bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile
Authors: Burban Audrey , Tessier Cloe , Pinglaut Mathis , Guyon Joris , Galvis Johanna , Dartigues Benjamin , Toujas Maxime , Larroquette Mathieu , Luchman H Artee , Weiss Samuel , Nicot Nathalie , Klink Barbara , Nikolski Macha , Brisson Lucie , Mathivet Thomas , Bikfalvi Andreas , Daubon Thomas , Sharanek Ahmad 
Published: January 2024

AbstractGlioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employedin vivopharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies in mice revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.
Domain-general cognitive control processes in bilingual switching: evidence from midfrontal theta oscillations
Authors: Cui Ningjing , Piai Vitoria , Zheng Xiaochen Y. 
Published: January 2024

AbstractLanguage control in bilingual speakers is thought to be implicated in effectively switching between languages, inhibiting the non-intended language, and continuously monitoring what to say and what has been said. It has been a matter of controversy concerning whether language control operates in a comparable manner to cognitive control processes in non-linguistic domains (domain-general) or if it is exclusive to language processing (domain-specific). As midfrontal theta oscillations have been considered as an index of cognitive control, examining whether a midfrontal theta effect is evident in tasks requiring bilingual control could bring new insights to the ongoing debate. To this end, we reanalysed the EEG data from two previous bilingual production studies where Dutch-English bilinguals named pictures based on colour cues. Specifically, we focused on three fundamental control processes in bilingual production: switching between languages, inhibition of the nontarget language, and monitoring of speech errors. Theta power increase was observed in switch trials compared to repeat trials, with a midfrontal scalp distribution. However, this midfrontal theta effect was absent in switch trials following a short sequence of same-language trials compared to a long sequence, suggesting a missing modulation of inhibitory control. Similarly, increased midfrontal theta power was observed when participants failed to switch to the intended language compared to correct responses. Altogether, these findings tentatively support the involvement of domain-general cognitive control mechanisms in bilingual switching.
The long distance relationship of regional amyloid burden and tau pathology spread
Authors: Hoenig Merle C. , Doering Elena , Bischof Gérard N. , Drzezga Alexander , van Eimeren Thilo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2024

AbstractIntroductionConsistent with the amyloid-cascade-hypothesis, we tested whether regional amyloid burden is associated with tau pathology increases in spatially independent brain regions and whether functional connectivity serves as a mediator bridging the observed spatial gap between these pathologies.MethodsData of 98 amyloid-positive and 35 amyloid-negative subjects with baseline amyloid (18F-AV45) and longitudinal tau (18F-AV1451) PET were selected from ADNI. Annual tau change maps were computed. All images were z-transformed using the amyloid-negative subjects as reference. Z-maps of baseline amyloid and annual tau change were submitted to a parallel independent component analysis in GIFT, yielding six component pairs linking spatial patterns of baseline amyloid to longitudinal tau increase. Next, we used the region of maximum coefficient per component as seeds for functional connectivity analyses in a healthy control dataset. This resulted in six pairs of amyloid and tau seed-based networks (SBN). The spatial overlap between these SBNs and components (amyloid OR tau change) and the combined component pairs (amyloid AND tau change) were quantified.ResultsAmyloid SBNs presented greater spatial overlap with their respective amyloid components (24%-54%) than tau SBNs with the respective tau change components (16%-40%). However, the spatial combination of amyloid and tau component pairs showed highest spatial overlap with the amyloid SBNs (up to 62% vs. 39% for the tau SBNs).ConclusionMechanistically, regional associations of amyloid and tau pathology may be driven by underlying large-scale functional networks. Functional connections may thereby transmit soluble amyloid to remote brain regions within the same network, likely triggering tau aggregation.
Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses
Authors: Copenhaver Ashley E. , LeGates Tara A. 
Published: January 2024

ABSTRACTSex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary in order to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp-NAc synapses is rewarding, and that mice can make learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigate sex differences in the mechanisms underlying Hipp-NAc LTP using whole-cell electrophysiology and pharmacology. We found that males and females display similar magnitudes of Hipp-NAc LTP which occurs postsynaptically. However, LTP in females requires L-type voltage-gated Ca2+channels (VGCC) for postsynaptic Ca2+influx, while males rely on NMDA receptors (NMDAR). Additionally, females require estrogen receptor α (ERα) activity for LTP while males do not. These differential mechanisms converge as LTP in both sexes depends on CAMKII activity and occurs independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral excitatory pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.SIGNIFICANCE STATEMENTStrengthening of Hipp-NAc synapses drives reward-related behaviors. Male and female mice have similar magnitudes of long-term potentiation (LTP) and both sexes have a predicted postsynaptic locus of plasticity. Despite these similarities, we illustrate here that sex-specific molecular mechanisms are used to elicit LTP. Given the bidirectional relationship between Hipp-NAc synaptic strength in mediating reward-related behaviors, the use of distinct molecular mechanisms may explain sex differences observed in stress susceptibility or response to rewarding stimuli. Discovery and characterization of convergent sex differences provides mechanistic insight into the sex-specific function of Hipp-NAc circuitry and has widespread implications for circuits mediating learning and reward-related behavior.
Dynamically driven correlations in elastic net models reveal sequence of events and causality in proteins
Authors: Erkip Albert , Erman Burak 
Published: January 2024

AbstractProtein dynamics orchestrate allosteric regulation, but elucidating the sequence of events and causal relationships within these intricate processes remains challenging. We introduce the Dynamically Perturbed Gaussian Network Model (DP-GNM), a novel approach that uncovers the directionality of information flow within proteins. DP-GNM leverages time-dependent correlations to achieve two goals: identifying driver and driven residues and revealing communities of residues exhibiting synchronized dynamics. Applied to wild type and mutated structures of Cyclophilin A, DP-GNM unveils a hierarchical network of information flow, where key residues initiate conformational changes that propagate through the protein in a directed manner. This directional causality illuminates the intricate relationship between protein dynamics and allosteric regulation, providing valuable insights into protein function and potential avenues for drug design. Furthermore, DP-GNM’s potential to elucidate dynamics under periodic perturbations like the circadian rhythm suggests its broad applicability in understanding complex biological processes governed by environmental cycles.
Generative AI for Cell Type-Specific Fluorescence Image Generation of hPSC-derived Cardiac Organoid
Authors: Kandula Arun Kumar Reddy , Phamornratanakun Tanakit , Gomez Angello Huerta , El-Mokahal Marcel , Ma Zhen , Feng Yunhe , Yang Huaxiao 
Published: January 2024

AbstractHuman pluripotent stem cell (hPSC)-derived cardiac organoid is the most recent three-dimensional tissue structure that mimics the structure and functionality of the human heart and plays a pivotal role in modeling heart development and disease. The hPSC-derived cardiac organoids are commonly characterized by bright-field microscopic imaging for tracking daily organoid differentiation and morphology formation. Although the brightfield microscope provides essential information about hPSC- derived cardiac organoids, such as morphology, size, and general structure, it does not extend our understanding of cardiac organoids on cell type-specific distribution and structure. Then, fluorescence microscopic imaging is required to identify the specific cardiovascular cell types in the hPSC-derived cardiac organoids by fluorescence immunostaining fixed organoid samples or fluorescence reporter imaging of live organoids. Both approaches require extra steps of experiments and techniques and do not provide general information on hPSC-derived cardiac organoids from different batches of differentiation and characterization, which limits the biomedical applications of hPSC-derived cardiac organoids. This research addresses this limitation by proposing a comprehensive workflow for colorizing phase contrast images of cardiac organoids from brightfield microscopic imaging using conditional Generative Adversarial Networks (GANs) to provide cardiovascular cell type-specific information in hPSC-derived cardiac organoids. By infusing these phase contrast images with accurate fluorescence colorization, our approach aims to unlock the hidden wealth of cell type, structure, and further quantifications of fluorescence intensity and area, for better characterizing hPSC-derived cardiac organoids.
Rapid dynamics of electrophysiological connectome states are heritable
Authors: Jun Suhnyoung , Malone Stephen M. , Iacono William G. , Harper Jeremy , Wilson Sylia , Sadaghiani Sepideh 
Published: January 2024

AbstractTime-varying changes in whole-brain connectivity patterns, or connectome state dynamics, are a prominent feature of brain activity with broad functional implications. While infra-slow (<0.1Hz) connectome dynamics have been extensively studied with fMRI, rapid dynamics highly relevant for cognition are poorly understood. Here, we asked whether rapid electrophysiological connectome dynamics constitute subject-specific brain traits and to what extent they are under genetic influence. Using source-localized EEG connectomes during resting-state (N=928, 473 females), we quantified heritability of multivariate (multi-state) features describing temporal or spatial characteristics of connectome dynamics. States switched rapidly every ∼60-500ms. Temporal features were heritable, particularly, Fractional Occupancy (in theta, alpha, beta, and gamma bands) and Transition Probability (in theta, alpha, and gamma bands), representing the duration spent in each state and the frequency of state switches, respectively. Genetic effects explained a substantial proportion of phenotypic variance of these features: Fractional Occupancy in beta (44.3%) and gamma (39.8%) bands and Transition Probability in theta (38.4%), alpha (63.3%), beta (22.6%), and gamma (40%) bands. However, we found no evidence for heritability of spatial features, specifically states’ Modularity and connectivity pattern. We conclude that genetic effects strongly shape individuals’ connectome dynamics at rapid timescales, specifically states’ overall occurrence and sequencing.
Cognitive abilities are associated with rapid dynamics of electrophysiological connectome states
Authors: Jun Suhnyoung , Malone Stephen M. , Iacono William G. , Harper Jeremy , Wilson Sylia , Sadaghiani Sepideh 
Published: January 2024

AbstractTime-varying changes in whole-brain connectivity patterns, or connectome state dynamics, hold significant implications for cognition. However, connectome dynamics at fast (> 1Hz) timescales highly relevant to cognition are poorly understood due to the dominance of inherently slow fMRI in connectome studies. Here, we investigated the behavioral significance of rapid electrophysiological connectome dynamics using source-localized EEG connectomes during resting-state (N=926, 473 females). We focused on dynamic connectome features pertinent to individual differences, specifically those with established heritability: Fractional Occupancy (i.e., the overall duration spent in each recurrent connectome state) in beta and gamma bands, and Transition Probability (i.e., the frequency of state switches) in theta, alpha, beta, and gamma bands. Canonical correlation analysis found a significant relationship between the heritable phenotypes of sub-second connectome dynamics and cognition. Specifically, principal components of Transition Probabilities in alpha (followed by theta and gamma bands) and a cognitive factor representing visuospatial processing (followed by verbal and auditory working memory) most notably contributed to the relationship. We conclude that the specific order in which rapid connectome states are sequenced shapes individuals’ cognitive abilities and traits. Such sub-second connectome dynamics may inform about behavioral function and dysfunction and serve as endophenotypes for cognitive abilities.
Spatial arrangement of the whiskers of harbor seals (Phoca vitulina) compared to whisker arrangements of house mice (Mus musculus) and brown rats (Rattus norvegicus)
Authors: Graff Matthew M. , Belli Hayley M. , Wieskotten Sven , Bresee Chris S. , Krüger Yvonne , Janssen Thomas L. , Dehnhardt Guido , Hartmann Mitra J.Z. 
Published: January 2024

AbstractWhiskers (vibrissae) are important tactile sensors for most mammals. We introduce a novel approach to quantitatively compare 3D geometry of whisker arrays across species with different whisker numbers and arrangements, focusing on harbor seals (Phoca vitulina), house mice (Mus musculus) and Norway rats (Rattus norvegicus). Whiskers of all three species decrease in arclength and increase in curvature from caudal to rostral. They emerge from the face with elevation angles that vary linearly with dorsoventral position, and with curvature orientations that vary diagonally as linear combinations of dorsoventral and rostrocaudal positions. In seals, this diagonal varies linearly with horizontal emergence angles, and is orthogonal to the diagonal for rats and mice. This work provides the first evidence for common elements of whisker arrangements across species in different mammalian orders. Placing the equation-based whisker array on a CAD model of a seal head enables future mechanical studies of whisker-based sensing, including wake-tracking.SUMMARY STATEMENTWe quantify the three-dimensional positions and orientations of the whiskers across the face of the harbor seal, and compare this geometry with the whisker arrays of rats and mice.
Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes
Authors: Patel Divyesh , Tiusanen Ville , Pihlajamaa Päivi , Sahu Biswajyoti 
Published: January 2024

AbstractThe combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.
Rapid learning of temporal dependencies at multiple timescales
Authors: Smith Cybelle M. , Thompson-Schill Sharon L. , Schapiro Anna C. 
Published: January 2024

AbstractOur environment contains temporal information unfolding simultaneously at multiple timescales. How do we learn and represent these dynamic and overlapping information streams? We investigated these processes in a statistical learning paradigm with simultaneous short and long timescale contingencies. Human participants (N=96) played a game where they learned to quickly click on a target image when it appeared in one of 9 locations, in 8 different contexts. Across contexts, we manipulated the order of target locations: at a short timescale, the order of pairs of sequential locations in which the target appeared; at a longer timescale, the set of locations that appeared in the first vs. second half of the game. Participants periodically predicted the upcoming target location, and later performed similarity judgements comparing the games based on their order properties. Participants showed context dependent sensitivity to order information at both short and long timescales, with evidence of stronger learning for short timescales. We modeled the learning paradigm using a gated recurrent network trained to make immediate predictions, which demonstrated multilevel learning timecourses and patterns of sensitivity to the similarity structure of the games that mirrored human participants. The model grouped games with matching rule structure and dissociated games based on low-level order information more so than high-level order information. The work shows how humans and models can rapidly and concurrently acquire order information at different timescales.
5-Fluorouracil Treatment Represses Pseudouridine-Containing Small RNA Export into Extracellular Vesicles
Authors: Qu Sherman , Nelson Hannah , Liu Xiao , Semler Elizabeth , Michell Danielle L. , Massick Clark , Franklin Jeffrey L. , Karijolich John , Weaver Alissa M. , Coffey Robert J. , Liu Qi , Vickers Kasey C. , Patton James G. 
Published: January 2024

Abstract5-fluorouracil (5-FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5-FU is also incorporated into RNA causing toxicity due to defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. Here, we examine the impact of 5-FU on the expression and export of small RNAs (sRNAs) into small extracellular vesicles (sEVs). Moreover, we assess the role of 5-FU in regulation of post-transcriptional sRNA modifications (PTxM) using mass spectrometry approaches. EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell-cell communication. PTxMs on cellular and extracellular sRNAs provide yet another layer of gene regulation. We found that treatment of the colorectal cancer (CRC) cell line DLD-1 with 5-FU led to surprising differential export of miRNA snRNA, and snoRNA transcripts. Strikingly, 5-FU treatment significantly decreased the levels of pseudouridine on both cellular and secreted EV sRNAs. In contrast, 5-FU exposure led to increased levels of cellular sRNAs containing a variety of methyl-modified bases. Our results suggest that 5-FU exposure leads to altered expression, base modifications, and mislocalization of EV base-modified sRNAs.
The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences
Authors: Brown Grant W. 
Published: January 2024

AbstractAPOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, its deamination target preferences are unknown. By expressing humanAPOBEC3Cin a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes.