bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning sequence-based regulatory dynamics in single-cell genomics
Authors: Ibarra Ignacio L. , Schneeberger Johanna , Erdogan Ege , Redl Lennart , Martens Laura , Klein Dominik , Aliee Hananeh , Theis Fabian J. 
Published: August 2024

Epigenomics assays, such as chromatin accessibility, can identify DNA-sequence-specific regulatory factors. Models that predict read counts from sequence features can explain cell-based readouts using specific DNA patterns (genomic motifs) but do not encode the changes in genomic regulation over time, which is crucial for understanding biological events during cell transitions.To bridge this gap, we presentmuBind, a deep learning model that accurately predicts genomic counts of single-cell datasets based on DNA sequence features, their cell-based activities, and cell relationships (graphs) in a single architecture, enhancing the interpretability of cell transitions due to the possibility of inspecting motif activities weighted by nearest neighbors.MuBindshows competitive performance in bulk and single-cell genomics. When complemented with graphs learned from RNA-based dynamical models used as injected priors in our model,muBindenhances through motif-graph interactions the identification of transcriptional regulators explaining cell transition events, including Sox9 in pancreatic endocrinogenesis scATAC-seq, and Gli3/Prdm16 in mouse neurogenesis and human organoids scRNA-seq, both supported by independent evidence, including associations between chromatin and motif activities over pseudotime, TF-gene expression patterns, and biological knowledge of these regulators.muBindadvances our understanding of cell transitions by revealing regulatory motifs and their interactions, providing valuable insights for genomic research and gene regulatory network dynamics. It is available athttps://github.com/theislab/mubind.
Dihydroxyhexanoic acid biosynthesis controls turgor in pathogenic fungi
Authors: Kumakura Naoyoshi , Motoyama Takayuki , Miyazawa Keisuke , Nogawa Toshihiko , Yonehara Katsuma , Sakai Kaori , Ishihama Nobuaki , Matsumori Kaisei , Gan Pamela , Koshino Hiroyuki , Fukuma Takeshi , O’Connell Richard J. , Shirasu Ken 
Published: August 2024

AbstractMany plant pathogenic fungi penetrate host surfaces mechanically, using turgor pressure generated by appressoria, specialized infection cells. These appressoria develop semipermeable cell walls and accumulate osmolytes internally to create turgor by osmosis. While melanin is known to be important for turgor generation, the mechanism for wall semipermeability has remained unclear. Here we identifyPKS2andPBG13, by reverse genetics, as crucial for forming the semipermeable barrier in anthracnose and rice blast fungi. These genes encode enzymes that synthesize 3,5-dihydroxyhexanoic acid polymers essential for the cell wall properties. Deleting these enzymes impairs cell wall porosity, abolishing turgor and pathogenicity without affecting melanization. Our findings uncover a novel mechanism of turgor generation, linking enzyme function to pathogen penetration and disease potential, presenting new targets for disease control.
Deep learning–based automated prediction of mouse seminiferous tubule stage by using bright-field microscopy
Authors: Tokuoka Yuta , Endo Tsutomu , Morikura Takashi , Hiradate Yuki , Ikawa Masahito , Funahashi Akira 
Published: August 2024

AbstractInfertility is a global issue, with approximately 50% of cases attributed to defective spermatogenesis. For studies into spermatogenesis and spermatogenic dysfunction, evaluating the seminiferous tubule stage is essential. However, the current method of evaluation involves labor-intensive and time-consuming manual tasks such as staining, observation, and image analysis. Lack of reproducibility is also a problem owing to the subjective nature of visual evaluation by experts. In this study, we propose a deep learning–based method for automatically and objectively evaluating the seminiferous tubule stage. Our approach automatically predicts which of 12 seminiferous tubule stages is represented in bright-field microscopic images of mouse seminiferous tubules stained by hematoxylin-PAS. For training and validation of our model, we created a dataset of 1229 tissue images, each labeled with one of 12 distinct seminiferous tubule stages. The maximum prediction accuracy was 79.58% which rose to 98.33% with allowance for a prediction error of ±1 stage. Remarkably, although the model was not explicitly trained on the patterns of transition between stages, it inferred characteristic structural patterns involved in the process of spermatogenesis. This method not only advances our understanding of spermatogenesis but also holds promise for improving the automated diagnosis of infertility.
Cortisol dynamics and GR-dependent feedback regulation in zebrafish larvae exposed to repeated stress
Authors: Castillo-Ramírez Luis A. , Ryu Soojin , De Marco Rodrigo J. 
Published: August 2024

AbstractZebrafish larvae show a rapid increase in cortisol in response to acute stressors, followed by a decline. While these responses are documented, both the duration of the refractory period to repeated stressors and the role of glucocorticoid receptors (GR) in specific phases of the glucocorticoid negative feedback are still being clarified. We explored these questions using water vortices as stressors, combined with GR blockage and measurements of whole-body cortisol in zebrafish larvae subjected to single and repeated stress protocols. Cortisol levels were elevated 10 minutes after stress onset and returned to baseline within 30-40 minutes, depending on the stressor strength. In response to homotypic stress, cortisol levels rose above baseline if the second stressor occurred 60 or 120 minutes after the first, but not with a 30-minute interval. This suggests a rapid cortisol-mediated feedback loop with a refractory period of at least 30 minutes. Treatment with a GR blocker delayed the return to baseline and suppressed the refractory period, indicating GR-dependent early-phase feedback regulation. These findings are consistent with mammalian models and provide a framework for further analyses of early-life cortisol responses and feedback in zebrafish larvae, ideal for non-invasive imaging and high-throughput screening.Summary statementThis study investigates cortisol responses in zebrafish larvae to acute stress, revealing a rapid feedback loop and the glucocorticoid receptor’s role, offering insights for future research in stress biology.
On the rate-limiting dynamics of force development in muscle
Authors: van der Zee Tim J. , Wong Jeremy D. , Kuo Arthur D. 
Published: August 2024

AbstractSkeletal muscles produce forces relatively slowly compared to the action potentials that excite them. The dynamics of force production are governed by multiple processes, such as calcium activation, cycling of crossbridges between myofilaments, and contraction against elastic tissues and the body. These processes have been included piecemeal in some muscle models, but not integrated to reveal which are the most rate limiting. We therefore examined their integrative contributions to force development in two conventional types of muscle models—Hill-type and crossbridge. We found that no combination of these processes can self-consistently reproduce classic data such as twitch and tetanus. Rather, additional dynamics are needed following calcium activation and facilitating crossbridge cycling, such as for cooperative myofilament interaction and reconfiguration. We provisionally lump such processes into a simple first-order model of “force facilitation dynamics” that integrate into a crossbridge-type muscle model. The proposed model self-consistently reproduces force development for a range of excitations including twitch and tetanus and electromyography-to-force curves. The model’s step response reveals relatively small timing contributions of calcium activation (3%), crossbridge cycling (3%), and contraction (27%) to overall force development of human quadriceps, with a remainder (67%) explained by force facilitation. The same set of model parameters predicts the change in force magnitude (gain) and timing (phase delay) as a function of excitatory firing rate, or as a function of cyclic contraction frequency. Although experiments are necessary to reveal the dynamics of muscle, integrative models are useful for identifying the main rate-limiting processes.Summary statementMuscles produce forces relatively slowly, not explained by conventional muscle processes. Quantitative modeling suggests that an intermediate process facilitating force development may be rate limiting.
scACCorDiON: A clustering approach for explainable patient level cell cell communication graph analysis
Authors: Nagai James S. , Schaub Michael T. , G.Costa Ivan 
Published: August 2024

ABSTRACTMotivationThe combination of single-cell sequencing with ligand-receptor analysis paves the way for the characterization of cell communication events in complex tissues. In particular, directed weighted graphs stand out as a natural representation of cell-cell communication events. However, current computational methods cannot analyze sample-specific cell-cell communication events, as measured in single-cell data produced in large patient cohorts. Cohort-based cell-cell communication analysis presents many challenges, such as the non-linear nature of cell-cell communication and the high variability presented by the patient-specific single-cell RNAseq datasets.ResultsHere, we present scACCorDiON (single-cell Analysis of Cell-Cell Communication in Disease clusters using Optimal transport in Directed Networks), an optimal transport algorithm exploring node distances on the Markov Chain as the ground metric between directed weighted graphs. Additionally, we derive ak-barycenter algorithm using the Wasserstein-based distance, which is able to cluster directed weighted graphs. We compare our approach with competing methods in several large cohorts of scRNA-seq data. Our results show that scACCorDiON can predict clusters better, matching the disease status of samples. Moreover, we show that barycenters provide a robust and explainable representation of cell cell communication events related to the detected clusters. We also provide a case study of pancreas adenocarcinoma, where scACCorDion detects a sub-cluster of disease samples associated with changes in the tumor microenvironment.AvailabilityThe code of scACCorDiON is available athttps://scaccordion.readthedocs.io/en/latestContactivan.costa@rwth-aachen.de
Selective injury of thalamocortical tract in neonatal rats impairs forelimb use: model validation and behavioral effects
Authors: Wen Tong Chun , Corkrum Michelle , Carmel Jason B. 
Published: August 2024

AbstractUnilateral brain injury in neonates results in largely contralateral hand function in children. Most research investigating neurorehabilitation targets for movement recovery has focused on the effects of brain injury on descending motor systems, especially the corticospinal tract. However, a recent human study demonstrated that sensory tract injury may have larger effects on dexterity than motor tract injury. To validate that the sensory tract injury impairs dexterity, we modeled the most common site of sensory tract injury in neonates by targeting the thalamocortical tract. In the postnatal day 7 rats, we used three types of lesions to the thalamocortical tract: periventricular blood injection, photothrombotic lesion, and electrolytic lesion. To test the sensitivity and specificity of these techniques, viral tracers were injected into the primary sensory or motor cortex immediately after injury. Electrolytic lesions were the most specific and reproducible for inducing a lesion compared to the other two methods. Electrolytic lesions disrupted 63% of the thalamocortical tract, while sparing the adjacent corticospinal tract in the internal capsule. To measure the impact on dexterity, the cylinder exploration and pasta handling tests were used to test the changes of forelimb use at 8 weeks after injury when the rats reached maturity. Lesions to the thalamocortical tract were associated with a significant decrease in the use of the contralateral forelimb in the cylinder task, and the degree of impairment positively correlated with the degree of injury. Overall, specific sensory system lesions of the thalamocortical tract impair forelimb use, suggesting a key role for skilled movement.
Stability of cross-sensory input to primary somatosensory cortex across experience
Authors: Kato Daniel D , Bruno Randy M 
Published: August 2024

AbstractMerging information from across sensory modalities is key to forming robust, disambiguated percepts of the world, yet how the brain achieves this feat remains unclear. Recent observations of cross-modal influences in primary sensory cortical areas have suggested that multisensory integration may occur in the earliest stages of cortical processing, but the role of these responses is still poorly understood. We address these questions by testing several hypotheses about the possible functions served by auditory influences on the barrel field of mouse primary somatosensory cortex (S1) usingin vivo2-photon calcium imaging. We observed sound-evoked spiking activity in a small fraction of cells overall, and moreover that this sparse activity was insufficient to encode auditory stimulus identity; few cells responded preferentially to one sound or another, and a linear classifier trained to decode auditory stimuli from population activity performed barely above chance. Moreover S1 did not encode information about specific audio-tactile feature conjunctions that we tested. Our ability to decode auditory audio-tactile stimuli from neural activity remained unchanged after both passive experience and reinforcement. Collectively, these results suggest that while a primary sensory cortex is highly plastic with regard to its own modality, the influence of other modalities are remarkably stable and play a largely stimulus-non-specific role.
Mapping Eelgrass Cover and Biomass at Izembek Lagoon, Alaska, Using In-situ Field Data and Sentinel-2 Satellite Imagery
Authors: Douglas David C. , Fleming Michael D. , Patil Vijay P. , Ward David H. 
Published: August 2024

