bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping cancer gene dynamics through state-specific interactions
Authors: Maqueda-Real Adrián , Ollé-Monràs Laia , Park Solip 
Published: January 2025

ABSTRACTMetastatic cancer, a major cause of mortality, has been understudied compared to primary tumors, leaving gaps in our understanding of how cancer genes adapt between these states. We analyzed the association between mutations and copy-number alterations in 25,000 tumor samples from both primary and metastatic cancers. Our findings show that cancer genes display distinct interaction strengths across these states, with 27.45% of genes, includingARID1A,FBXW7, andSMARCA4, shifting between one-hit and two-hit drivers. Interaction strengths varied by cancer state and treatment conditions, revealing seven state-specific interactions. We also identified 38 primary-specific and 21 metastatic-specific high-order interactions, enriched in cancer hallmarks, indicating unique tumor progression mechanisms. These findings highlight dynamic tumor progression mechanisms and underscore the importance of considering cancer state in research and treatment strategies for precise therapeutic interventions.
Phosphoproteomics reveals novel BCR::ABL1-independent mechanisms of resistance in chronic myeloid leukemia
Authors: Bica Valeria , Venafra Veronica , Massacci Giorgia , Graziosi Simone , Gualdi Sara , Minnella Gessica , Sorà Federica , Chiusolo Patrizia , Brunetti Maria Elsa , Napolitano Gennaro , Breccia Massimo , Mougiakakos Dimitrios , Böettcher Martin , Fischer Thomas , Perfetto Livia , Sacco Francesca 
Published: January 2025

AbstractBCR::ABL1 drives chronic myeloid leukemia (CML) disease and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular pathways, acting as BCR::ABL1 independent mechanisms, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, TKI resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with theSignalingProfilerpipeline, we obtained two signaling maps offering a comprehensive description of the BCR::ABL1 dependent and independent pro-survival signalling mechanisms. We leveraged these maps to unbiasedly and systematically discover therapeutic vulnerabilities, by implementing theDruggability Scorecomputational algorithm. By this strategy, and in combination within vitroand inex vivofunctional assays, we show a crucial role of acquired FLT3-dependency in resistant CML models. In conclusion, we reposition FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for TKI resistant CML patients.
Spatial density and habitat associations of Atlantic Cod on the Northeastern US Continental Shelf
Authors: Lankowicz Katie , Sherwood Graham D. , Grabowski Jonathan H. , Kerr Lisa 
Published: January 2025

AbstractThe spatial distribution of the Atlantic cod (Gadus morhua) stock is shaped in part by several habitat and oceanographic variables. In this study, Vector Autoregressive Spatio-Temporal (VAST) models were used to combine data from multiple survey programs to hindcast seasonal spatial densities of three size classes of cod within the Northeast US Continental Shelf from 1982 to 2021. Bottom habitat characteristics, bottom water temperature, depth, and basin-averaged climate indices were included as density covariates. Depth, bottom temperature, and gravel sediments were strongly associated with spatial density. The relative abundance of all size classes generally decreased throughout the time series. Model outputs highlighted patches with persistently high spatial density despite range losses and declining abundance. This aligns with the basin model, a spatial dynamic frequently reported in collapsed fish stocks. The availability of habitat with suitable depth and temperature will likely be reduced under current projections of bottom water temperature, further endangering the recovery of the stock. Improving our understanding of cod habitat preferences and variation in spatial density will be important for future management efforts.
Perceived risk of forward versus backward balance disturbances while walking in young and older adults
Authors: Jain Shreya , Schweighofer Nicolas , Finley James M. 
Published: January 2025

AbstractFalls, which often result from trips or slips, pose a major health concern, particularly among older adults. Experiencing falls or near-falls from balance disturbances can shape subsequent gait-related decisions, as individuals may avoid situations they perceive as risky. Here, we explore whether perceptions of risk are sensitive to the direction of previously experienced balance disturbances – forward or backward – and whether these perceptions change with age. Twenty young and twenty older adults walked on a split-belt treadmill while performing a two-alternative forced-choice task, where they indicated their preference between a forward-falling trip and a backward-falling slip. We varied the perturbation magnitudes using an adaptive staircase algorithm to obtain multiple trip-slip equivalence points. Using a mixed- effects linear model, we estimated the slope of the trip-slip relationship, which quantified the direction and strength of the sensitivity of perceived risk to perturbation type. To assess reliability, we repeated the procedure on a second day. Additionally, we investigated two potential reasons underlying any observed sensitivity – 1) emotional responses measured by state anxiety, and 2) physical responses measured by peak center of mass velocity. We found that both young and older adults perceived slips to be riskier than trips, with no group difference in sensitivity. The relative sensitivity to slips versus trips was moderately reliable across two days of testing, though most participants were less sensitive to perturbation direction on the second day. Neither state anxiety responses nor peak center of mass (CoM) velocity explained the directional sensitivity, though CoM velocity was higher during slips than trips for both age groups. These results suggest that the characteristics of experienced balance disturbances may influence behavioral decisions. Objectively measuring individual differences in the perceived risk of balance disturbances and the ability to recover from these disturbances, can potentially improve fall risk assessment and inform personalized training interventions.
Brain dynamics during architectural experience: prefrontal and hippocampal regions track aesthetics and spatial complexity
Authors: Gregorians Lara , Patai Zita , Velasco Pablo Fernandez , Zisch Fiona E. , Spiers Hugo J. 
Published: January 2025

AbstractArchitectural experience involves processing the spatial layout of an environment and our emotional reaction to it. However, these two processes are largely studied separately. Here we used functional magnetic resonance imaging (fMRI) and first-person movies of journeys through buildings and cities to determine the contribution of different brain regions to spatial and aesthetic aspects of the built environment. During scanning, participants watched 48 movies that show first-person-view travel through different spaces; immediately after each video, they either judged the spatial layout complexity or valence of the environment. After scanning, participants also reported the memorability of the spaces encountered. Activity in brain regions previously linked to valence processing (e.g. ventromedial prefrontal cortex) were modulated by aesthetic qualities of the stimuli (i.e. increased for pleasant spaces compared to unpleasant spaces) and the task (more active when judging valence), whereas activity in brain regions linked with spatial processing (e.g. parahippocampal regions) increased in complex layouts compared to simple layouts. The hippocampus and parahippocampal cortex were associated with the memorability of spaces and were modulated by both aesthetic and spatial qualities. We also tested for curvature, fascination, coherence and hominess - qualities linked to aesthetic judgement in architecture. We replicated findings activating right lingual gyrus for fascination, left inferior occipital gyrus for coherence, and left cuneus for hominess, and found inverse curvature (increasing rectilinearity) activated spatial, valence and visual processing regions. Overall, these findings provide important insights into how different brain regions respond whilst experiencing new buildings and city spaces, which is needed to advance the field of neuroarchitecture.
pH-Responsive Phase Separation Dynamics of Intrinsically Disordered Peptides
Authors: Nandy Manali , Ganar Ketan A. , Ippel Hans , Dijkgraaf Ingrid , Deshpande Siddharth 
Published: January 2025

AbstractLiquid-liquid phase separation of biomolecules is crucial for maintaining the functional organization in biological systems. Intrinsically disordered proteins are particularly prone to form phase-separated condensates in response to various physicochemical triggers. While the effect of ionic strength and temperature on phase separation dynamics have been studied extensively, the influence of pH is less explored. Here, we study a model glycine-rich protein present in the tick bioadhesive, given its capability to undergo phase separation. After confirming its disordered nature through spectroscopy, we investigated its pH dependence and underlying molecular mechanisms. Our findings reveal that pH significantly influences the protein hydrophobicity via ionic residues, driving notable variations in the coacervation behavior (propensity, progression) and in shaping the material properties (viscosity, interfacial activity) of the formed condensates. Given the ubiquitous presence of disordered proteins in biology, this study provides valuable insights about the broad implications of the pH-dependent behavior of intrinsically disordered proteins.
Evolution of CYP71D as a driving force of the diversification of monoterpene indole alkaloid biosynthesis
Authors: Besseau Sébastien , Durand Mickael , Zamar Duchesse-Lacours , Lezin Enzo , Méteignier Louis-Valentin , Birer Williams Caroline , Dutilleul Christelle , Perrot Thomas , Lanoue Arnaud , Oudin Audrey , Papon Nicolas , Sun Chao , St-Pierre Benoit , Courdavault Vincent 
Published: January 2025

ABSTRACTMonoterpene indole alkaloids (MIAs) constitute a vast group of plant natural products synthesized within the Gentianales order. MIAs possess outstanding pharmacological properties that explain their wide use in the treatment of human diseases. These biological activities result from the complex structure of MIAs that originate from intricated biosynthetic pathways involving several enzyme families and notably cytochrome P450s. The early steps of MIA synthesis involve several P450s from the 71 clade, which catalyse the conversion of various reduced strictosidine aglycones into MIAs from the mavacurane, strychnane, akuammilane, sarpagane, and heteroyohimane groups. An extensive study of these P450 distribution in genomic resources reveals that they all belong to a single evolutionary lineage named GAS clade, restricted to the MIA producing Gentianales (Gelsemiaceae and Rauvolfioideae). A related but distinct P450 lineage (named sister GAS clade) was found in non-MIA producing Gentianales and species producing structurally distinct MIAs (Rubiaceae). Functional characterization of 36 members of the GAS clade revealed that these enzymes felt into four main groups of activity depending on substrate acceptance (ex: tetrahydroalstonine, geissoschizine, ajmalicine…) and the nature of the catalyzed reaction (aromatization, cyclisation). These characterizations also lead to the identification of a yohimbane aromatization activity for several of these P450s, increasing the number of MIA scaffolds associated with GAS activity to six. Lastly, the chronology of emergence of these GAS activities was assessed by using ancestral sequence reconstitution, establishing that the initial ancestor of the whole GAS clade exhibits a main alstonine synthase activity. Subsequent gene duplication events, combined with neofunctionalization, facilitated the progressive emergence of eight additional activities, variably distributed among the four GAS subgroups. This comprehensive enzyme characterization establishes the evolutionary trajectory of the GAS clade, demonstrating how its diversification has progressively shaped the chemical diversity of MIAs in Gentianales.
TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PrimPol-dependent repair
Authors: In Suna , Renck Nunes Patricia , Valador Fernandes Rita , Lingner Joachim 
Published: January 2025

AbstractTERRA long noncoding RNAs associate with telomeres post transcription through base-pairing with telomeric DNA forming R-loop structures. TERRA regulates telomere maintenance but its exact modes of action remain unknown. Here, we induce TERRA transcription and R-loop formation in telomerase-expressing cells and determine that TERRA R-loop formation requires non-redundant functions of the RAD51 DNA recombinase and its enhancer RAD51AP1. TERRA R-loops interfere with semiconservative DNA replication promoting telomere maintenance by a homology-directed repair (HDR) mechanism known as Break Induced Replication (BIR), which ensures telomere maintenance in ALT cancer cells. In addition, TERRA induced PrimPol-dependent repair, which can initiate DNA synthesis de novo downstream of replication obstacles. PrimPol acts in parallel to BIR for telomere maintenance of TERRA over-expressing cells promoting their survival. Similarly, we find that PrimPol depletion is synthetic lethal with BIR deficiency in U2OS ALT cancer cells. Therefore, in the absence of other ALT-typical telomeric chromatin changes, TERRA R-loops per se are sufficient to induce ALT-typical telomere repair mechanisms.
Astroglial deficiency for oligophrenin-1 contributes to intellectual disability
Authors: Cresto Noémie , Ezan Pascal , Pillet Laure-Elise , Mazaud David , Mailly Philippe , Bemelmans Alexis , Meziane Hamid , Selloum Mohammed , Sorg Tania , Marchi Nicola , Hérault Yann , Billuart Pierre , Rouach Nathalie 
Published: January 2025

ABSTRACTNeurodevelopmental disorders, including X-linked intellectual disability, autism spectrum disorder or schizophrenia, can result from the mutation of oligophrenin-1 (Ophn1), encoding a Rho-GTPase-activating protein.Ophn1regulates synaptic development and function, in part via cytoskeleton reorganization, and is expressed in both neurons and astrocytes. Despite the crucial role of astrocytes in synapse function, altered in neurodevelopmental disorders, and theirOphn1expression, the specific impact of astroglialOphn1deficiency on synaptic transmission and behavior remains unknown. Here, we show thatOphn1deficiency postnatally in hippocampal astrocytes impairs synaptic transmission, short-term plasticity and spatial working memory in adults. This involves an adenosine A1 receptor-dependent presynaptic mechanism associated with astroglial morphological rearrangements resulting in increased astroglial synapse coverage. The structural, functional and behavioral alterations induced by astroglialOphn1deficiency are rescued in adults by pharmacological inhibition of the RhoA/ROCK pathway. Our findings uncover an important role for astroglialOphn1deficiency in synaptic and behavioral dysfunctions, pointing to a novel cellular therapeutic target for neurodevelopmental disorders.
Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor
Authors: Grant Zoe L. , Kuang Shuzhen , Zhang Shu , Horrillo Abraham J. , Rao Kavitha S. , Kameswaran Vasumathi , Joubran Carine , Lau Pik Ki , Dong Keyi , Yang Bing , Bartosik Weronika M. , Zemke Nathan R. , Ren Bing , Kathiriya Irfan S. , Pollard Katherine S. , Bruneau Benoit G. 
Published: January 2025

AbstractDosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, and cell-type specific gene regulation is linked to the reorganization of 3D chromatin during cellular differentiation. Here, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)- linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reducedTBX5dosage in a human model of CHD, with variations in response across individual cells. Regions normally bound by TBX5 are especially sensitive, while co-occupancy with CTCF partially protects TBX5-bound TAD boundaries and loop anchors. These results highlight the importance of lineage-restricted TF dosage in cell-type specific 3D chromatin dynamics, suggesting a new mechanism for TF-dependent disease.
Endemic and invasion dynamics of wild tomato species on the Galápagos Islands, across two centuries of collection records
Authors: Kutza Alex D. , Hert Zoe L. , Moyle Leonie C. 
Published: January 2025

SummaryWe aggregated digitized herbarium and other collection records—spanning >225 years since 1795—to assess the biological, geographical, and historical factors shaping distributions of three wild tomato species on the Galápagos Islands, and to infer future threats to the two endemic species (Solanum cheesmaniaeandS. galapagense) and risks posed by their invasive congener (S. pimpinellifolium).Combining >400 unique geolocated Galápagos records with bioclimate data and species distribution modelling, we quantified the geo-spatial distribution of each species, bracketed the historical timing and location of introductions of the invasive species, characterized species bioclimate envelopes, and projected suitable habitat overlap.We infer that dispersal limitation and alternative selective histories shape current species distributions, and that anthropogenic change has and will continue to have different impacts on the two endemic species—closely associated with their different geographic and environmental distributions. We also identify plausible avenues for, and limits to, future invasive expansion.These data vastly extend the temporal and spatial reach of our direct historical inferences, provide a critical complement to genomic analyses of contemporary Galápagos populations, and demonstrate that scientific collections are especially valuable for interpreting factors shaping species distributions on high-endemism islands with recent rapid environmental change.
Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions
Authors: Peat Cormac , Prasad Asheeta , Finkelstein David , Sue Caroline , Johnston Jennifer A. , Parish Clare L. , Thompson Lachlan , Kirik Deniz , Halliday Glenda M. 
Published: January 2025

AbstractParkinson’s disease is considered biologically a neuronal α-synuclein disease, largely ignoring the more widespread α-synuclein deposition that occurs in astrocytes. Recent single cell transcriptomics have identified early astrocytic differences in both Parkinson’s disease and mouse models with an increase in reactive astrocytes associated with proteostasis. To identify whether astrocytes accumulate α-synuclein before or after neurons, the present study histologically assessed astrocytes and α-synuclein accumulation in the M83 A53T transgenic mouse model of Parkinson’s disease prior to significant neuronal α-synuclein accumulation.The brains of M83 A53T transgenic (n=5) and wild-type (n=4) mice were perfusion fixed and serial sections of the midbrain and striatum processed for multiplex labelling. Digital images were captured from standardised sampling regions and astrocyte quantitation performed using QuPath software. Multivariate linear region models with Turkey posthoc tests were used to evaluate the effects of genotype on regional astrocyte morphology and numbers.The density of astrocytes within the substantia nigra pars compacta was approximately 30% greater compared with other sampled regions (P<0.005). Small aggregates of α-synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious α-synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas (P<0.001) with more processes (P<0.001) consistent with a reactive phenotype. The expression of vascular endothelial growth factor A was present in analysed astrocytes, but not the synthesising enzyme for vitamin D CYP27B1. The A53T transgenic mice had more than double the numbers of astrocytes (P<0.001) and 2.5 times more astrocytes with α-synuclein aggregates compared to wild-type mice (P<0.001).These data suggest that α-synuclein is normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra. In the A53T transgenic mouse model, astrocytes have an early upregulation of their clearance of α-synuclein aggregates. While speculative, a loss of this ability to take up α-synuclein in these regions may precipitate the selective neuronal degeneration and pathologies observed in Parkinson’s disease. As we move to a biological definition for this disease, understanding this early role astrocytes needs to be considered further.
Daily Experiences of Urinary and Fecal Incontinence in Young Adults with Spina Bifida: Preliminary Results from an Ecological Momentary Assessment Study
Authors: Hensel Devon J. , Young Audrey I. , Szymanski Konrad M. 
Published: January 2025

BackgroundUrinary (UI) and fecal (FI) incontinence are prevalent secondary chronic conditions among young adults with spina bifida (YASB). UI and FI decrease daily functioning for YASB, but no research has prospectively examined characteristics of UI and FI among YASB. We used ecological momentary assessment (EMA) over 30 days to describe the prevalence, episode-specific characteristics and negativity associated with UI and FI among a cohort of YASB.MethodData were collected as part of a larger 30-day EMA study prospectively examining the daily prevalence and context of UI and FI in adults with SB. We drew an analytic sample of young adults (YASB) participants aged 18-27 years (N=23 [26.1% of all study-participants [N=88];). Participants completed an end- of-day EMA tracking the frequency, dry intervals, volume, activity avoidance, management, positive and negative mood, current UI (UIA) or FI (FIA) anxiety, past UIA and FIA and past number of UI or FI events.ResultsYASB contributed a 643 daily EMAs. Nearly 60% (370/643) of all daily entries was associated with a general report of incontinence (UI: 54.1% [348/643]; FI: 20.8% [134/643]). Prevalence, characteristics and negativity associated with UI and FI varied significantly from day-to-day. Higher UI frequency, shorter dry intervals, greater UI volume, needing management help, avoiding activities because of UI, higher past median UIA, higher negative mood and fewer past UI events were associated with higher daily UIA. Shorter FI dry intervals, higher past median FIA, higher negative mood and fewer past FI events were associated with higher daily FIA.DiscussionDay-to-day experiences of UI and FI vary among adults with SB across multiple dimensions. Negativity about incontinence when it occurs varies not only based on individual- and episode-specific characteristics, but also on incontinence in the preceding days. Operationalizing these insights into potential clinical interventions warrants further investigation.Discussion and ImplicationsYoung people with SB (YASB) experience day-to-day differences in the characteristics of urinary (UI) and fecal (FI) incontinence (e.g. frequency, self-management) events and the way they felt (e.g. affect) about UI and FI. The unique relationship of these factors to UI and FI anxiety suggest novel potential points of intervention.