bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic Norm-Based Coding of Vocal Identity in the Primate Auditory Cortex
Authors: Esposito Yoan , Boë Louis-Jean , Trapeau Régis , Renaud Luc , Brochier Thomas , Giamundo Margherita , Belin Pascal 
Published: January 2025

AbstractVoice identity recognition is vital for social communication, yet its neural encoding mechanisms remain unclear. We investigated whether neurons in the anterior temporal voice area (aTVA) of macaques use norm-based coding (NBC), similar to face encoding in vision. Using synthetic vocalizations morphed along identity trajectories, we found that early neuronal responses (100 to 150 ms) exhibited V-shaped tuning, with minimal activity for the average voice and increased responses for extreme identities. Later (200 ms), a distinct rebound in activity for the average voice emerged, driven by a unique subpopulation. These results highlight a dynamic, multi-stage encoding strategy, extending NBC principles to auditory processing.
Neural correlates of approach and avoidance tendencies toward physical activity and sedentary stimuli: An fMRI study
Authors: Cheval Boris , Ceravolo Leonardo , Igloi Kinga , Sander David , Zimmermann Myriam , van Ruitenbeek Peter , Boisgontier Matthieu P. 
Published: January 2025

AbstractAutomatic tendencies toward physical activity and sedentary stimuli are involved in the regulation of physical activity behavior. However, the brain regions underlying these automatic tendencies remain largely unknown. Here, we used an approach-avoidance task and magnetic resonance imaging (MRI) in 42 healthy young adults to investigate whether cortical and subcortical brain regions underpinning reward processing and executive function are associated with these tendencies. At the behavioral level, results showed more errors in avoidance behavior following sedentary stimuli than physical activity stimuli. At the brain level, avoidance behavior following sedentary stimuli was associated with more activation of the motor control network (dorsolateral-prefrontal cortex, primary and secondary motor cortices, somatosensory cortex). In addition, increased activation of the bilateral parahippocampal gyrus — and structural deformation of the right hippocampus - were associated with a tendency toward approaching sedentary stimuli. Together, these results suggest that avoiding sedentary stimuli requires higher levels of behavioral control than avoiding physical activity stimuli.
The dependency of TMS-evoked potentials on electric-field orientation in the cortex
Authors: Granö Ida , Mutanen Tuomas P. , Nieminen Aino E. , Nieminen Jaakko O. , Souza Victor H. , Ilmoniemi Risto J. , Lioumis Pantelis 
Published: January 2025

AbstractTranscranial magnetic stimulation (TMS) stimulates the brain by electromagnetic induction. The outcome depends on multiple stimulation parameters such as the induced electric-field pattern (in particular, the location of the peak field and its orientation), intensity and timing. However, it is not clear how the TMS-evoked responses are affected by all the stimulation parameters. This study elucidates the dependency of the TMS-evoked electroencephalography (EEG) responses on the orientation of the stimulating electric field. To achieve this, we analysed a dataset from six subjects who were given pulses with 36 stimulus orientations to the pre-supplementary motor area (pre-SMA). The TMS-evoked potentials (TEPs) and induced oscillations were analysed with cluster-based statistics. Source estimation was performed to assess the effects of stimulus orientation on the TMS-evoked signal propagation. The amplitudes of the early peaks (20 and 40 ms after the TMS pulse) strongly depended on the electric field orientation. Our analysis suggested orientation dependency up to 100 ms post-stimulus in most subjects, indicating changes in stimulation efficacy and potential changes in signal propagation from the stimulated site. These results suggest that different orientations may perturb different networks. Thus, the orientation is a crucial parameter for the stimulation outcome and should be adjusted according to the cortical network under investigation.
Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells
Authors: Cooke Sean F. , Wright Thomas A. , Lappin Gillian , Kyurkchieva Elka , Sin Yuan Yan , Ling Jiayue , Zorn Alina , O’Gorman Bria , Banyard William , Chang Chih-Jung , Wheadon Helen , Huang Danny T. , Baillie George S. , Blair Connor M. 
Published: January 2025

AbstractNovel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represents an increasingly attractive therapeutic strategy to treating solid and haematological cancers that are depdendent upon MDM2/MDMX, regardless of TP53 mutational status. Utilising a novel first-in-class cell-penetrating peptide disruptor of MDM2 homo- and heterodimerisation (DRx-098D), we demonstrate the anti-proliferative effect of blocking MDM2 dimerisation against a a panel of human cancer cell lines that are TP53 wild-type, mutant or null. DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. Idasanutlin (a Phase III clinical candidate MDM2-p53 small molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting MDM2 dimerisation in TP53 wild-type and mutant cancers.
Manual versus automatic annotation of transposable elements: case studies inDrosophila melanogasterandAedes albopictus, balancing accuracy and biological relevance
Authors: Carrasco-Valenzuela Tomas , Marino Alba , Storer Jessica M. , Bonnici Iago , Mazzoni Camila J. , Fontaine Michael C. , Haudry Annabelle , Boulesteix Matthieu , Fiston-Lavier Anna-Sophie 
Published: January 2025

AbstractTransposable elements (TEs) play a pivotal role in genome evolution, yet their detection and annotation remain challenging due to the limitations of current methods. Manual curation is considered the gold standard for generating TE libraries, particularly for TE-focused studies, although it requires extensive training and time. With the rapid increase in the number of genome assembly publications and the growing need for large-scale comparative analyses, automated software for TE annotation has become indispensable. This study compares manual and automated approaches to TE detection and annotation, focusing on two species:Drosophila melanogasterandAedes albopictus.InD. melanogaster, a species with a well-annotated TE repertoire and a smaller genome, the differences between manual curation (MCTE) and automated annotation (ATTE) are relatively minor. However, significant differences arise when analysingAe. albopictus, a species with a relatively large genome and high TE diversity. While automated methods identified a greater number of TEs, including many smaller and fragmented elements, manual curation provided more detailed classifications and, on average, larger consensi. Automated pipelines offer a viable alternative for genome-wide analyses such as TE content estimation, particularly when time and resources are limited. However, caution is advised when interpreting results, as finer details of TE dynamics may be overlooked.This study highlights that the choice of annotation method depends on the intended analysis. Manual curation is more suitable for TE population genomics and studies focusing on recent transposable element activity, whereas automated methods are appropriate for larger comparative analyses or genome assembly projects. Both methods have strengths and limitations, and understanding the specific features of the genome and repeatome under study is essential for selecting the appropriate approach.
Pre-clinical validation of in vitro engineered but cell-free human tissue grafts for skeletal regeneration
Authors: Garcia Alejandro Garcia , Prithiviraj Sujeethkumar , Raina Deepak B. , Schmidt Tobias , Baudet-Quintino Aurelie , Anton Sara Gonzalez , Cajal Laura Rabanal , Kahn Robin , Tägil Magnus , Bourgine Paul 
Published: January 2025

AbstractTissue engineering strategies predominantly consist in the autologous generation of living substitutes capable of restoring damaged body parts. Persisting challenges with patient-specific approaches include an inconsistent performance, high costs and delayed graft availability. Towards developing a one-for-all solution, a more attractive paradigm lies in the exploitation of dedicated cell lines for the fabrication of human tissue grafts. Following decellularization, this new class of biomaterials relies on the sole extracellular matrix scaffold and embedded growth factors instructing endogenous repair. This conceptual approach was previously validated by manufacturing human cartilage using a custom mesenchymal line, exhibiting remarkable osteoinductive capacity following lyophilization. However, key criteria to ensure clinical translation include a proper decellularization as well as stringent assessment of both immunogenicity and regenerative performance. Here, we report the engineering and decellularization of human cartilage tissue with minimal matrix impairment. Ectopic evaluation in immunocompetent and immunocompromised animals reveal preserved osteoinductivity which correlates with M0 to M2 polarization from Day 7 post-implantation. By establishing in vitro human allogeneic co-culture models, we evidenced the immuno-regulatory properties of cell-free human cartilages, suppressing T cell activation upon mounting of an immune response by activated macrophages, monocytes and dendritic cells. Last, the regenerative performance was stringently assessed in a competent rat orthotopic models whereby human cartilage grafts fully restored critical-sized femoral defects within six weeks, achieving native bone-like biomechanical properties by twelve weeks. Taken together, our study compiles safety and efficacy pre-requisites towards a first-in-human trial for engineered and decellularized human tissue grafts.
An expanded palette of bright and photostable organellar Ca2+sensors
Authors: Moret Agathe , Farrants Helen , Fan Ruolin , Zingg Kelsey , Gee Christine E. , Oertner Thomas G. , Rangaraju Vidhya , Schreiter Eric R. , de Juan-Sanz Jaime 
Published: January 2025

AbstractThe use of fluorescent sensors for functional imaging has revolutionized the study of organellar Ca2+signaling. However, understanding the dynamic interplay between intracellular Ca2+sinks and sources requires bright, photostable and multiplexed measurements in each signaling compartment of interest to dissect the origins and destinations of Ca2+fluxes. We introduce a new toolkit of chemigenetic indicators based on HaloCaMP, optimized to report Ca2+dynamics in the endoplasmic reticulum (ER) and mitochondria of mammalian cells and neurons. Both ER-HaloCaMP and Mito-HaloCaMP present high brightness and responsiveness, and the use of different HaloTag ligands enables tunable red and far-red emission when quantifying organelle Ca2+dynamics, expanding significantly multiplexing capacities of Ca2+signaling. The improved brightness of ER-HaloCaMP using either red or far-red HaloTag ligands enabled measuring ER Ca2+fluxes in axons of neurons, in which the ER is formed by a tiny tubule of 30-60 nanometers of diameter that impeded measurements with previous red ER Ca2+sensors. When measuring ER Ca2+fluxes in activated neuronal dendritic spines of cultured neurons, ER-HaloCaMP presented increased photostability compared to the gold-standard ER Ca2+sensor in the field, ER-GCaMP6-210, while presenting the same responsiveness. On the other hand, Mito-HaloCaMP presented higher responsiveness than current red sensors, and enabled the first measurements of mitochondrial Ca2+signaling in far-red in cell lines and primary neurons. As a proof-of-concept, we used 3-plex multiplexing to quantify interorganellar Ca2+signaling. We show that effective transfer of Ca2+from the ER to mitochondria depends on the ER releasing a critical amount of Ca2+. When this threshold is not met, the mobilized Ca2+is diverted to the cytosol instead. Our new toolkit provides an expanded palette of bright, photostable and responsive organellar Ca2+sensors, which will facilitate future studies of intracellular Ca2+signaling.
Endogenously expressed P2X5 includes a proportion of isoforms or transcript variants sensitive to extracellular ATP
Authors: Yang Xiao-Na , Wang Dong-Ping , Shen Chen-Hui , Xi-Chen  , Yang Hui , Zhou Xing , Guo Chang-Run , Tian Yun , Zhu Michael X. , Yu Ye 
Published: January 2025

AbstractThe P2X receptor family comprises ATP-gated non-selective cation channels central to physiological processes across the nervous, immune, cardiovascular, respiratory, and reproductive systems. While P2X1, P2X2, P2X3, P2X4, and P2X7 are well-established as ATP-sensitive, P2X5 isoforms and transcript variants (TVs) have traditionally been considered ATP-insensitive, limiting their functional exploration. This study identifies previously overlooked ATP-sensitive P2X5 isoforms across diverse species. Through gene profiling and next-generation sequencing (NGS), we found that the zfP2X5TV2isoform dominates ATP-sensitive forms in zebrafish. In mice, ATP-sensitive mP2X5G317(mP2X5.1) comprises ∼90% of transcripts, while in rats, exon 3-containing rP2X5F191accounts for over 70%. In human cell lines, ATP-sensitive isoforms retaining exons 3, 7, and 10 represent ∼15-30% of P2X5 transcripts. RNA-seq from human tissues confirms frequent retention of exons 3 and 7 and polymorphic exon 10 expression. ATP-sensitive P2X5 variants were also identified in chickens, bullfrogs, dogs, cows, and naked mole-rats. These findings challenge the prevailing assumption of ATP-insensitivity, highlighting the need to reassess P2X5’s roles in physiological and pathological contexts.
The Neurocognitive efficiency score: Derivation, validation, and application of a novel combination of concurrent electrophysiological and behavioral data
Authors: Wenger Michael J. , Townsend James T. , Newbolds Sarah F. 
Published: January 2025

AbstractPerceptual and cognitive work require the expenditure of brain energy, and the efficiency of that energy expenditure can vary as a function of a range of exogenous and endogenous factors. The same is true for physical work, and tools have been developed to quantify energetic efficiency in the performance of physical work. The same is not true for the study of perceptual and cognitive work. We here draw on two lines of research—the formal characterization of workload capacity in perception and cognition, and the study of physical work—to propose a novel measure of neurocognitive efficiency. This neurocognitive efficiency score (NES) combines reaction time data with measures on concurrently acquired electroencephalographic (EEG) data to form a ratio that can be interpreted in terms of work accomplished relative to energy. We consider three measures on the EEG and show that one of them—global field power (GFP)—evidences a strong relationship to measures of metabolic energy expended. We then show how the NES can provide insights into differences in perceptual performance as a function of biological state. We argue that the NES has the potential for a wide range of applications in the study of perception and cognition in the context of factors including (but not limited to) aging, disease, stress, and differences in levels of expertise.
ANGPTL6 variant induces cerebral vascular dysfunction and predisposes to intracranial aneurysm in mice
Authors: Baron-Menguy Céline , Freneau Milène , Mrad Mary-Adel , Lebot Corentin , Rio Marc , L’allinec Vincent , Quillard Thibaut , Desal Hubert , Redon Richard , Bourcier Romain , Vion Anne-Clémence , Loirand Gervaise 
Published: January 2025

AbstractBackgroundIntracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal sub-arachnoid hemorrhage. Pathophysiological mechanisms responsible for AI remains largely unknown, but increasing evidence suggest that genetic susceptibility plays a predominant role. We recently identified a rare nonsense variant inANGPTL6gene that prevented angiopoietin-like 6 (ANGPTL6) secretion and predisposed to IA. The aim of this study is now to understand why the ANGPTL6 variant predisposes to IA.MethodsAngptl6-knock in mice were generated by homologous recombination. Cerebral arteries of the circle of Willis have been analyzed under basal and hemodynamic overload conditions. Functional properties of cerebral arteries have been analyzed by pressure arteriography. Effect of recombinant ANGPTL6 have been assessed on vascular smooth muscle cells and ANGPTL6 partners have been analyzed by surface plasmon resonance.ResultsAngptl6-knock in mice display endothelial dysfunction expressed by reduced NO production in response to flow in cerebral arteries. They present exaggerated dilatation of cerebral arteries under hypertensive stress, and aggravated wall damage and aneurysmal remodeling of the intima and media at arterial bifurcations of the circle of Willis under hemodynamic overload. Matrix bound ANGPTL6 decreased VSMC migration and increased adhesion and FAK signaling activation, without affecting VSMC phenotype. Surface plasmon resonance analyses identified αvβ5 integrin as a new ANPTL6 receptor.ConclusionsAngptl6-knock in mice mimicked the main features of IA in humans. ANGPTL6 appears to be an extracellular matrix component regulating vascular cell function, which may be involved in mechanosensing and generating adapted vascular cell responses to hemodynamic stress. Non-secreted ANGPTL6 variants would result in the loss of this function, thus favoring IA under conditions of hemodynamic overload.
Subthalamic Signature of Freezing of Gait in Parkinson’s Disease
Authors: Collomb-Clerc Antoine , Yeche Mathieu , Demain Adèle , Hamme Angèle Van , Olivier Claire , Belaid Hayat , Ziri Déborah , Derrey Stéphane , Fernandez-Vidal Sara , Lehongre Katia , Karachi Carine , Lau Brian , Welter Marie-Laure 
Published: January 2025

AbstractFreezing of gait (FOG) is a significant disability in Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) only partially alleviates it, with approximately one-third of patients experiencing worsening FOG within a year after surgery. The precise role of STN dysfunction in gait disabilities and FOG remains not fully elucidated. To investigate this, we recorded gait and STN local field potential (LFP) activity in 38 PD patients, both Off and On dopamine medication. Our analysis focused on the relationship between gait performance and STN neuronal activity, particularly examining differences in LFP activity across the posterior-sensorimotor and central-associative regions of the STN. When Off dopamine medication, 12 patients experienced FOG during recordings, with a total of 263 FOG episodes documented. Even in trials without FOG episodes, these patients exhibited altered gait initiation strategies, prioritizing stepping rhythm to manage balance and initiate walking. In contrast, non-FOG patients maintained a higher walking pace. STN activity patterns revealed key differences. In FOG patients, weaker STN alpha/low beta band activity in the STN was associated with walking pace, while stronger decreased low beta band activity correlated with rhythm and balance control. This low beta band association extended from the posterior-sensorimotor to the central-associative STN. In contrast, non-FOG patients showed a more restricted relationship between low beta band activity and gait performance, confined to the posterior STN. As stepping rhythm deteriorated further in FOG patients, FOG episodes occurred. FOG episodes were preceeded by a significant positive relationship between high beta power and rhythm restricted to the posterior STN, with a reverse negative relationship with pace, and a disruption in low beta desynchronization across both posterior and central STN regions. Dopamine medication significantly improved gait patterns, and partially restored STN neuronal activity, reducing differences between FOG and non-FOG patients. These findings differentiate two FOG states, i.e. predisposition and occurrence, each associated with distinct gait initiation strategies and STN activity patterns. They suggest distinct pathophysiological roles of low and high beta band STN activity within specific STN regions in regulating gait and FOG. These findings provide key insights for refining targeted DBS therapies.
Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting
Authors: Yadollahi P. , McCord K.A. , Li Y. , Dayoub H. , Saab K. , Essien F. , Hyslop S. , Kan E. , Ahmed K.M. , Kirby P. R. , Putluri V. , Ambati C.S.R , Kami Reddy K.R. , Castro P. , Skinner H.D. , Coarfa C. , Decker W.K. , Osman A.A , Patel R. , Myers J.N. , Lai S.Y. , Putluri N. , Johnson F.M. , Frederick M.J. , Hudson W.H. , Sandulache V.C. 
Published: January 2025

AbstractBackgroundFor patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g.,NOTCH1mutations).PurposeWe evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC.MethodsWe measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCsin vitroand tested efficacyin vivoin subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics.ResultsThe PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in anin vivoshRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T lymphocytes.ConclusionOur findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC.Statement of translational relevanceCisplatin resistance, whether intrinsic or acquired, translates to treatment failure and nearly universal death in head and neck squamous cell carcinoma (HNSCC). However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease.