bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolving copy number gains promote tumor expansion and bolster mutational diversification
Authors: Wang Zicheng , Xia Yunong , Mills Lauren , Nikolakopoulos Athanasios N. , Maeser Nicole , Sheltzer Jason M. , Sun Ruping 
Published: June 2022

AbstractCharting the evolutionary history of rampant somatic copy number alterations (SCNA) is an indispensable step toward a deeper understanding of their roles in tumor development. However, the existing SCNA timing analysis is limited to low copy number states and initiating gains, which are not necessarily close to the onset of the malignant proliferation. Moreover, it remains a critical question if the timing of an SCNA reveals the corresponding variant’s fitness effect. Here we propose a framework to estimate the arrival time of a clonal SCNA, i.e., the time delay from its last alteration to the start of population expansion, in addition to its initiation time when the first alteration occurs. Our method leverages the bias that a genomic segment, when resting on a copy number (CN) state, accumulates somatic single nucleotide variants (SSNV) at a rate proportional to its CN. From the whole genome sequencing data of 184 samples from 75 patients across five tumor types, we commonly observed late clonal CN gains following early initiating events, which appear right before the expansion leading to the observed tumor sample(s). Genome doubling (GD) can be late, but post-GD CN evolution is prevalent in the genealogy of the most recent common ancestor of patient tumors. Notably, mathematical modeling suggests that late evolving events could contain rate-limiting drivers. The advantage of evolving gains could arise from the dosage increase of cancer genes in proliferative signaling and amplification of early functional variants. In addition, evolving SCNAs bolster the diversification of SSNVs between sub-populations, exacerbating the vicious circle between malignant growth and accumulation of genomic heterogeneity. Our findings have broad implications for resolving the trajectory of SCNAs, discerning the CN markers of malignant growth in vivo, and properly quantifying tumor heterogeneity in aneuploid tumors.
Skull allometries in three species of Didelphis (Didelphimorphia, Didelphidae)
Authors: Parés-Casanova Pere M. 
Published: June 2022

AbstractAs biological shape is usually complex and evolves on different constraints, it can be assessed using integrative methods such as geometric morphometrics. Allometric changes were analysed in three species of Didelphis genus (D. albiventris n=20, D. marsupialis n=82, D. pernigra n=35) by means of geometric morphometric techniques. A significant correlation between shape and size was found, suggesting an allometric change pattern for all three species studied. However, allometries appeared to be different between D. marsupialis and D. pernigra, both of which belong to different groups (the so-called black-eared group and the white-eared group, respectively). Results are consistent with taxonomic recognition at the group level and can help to elucidate phylogenetic relationships between these three Didelphis species.
Validation of a new coil array tailored for dog functional magnetic resonance imaging (fMRI) studies
Authors: Alexandrina Guran C.-N. , Sladky Ronald , Karl Sabrina , Boch Magdalena , Laistler Elmar , Windischberger Christian , Huber Ludwig , Lamm Claus 
Published: June 2022

AbstractComparative neuroimaging allows for the identification of similarities and differences between species. It provides an important and promising avenue, to answer questions about the evolutionary origins of the brain’s organization, in terms of both structure and function. Dog fMRI has recently become one particularly promising and increasingly used approach to study brain function and coevolution. In dog neuroimaging, image acquisition has so far been mostly performed with coils originally developed for use in human MRI. Since such coils have been tailored to human anatomy, their sensitivity and data quality is likely not optimal for dog MRI. Therefore, we developed a multi-channel receive coil (K9 coil) tailored for high-resolution functional imaging in canines, optimized for dog cranial anatomy. In this paper we report structural (n = 9) as well as functional imaging data (resting-state, n = 6; simple visual paradigm, n = 9) collected with the K9 coil in comparison to reference data collected with a human knee coil. Our results show that the K9 coil significantly outperforms the human knee coil, improving the signal-to-noise ratio across the imaging modalities. We noted increases of roughly 45% signal-to-noise in the structural and functional domain. In terms of translation to functional fMRI data collected in a visual flickering checkerboard paradigm, group-level analyses show that the K9 coil performs better than the knee coil as well. These findings demonstrate how hardware improvements may be instrumental in driving data quality, and thus, quality of imaging results, for dog-human comparative neuroimaging.Significance StatementComparative neuroimaging is a powerful avenue to discover evolutionary mechanisms at the brain level. However, data quality is a major constraint in non-human functional magnetic resonance imaging. We describe a novel canine head coil for magnetic resonance imaging, designed specifically for dog cranial anatomy. Data quality performance and improvements over previously used human knee coils are described quantitatively. In brief, the canine coil improved signal quality substantially across both structural and functional imaging domains, with strongest improvements noted on the cortical surface.
Timbral effects on consonance illuminate psychoacoustics of music evolution
Authors: Marjieh Raja , Harrison Peter M. C. , Lee Harin , Deligiannaki Fotini , Jacoby Nori 
Published: June 2022

