bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial sites of contact with the nucleus aid in chemotherapy evasion of glioblastoma cells
Authors: Strobbe Daniela , Bueno Mardja , De Vitis Claudia , Hassan Sarah , Faccenda Danilo , Bruqi Krenare , Romano Elena , Pedace Lucia , Yurchenko Andrey A. , Dhoot Gurtej K , Bistrot Ivi J , Klamt Fabio , Lenz Luana S. , Filippi–Chiela Eduardo Cremonese , D’Urso Pietro Ivo , Lally Imogen , Miele Eveline , Falasca Laura , Nikolaev Sergey , Mancini Rita , Roncaroli Federico , Lenz Guido , Campanella Michelangelo 
Published: August 2024

ABSTRACTGlioblastoma (GBM) is the most common form of a malignant primary brain tumour in adults for which therapeutic options are minimal. The rapid onset of the resistance mechanisms against the chemotherapeutic agent Temozolomide (TMZ), the first line of pharmacological care for patients, prevents the long-term validity of this approach. The underpinning biology for this remains poorly understood thus compromising the efficacy of this approach. The Translocator Protein (TSPO) is an 18kDa ubiquitous cholesterol-binding molecule on the outer membrane of mitochondria (OMM). Upregulated in cancers TSPO is required to form contacts between mitochondria and the nucleus termed: Nucleus Associated Mitochondria (NAM). In GBM tissues as well as in 2D and 3D cell cultures we assayed patterns of TSPO expression (i), autophagy/mitophagy (ii), transcription factors (iii) and susceptibility to TMZ-induced demise (iv). Confocal and ultrastructural imaging detailed the organization and redistribution of the mitochondrial network (v).Our findings show that TMZ exploits mitochondria via TSPO to aid the formation of NAM which couples the expression of the nuclear transcription factor Sterol regulatory element-binding transcription factor 1 (SREBP1) and the stabilization of YAP/TAZ.Pharmacological modulation of TSPO counteracts all the above and re-instates susceptibility to TMZ-induced demise. NAM is therefore proposed as a variable in the engagement and execution of pro-survival mechanisms in GBM thus offering a means to both insight into the pathophysiology of this disease and offer novel therapeutic strategies.Key PointsTMZ exploits TSPO to curb mitochondrial quality control in glioblastoma cells.TMZ-mediated MRR is associated with the relocation of mitochondria to the nucleus and modulation of transcriptional factors involved in cholesterol metabolism and adaptation to aggressive growth.TSPO represents a pharmacological target to revert chemoresistance in glioblastoma cells.Importance of the StudyThis study elucidates a mitochondrion-driven mechanism of chemoresistance in human glioblastoma cells, which depends on the mitochondrial translocator protein TSPO. The administration of TSPO ligands restores susceptibility to TMZ by influencing the dynamics of transcriptional factors associated with cholesterol metabolism and mechanical transduction.
Developmental trajectory of thalamus topography during the late preterm and perinatal period in normal development, after premature birth and in congenital heart defects
Authors: Ji Hui , Wu Zhexin , Speckert Anna , Tuura Ruth , Hagmann Cornelia , Latal Beatrice , Knirsch Walter , Jakab Andras 
Published: August 2024

The thalamus plays a critical role in neural circuit maturation and brain connectivity. It is well known to show a characteristic topographical organization of local and long-range connectivity, yet developmental changes in this topography remains incompletely understood. Our study aims to first validate the use of diffusion MRI for the topographic delineation of thalamic subdivisions (nuclei), to characterize thalamic topography during development and assess the impact of congenital heart defects (CHD) on thalamus development.We used local fiber orientation distribution functions, derived from diffusion MRI (dMRI) data, to subdivide the thalamus into seven clusters. We first evaluated the within-subject reproducibility of a dMRI based clustering method across 30 adults scan-rescan datasets (n = 30) using K-means clustering, achieving reproducible segmentation of the thalamus into seven parts. This was applied to a large developmental cohort comprising normally developing infants from the term-born dHCP cohort (n = 68, gestational age [GW] at MRI scan ranging from 37.4 to 44.8 weeks, mean ± SD: 41.4 ± 2.1 weeks) and the Zurich cohort (n = 42, GW at MRI ranging from 39.0 to 48.7 weeks, mean ± SD: 42.55 ± 1.96 weeks). The cohort also included preterm-born dHCP cohort (n = 48, GW at MRI scan ranging from 29.3 to 37.4 corrected gestational weeks, mean ± SD: 34.4 ± 2.02 weeks) and one case of a postmortem fetal specimen (n = 1, GW at MRI = 21 weeks). Cluster volumes were analyzed as a function of age using multivariate linear regression. Differences in cluster volumes between control subjects (n = 42, GW at MRI ranging from 39.0 to 48.7 weeks, mean ± SD: 42.55 ± 1.96 weeks) and newborns with congenital heart disease (CHD) (n = 49, GW at MRI ranging from 37.6 to 42.9 weeks, mean ± SD: 40.23 ± 1.30 weeks) were analyzed using variance analysis, controlling for sex and age at MRI scan.The clustering on average had a within-subject overlap of 0.811 (Dice overlap metric). While absolute thalamus volumes increased with age, their relative volumes remained stable in the studied developmental period. CHD infants shown reduced absolute volumes in six of the seven thalamic nuclei, with significant increasing in the relative volume of the cluster overlapping with the mediodorsal nucleus.While the perinatal period comprises rapid developmental events including the maturation of white matter, the topography of thalamic circuitry remains stable. Our study highlights alterations in thalamic topology and potential impacts on brain connectivity in CHD infants. By leveraging local diffusion properties from diffusion MRI, our validated segmentation technique offers a robust, data-centric approach to thalamic delineation.
Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial
Authors: Costa Kevin D. , Wong Andy O. T. , Mak Suet Yee , Roberts Erin G. , Keung Wendy , Correia Claudia , Walentinsson Anna , Christoffersson Jonas , Cheung Alice , Lieu Deborah K. , Jennbacken Karin , Wang Qing-Dong , Hajjar Roger J. , Li Ronald A. 
Published: August 2024

AbstractAimsHeart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing. Aligned with FDA Modernization Act 2.0, we aimed to create the firstin vitrohuman-specific mini-heart models of HFpEF, and to test the efficacy of a candidate gene therapy to improve cardiac kinetics and correct the disease phenotype.Methods and ResultsHealthy human pluripotent stem cell-derived ventricular cardiomyocytes were used to bioengineer beating cardiac tissue strips and pumping cardiac chambers. When conditioned with transforming growth factor-β1 and endothelin-1, these mini-heart models exhibited signature disease phenotypes of significantly elevated diastolic force and tissue stiffness, and slowed contraction and relaxation kinetics, with no significant deficit in systolic force or ejection fraction versus unconditioned controls. Bioinformatic analysis of bulk RNA sequencing data from HFpEF mini-heart models and patient ventricular samples identified downregulation of SERCA2a of the calcium signalling pathway as a key differentially expressed gene. After dosage optimization, AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-Hearts.ConclusionsThese findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation. We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.Translational PerspectiveHeart failure with preserved ejection fraction (HFpEF) is a significant and growing global health concern lacking disease-modifying therapeutic options, reflecting inadequate preclinical models of the disease. Aligned with FDA Modernization Act 2.0, we created the firstin vitrohuman-specific mini-heart models of HFpEF, demonstrated phenotypic disease characteristics of elevated stiffness and slowed kinetics, showed transcriptomic consistency with HFpEF patient data, identified SERCA2a as a key downregulated gene, performed dosing titration of SERCA2a gene therapy, and showed improvement of cardiac kinetics post-treatment. The findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF.
Multiple polyploidizations inArabidopsis lyratastabilized by long-range adaptive introgression across Eurasia
Authors: Scott Alison D. , Kolesnikova Uliana , Glushkevich Anna , Steinmann Laura , Tikhomirov Nikita , Pfordt Ursula , Bohutínská Magdalena , Burns Robin , Seregin Alexey P. , Kolar Filip , Schmickl Roswitha , Novikova Polina Yu. 
Published: August 2024

AbstractAbundance of polyploidy varies across lineages, evolutionary time and geography, suggesting both genetics and environment play a role in polyploid persistence.Arabidopsis lyrataappears to be the most polyploidy-rich species-complex in theArabidopsisgenus, with multiple origins of autotetraploidy. This is revealed by genomic data from over 400 samples across Eurasia. We found over 30 previously undescribed autotetraploid populations in Siberia with a minimum of two separate origins, independent of those previously reported in Central Europe. The establishment of Siberian tetraploids is mediated by meiotic adaptation at the same genes as in European tetraploidA. lyrataandArabidopsis arenosa,despite high divergence and geographical separation. Haplotype analysis based on synthetic long-read assemblies supports the long-range introgression of adaptive alleles from the tetraploid interspecific pool of EuropeanA. lyrataandA. arenosato tetraploid SiberianA. lyrata. Once evolved, adaptation to polyploidy promotes the establishment of new polyploid lineages through adaptive inter– and intraspecific introgression.
NEBULA101: an open dataset for the study of language aptitude in behaviour, brain structure and function
Authors: Rampinini Alessandra , Balboni Irene , Kepinska Olga , Berthele Raphael , Golestani Narly 
Published: August 2024

AbstractThis paper introduces the “NEBULA101 - Neuro-behavioural Understanding of Language Aptitude” dataset, which comprises behavioural and brain imaging data from 101 healthy adults to examine individual differences in language and cognition. Human language, a multifaceted behaviour, varies significantly among individuals, at different processing levels. Recent advances in cognitive science have embraced an integrated approach, combining behavioural and brain studies to explore these differences comprehensively. The NEBULA101 dataset offers brain structural, diffusion-weighted, task-based and resting-state MRI data, alongside extensive linguistic and non-linguistic behavioural measures to explore the complex interaction of language and cognition in a highly multilingual sample. By sharing this multimodal dataset, we hope to promote research on the neuroscience of language, cognition and multilingualism, enabling the field to deepen its understanding of the multivariate panorama of individual differences and ultimately contributing to open science.
SCRATCH: A programmable, open-hardware, benchtop robot that automatically scratches cultured tissues to investigate cell migration, healing, and tissue sculpting
Authors: Lin Yubin , Silverman-Dultz Alexander , Bailey Madeline , Cohen Daniel J. 
Published: August 2024

AbstractDespite the widespread popularity of the ‘scratch assay’, where a pipette is dragged through cultured tissue to create an injury gap to study cell migration and healing, the manual nature of the assay carries significant drawbacks. So much of the process depends on individual manual technique, which can complicate quantification, reduce throughput, and limit the versatility and reproducibility of the approach. Here, we present a truly open-source, low-cost, accessible, and robotic scratching platform that addresses all of the core issues. Compatible with nearly all standard cell culture dishes and usable directly in a sterile culture hood, our robot makes highly reproducible scratches in a variety of complex cultured tissues with high throughput. Moreover, we demonstrate how scratching can be programmed to precisely remove areas of tissue to sculpt arbitrary tissue and wound shapes, as well as enable truly complex co-culture experiments. This system significantly improves the usefulness of the conventional scratch assay, and opens up new possibilities in complex tissue engineering and cell biological assays for realistic wound healing and migration research.
EEG During Dynamic Facial Emotion Processing Reveals Neural Activity Patterns Associated with Autistic Traits in Children
Authors: Hill Aron T. , Ford Talitha C. , Bailey Neil W. , Lum Jarrad A. G. , Bigelow Felicity J. , Oberman Lindsay M. , Enticott Peter G. 
Published: August 2024

AbstractAltered brain connectivity and atypical neural oscillations have been observed in autism, yet their relationship with autistic traits in non-clinical populations remains underexplored. Here, we employ electroencephalography (EEG) to examine functional connectivity, oscillatory power, and broadband aperiodic activity during a dynamic facial emotion processing (FEP) task in 101 typically developing children aged 4-12 years. We investigate associations between these electrophysiological measures of brain dynamics and autistic traits as assessed by the Social Responsiveness Scale, 2nd Edition (SRS-2). Our results revealed that increased FEP-related connectivity across theta (4-7 Hz) and beta (13-30 Hz) frequencies correlated positively with higher SRS-2 scores, predominantly in right-lateralized (theta) and bilateral (beta) cortical networks. Additionally, a steeper 1/f-like aperiodic slope (spectral exponent) across fronto-central electrodes was associated with higher SRS-2 scores. Greater aperiodic-adjusted theta and alpha oscillatory power further correlated with both higher SRS-2 scores and steeper aperiodic slopes. These findings underscore important links between FEP-related brain dynamics and autistic traits in typically developing children. Future work could extend these findings to assess these EEG-derived markers as potential mechanisms underlying behavioural difficulties in autism.
Effects of connectivity hyperalignment (CHA) on estimated brain network properties: from coarse-scale to fine-scale
Authors: Farahani Farzad V. , Nebel Mary Beth , Wager Tor D. , Lindquist Martin A. 
Published: August 2024

AbstractRecent gains in functional magnetic resonance imaging (fMRI) studies have been driven by increasingly sophisticated statistical and computational techniques and the ability to capture brain data at finer spatial and temporal resolution. These advances allow researchers to develop population-level models of the functional brain representations underlying behavior, performance, clinical status, and prognosis. However, even following conventional preprocessing pipelines, considerable inter-individual disparities in functional localization persist, posing a hurdle to performing compelling population-level inference. Persistent misalignment in functional topography after registration and spatial normalization will reduce power in developing predictive models and biomarkers, reduce the specificity of estimated brain responses and patterns, and provide misleading results on local neural representations and individual differences. This study aims to determine how connectivity hyperalignment (CHA)—an analytic approach for handling functional misalignment—can change estimated functional brain network topologies at various spatial scales from the coarsest set of parcels down to the vertex-level scale. The findings highlight the role of CHA in improving inter-subject similarities, while retaining individual-specific information and idiosyncrasies at finer spatial granularities. This highlights the potential for fine-grained connectivity analysis using this approach to reveal previously unexplored facets of brain structure and function.
Are super-predators also super-scary? A systematic review and meta-analysis of animal responses to human interactions
Authors: Dsouza Shawn , Shanker Kartik , Thaker Maria 
Published: August 2024

AbstractHuman induced rapid environmental change has been recognized as a global threat to natural systems and the organisms that inhabit them. Human hunters and fishers interact with animals in natural spaces as predators, and are more effective in capturing prey and reducing populations than natural predators overall. On the other hand, seemingly benign interactions with humans, such as tourism, may also be perceived as threatening and have negative impacts on animal populations. Here, we provide a synthesis of the current knowledge of the combined effects of lethal and non-lethal human interactions on the behavioural responses of animals in natural spaces. We conducted a systematic review and meta-analysis of literature published over the past three decades, and built a dataset to determine the relative effect of lethal and non-lethal human interactions on foraging, vigilance, and movement behaviors of wild animals. Lethal human interactions included hunting, fishing, and retaliatory killing in response to conflict, and non-lethal human interactions were distinguished as active (snorkeling, scuba diving, pedestrians, hiking, and tourists) or passive (roads, human settlements, sonar, and boat traffic). We also considered how the trophic level of the species and body size could influence the effect of human interactions on animal behavior. Our findings show that lethal human interactions had a significant effect on the behaviors of animals, causing animals that are actively hunted by humans to increase vigilance, reduce foraging, and alter movements. Both active and passive non-lethal interactions had weaker and non-significant effects on altering these behaviours of animals. Overall, our meta-analysis shows that the impact of non-lethal human activities in eliciting fear-driven behavioural changes in prey does not seem to have broad empirical support. It also suggests that the intensity of effect of the “human super-predator” may depend on the trophic level of affected species, or the history of the human-animal interactions in that landscape, In order to understand the nuances of these effects, systematic studies across more species and geographic regions are needed.
Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I
Authors: Neumann Bryan , McCarthy Stephen , Gonen Shane 
Published: August 2024

AbstractVoltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaVisoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarised potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-NaV1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDIwas unresolvable. We find that Protoxin-I binds to and displaces the VSDIIS3-S4 linker, hindering translocation of the S4IIhelix during activation.
Exploration of Natural Products for Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia Through Ligand-Based Pharmacophore Screening and Molecular Dynamic Simulation Approaches
Authors: Das Uddalak , Regati Dheemanth , Kumar Jitendra , Sowdhamini R. 
Published: August 2024

ABSTRACTBackgroundMutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are prevalent drivers of acute myeloid leukemia (AML). While targeted therapies exist, resistance can emerge. This study explored the potential of natural products to identify novel dual IDH inhibitors.MethodsIn-silicoscreening of the COCONUT database was performed using Lipinski’s Rule of Five. Pharmacophore modelling identified crucial features for IDH binding. Docking simulations with Glide (Schrödinger) assessed binding affinity, followed by MM-GBSA calculations for free energy estimation. The most promising candidate underwent ADME/T and toxicity analysis. Finally, molecular dynamics (MD) simulations evaluated the stability of protein-ligand complexes and binding interactions, followed by trajectory analysis using DCCM and PCA.ResultsThe study identified Ternstroside D (CNP0166496) as a potential dual inhibitor for IDH1 and IDH2 mutations. Docking simulations and MM-GBSA calculations predicted favourable binding affinities. MD simulations revealed stable protein-ligand complexes, and in-silico ADME/T analysis suggested good drug-like properties and a favorable safety profile for CNP0166496.ConclusionThisin-silicostudy provides compelling evidence for Ternstroside D (CNP0166496) as a promising dual inhibitor for IDH1 and IDH2 mutations in AML. Furtherin-vitroandin-vivostudies are warranted to validate these findings.