bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalization of deep learning models for predicting spatial gene expression profiles using histology images: A breast cancer case study
Authors: Jiang Yuanhao , Xie Jacky , Tan Xiao , Ye Nan , Nguyen Quan 
Published: September 2023

AbstractSpatial transcriptomics is a breakthrough technology that enables spatially-resolved measurement of molecular profiles in tissues, opening the opportunity for integrated analyses of morphology and transcriptional profiles through paired imaging and gene expression data. However, the high cost of generating data has limited its widespread adoption. Predicting gene expression profiles from histology images only can be an effective and cost-efficientin-silico spatial transcriptomicssolution but is computationally challenging and current methods are limited in model performance. To advance research in this emerging and important field, this study makes the following contributions. We first provide a systematic review of deep learning methods for predicting gene expression profiles from histology images, highlighting similarities and differences in algorithm, model architecture, and data processing pipelines. Second, we performed extensive experiments to evaluate the generalization performance of the reviewed methods on several spatial transcriptomics datasets for breast cancer, where the datasets are generated using different technologies. Lastly, we propose several ideas for model improvement and empirically investigate their effectiveness. Our results shed insight on key features in a neural network model that either improve or not the performance ofin-silico spatial transcriptomics, and we highlight challenges in developing algorithms with strong generalization performance.Key MessagesWe comprehensively compared the performance of existing methods for predicting spatial gene expression profiles from histology imagesWe assessed the roles of different algorithms, model architectures, and data processing pipelines to model performanceWe performed extensive experiments to evaluate the generalization of the models on in-distribution and out-of-distribution spatial transcriptomics datasetsWe proposed several strategies for improving existing models and empirically investigated their effectiveness
The precision of signals encoding active self-movement
Authors: Haynes Joshua D. , Gallagher Maria , Culling John F. , Freeman Tom C.A. 
Published: September 2023

ABSTRACTEveryday actions like moving the head, walking around and reaching out to grasp objects are typically self-controlled. This presents a problem when studying the signals encoding such actions because active self-movement is difficult to experimentally control. Available techniques demand repeatable trials, but each action is unique, making it difficult to measure fundamental properties like psychophysical thresholds. Here, we present a novel paradigm that can be used to recover both precision and bias of self-movement signals with minimal constraint on the participant. The paradigm takes care of a hidden source of external noise not previously accounted for in techniques that link display motion to self-movement in real time (e.g. virtual reality). We use head rotations as an example of self-movement, and show that the precision of the signals encoding head movement depends on whether they are being used to judge visual motion or auditory motion. We find perceived motion is slowed during head movement in both cases, indicating that the ‘non-image’ signals encoding active head rotation (motor commands, proprioception and vestibular cues) are biased to lower speeds and/or displacements. In a second experiment, we trained participants to rotate their heads at different rates and found that the precision of the head rotation signal rises proportionally with head speed (Weber’s Law). We discuss the findings in terms of the different motion cues used by vision and hearing, and the implications they have for Bayesian models of motion perception.NEW AND NOTEWORTHYWe present a psychophysical technique for measuring the precision of signals encoding active self-movements. Using head movements, we show that: (1) precision declines when active head rotation is combined with auditory as opposed to visual motion; (2) precision rises with head speed (Weber’s Law); (3) perceived speed is lower during head movement. The findings may reflect the steps needed to convert different cues into common currencies, and challenge standard Bayesian models of motion perception.
Corticofugal oscillatory modulation of the cochlear receptor during auditory and visual attention in tinnitus
Authors: Martín Rodrigo Donoso-San , Leiva Alexis , Dragicevic Constantino D. , Medel Vicente , Delano Paul H. 
Published: September 2023

AbstractThe mechanisms underlying tinnitus perception are still under research. One of the proposed hypotheses involves an alteration in top-down processing of auditory activity. Low-frequency oscillations in the delta and theta bands have been recently described in brain and cochlear infrasonic signals during selective attention paradigms in normal hearing controls. Here, we propose that the top-down oscillatory activity observed in brain and cochlear signals during auditory and visual selective attention in normal subjects, is altered in tinnitus patients, reflecting an abnormal functioning of the corticofugal pathways that connect brain circuits with the cochlear receptor.Methods:To test this hypothesis, we used a behavioral task that alternates between auditory and visual top-down attention while we simultaneously measured electroencephalogram (EEG) and distortion-product otoacoustic emissions (DPOAE) signals in 14 tinnitus and 14 control subjects.Results:We found oscillatory activity in the delta and theta bands in cortical and cochlear channels in control and tinnitus patients. There were significant decreases in the DPOAE oscillatory amplitude during the visual attention period as compared to the auditory attention period in tinnitus and control groups, while frontal EEG oscillatory activity (Fz) was increased during the visual attention task only in the tinnitus group. The difference between auditory and visual DPOAE oscillatory power in the delta band was stronger in tinnitus individuals as compared to controls.Conclusions:These results confirm the presence of top-down infrasonic low-frequency cochlear oscillatory activity in the delta and theta bands in tinnitus patients. Our results show an increase in the EEG theta oscillatory power in frontal regions of tinnitus sufferers concomitant with a stronger corticofugal suppression of cochlear oscillations in the delta band during visual attention in tinnitus. These findings suggest an increased compensatory corticofugal inhibitory mechanism to the cochlear receptor in tinnitus.
Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to Low-Voltage-Fast onset seizures in Dravet syndrome
Authors: Capitano Fabrizio , Kuchenbuch Mathieu , Lavigne Jennifer , Nabbout Rima , Mantegazza Massimo 
Published: September 2023

AbstractEpilepsies have numerous specific mechanisms. Understanding neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing targeted therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction.We analyzed EEGs from DS patients carrying aSCN1Apathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials and hippocampal single-unit neuronal activities inScn1a+/-knock-out andScn1aRH/+knock-in DS mice.Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal period) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential ofScn1amice and of patients’ EEG, which are consistent with the dysfunctions that we observed in single neurons.Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Spectral features may be used as predictive seizure biomarker.Significance statementDravet syndrome (DS) is caused by mutations of the NaV1.1 sodium channel (SCN1Agene) leading to hypoexcitability of GABAergic interneurons. We found that most of the seizures in both DS patients and mouse models have low-voltage-fast onset, which is instead thought to be generated by hyperactivity of GABAergic neurons. We disclosed a disorganization in the temporal pattern of the firing of single interneurons before the seizure (preictal period), and a rebound hyperactivity at seizure onset. Consistently, the electrographic signal showed a decrease of fast oscillations in the preictal period. Thus, perturbed interneurons’ preictal activity, consistent with the main mechanism of DS, leads to their hyperactivity at seizure onset and induces specific electrographic signatures that may be exploited for seizure prediction.
Enhanced Diffusion through Multivalency
Authors: Bartoš Ladislav , Lund Mikael , Vácha Robert 
Published: September 2023

AbstractIn multivalent systems, multiple ligands from one entity simultaneously bind to multiple receptors on another entity. These interactions are of crucial significance in a wide range of biological and technological mechanisms, encompassing selectivity, host recognition, viral penetration, therapeutic delivery, as well as the adhesion phenomena found in cells, polymers, and nanoparticles. In this study, we used computer simulations to investigate 1D and 2D diffusion of adsorbed particles with varying valency but with the same overall affinity to the host. We demonstrate a remarkable diffusion acceleration for particles with increasing valency. Non-diffusing monovalent particle can attain almost unrestricted diffusion when becoming multivalent while retaining its affinity for the host tether or surface. Moreover, diffusion of multivalent particles with rigid ligand distribution can be controlled by patterned host receptors. Our results have practical implications for the design of fast-diffusing particles that maintain a strong affinity for target surfaces or molecules.TOC GraphicSignificanceWe investigated how the number of binding sites (referred to as valency) on particles or entities impacts their movement when attached to surfaces or filaments. Valency can be understood as how many “hands” a particle has to grip the surface. Surprisingly, particles with more “hands” move faster if they hold onto the surface with the same strength. Furthermore, the motion of these particles can be controlled by designing surfaces with specific patterns that the “hands” can grasp. This means that we can design particles that move rapidly while remaining attached to the desired locations. These findings hold promise for applications like drug delivery and materials technology, and for understanding biological processes.
DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis
Authors: Pal Arun , Grossmann Dajana , Glaß Hannes , Zimyanin Vitaly , Günther René , Catinozzi Marica , Boeckers Tobias M. , Sterneckert Jared , Storkebaum Erik , Petri Susanne , Wegner Florian , Grill Stefan , Pan-Montojo Francisco , Hermann Andreas 
Published: September 2023

AbstractAmyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease leading to death within 2-5 years. Currently available drugs can only slightly prolong survival. Despite the progress that has been achieved in unravelling the molecular mechanisms of the disease so far, the underlying pathophysiology is not fully understood. We present novel insights into the pathophysiology ofSuperoxide Dismutase 1(SOD1)- and in particularFused In Sarcoma(FUS)-ALS by revealing a putatively central role of the Parkinson’s disease (PD) associated glyoxylase DJ-1 and its products glycolic acid (GA) and D-lactic acid (DL). Combined, but not single, treatment with GA and DL restored axonal trafficking deficits of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was accompanied by restoration of mitochondrial membrane potential as well as mitochondrial fragmentation (FUS-ALS) or elongation (SOD1-ALS). Furthermore, GA and DL restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites. We further show that despite presenting an early axonal transport deficiency as well, TDP-43 patient-derived MNs did not share this mechanism. While this points towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different gene variants of ALS. Thus, we introduce a putative novel treatment for ALS based on a combination of the two substances GA and DL which might be not only an interesting novel drug candidate in subsets of ALS cases but also in other neurodegenerative diseases characterized by mitochondrial depolarization.
Label-free, real-time monitoring of membrane binding events at zeptomolar concentrations using frequency-locked optical microresonators
Authors: Gin Adley , Nguyen Phuong-Diem , Melzer Jeffrey E. , Li Cheng , Strzelinski Hannah , Liggett Stephen B. , Su Judith 
Published: September 2023

ABSTRACTBinding events to elements of the cell membrane act as receptors which regulate cellular function and communication and are the targets of many small molecule drug discovery efforts for agonists and antagonists. Conventional techniques to probe these interactions generally require labels and large amounts of receptor to achieve satisfactory sensitivity. Whispering gallery mode microtoroid optical resonators have demonstrated sensitivity to detect single-molecule binding events. Here, we demonstrate the use of frequency-locked optical microtoroids for characterization of membrane interactionsin vitroat zeptomolar concentrations using a supported biomimetic membrane. Arrays of microtoroids were produced using photolithography and subsequently modified with a biomimetic membrane, providing high quality (Q) factors (>106) in aqueous environments. Fluorescent recovery after photobleaching (FRAP) experiments confirmed the retained fluidity of the microtoroid supported-lipid membrane with a diffusion coefficient of 3.38 ± 0.26 μm2·s-1. Utilizing this frequency-locked membrane-on-a-chip model combined with auto-balanced detection and non-linear post-processing techniques, we demonstrate zeptomolar detection levels The binding of Cholera Toxin B-monosialotetrahexosyl ganglioside (GM1) was monitored in real-time, with an apparent equilibrium dissociation constant (kd) = 1.53 nM. The measured affiny of the agonist dynorphin A 1-13 to the κ-opioid receptor revealed a kd= 3.1 nM using the same approach. Radioligand binding competition with dynorphin A 1-13 revealed a Kdin agreement (1.1 nM) with the unlabeled method. The biosensing platform reported herein provides a highly sensitive real-time characterization of membrane embedded protein binding kinetics, that is rapid and label-free, for toxin screening and drug discovery, among other applications.
No support for the effect of tDCS on frontal alpha asymmetry and behavioral and brain activity indices of inhibitory control
Authors: Akil Atakan M. , Cserjési Renáta , Nagy Tamás , Demetrovics Zsolt , Németh Dezső , Logemann H.N. Alexander 
Published: September 2023

AbstractPrior research links self-regulation failure to psychiatric disorders. While the left and right dorsolateral prefrontal cortices are associated with distinct components of self-regulation—approach and inhibitory systems, respectively—existing measures are considered indirect. Our preregistered study explored frontal alpha asymmetry (FAA) as a potential biomarker for self-regulation. We explored whether the assumed effects of transcranial direct current stimulation (tDCS) on behavioral and brain activity indices of inhibitory control are mediated through changes in FAA. We used a randomized controlled sham-feedback design with 65 healthy humans (46 females). Before and after 2 mA anodal tDCS on the right frontal site, we collected resting-state EEG data to assess FAA scores, and participants also completed a stop signal task with neutral and intrinsic reward (food) conditions. The tDCS had no impact on FAA or any behavioral or neural indices of inhibitory control. However, event-related potential analyses revealed a correlation between inhibitory brain activity in the reward condition and trait FAA. Higher right relative to left frontal brain activity was linked to lower early-onset inhibitory activity, possibly originating from the inferior Frontal Gyrus, but correlated with higher late-onset inhibitory control, presumably originating from the superior Frontal Gyrus. While tDCS yielded unexpected outcomes in FAA and inhibitory control metrics, we found an interesting dissociation regarding the lateralization of frontal brain activity and early and late onset inhibitory brain activity.
Insight into differing decision-making strategies that underlie cognitively effort-based decision making using computational modeling in rats
Authors: Hales Claire A. , Silveira Mason M. , Calderhead Lucas , Mortazavi Leili , Hathaway Brett A. , Winstanley Catharine A. 
Published: September 2023

AbstractRationaleThe rat Cognitive Effort Task (rCET), a rodent model of cognitive rather than physical effort, requires animals to choose between an easy or hard visuospatial discrimination, with a correct hard choice more highly rewarded. Like in humans, there is stable individual variation in choice behavior. In previous reports, animals were divided into two groups - workers and slackers - based on their mean preference for the harder option. Although these groups differed in their response to pharmacological challenges, the rationale for using this criterion for grouping was not robust.MethodsWe collated experimental data from multiple cohorts of male and female rats performing the rCET, and used a model-based framework combining drift diffusion modeling with cluster analysis to identify the decision-making processes underlying variation in choice behavior.ResultsWe verified that workers and slackers are statistically different groups, but also found distinct intra-group profiles. These subgroups exhibited dissociable performance during the attentional phase, linked to distinct decision-making profiles during choice. Reanalysis of previous pharmacology data using this model-based framework showed that serotonergic drug effects were explained by changes in decision boundaries and non-decision times, whilst scopolamine’s effects were driven by changes in decision starting points and rates of evidence accumulation.ConclusionsModeling revealed the decision-making processes that are associated with cognitive effort costs, and how these differ across individuals. Reanalysis of drug data provided insight into the mechanisms through which different neurotransmitter systems impact cognitively effortful attention and decision-making processes, with relevance to multiple psychiatric disorders.
Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains
Authors: Zwick Rachel K. , Kasparek Petr , Palikuqi Brisa , Viragova Sara , Weichselbaum Laura , McGinnis Christopher S. , McKinley Kara L. , Rathnayake Asoka , Vaka Dedeepya , Nguyen Vinh , Trentesaux Coralie , Reyes Efren , Gupta Alexander R. , Gartner Zev J. , Locksley Richard M. , Gardner James M. , Itzkovitz Shalev , Boffelli Dario , Klein Ophir D. 
Published: September 2023

AbstractA key aspect of nutrient absorption is the exquisite division of labor across the length of the small intestine, with individual classes of micronutrients taken up at different positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum, and ileum. By examining fine-scale longitudinal segmentation of the mouse and human small intestines, we identified transcriptional signatures and upstream regulatory factors that define five domains of nutrient absorption, distinct from the three traditional sections. Spatially restricted expression programs were most prominent in nutrient-absorbing enterocytes but initially arose in intestinal stem cells residing in three regional populations. While a core signature was maintained across mice and humans with different diets and environments, domain properties were influenced by dietary changes. We established the functions ofPpar-ẟandCdx1in patterning lipid metabolism in distal domains and generated a predictive model of additional transcription factors that direct domain identity. Molecular domain identity can be detected with machine learning, representing the first systematic method to computationally identify specific intestinal regions in mice. These findings provide a foundational framework for the identity and control of longitudinal zonation of absorption along the proximal:distal small intestinal axis.