bluuebunny/crossref_metadata_2025_split huggingface dataset:
MultiNicheNet: a flexible framework for differential cell-cell communication analysis from multi-sample multi-condition single-cell transcriptomics data
Authors: Browaeys Robin , Gilis Jeroen , Sang-Aram Chananchida , De Bleser Pieter , Hoste Levi , Tavernier Simon , Lambrechts Diether , Seurinck Ruth , Saeys Yvan 
Published: June 2023

AbstractDysregulated cell-cell communication is a hallmark of many disease phenotypes. Due to recent advances in single-cell transcriptomics and computational approaches, it is now possible to study intercellular communication on a genome- and tissue-wide scale. However, most current cell-cell communication inference tools have limitations when analyzing data from multiple samples and conditions. Their main limitation is that they do not address inter-sample heterogeneity adequately, which could lead to false inference. This issue is crucial for analyzing human cohort scRNA-seq datasets, complicating the comparison between healthy and diseased subjects.Therefore, we developed MultiNicheNet (https://github.com/saeyslab/multinichenetr), a novel framework to better analyze cell-cell communication from multi-sample multi-condition single-cell transcriptomics data. The main goals of MultiNicheNet are inferring the differentially expressed and active ligand-receptor pairs between conditions of interest and predicting the putative downstream target genes of these pairs. To achieve this goal, MultiNicheNet applies the principles of state-of-the-art differential expression algorithms for multi-sample scRNA-seq data. As a result, users can analyze differential cell-cell communication while adequately addressing inter-sample heterogeneity, handling complex multifactorial experimental designs, and correcting for batch effects and covariates. Moreover, MultiNicheNet uses NicheNet-v2, our new and substantially improved version of NicheNet’s ligand-receptor network and ligand-target prior knowledge model.We applied MultiNicheNet to patient cohort data of several diseases (breast cancer, squamous cell carcinoma, multisystem inflammatory syndrome in children, and lung fibrosis). For these diseases, MultiNicheNet uncovered known and novel aberrant cell-cell signaling processes. We also demonstrated MultiNicheNet’s potential to perform non-trivial analysis tasks, such as studying between- and within-group differences in cell-cell communication dynamics in response to therapy. As a final example, we used MulitNicheNet to elucidate dysregulated intercellular signaling in idiopathic pulmonary fibrosis while correcting batch effects in integrated atlas data.Given the anticipated increase in multi-sample scRNA-seq datasets due to technological advancements and extensive atlas-building integration efforts, we expect that MultiNicheNet will be a valuable tool to uncover differences in cell-cell communication between healthy and diseased states.
Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma
Authors: Gupta Priyanka , Herring Brendon , Kumar Nilesh , Telange Rahul , Garcia-Buntley Sandra S. , Caceres Tessa W. , Colantonio Simona , Williams Ford , Kurup Pradeep , Carter Angela M. , Lin Diana , Chen Herbert , Rose Bart , Jaskula-Sztul Renata , Mukhtar Shahid , Reddy Sushanth , Bibb James A. 
Published: June 2023

AbstractMechanistic modeling of cancers such as Medullary Thyroid Carcinoma (MTC) to emulate patient-specific phenotypes is challenging. The discovery of potential diagnostic markers and druggable targets in MTC urgently requires clinically relevant animal models. Here we established orthotopic mouse models of MTC driven by aberrantly active Cdk5 using cell-specific promoters. Each of the two models elicits distinct growth differences that recapitulate the less or more aggressive forms of human tumors. The comparative mutational and transcriptomic landscape of tumors revealed significant alterations in mitotic cell cycle processes coupled with the slow-growing tumor phenotype. Conversely, perturbation in metabolic pathways emerged as critical for aggressive tumor growth. Moreover, an overlapping mutational profile was identified between mouse and human tumors. Gene prioritization revealed putative downstream effectors of Cdk5 which may contribute to the slow and aggressive growth in the mouse MTC models. In addition, Cdk5/p25 phosphorylation sites identified as biomarkers for Cdk5-driven neuroendocrine tumors (NETs) were detected in both slow and rapid onset models and were also histologically present in human MTC. Thus, this study directly relates mouse and human MTC models and uncovers vulnerable pathways potentially responsible for differential tumor growth rates. Functional validation of our findings may lead to better prediction of patient-specific personalized combinational therapies.Graphical abstractHighlightsCGRP driven aberrant Cdk5 activation develops early onset aggressive MTCGenetic alterations in mouse and human tumors disrupt common pathwaysAggressive tumor model characterized by alterations in metabolic pathwaysSlow growing tumor model elicits disruption of mitotic spindle assembly
The Single-Cell Transcriptome Program of Nodule Development Cellular Lineages inMedicago truncatula
Authors: Pereira Wendell J. , Boyd Jade , Conde Daniel , Triozzi Paolo M. , Balmant Kelly M. , Dervinis Christopher , Schmidt Henry W. , Boaventura-Novaes Carolina , Chakraborty Sanhita , Knaack Sara A. , Gao Yueyao , Feltus Frank Alexander , Roy Sushmita , Ané Jean-Michel , Frugoli Julia , Kirst Matias 
Published: June 2023

SummaryLegumes can establish a symbiotic relationship with nitrogen-fixing rhizobia by developing nodules after root exposure to lipo-chito-oligosaccharides secreted by the bacteria. Nodule development initiates with anticlinal mitotic divisions in the pericycle and endodermal and inner cortical cells, establishing cell lineages that ultimately form each nodule compartment. We characterized these lineages by isolating and sequencing the transcriptome ofMedicago truncatulasingle nuclei derived from uninoculated roots and roots undergoing early nodule development at 24, 48, and 96 hours after inoculation. To enrich samples for cells responding to the rhizobia, we complemented the analysis of theMedicagowild-type genotype A17 with a mutant for the autoregulation of nodulation,sunn-4. Analysis of cell lineage trajectories derived from the cortex indicates that their transcriptome is initially enriched for cytokinin perception and signaling while repressing auxin accumulation. As these cells differentiate to form nodules, expression of genes related to auxin biosynthesis, transport, and signaling was enhanced, while genes involved in cytokinin degradation were activated as lineages bifurcated to form the nodule meristem and infection zones. While the contribution of auxin and cytokinin in nodule development has been recognized, this single-cell resource quantifies the expression of each of their regulators, receptors and targets as cells divide and differentiate to form each nodule compartment.
Predicting glycan structure from tandem mass spectrometry via deep learning
Authors: Urban James , Jin Chunsheng , Thomsson Kristina A. , Karlsson Niclas G. , Ives Callum M. , Fadda Elisa , Bojar Daniel 
Published: June 2023

AbstractGlycans constitute the most complicated post-translational modification, modulating protein activity in health and disease. However, structural annotation from tandem mass spectrometry data is a bottleneck in glycomics, preventing high-throughput endeavors and relegating glycomics to a few experts. Trained on a newly curated set of 300,000 annotated MS/MS spectra, we present CandyCrunch, a dilated residual neural network predicting glycan structure from raw LC-MS/MS data in seconds (Top1 Accuracy: 87.7%). We developed an open-access Python-based workflow of raw data conversion and prediction, followed by automated curation and fragment annotation, with predictions recapitulating and extending expert annotation. We demonstrate that this can be used forde novoannotation, diagnostic fragment identification, and high-throughput glycomics. For maximum impact, this entire pipeline is tightly interlaced with our glycowork platform and can be easily tested athttps://colab.research.google.com/github/BojarLab/CandyCrunch/blob/main/CandyCru nch.ipynb. We envision CandyCrunch to democratize structural glycomics and the elucidation of biological roles of glycans.
The protein phosphatase PPKL is a key regulator of daughter parasite development inToxoplasma gondii
Authors: Yang Chunlin , Doud Emma H. , Sampson Emily , Arrizabalaga Gustavo 
Published: June 2023

AbstractApicomplexan parasites, includingToxoplasma gondii, encode many plant-like proteins, which play significant roles and present attractive targets for drug development. In this study, we have characterized the plant-like protein phosphatase PPKL, which is unique to the parasite and absent in its mammalian host. We have shown that its localization changes as the parasite divides. In non-dividing parasites, it is present in the cytoplasm, nucleus, and preconoidal region. As the parasite begins division, PPKL is enriched in the preconoidal region and the cortical cytoskeleton of the nascent parasites. Later in the division, PPKL is present in the basal complex ring. Conditional knockdown of PPKL showed that it is essential for parasite propagation. Moreover, parasites lacking PPKL exhibit uncoupling of division, with normal DNA duplication but severe defects in forming daughter parasites. While PPKL depletion does not impair the duplication of centrosomes, it affects the rigidity and arrangement of the cortical microtubules. Both Co-Immunoprecipitation and proximity labeling identified the kinase DYRK1 as a potential functional partner of PPKL. Complete knockout ofDYRK1phenocopies lack of PPKL, strongly suggesting a functional relationship between these two signaling proteins. Global phosphoproteomics analysis revealed a significant increase in phosphorylation of the microtubule-associated proteins SPM1 in PPKL-depleted parasites, suggesting PPKL regulates the cortical microtubules by mediating the phosphorylation state of SPM1. More importantly, the phosphorylation of cell cycle-associated kinase Crk1, a known regulator of daughter cell assembly, is altered in PPKL-depleted parasites. Thus, we propose that PPKL regulates daughter parasite development by influencing the Crk1-dependent signaling pathway.ImportanceToxoplasma gondiican cause severe disease in immunocompromised or immunosuppressed patients and during congenital infections. Treating toxoplasmosis presents enormous challenges since the parasite shares many biological processes with its mammalian hosts, which results in significant side effects with current therapies. Consequently, proteins that are essential and unique to the parasite represent favorable targets for drug development. Interestingly,Toxoplasma, like other members of the phylum Apicomplexa, has numerous plant-like proteins, many of which play crucial roles and do not have equivalents in the mammalian host. In this study, we found that the plant-like protein phosphatase, PPKL, appears to be a key regulator of daughter parasite development. With the depletion of PPKL, the parasite shows severe defects in forming daughter parasites. This study provides novel insights into the understanding of parasite division and offers a new potential target for the development of antiparasitic drugs.
Single-cell transcriptional landscapes of bovine peri-implantation development
Authors: Scatolin Giovanna Nascimento , Ming Hao , Wang Yinjuan , Zhu Linkai , Castillo Emilio Gutierrez , Bondioli Kenneth , Jiang Zongliang 
Published: June 2023

AbstractSupporting healthy pregnancy outcomes requires a comprehensive understanding of the cellular hierarchy and underlying molecular mechanisms during peri-implantation development. Here, we present a single-cell transcriptome-wide view of the bovine peri-implantation embryo development at day 12, 14, 16 and 18, when most of the pregnancy failure occurs in cattle. We defined the development and dynamic progression of cellular composition and gene expression of embryonic disc, hypoblast, and trophoblast lineages during bovine peri-implantation development. Notably, the comprehensive transcriptomic mapping of trophoblast development revealed a previously unrecognized primitive trophoblast cell lineage that is responsible for pregnancy maintenance in bovine prior to the time when binucleate cells emerge. We analyzed novel markers for the cell lineage development during bovine early development. We also identified cell-cell communication signaling underling embryonic and extraembryonic cell interaction to ensure proper early development. Collectively, our work provides foundational information to discover essential biological pathways underpinning bovine peri-implantation development and the molecular causes of the early pregnancy failure during this critical period.Significance StatementPeri-implantation development is essential for successful reproduction in mammalian species, and cattle have a unique process of elongation that proceeds for two weeks prior to implantation and represents a period when many pregnancies fail. Although the bovine embryo elongation has been studied histologically, the essential cellular and molecular factors governing lineage differentiation remain unexplored. This study profiled the transcriptome of single cells in the bovine peri-implantation development throughout day 12, 14, 16, and 18, and identified peri-implantation stage-related features of cell lineages. The candidate regulatory genes, factors, pathways and embryonic and extraembryonic cell interactions were also prioritized to ensure proper embryo elongation in cattle.
Structure and dynamics of endogenous protein complexes in human heart tissue captured by native nanoproteomics
Authors: Chapman Emily A. , Roberts David S. , Tiambeng Timothy N. , Andrews Jãán , Wang Man-Di , Reasoner Emily A. , Melby Jake A. , Li Brad H. , Kim Donguk , Alpert Andrew J. , Jin Song , Ge Ying 
Published: June 2023

AbstractProtein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present tremendous challenges to study using conventional structural biology techniques. Here we develop a “native nanoproteomics” strategy for the native enrichment and subsequent native top-down mass spectrometry (nTDMS) of of low-abundance protein complexes. Specifically, we demonstrate the first comprehensive characterization of the structure and dynamics of cardiac troponin (cTn) complexes directly from human heart tissue. The endogenous cTn complex is effectively enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complexes, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the heterotrimeric cTn complex, localizes Ca2+binding domains (II-IV), defines cTn-Ca2+binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a new paradigm for structural characterization of low-abundance native protein complexes.
Intrinsic Homeostatic Plasticity in Mouse and Human Sensory Neurons
Authors: McIlvried Lisa A. , Del Rosario John Smith , Pullen Melanie Y. , Wangzhou Andi , Sheahan Tayler D. , Shepherd Andrew J. , Slivicki Richard A. , Lemen John A. , Price Theodore J. , Copits Bryan A. , Gereau Robert W. 
Published: June 2023

SUMMARYIn response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons under normal conditions or altered after chronic pain is unknown. Here, we showed that sustained depolarization induced by 30mM KCl induces a compensatory decrease in the excitability in mouse and human sensory neurons. Moreover, voltage-gated sodium currents are robustly reduced in mouse sensory neurons contributing to the overall decrease in neuronal excitability. Decreased efficacy of these homeostatic mechanisms could potentially contribute to the development of the pathophysiology of chronic pain.
SpatialView: An interactive web application for visualization of multiple samples in spatial transcriptomics experiments
Authors: Mohanty Chitrasen , Prasad Aman , Cheng Lingxin , Arkin Lisa M. , Shields Bridget E. , Drolet Beth , Kendziorski Christina 
Published: June 2023

AbstractSpatial transcriptomics (ST) experiments provide spatially localized measurements of genome-wide gene expression allowing for an unprecedented opportunity to investigate cellular heterogeneity and organization within a tissue. Statistical and computational frameworks exist that implement robust methods for pre-processing and analyzing data in ST experiments. However, the lack of an interactive suite of tools for visualizing ST data and results currently limits the full potential of ST experiments. To fill this gap, we developed SpatialView, an open-source web browser-based interactive application for visualizing data and results from multiple 10x Genomics ST experiments. We anticipate SpatialView will be useful to a broad array of clinical and basic science investigators utilizing ST to study disease.AvailabilitySpatialView is available athttps://github.com/kendziorski-lab/SpatialView; a demo application is available athttps://www.biostat.wisc.edu/~kendzior/spatialviewdemo/Contactcmohanty2@wisc.edu,ckendziorski@wisc.eduSupplementary informationSupplementary data are available atBioinformaticsonline.
Impact of inoculation practices on microbiota assembly and community stability in a fabricated ecosystem
Authors: Lin Hsiao-Han , Torres Marta , Adams Catharine A. , Andeer Peter F. , Owens Trenton K. , Zhalnina Kateryna , Jabusch Lauren K. , Carlson Hans K. , Kuehl Jennifer V. , Deutschbauer Adam M. , Northen Trent R. , Glass N. Louise , Mortimer Jenny C. 
Published: June 2023

ABSTRACTStudying plant-microbe-soil interactions is challenging due to their high complexity and variability in natural ecosystems. While fabricated ecosystems provide opportunities to recapitulate aspects of these systems in reduced complexity and controlled environments, inoculation can be a significant source of variation. To tackle this, we evaluated how different bacteria inoculation practices and plant harvesting time points affect the reproducibility of a microbial synthetic community (SynCom) in association with the model grassBrachypodium distachyon. We tested three microbial inoculation practices: seed inoculation, transplant inoculation, and seedling inoculation; and two harvesting points: early (14-day-old plants) and late (21 days post-inoculation). We grew our plants and bacterial strains in sterile devices (EcoFABs) and characterized the microbial community from root, rhizosphere, and sand using 16S ribosomal RNA gene sequencing. The results showed that inoculation practices significantly affected the rhizosphere microbial community only when harvesting at an early time point but not at the late stage. As the SynCom showed a persistent association withB. distachyonat 21 days post-inoculation regardless of inoculation practices, we assessed the reproducibility of each inoculation method and found that transplant inoculation showed the highest reproducibility. Moreover, plant biomass was not adversely affected by transplant inoculation treatment. We concluded that bacteria inoculation while transplanting coupled with a later harvesting time point gives the most reproducible microbial community in the EcoFAB-B. distachyon-SynCom fabricated ecosystem and recommend this method as a standardized protocol for use with fabricated ecosystem experimental systems.
Super-resolution histology of paraffin-embedded samples via photonic chip-based microscopy
Authors: Villegas-Hernández Luis E. , Dubey Vishesh K. , Mao Hong , Pradhan Manohar , Tinguely Jean-Claude , Hansen Daniel H. , Acuña Sebastián , Zapotoczny Bartłomiej , Agarwal Krishna , Nystad Mona , Acharya Ganesh , Fenton Kristin A. , Danielsen Håvard E. , Ahluwalia Balpreet Singh 
Published: June 2023

AbstractFluorescence-based super-resolution optical microscopy (SRM) techniques allow the visualization of biological structures beyond the diffraction limit of conventional microscopes. Despite its successful adoption in cell biology, the integration of SRM into the field of histology has been deferred due to several obstacles. These include limited imaging throughput, high cost, and the need for complex sample preparation. Additionally, the refractive index heterogeneity and high labeling density of commonly available formalin-fixed paraffin-embedded (FFPE) tissue samples pose major challenges to applying existing super-resolution microscopy methods. Here, we demonstrate that photonic chip-based microscopy alleviates several of these challenges and opens avenues for super-resolution imaging of FFPE tissue sections. By illuminating samples through a high refractive-index waveguide material, the photonic chip-based platform enables ultra-thin optical sectioning via evanescent field excitation, which reduces signal scattering and enhances both the signal-to-noise ratio and the contrast. Furthermore, the photonic chip provides decoupled illumination and collection light paths, allowing for total internal reflection fluorescence (TIRF) imaging over large and scalable fields of view. By exploiting the spatiotemporal signal emission via MUSICAL, a fluorescence fluctuation-based super-resolution microscopy (FF-SRM) algorithm, we demonstrate the versatility of this novel microscopy method in achieving superior contrast super-resolution images of diverse FFPE tissue sections derived from human colon, prostate, and placenta. The photonic chip is compatible with routine histological workflows and allows multimodal analysis such as correlative light-electron microscopy (CLEM), offering a promising tool for the adoption of super-resolution imaging of FFPE sections in both research and clinical settings.