wallerian degeneration of VIM output neurons or plasticity due to decreased sensory input following tremor improvement.
The thermotolerant Arabian killifish,Aphanius dispar, as a novel infection model for human fungal pathogens
Authors: Minhas Rashid , Bedekovic Tina , Veale Teigan , John Larissa L. H. , Hamied Atyaf Saied , Scrase Elliott , Read Sienna , Davies Chantelle , Gifford Hugh , Farrer Rhys , Bates Steven , Brand Alexandra C. , Ramsdale Mark , Kudoh Tetsuhiro 
Published: October 2024

AbstractCandida albicans: a fungal pathogen, can cause superficial and fatal infections in humans. An important virulence factor inC. albicansdissemination is the transformation from yeast to an invasive hyphal form, which is favoured at human body temperature. Zebrafish, a useful model for studyingC. albicansinfections, cannot survive at 37°C. Arabian killifish,Aphanius dispar, an emerging teleost model can tolerate temperatures up to 40 °C for up to 12 days (independent feeding time) allowing for longer analysis compared to zebrafish. This study introducesA. disparas a thermo-relevant and a more accurate reporter of the virulence mechanisms relevant toC. albicansas a human pathogen. UsingA. dispar, we tested virulence at human skin (30 °C), body temperature (37 °C) and a high fever condition (40°C). Infection byC. albicansat 37°C and 40°C significantly increased virulence, reduced survival of AKF embryos and formed invasive hyphal network compared to 30 °C. Two mutant strains ofC. albicans. pmr1Δ(with aberrant cell surface glycans) exhibited reduced virulence at 37°C, whereasrsr1Δ (lacking a cell polarity marker) showed less virulence at 30 °C. Additionally, anti-fungal treatment rescued AKF survival in a dose-dependent manner, indicating AKF’s potential forin vivodrug testing. Our data indicates the quantitative and qualitative importance of examining virulence traits at physiologically relevant temperatures and demonstrates an equivalence to findings for systemic infection derived in mouse models. TheA. disparembryo therefore provides an excellentin vivomodel system for assessing virulence, drug-testing, and real-time imaging of host-pathogen interactions.Significance StatementThe virulence of many pathogens is dependent on host temperature. We demonstrate that theA. disparembryo provides an excellent new thermo-relevant alternative to zebrafish and mouse models, which have limitations in terms of the range of temperatures that can be assessed in real-time. In this study, we have assessedC. albicanstemperature-based virulence, focusing on human body and human skin temperatures (37, 40 and 30 °C, respectively) by examining different genetic backgrounds ofC. albicansstrains. The results indicate differentC. albicansstrains with genetic background show varied virulence depending on temperature indicating importance of examination of virulence mechanisms at physiological temperatures.
Estimating the mean: behavioral and neural correlates of summary representations for time intervals
Authors: Otsuka Taku , Karsilar Hakan , van Rijn Hedderik 
Published: October 2024

AbstractOur behavior is guided by the statistical regularities in the environment. Prior research on temporal context effects has demonstrated the dynamic processes through which humans adapt to the environment’s temporal regularities. However, learning temporal regularities not only entails dynamic adaptation to traces of previous individual events but also often requires the extraction and retention of summary statistics (e.g., the mean) of temporal distributions. To investigate these summary representations for temporal distributions and to test their sensitivity to distributional changes, we explicitly asked participants to extract the mean of different distributions of time intervals, which shared the same mean but varied in their variability specifically operationalized by the width and presentation frequency of the intervals. Our findings showed that the variability of the estimated mean increased with the distributions’ variability, even though the actual mean remained constant. We further examined how such learning of temporal distributions modulates EEG signals during subsequent temporal judgments. Analysis revealed that the contingent negative variation (CNV), predictive of single-trial RTs, was correlated with how much individuals’ estimates of the mean were affected by the distributions’ variability. Conversely, the post-interval P2 was not modulated by the distributions but predicted participants’ responses, suggesting that P2 reflects the perceived duration of an interval. Taken together, our results demonstrate not only that humans can accurately estimate the mean of a temporal distribution, but also that the representation of the mean becomes more uncertain as the variability of the distribution increases, as reflected neurally in the preparation-related CNV during temporal decisions.
Whole-Process 3D ECM-Encapsulated Organoid-Based Automated High-Throughput Screening Platform Accelerates Drug Discovery for Rare Diseases
Authors: Xu Zhaoting , Yang Hui , Zhou Yuru , Dzakah Emmanuel Enoch , Zhao Bing 
Published: October 2024

AbstractThe use of organoids, especially patient-derived organoids, for high-throughput screening (HTS) is widely accepted due to their ability to mimic the three-dimensional (3D) structure, function, and drug responses of in vivo tissues. However, the complexity of handling extracellular matrix (ECM) components with traditional HTS devices leads to the utilization of suspension cultures in matrix-free or matrix-low conditions during HTS, which can alter their transcriptomic landscape and drug responses. Here, we develop a whole-process 3D ECM-encapsulated organoid-based automated HTS (wp3D-OAHTS) platform, which enables the rapid and accurate generation of uniformly distributed 3D cell-matrix mixture domes at the center of each well in 96-well plates. This approach replicates the process of manual organoid culture but with superior stability and reproducibility. Utilizing this platform, we screened 2,802 compounds on neuroendocrine cervical cancer organoids, a rare malignancy with significant unmet clinical needs. We identified 7 top hits that display strong anti-tumor effects with remarkably low half-maximal inhibitory concentration (IC50) and validated the in vivo efficacy of Quisinostat 2HCl. Additionally, we demonstrated that employing 3D ECM-encapsulated organoid cultures for HTS, rather than suspended cultures, provides optimal conditions for drug discovery. Our wp3D-OAHTS platform significantly improves the rapidity and efficiency of new drug discovery for rare diseases.
Recursive Cleaning for Large-scale Protein Data via Multimodal Learning
Authors: Jiang Zixuan , Zhang Sitao , Cao Jiahang , Zhang Qiang , Liu Shiyi , Fang Yuetong , Zhang Lingfeng , Qing Rui , Xu Renjing 
Published: October 2024

AbstractReliable datasets and high-performance models work together to drive significant advancements in protein representation learning in the era of Artificial Intelligence. The size of protein models and datasets has grown exponentially in recent years. However, the quality of protein knowledge and model training has suffered from the lack of accurate and efficient data annotation and cleaning methods. To address this challenge, we introduceProtAC, which corrects largeProtein datasets with a scalableAutomaticCleaning framework that leverages both sequence and functional information through multimodal learning. To fulfill data cleaning, we propose the Sequence-Annotation Matching (SAM) module in the model, which filters the functional annotations that are more suitable for the corresponding sequences. Our approach is a cyclic process consisting of three stages: first pretraining the model on a large noisy dataset, then finetuning the model on a small manually annotated dataset, and finally cleaning the noisy dataset using the finetuned model. Through multiple rounds of “train-finetune-clean” cycles, we observe progressive improvement in protein function prediction and sequenceannotation matching. As a result, we achieve(1)a state-of-the-art (SOTA) model that outperforms competitors with fewer than 100M parameters, evaluated on multiple function-related downstream tasks, and(2)a cleaned UniRef50 dataset containing ∼50M proteins with well-annotated functions. Performing extensive biological analysis on a cleaned protein dataset, we demonstrate that our model is able to understand the relationships between different functional annotations in proteins and that proposed functional annotation revisions are reasonable.
WNT-mediating TCF/LEF transcription factor gene expression in early human pluripotency and cell lineages differs from the rodent paradigm
Authors: Ross Connor , Azami Takuya , Salonna Marika , Gyuris Richard , Nichols Jennifer , Hoppler Stefan 
Published: October 2024

AbstractEmbryonic stem cell research has uncovered different requirements for WNT/β-catenin signalling in human naïve pluripotent cells compared to the mouse paradigm. It is therefore important to study WNT/β-catenin signalling directly in models of early human development. Since TCF/LEF factors mediate the regulation of target genes downstream of WNT/β-catenin signalling, we studied the expression and protein localisation of the four TCF/LEF genes by analysingin vitro“snapshots” of human development, leveraging naïve and primed pluripotent cells as well as extraembryonic and early embryonic cell lineages. Strikingly, we comprehensively confirm clear differences between mouse and human pluripotent stem cells, suggesting species-specific requirements for WNT signalling that may reflect differences in states of pluripotency. Human naïve ES cells express very low TCF7L1, unlike their mouse counterparts. TCF7L2 is robustly expressed in human naïve ES-derived trophectoderm cells. In human primed pluripotent stem cells, activation of WNT/β-Catenin signalling is required to induce expression of bothTCF7andLEF1, concomitant with hallmark gastrulation markers. This expression of human TCF/LEF genes benchmarks differential requirements for WNT/β-catenin signalling throughout early human embryo development that requires further investigation.
Amplification of disease by nutrient addition: Testing mechanisms from individual to community levels
Authors: Green Elizabeth T. , Heckman Robert W. , Mitchell Charles E. 
Published: October 2024

AbstractNutrient supply can amplify disease epidemics through mechanisms from individual to community levels. Within host individuals, nutrient addition can drive pathogen replication or growth. Across a host population, nutrient addition can drive disease transmission by increasing host growth and abundance relative to defense. Furthermore, such effects may be influenced by pathogen species interactions. Understanding how nutrients impact disease epidemics requires a framework that integrates these mechanisms across biological levels. To build such a framework, we conducted a field experiment in an old field on tall fescue,Lolium arundinaceum, and used structural equation models to integrate multiple hypothesized mechanisms. Nutrient addition (NPK fertilizer) increased brown patch disease but was best modeled as a direct path and not mediated by host abundance. To expand our framework, we also re-analyzed a previous experiment. That experiment reproduced the direct path from nutrients to disease, and added an indirect path mediated by host population abundance. Nutrient addition also increased foliar nitrogen, consistent with individual-level mechanism, but this did not increase disease. Brown patch decreased with burden of another disease, anthracnose, independently of nutrients. These results partially support both individual- and population-level hypotheses, emphasizing the importance of considering multiple biological levels underlying impacts of abiotic change.
RiboTag RNA Sequencing Identifies Local Translation of HSP70 In Astrocyte Endfeet After Cerebral Ischemia
Authors: Shim Bosung , Ciryam Prajwal , Tosun Cigdem , Serra Riccardo , Tsymbalyuk Natalia , Keledjian Kaspar , Gerzanich Volodymyr , Simard J. Marc 
Published: October 2024

AbstractBrain ischemia causes disruption in cerebral blood flow and blood-brain barrier (BBB) integrity which are normally maintained by the astrocyte endfeet. Emerging evidence points to dysregulation of the astrocyte translatome during ischemia, but its effects on the endfoot translatome are unknown. In this study, we aimed to investigate the early effects of ischemia on the astrocyte endfoot translatome in a rodent model of cerebral ischemia-reperfusion. To do so, we immunoprecipitated astrocyte-specific tagged ribosomes (RiboTag IP) from mechanically isolated brain microvessels. In mice subjected to middle cerebral artery occlusion and reperfusion and contralateral controls, we sequenced ribosome-bound RNAs from perivascular astrocyte endfeet and identified 205 genes that were differentially expressed in the translatome after ischemia. Pathways associated with the differential expressions included proteostasis, inflammation, cell cycle, and metabolism. Transcription factors whose targets were enriched amongst upregulated translating genes included HSF1, the master regulator of the heat shock response. The most highly upregulated genes in the translatome were HSF1-dependentHspa1aandHspa1b, which encode the inducible HSP70. We found that HSP70 is upregulated in astrocyte endfeet after ischemia, coinciding with an increase in ubiquitination across the proteome. These findings suggest a robust proteostasis response to proteotoxic stress in the endfoot translatome after ischemia. Modulating proteostasis in endfeet may be a strategy to preserve endfeet function and BBB integrity after ischemic stroke.
A Novel Genomic Rearrangement in theAmaranthus palmeriExtrachromosomal Circular DNA Provides Dual Herbicide Resistance to Glyphosate and Glufosinate
Authors: Carvalho-Moore Pâmela , Borgato Ednaldo A. , Cutti Luan , Porri Aimone , Meiners Ingo , Lerchl Jens , Norsworthy Jason K. , Patterson Eric L. 
Published: October 2024

AbstractAmplification of chloroplastic glutamine synthetase (GS2) has been characterized as one of the resistance mechanisms in glufosinate-resistantAmaranthus palmeriaccession (MSR2). Previously, the overamplification of the glyphosate-resistance gene, 5-enolpyruvylshikimate-3-phosphate (EPSPS), inA. palmeriwas determined to be driven by an extrachromosomal circular DNA (eccDNA). Here, a novel eccDNA is described that carries both glyphosate and glufosinate-ammonium target site due to co-duplication of their chromosomic native region, conferring resistance. BesidesEPSPS, the novel replicon has a region replaced by a fragment carrying theGS2isoforms (GS2.1andGS2.2) and other genes. The co-existence of eccDNA carrying onlyEPSPSwas confirmed in MSR2 samples harboring dual targeting eccDNA. The genomic structure ofGS2andEPSPSamplification was also assessed in a different glufosinate-resistantA. palmeriaccession (MSR1) along with MSR2. The accessions showed distinctGS2.1andGS2.2amplification patterns suggesting the existence of diverse replicons that were not assembled here. TheEPSPSwas amplified in both accessions, and a correlation was observed with theGS2isoforms in MSR2, further supporting the co-existence of these genes in the same replicon. These findings shed light on the complexity of eccDNA formation in plant systems, with the collection and accumulation of extra pieces of DNA.
Oxygen chemoreceptor inhibition by dopamine D2receptors in isolated zebrafish gills
Authors: Reed Maddison , Jonz Michael G. 
Published: October 2024

AbstractDopamine is an essential modulator of oxygen sensing and control of ventilation and was the first neurotransmitter described in the carotid body. Little is known of the evolutionary significance of dopamine in oxygen sensing, or whether it plays a similar role in anamniotes. In the model vertebrate, zebrafish (Danio rerio), presynaptic dopamine D2receptor expression was demonstrated in gill neuroepithelial cells (NECs)—analogues of mammalian oxygen chemoreceptors; however, a mechanism for dopamine and D2in oxygen sensing in the gills had not been defined. The present study tested the hypothesis that presynaptic D2receptors provide a feedback mechanism that attenuates the chemoreceptor response to hypoxia. Using an isolated gill preparation from Tg(elavl3:GCaMP6s) zebrafish, we measured hypoxia-induced changes in intracellular Ca2+concentration ([Ca2+]i) in NECs and postsynaptic neurons. Activation of D2with dopamine or specific D2agonist, quinpirole, decreased hypoxic responses in NECs; whereas D2antagonist, domperidone, had the opposite effect. Addition of SQ22536, an adenylyl cyclase (AC) inhibitor, decreased the effect of hypoxia on [Ca2+]i, similar to dopamine. Activation of AC by forskolin partially recovered the suppressive effect of dopamine on the Ca2+response to hypoxia. Further, we demonstrate that the response to hypoxia in postsynaptic sensory neurons was dependent upon innervation with NECs, and was subject to modulation by activation of presynaptic D2. Our results provide the first evidence of neurotransmission of the hypoxic signal at the NEC-nerve synapse in the gill and suggest that a presynaptic, modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.Key pointsFor the first time, we present an experimental model that permits imaging of intracellular Ca2+in identified vertebrate oxygen chemoreceptors using GCaMP in a whole/intact sensing organ.The hypoxic response of zebrafish chemoreceptors is attenuated by dopamine through a mechanism involving D2receptors and adenylyl cyclase.Zebrafish oxygen chemoreceptors send a hypoxic signal to postsynaptic (sensory) neurons.Postsynaptic neuronal responses to hypoxia are modulated by presynaptic D2receptors, suggesting a link between chemoreceptor inhibition by dopamine and modulation of the hypoxic ventilatory response.Our results suggests that a modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.