The phenomenon of musical ‘consonance’ is an essential feature in diverse musical styles. The traditional belief, supported by centuries of Western music theory and psychological studies, is that consonance derives from simple (‘harmonic’) frequency ratios between tones. Here we show through massive large-scale behavioral experiments (235,440 judgments) that harmonic consonance preferences can be deeply reshaped by timbral manipulations, even as far as to induce preferences for inharmonic intervals. We show how such effects may have shaped the cultural evolution of diverse scale systems ranging from the gamelan’s ‘slendro’ scale to the tuning of Western ‘mean-tone’ and ‘equal-tempered’ scales. Through computational modeling we show that these timbral manipulations elegantly dissociate competing psychoacoustic mechanisms underlying consonance, and we derive an updated computational model combining liking of harmonicity, disliking of fast beats (roughness), and liking of slow beats. Altogether, this work showcases how large-scale behavioral experiments can inform classical questions in auditory perception.Author summary“We reveal effects of timbre on consonance perception that motivate a new understanding of the evolution of musical scales.”
Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles
Authors: Ragusa Denise , Cicirò Ylenia , Federico Concetta , Saccone Salvatore , Bruno Francesca , Saeedi Reza , Sisu Cristina , Pina Cristina , Sala Arturo , Tosi Sabrina 
Published: June 2022

AbstractAcute myeloid leukaemia carrying the translocation t(7;12)(q36;p13) is an adverse-risk leukaemia uniquely observed in infants. Despite constituting up to 30% of cases in under 2-year-olds, it remains poorly understood. Known molecular features are ectopic overexpression of the MNX1 gene and generation of a fusion transcript in 50% of patients. Lack of research models has hindered understanding of t(7;12) biology, which has historically focused on MNX1 overexpression rather than the cytogenetic entity itself. Here, we employed CRISPR/Cas9 to generate t(7;12) in the human K562 cell line, and in healthy CD34+ haematopoietic progenitors where the translocation was not sustained in long-term cultures or through serial replating. In contrast, in K562 cells, t(7;12) was propagated in self-renewing clonogenic assays, with sustained myeloid bias in colony formation and baseline depletion of erythroid signatures. Nuclear localisation analysis revealed repositioning of the translocated MNX1 locus to the interior of t(7;12)-harbouring K562 nuclei - a known phenomenon in t(7;12) patients which associates with ectopic overexpression of MNX1. Crucially, the K562-t(7;12) model successfully recapitulated the transcriptional landscape of t(7;12) patient leukaemia. In summary, we engineered a clinically-relevant model of t(7;12) acute myeloid leukaemia with the potential to unravel targetable molecular mechanisms of disease.
Astrocyte Autophagy Response Upon Neuronal Cilia Loss in the Aging Brain
Authors: de las Heras-García Laura , Pampliega Olatz 
Published: June 2022

ABSTRACTPrimary cilia are microtubule-based signaling organelles present in the plasma membrane of most cell types, including mature astrocytes and neurons. However, little is known about the role of this organelle in the mature brain. Data from our lab show that neuronal primary cilia (nPC) is required for soluble amyloid beta oligomer signaling and modulation of autophagy, and that these events are age dependent. Here, we hypothesize that astrocytes react to the loss of nPC and that aging might impact these events. For that purpose, we have characterized morphological changes in astrocytes as well as in the cilium and autophagy of these cells in brain tissue from young and old mice with impaired PC in neurons. Our results show that upon loss of PC in neurons astrocytes become reactive and reduce their lysosomal capacity, an effect that is reinforced with aging. Moreover, aging reduced the pool of ciliated astrocytes, which might impact their ability to react to extracellular events. Overall, our data suggest that the PC might act an intermediary in the communication between astrocytes and neurons.Highlights of the paperAstrocytes become reactive upon loss of primary cilia in neurons, which is reinforced during aging.Astrocytes in the old brain are less ciliated.Loss of neuronal primary cilia decreases lysosomal capacity in astrocytes in age-dependent manner.
Gray matter cortical thickness predicts individual pain sensitivity: a multi-center machine learning approach
Authors: Kotikalapudi Raviteja , Kincses Balint , Zunhammer Matthias , Schlitt Frederik , Schmidt-Wilcke Tobias , Kincses Zsigmond T. , Asan Livia , Bingel Ulrike , Spisak Tamas 
Published: June 2022

AbstractPain sensitivity is known to considerably vary across individuals. While the variability in pain has been linked to structural neural correlates, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity utilising structural MRI-based cortical thickness data from a multi-center dataset (3 centers, 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson’s r = 0.36, p < 0.0005). The predictions were found to be specific to pain sensitivity and not biased towards potential confounding effects (e.g., anxiety, stress, depression, center-effects). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain.HighlightsWe present a robust, brain structure-based multi-center predictive model for pain sensitivity.Our model based on gray matter cortical thickness explains 13% of the variance in pain sensitivity and generalizes to out-of-center data.The predictions are specific to pain sensitivity and not driven by potential confounders such as stress, depression, anxiety, and center-effects.The most important predictors were rostral anterior cingulate cortex, parahippocampal gyrus and temporal pole, all negatively correlated with pain sensitivity.
Changes in neural readout of response magnitude during auditory streaming do not correlate with behavioral choice in the auditory cortex
Authors: Banno Taku , Shirley Harry , Fishman Yonatan I. , Cohen Yale E. 
Published: June 2022

SummaryAlthough previous studies have identified neural mechanisms that may underlie auditory scene analysis, the relationship between these mechanisms and behavior remains elusive. To fill these gaps, we recorded multiunit activity (MUA) from the posterior and anterior auditory fields while monkeys participated in an auditory streaming task. We found that MUA magnitude was reduced as the streaming stimulus unfolded over time, and this reduction depended on the frequency difference between the tone bursts comprising the streaming stimulus. We then examined whether this frequency-dependent reduction in activity could be utilized by downstream neurons to read out “one stream” versus “two streams” and found that, as the frequency difference increased, an ideal observer consistently classified neural activity as “two streams”. However, because this classification was not modulated by the monkeys’ choices, it suggests that this activity may not reflect the segregation of stimuli into perceptually distinct auditory streams but may simply reflect bottom-up processes.
Product inhibition can accelerate evolution
Authors: Ruth Beatrice , Dittrich Peter 
Published: June 2022

Molecular replicators studied in-vitro exhibit product inhibition, typically caused by the hybridization of products into dimer complex that are not able to replicate. As a result, the replication rate and the selection pressure is reduced, potentially allowing the “survival of everyone”. Here, we introduce a stochastic evolution model of replicating and hybridizing RNA strands to study the effect of product inhibition on evolution. We found that hybridization, though reducing the rate of replication, can increase the rate of evolution, measured as fitness gain within a period of time. The positive effect has been observed for a mutation error smaller than half of the error threshold. In this situation, frequency-dependent competition causes an increased diversity that spreads not only within a neutral network but also over various neutral networks through a dynamical modulation of the fitness landscape, resulting in a more effective search for better replicators. The underlying model is inspired by RNA virus replication and the RNA world hypothesis. Further investigations are needed to validate the actual effect of accelerated evolution through product inhibition in those systems.Significance StatementIn this paper we present a novel evolutionary phenomenon, where product inhibition, though reducing the effective replication rate, can accelerate the rate of evolution. We show this phenomenon in a model of simulated single-stranded RNA (sRNA) sequence evolution extended by hybridization of sRNA, causing product inhibition. The evolutionary phenomenon could be relevant in (a) prebiotic evolution, where replicating polymers hypothetically emerged and where very likely subject to product inhibition, (b) biotic evolution, e.g., where RNA strands of viruses replicate within a biological cell, or (c) artificial molecular or chemical evolution, where product inhibition might be used to evolve molecules with desired properties more efficiently.
A wireless, user-friendly, and unattended robotic flower system to assess pollinator foraging behaviour
Authors: Debeuckelaere Kamiel , Janssens Dirk , Asensio Estefanía Serral , Wenseleers Tom , Jacquemyn Hans , Pozo María I. 
Published: June 2022

AbstractUnderstanding the complex interactions between external and internal factors that influence pollinator foraging behaviour is essential for developing effective conservation strategies. However, collecting large datasets that incorporate data from various sources has been challenging.To address this issue, we present a wireless and cost-effective robotic flower equipped with Internet of Things (IoT) technology that automatically offers nectar to visiting insects while monitoring visitation time and duration. The robotic flower is easy to manipulate and settings such as nectar refill rates can be remotely altered, making it ideal for field settings. The system transmits data completely wirelessly and autonomously, is mobile and easy to clean.The prototype settings allow for approximately two weeks of uninterrupted data collection for each battery charge. As a proof-of-concept application, a foraging-preference dual choice experiment with bumblebees was performed. On average, more than 14 000 flower visits were registered daily with a setup consisting of 16 robotic flowers. The data show a gradual preference shift from the pre-trained, lower quality food source towards the higher quality source.The robotic flower provides accurate and reliable data on insect behaviour, dramatically reducing the price and/or labour costs. Although primarily designed for (bumble)bees, the system could be easily adapted for other flower-visiting insects. The robotic flower is user-friendly and can be easily adapted to address a wide range of research questions in pollination ecology, conservation biology, biocontrol and ecotoxicology, and allows for detailed studies on how nectar traits, flower colour and shape and pollutants would affect foraging behaviour.
The Impact of Storage Condition and Duration on Function of Native and Cargo-Loaded Mesenchymal Stromal Cell Extracellular Vesicles
Authors: Levy Daniel , Jeyaram Anjana , Born Louis J. , Chang Kai-Hua , Abadchi Sanaz Nourmohammadi , Wei Hsu Angela Ting , Solomon Talia , Aranda Amaya , Stewart Samantha , He Xiaoming , Harmon John W. , Jay Steven M. 
Published: June 2022

