bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparison of Tokenization Impact in Attention Based and State Space Genomic Language Models
Authors: Lindsey LeAnn M. , Pershing Nicole L. , Habib Anisa , Stephens W. Zac , Blaschke Anne J. , Sundar Hari 
Published: September 2024

Genomic language models have recently emerged as powerful tools to decode and interpret genetic sequences. Existing genomic language models have utilized various tokenization methods including character tokenization, overlapping and non-overlapping k-mer tokenization, and byte-pair encoding, a method widely used in natural language models. Genomic models have significant differences from natural language and protein language models because of their low character variability, complex and overlapping features, and inconsistent directionality. These differences make sub-word tokenization in genomic language models significantly different from traditional language models.This study explores the impact of tokenization in attention-based and state-space genomic language models by evaluating their downstream performance on various fine-tuning tasks. We propose new definitions forfertility, the token per word ratio, in the context of genomic language models, and introduceto-kenization parity, which measures how consistently a tokenizer parses homologous sequences. We also perform an ablation study on the state-space model, Mamba, to evaluate the impact of character-based tokenization compared to byte-pair encoding. Our results indicate that the choice of tokenizer significantly impacts model performance and that when experiments control for input sequence length, character tokenization is the best choice in state-space models for all evaluated task categories except epigenetic mark prediction.
Cognitive-and lifestyle-related microstructural variation in the ageing human hippocampus
Authors: Agyekum Tyler , García Cindy L. , Fay Felix , Parent Olivier , Bussy Aurélie , Devenyi Gabriel A. , Chakravarty M. Mallar 
Published: September 2024

AbstractAgeing is a biological process associated with the natural degeneration of various regions of the brain. Alteration of neural tissue in the hippocampus with ageing typically results in cognitive decline that may serve as a risk factor for dementia and other neurodegenerative diseases. Modifiable lifestyle factors may help preserve hippocampal neural tissue (microstructure) and slow down neurodegeneration and thus promote healthy cognition in old age. In this study, we sought to identify potential modifiable lifestyle factors that may help preserve microstructure in the hippocampus. We used data from 494 subjects (36-100 years old) without clinical cognitive impairment from the Human Connectome Project-Aging study. We estimated hippocampal microstructure using myelin-sensitive (T1w/T2w ratio), inflammation-sensitive (MD) and fibre-sensitive (FA) MRI markers. Non-negative matrix factorization was used to integrate the signals of these images into a multivariate spatial signature of microstructure covariance across the hippocampus. The associations between hippocampal microstructural patterns and lifestyle factors & cognition were identified using partial least squares analysis. Our results reveal that the preservation of axon density and myelin in regions corresponding to subicular regions and CA1 to CA3 regions of the hippocampi of younger adults is associated with improved performance in executive function tasks, however, this is also associated with a decreased performance in memory tasks. We also show that microstructure is preserved across the hippocampus when there is normal hearing levels, physical fitness and normal insulin levels in younger adults of our study even in the presence of cardiovascular risk factors like high body mass index, blood pressure, triglycerides and blood glucose known to be associated with hippocampal neurodegeneration. This preservation is not observed in older adults when there are no normal levels of insulin, physical fitness and hearing. Taken together, our results suggest that certain lifestyle factors like normal hearing, physical fitness and normal insulin levels may help preserve hippocampal microstructure which may be useful in maintaining optimum performance on executive function tasks and potentially other modes of cognition.
Unsupervised, piecewise linear decoding enables an accurate prediction of muscle activity in a multi-task brain computer interface
Authors: Ma Xuan , Rizzoglio Fabio , Bodkin Kevin L. , Miller Lee E. 
Published: September 2024

AbstractObjectiveCreating an intracortical brain-computer interface (iBCI) capable of seamless transitions between tasks and contexts would greatly enhance user experience. However, the nonlinearity in neural activity presents challenges to computing a global iBCI decoder. We aimed to develop a method that differs from a globally optimized decoder to address this issue.ApproachWe devised an unsupervised approach that relies on the structure of a low-dimensional neural manifold to implement a piecewise linear decoder. We created a distinctive dataset in which monkeys performed a diverse set of tasks, some trained, others innate, while we recorded neural signals from the motor cortex (M1) and electromyographs (EMGs) from upper limb muscles. We used both linear and nonlinear dimensionality reduction techniques to discover neural manifolds and applied unsupervised algorithms to identify clusters within those spaces. Finally, we fit a linear decoder of EMG for each cluster. A specific decoder was activated corresponding to the cluster each new neural data point belonged to.Main resultsWe found clusters in the neural manifolds corresponding with the different tasks or task sub-phases. The performance of piecewise decoding improved as the number of clusters increased and plateaued gradually. With only two clusters it already outperformed a global linear decoder, and unexpectedly, it outperformed even a global recurrent neural network (RNN) decoder with 10-12 clusters.SignificanceThis study introduced a computationally lightweight solution for creating iBCI decoders that can function effectively across a broad range of tasks. EMG decoding is particularly challenging, as muscle activity is used, under varying contexts, to control interaction forces and limb stiffness, as well as motion. The results suggest that a piecewise linear decoder can provide a good approximation to the nonlinearity between neural activity and motor outputs, a result of our increased understanding of the structure of neural manifolds in motor cortex.
Glassy Surfactants Enable Ultra-High Concentration Biologic Therapeutics
Authors: Jons Carolyn K. , Prossnitz Alexander N. , Eckman Noah , Dong Changxin , Utz Ashley , Appel Eric A. 
Published: September 2024

AbstractProtein therapeutics, like peptides and antibodies, have become critical to healthcare. Despite their exceptional potency and specificity, biopharmaceuticals are prone to aggregation, often necessitating low formulation concentrations as well as cold storage and distribution to maintain stability. Yet, high doses are required to treat many diseases. To achieve these doses, most approved protein drug products are administered intravenously, imposing excessive burdens on patients and the healthcare system. New approaches are needed to formulate proteins at high concentrations to enable less burdensome subcutaneous injection, preferably in an autoinjector format. To address this challenge, we report a subcutaneously injectable biotherapeutic delivery platform composed of spray-dried protein microparticles suspended in a non-solvent liquid carrier. These microparticles contain only active biopharmaceutical agent and a high glass transition temperature polyacrylamide-derived copolymer excipient affording several key benefits over traditional excipients, including: (i) improved stabilization of biopharmaceuticals through the spray drying process, and (ii) improved morphology and properties of the spray-dried particles, enhancing suspension injectability. Experiments with albumin and antibodies demonstrate that this technology enables ultra-high-concentration protein formulations (exceeding 500 mg/mL) that are injectable through standard needles with clinically relevant injection forces. Additionally, experiments in mice with two clinically relevant antibody drugs show these ultra-high- concentration formulations reduce required injection volumes without altering pharmacokinetics or efficacy. This approach could nearly triple the number of commercial protein drugs amenable to subcutaneous administration, dramatically reducing burden and improving access to these critical biopharmaceuticals.One Sentence SummaryHere we leverage a unique copolymer excipient to enable ultra-high concentration protein formulations with improved stability and amenable to subcutaneous injection that can reduce patient burden, lower costs, and improve access to critical drugs.
Attention and Retention Effects of Culturally Targeted Billboard Messages: An Eye-Tracking Study Using Immersive Virtual Reality
Authors: Jeon Moonsun , Lim Sue , Lapinski Maria K. , Spates Stephen A. , Bente Gary , Schmälzle Ralf 
Published: September 2024

AbstractTargeting, the creation of a match between message content and receiver characteristics, is a key strategy in communication message design. Cultural targeting, or adapting message characteristics to be congruent with a group’s cultural knowledge, appearance, or beliefs of recipients, is used in practice and is a potentially effective strategy to boost the relevance of a message, affecting attention to messages and enhancing effects. However, many open questions remain regarding the mechanisms and consequences of targeting. This is partly due to methodological challenges in experimentally manipulating messages that match cultural recipient characteristics while simultaneously measuring effects and balancing experimental control and realism. Here, we used a novel VR-based paradigm in which participants drove along a virtual highway flanked by billboards with varying message designs. Specifically, we manipulated the message design to either match or mismatch peoples’ cultures of origin. We used unobtrusive eye tracking to assess participants’ attention (i.e., for how long and how often they look at matched vs. unmatched billboards). Results show a tendency of the participants to inspect culturally matched billboards more often and for longer. We further found that matched billboards produce better recall, indicating more efficient encoding and storage of the messages. Our results underscore the effectiveness of cultural targeting and demonstrate how researchers can rigorously manipulate relevant message factors using virtual environments. We discuss the implications of these findings regarding theories of cultural targeting and methodological perspectives for the objective measurement of exposure factors through eye tracking.
Longitudinal trajectories of aperiodic EEG activity in early to middle childhood
Authors: Sacks Dashiell D. , Valdes Viviane , Wilkinson Carol L. , Levin April R. , Nelson Charles A. , Enlow Michelle Bosquet 
Published: September 2024

AbstractBackgroundEmerging evidence suggests that aperiodic EEG activity may follow a nonlinear growth trajectory in childhood. However, existing studies are limited by small assessment windows and cross-sectional samples that are unable to fully capture these patterns. The current study aimed to characterize the developmental trajectories of aperiodic activity longitudinally from infancy to middle childhood. We examined potential trajectory differences by sex and brain region. We further investigated whether aperiodic activity is associated with maternal anxiety symptoms, and whether these associations vary because of differential development trajectories.MethodsA community sample of children and their parents (N=391) enrolled in a longitudinal study of emotion processing were assessed at infancy, and at ages 3 years, 5 years, and 7 years. Analyses included individual growth curve and mixed effect models. Developmental trajectories of the aperiodic slope and offset were investigated across whole brain, frontal, central, temporal, and posterior regions. Associations of whole brain slope and offset with maternal anxiety symptoms were also examined.ResultsDevelopmental trajectories for both slope and offset were generally characterized by a relative increase in early childhood and a subsequent decrease or stabilization by age 7, with variation by brain region. Females showed relatively steeper slopes at some ages, and males showed relatively greater offset at certain ages. Maternal anxiety was negatively associated with slope at 3 years and positively associated with slope at 7 years.ConclusionsThe longitudinal developmental trajectory of aperiodic slope in early childhood is nonlinear and shows variation by sex and brain region. The magnitude and direction of associations with maternal anxiety varied by age, corresponding with changes in trajectories. Developmental stage should be considered when interpreting findings related to aperiodic activity in childhood.
Ethograms reveal a fear conditioned visual cue to organize diverse behaviors
Authors: Williams David C. , Chu Amanda , Gordon Nicholas T. , DuBois Aleah M. , Qian Suhui , Valvo Genevieve , Shen Selena , Boyce Jacob B. , Fitzpatrick Anaise C. , Moaddab Mahsa , Russell Emma L. , Counsman Liliuokalani , McDannald Michael A. 
Published: September 2024

AbstractRecognizing and responding to threat cues is essential to survival. In rats, freezing is the most common behavior measured. Previously we demonstrated a threat cue can organize diverse behaviors (Chu et al., 2024). However, the experimental design of Chu et al. (2024) was complex and the findings descriptive. Here, we gave female and male Long Evans rats simple paired or unpaired presentations of a light and foot shock (8 total) in a conditioned suppression setting, using a range of shock intensities (0.15, 0.25, 0.35 or 0.5 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.5 mA). We constructed comprehensive, temporal ethograms by scoring 22,272 frames of behavior for 12 mutually exclusive behavior categories in 200 ms intervals around cue presentation. A 0.5 mA and 0.35 mA shock-paired visual cue suppressed reward seeking, rearing and scaling, as well as light-directed rearing and light-directed scaling. The shock-paired visual paired cue further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Considering the complete ethogram data produced superior classification than considering subsets of behaviors. The results demonstrate diverse threat-elicited behaviors – in a simple Pavlovian fear conditioning design – containing sufficient information to distinguish the fear learning status of individual rats.
Contrasting patterns of specificity and transfer in human odor discrimination learning
Authors: Chang Xiaoyue , Tan Huibang , Niu Jiehui , Yuan Kaiqi , Chen Rui , Zhou Wen 
Published: September 2024

AbstractPractice enhances olfactory performance. However, laboratory studies to date suggest that olfactory learning is largely restricted to the trained odors, posing a significant challenge for training-based rehabilitation therapies for olfactory loss. In this study, we introduce various types of odors to olfactory discrimination training, conducted unilaterally. We demonstrate contrasting patterns of specificity and transfer of learning, independent of adaptation and task difficulty. Individuals trained with odor mixtures of different ratios show long-term perceptual gains that completely transfer to the untrained nostril and effectively generalize to untrained mixtures dissimilar in structure and odor quality from the trained ones. Conversely, those trained with odor enantiomers show no transfer of learning across nostrils or to unrelated enantiomers, replicating our earlier findings (Feng & Zhou, 2019). Our observations indicate that concentration ratio and chirality represent distinct olfactory attributes. Furthermore, discrimination learning occurs at different stages of olfactory processing, depending on which attribute is task-relevant. These findings open up new avenues to enhance the effectiveness of olfactory training.
The cardiac, respiratory and gastric rhythms independently modulate corticospinal excitability
Authors: Engelen Tahnée , Schuhmann Teresa , Sack Alexander T. , Tallon-Baudry Catherine 
Published: September 2024

AbstractInteroception refers to the sensing of the internal state of the body and encompasses various bodily axes. Yet many interoceptive signals display unique qualities. The heart, lungs, and stomach each have their distinct frequencies, afferent pathways, and respective functions. At the same time each of these organs has been demonstrated to interact with neural activity and behaviour. To what extent then should different organs be treated as separate modalities in interoception? We here aim to answer this question by assessing in human participants whether the phase of these visceral rhythms is coupled to the corticospinal excitability of the motor system, and whether this coupling happens in an organ-specific or organ-general manner. We combined continuous physiological recordings with single pulse Transcranial Magnetic Stimulation (TMS) to probe phase-amplitude coupling between the phase of the cardiac, respiratory, and gastric rhythm and the amplitude of Motor Evoked Potentials (MEP). All three visceral rhythms contributed to MEP amplitude with similar effect sizes at the group level. However, we found no relation between coupling strengths with corticospinal excitability between the three organs. Thus, participants displaying high coupling with one organ did not necessarily display high coupling to the other organs, suggestive of unique interoceptive profiles. There was also no link between self-reported awareness of the organ and the actual coupling, suggesting these are distinct dimensions of interoception. Together these results show that each coupling is mediated by at least partially independent mechanisms.
Adult oligodendrogenesis gates arcuate neuronal glucose sensing through remodelling of the blood-hypothalamus barrier via ADAMTS4
Authors: Buller Sophie , Staricoff Emily O. , Riches Christine , Tsang Anthony , Josipovic Masa , Ikemura Kentaro , Opoku Gabriel , Sato Ikumi , Hirohata Satoshi , Stenzel Saskia , Nayar Stuart G. , Vega Marta Ramos , Hecksher-Sørensen Jacob , Timmler Sebastian , Dowsett Georgina K.C. , Lam Brian Y.H. , Yeo Giles S.H. , Alonge Kimberly M. , Li Huiliang , Richardson William D. , Evans Mark L. , Blouet Clemence 
Published: September 2024

AbstractBrain glucose sensing is critical for survival during hypoglycaemia and tunes the level of defended blood glucose, which goes up in diabetes. Neuronal glucose sensing neurons and mechanisms have been identified, but how these neurons access blood concentrations of glucose to adjust their output and maintain glucose homeostasis is unclear. Here, we demonstrate that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. We show that genetic blockade of new OL production in adult mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and neuronal glucose sensing in the arcuate nucleus of the hypothalamus (ARH). Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, newly formed OLs exert their glucoregulatory actions via the synthesis of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase expressed exclusively by OLs and dependent on adult OL genesis to maintain its expression in the ME. Both lack ofAdamts4and ADAMTS4 gain-of-function are associated with impaired glucose homeostasis and remodelling of the blood-hypothalamus barrier, indicating that optimal ADAMTS4 expression is required for the integrity of vascular permeability and normal glycaemic control. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME OLs contribute to the regulation of glucose homeostasis.
Quantitative cytoarchitectural phenotyping of deparaffinized human brain tissues
Authors: Meo Danila Di , Sorelli Michele , Ramazzotti Josephine , Cheli Franco , Bradley Samuel , Perego Laura , Lorenzon Beatrice , Mazzamuto Giacomo , Emmi Aron , Porzionato Andrea , Caro Raffaele De , Garbelli Rita , Biancheri Dalila , Pelorosso Cristiana , Conti Valerio , Guerrini Renzo , Pavone Francesco S. , Costantini Irene 
Published: September 2024

AbstractAdvanced 3D imaging techniques and image segmentation and classification methods can profoundly transform biomedical research by offering deep insights into the cytoarchitecture of the human brain in relation to pathological conditions. Here, we propose a comprehensive pipeline for performing 3D imaging and automated quantitative cellular phenotyping on Formalin-Fixed Paraffin-Embedded (FFPE) human brain specimens, a valuable yet underutilized resource. We exploited the versatility of our method by applying it to different human specimens from both adult and pediatric, normal and abnormal brain regions. Quantitative data on neuronal volume, ellipticity, local density, and spatial clustering level were obtained from a machine learning-based analysis of the 3D cytoarchitectural organization of cells identified by different molecular markers in two subjects with malformations of cortical development (MCD). This approach will grant access to a wide range of physiological and pathological paraffin-embedded clinical specimens, allowing for volumetric imaging and quantitative analysis of human brain samples at cellular resolution. Possible genotype-phenotype correlations can be unveiled, providing new insights into the pathogenesis of various brain diseases and enlarging treatment opportunities.
MITF Targets in Gastrointestinal Stromal Tumors: Implications in Autophagy and Extracellular Vesicle Secretion
Authors: Proaño-Pérez Elizabeth , Serrano-Candelas Eva , Guerrero Mario , Gómez-Peregrina David , Llorens Carlos , Soriano Beatriz , Gámez-Valero Ana , Herrero-Lorenzo Marina , Martí Eulalia , Serrano César , Martin Margarita 
Published: September 2024

ABSTRACTPrevious studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITF’s role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.