AbstractTwo eelgrass (Zostera marina) maps of Izembek Lagoon, Alaska, were generated by first creating maps of spectrally unique classes from each of two Sentinel-2 satellite images collected on July 1, 2016, and August 14, 2020, then attributing the spectral classes with information about eelgrass conditions based on field data. Maps depicting various eelgrass metrics, such as percent cover and modeled biomass, were generated using summaries of the ground data that spatially intersected each spectral class. Comparisons between the 2016 and 2020 Sentinel-2 maps of eelgrass distributional extent, as well as a 2006 Landsat map, indicated that areas where eelgrass presence may have declined between 2006 and 2020 were most prevalent in the central part Izembek Lagoon, while areas of possible biomass decline were more prevalent in the southern part between 2016 and 2020. Monitoring eelgrass conditions at Izembek Lagoon with satellite imagery and concurrent ground data provides capabilities for making comparisons over time, but the influences of tide levels, growing season phenology, and spatiotemporal co-registration accuracy should be considered when designing and interpreting change detection analyses.
Identity-by-descent (IBD) segment outlier detection in endogamous populations using pedigree cohorts
Authors: Tan Shi Jie Samuel , Dang Huyen Trang , Keim Sarah , Bućan Maja , Mathieson Sara 
Published: August 2024

AbstractGenomic segments that are inherited from a common ancestor are referred to as identical-by-descent (IBD). Because these segments are inherited, they not only allow us to study diseases, population characteristics, and the sharing of rare variants, but also understand hidden familial relationships within populations. Over the past two decades, various IBD finding algorithms have been developed using hidden Markov models (HMMs), hashing and extension, and Burrows-Wheeler Transform (BWT) approaches. In this study, we investigate the utility of pedigree information in IBD outlier detection methods for endogamous populations. With the increasing prevalence of computationally efficient sequencing technology and proper documentation of pedigree structures, we expect complete pedigree information to become readily available for more populations. While IBD segments have been used toreconstructpedigrees, because we now have access to the pedigree, it is a natural question to ask if including pedigree information would substantially improve IBD segment finding for the purpose of studying inheritance. We propose an IBD pruning algorithm for reducing the number of false positives in IBD segments detected by existing software. While existing software already identify IBD segments with high success rates, our algorithm analyzes the familial relationships between cohorts of individuals who are initially hypothesized to share IBD segments to remove outliers. Our algorithm is inspired by a k-Nearest Neighbors (kNN) approach with a novel distance metric for pedigrees with loops. We apply our method to simulated genomic data under an Amish pedigree, but it could be applied to pedigrees from other human populations as well as domesticated animals such as dogs and cattle.
Calculation of minimum energy pathways in transport proteins
Authors: Yorke Briony A , Ginn Helen M 
Published: August 2024

1AbstractDiverse conformations of highly populated protein metastable states are well-studied, but the fleeting transitions between these states cannot be observed by experimental methods or molecular dynamics simulations. To address this, we present a computationally inexpensive algorithm, “cold-inbetweening”, which generates trajectories in torsion angle space, by minimising the overall kinetic energy needed to complete a transition between experimentally determined end-states. Here we demonstrate the application of cold-inbetweening to provide mechanistic insight into the ubiquitous alternate access model of operation in three membrane transporter superfamilies. The model proposes mutually exclusive outward and inward pore opening, allowing ligand translocation but preventing damage from free solvent flow. Here, we study DraNramp fromDeinococcus radiodurians, MalT fromBacillus cereus, and MATE fromPyrococcus furiosus. In MalT, the trajectory demonstrates elevator transport through unwinding of a supporter arm helix, maintaining adequate space to transport maltose. In DraNramp, outward-gate closure occurs prior to inward-gate opening, in agreement with the alternate access model. In the MATE transporter, switching conformation involves obligatory rewinding of an extended N-terminal helix to avoid steric backbone clashes. This concurrently plugs the cavernous ligand-binding site during the conformational change. More generally, cold-inbetweening can be used to inform hypotheses about large functionally relevant conformational changes.
Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas
Authors: Jeong Daeun , Danielli Sara G. , Maaß Kendra K. , Ghasemi David R. , Tetzlaff Svenja K. , Reyhan Ekin , Oliveira de Biagi-Junior Carlos Alberto , Neyazi Sina , Nascimento Andrezza , Haase Rebecca , Lo Cascio Costanza , Englinger Bernhard , Jiang Li , Nguyen Cuong M. , Baumgartner Alicia-Christina , Castellani Sophia , Rozowsky Jacob S. , Hack Olivia A. , Shaw McKenzie L. , Lotsch-Gojo Daniela , Bruckner Katharina , Pfister Stefan M. , Kool Marcel , Nowakowski Tomasz J. , Gojo Johannes , Baird Lissa , Alexandrescu Sanda , Pajtler Kristian W. , Venkataramani Varun , Filbin Mariella G. 
Published: August 2024

AbstractSupratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types and segregate into molecularly and clinically distinct subgroups, suggesting different developmental roots. The developmental signatures as well as microenvironmental factors underlying aberrant cellular transformation and behavior across each supratentorial ependymoma subgroup are unknown. Here we integrated single cell- and spatial transcriptomics, as well asin vitroandin vivolive-cell imaging to define supratentorial ependymoma cell states, spatial organization, and dynamic behavior within the neural microenvironment. We find that individual tumor subgroups harbor two distinct progenitor-like cell states reminiscent of early human brain development and diverge in the extent of neuronal or ependymal differentiation. We further uncover several modes of spatial organization of these tumors, including a high order architecture influenced by mesenchymal and hypoxia signatures. Finally, we identify an unappreciated role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and invasion mechanisms. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumor heterogeneity in supratentorial ependymoma and its potential clinical implications.
A minimal mathematical model for polarity establishment and centralspindlin-independent cytokinesis
Authors: Maxian Ondrej , Longhini Katrina M , Glotzer Michael 
Published: August 2024

AbstractCell polarization and cytokinesis are fundamental processes in organismal development. In theCaenorhabditis elegansmodel system, both processes are partially driven by a local inhibition of contractility at the cell poles. Polarization is triggered by centrosome-directed, local inhibition of cortical contractility at what becomes the posterior pole, inducing cortical flows towards the anterior. In cytokinesis, spindle elongation-dependent astral relaxation combines with centralspindlin-induced accumulation of myosin at the cell equator to set up a robust contractility gradient. During both processes, inhibition of contractility occurs through Aurora A (AIR-1) kinase, which is activated on the centrosomes and diffuses to the cortex, where it inhibits the guanine nucleotide exchange factor (GEF) ECT-2, which generates actomyosin-based contractility by activating the GTPase RHO-1. While these biochemical processes have been characterized experimentally, a quantitative understanding of how this circuit drives cortical dynamics in polarization and cytokinesis is still lacking. Here, we construct a mathematical model to test whether a minimal set of well characterized, essential elements are necessary and sufficient to explain the spatiotemporal dynamics of AIR-1, ECT-2, and myosin during polarization and cytokinesis ofC. elegans. We show that robust establishment of polarity can be obtained in response to a weak AIR-1 signal, and demonstrate the relevance of rapid ECT-2 exchange and a persistent AIR-1 cue during polarization. The tuned model also correctly predicts previously-observed ultrasensitive ECT-2 dynamics during cytokinesis, suggesting quantitatively that the same minimal circuit operates in both processes.