AbstractAs evidenced by ongoing clinical trials and increased activity in the commercial sector, extracellular vesicle (EV)-based therapies have begun the transition from bench to bedside. As this progression continues, one critical aspect to EV clinical translation is understanding the effects of storage and transport conditions. Several studies have assessed the impact of storage on EV characteristics such as morphology, uptake, and component content, but effects of storage duration and temperature on EV functional bioactivity and, especially, loaded cargo are scarcely reported. Here, EV outcomes following storage at different temperatures (room temperature, 4°C, -20°C, -80°C) for various durations as well as after lyophilization were assessed. Mesenchymal stem/stromal cell (MSC) EVs were observed to retain key aspects of their bioactivity (pro-vascularization, anti-inflammation) for up to 4-6 weeks at -20°C, -80°C, and after lyophilization. Furthermore, via in vitro assays and an in vivo wound healing model respectively, these same storage conditions were also demonstrated to enable preservation of the functionality of loaded microRNA (miRNA) as well as long non-coding RNA (lncRNA) cargo in MSC EVs. These findings extend the current understanding of how EV therapeutic potential is impacted by storage conditions and may inform best practices for handling and storage of MSC EVs for both basic research and translational purposes.
String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration
Authors: Oliveira Andreia C. , Santos Madalena , Pinho Mafalda , Lopes Carla S. 
Published: June 2022

AbstractTau pathology is defined by the intracellular accumulation of abnormally phosphorylated Tau and is prevalent in several neurodegenerative disorders. The identification of modulators of Tau abnormal phosphorylation and aggregation is key to understand disease progression and develop targeted therapeutic approaches. In this study we identify String/Cdc25 phosphatase as a suppressor of Tau abnormal phosphorylation and associated toxicity. Using aDrosophilamodel of tauopathy we show that Tau dephosphorylation by Stg/Cdc25 correlates with reduced Tau oligomerization, brain vacuolization and locomotor deficits in flies. Moreover, using a disease mimetic model, we provide evidence that Stg/Cdc25 reduces Tau phosphorylation levels independently of Tau aggregation status and delays neurodegeneration progression in the fly. These findings uncover a role for Stg/Cdc25 phosphatases as regulators of Tau biology, that extends beyond their well-characterized function as cell-cycle regulators during cell proliferation, and point-out Stg/Cdc25 based approaches as promising entry points to target abnormal Tau phosphorylation.
Adult Camk2a gene reinstatement restores the learning and plasticity deficits of Camk2a knockout mice
Authors: Rigter Pomme M.F. , Wallaard Ilse , Jolfaei Mehrnoush Aghadavoud , Kingma Jenina , Post Laura , Elgersma Minetta , Elgersma Ype , van Woerden Geeske M. 
Published: June 2022

AbstractWith the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there a critical developmental time window in which CAMK2A needs to be expressed for normal brain development, or whether expression of the protein at later stages is still beneficial to restore normal functioning. To answer this question, we generated an inducible Camk2a mouse model, which allows us to express CAMK2A at any desired time. Here, we show that adult expression of CAMK2A rescues the behavioural and electrophysiological phenotypes seen in the Camk2a knock-out mice, including spatial and conditional learning and synaptic plasticity. These results suggest that CAMK2A does not play a critical irreversible role in neurodevelopment, which is of importance for future therapies to treat CAMK2A-dependent disorders.
Nemacol is a Small Molecule Inhibitor of C. elegans Vesicular Acetylcholine Transporter with Anthelmintic Potential
Authors: Harrington Sean , Pyche Jacob , Burns Andrew R. , Spalholz Tina , Baker Rachel J. , Ching Justin , Lautens Mark , Kulke Daniel , Deuther-Conrad Winnie , Brust Peter , Roy Peter J. 
Published: June 2022

AbstractNematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol synergizes with the anthelmintic ivermectin to kill C. elegans. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through an identified viable anthelmintic target.One sentence summaryA small molecule screen identifies a vesicular acetylcholine transporter inhibitor scaffold that incapacitates parasitic nematodes