bluuebunny/crossref_metadata_2025_split huggingface dataset:
ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer
Authors: Schuhwerk Harald , Menche Constantin , Armstark Isabell , Gupta Pooja , Fuchs Kathrin , van Roey Ruthger , Mosa Mohammed H. , Geppert Carol I. , Bärthel Stefanie , Saur Dieter , Greten Florian R. , Brabletz Simone , Brabletz Thomas , Farin Henner F. , Stemmler Marc P. 
Published: March 2023

AbstractThe EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specificZeb1deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss ofZeb1. Single-cell transcriptomics, histological andin vitrocharacterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation.Zeb1deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, theZeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.
Exponential diversity-dependent diversification emerges from an individual-based model with Lotka-Volterra competition
Authors: Pannetier Théo , Brad Duthie A. , Etienne Rampal S. 
Published: March 2023

AbstractA long-standing question in macroevolution is whether diversification is governed by the same processes that structure diversity at ecological scales, particularly competition. This competition has led to the development of a model where diversification rates depend on diversity, analogous to density-dependence in population growth models. Various versions of this model have been widely used for inference, where the rate of speciation and/or extinction can be either a linear or a power function of species number. It is, however, unknown if either approximates the diversification process that arises from the general ecological setting proposed to lead to diversity-dependence. This is of concern for inference, as failure to include a model that appropriately represents the hypothesized scenario is likely to lead to erroneous inference. Here we use an individual-based model adapted from adaptive dynamics, where fitness is governed by resource availability and the density of competitors, to determine the shape of the diversity-dependence functions. We find that the diversity-dependent rate of speciation produced by the individual-based model is best approximated by an exponential function of species diversity, consistent with a view of macroevolution where diversity increases rapidly after mass extinctions or when new adaptive space becomes available. Although we do find diversity-dependence in the extinction rate, it remains low over the entire process and erases its own signal, so it cannot be recovered from reconstructed phylogenies. The support for a linear relationship for diversity-dependent diversification found in many empirical phylogenies suggests that either our adaptive dynamics model of speciation is inadequate or there is too little information contained in reconstructed phylogenies. We indeed find evidence for the latter when pruning extinct species from our simulated phylogenies, but this does not rule out the former.
Spatial structure, chemotaxis and quorum sensing shape biomass accumulation in complex systems
Authors: Scheidweiler David , Bordoloi Ankur Deep , Sentchilo Vladimir , Bollani Monica , Engel Philipp , de Anna Pietro 
Published: March 2023

AbstractBiological tissues, sediments, or engineered systems are spatially structured media with a tortuous and porous structure that host the flow of fluids. Such complex environments can influence the spatial and temporal colonization patterns of bacteria by controlling the transport of individual bacterial cells, the availability of resources, and the distribution of chemical signals for communication. Yet, due to the multi-scale structure of these complex systems, it is hard to assess how different biotic and abiotic properties work together to control the accumulation of bacterial biomass. Here, we explore how flow mediated interactions allow the gut commensal Escherichia coli to colonize a porous structure that is composed of heterogenous dead-end pores (DEPs) and connecting percolating channels, i.e. transmitting pores (TPs), mimicking the structured surface of mammalian guts. We find that in presence of flow, gradients of the quorum sensing (QS) signaling molecule autoinducer-2 (AI-2) promote E. coli chemotactic accumulation in the DEPs. In this crowded environment, the combination of growth and cell-to-cell collision favors the development of suspended bacterial aggregates. This results in hot-spots of resource consumption, which, upon resource limitation, triggers the mechanical evasion of biomass from glucose and oxygen depleted DEPs. Our findings demonstrate that microscale medium structure and complex flow coupled with bacterial quorum sensing and chemotaxis control the heterogenous accumulation of bacterial biomass in a spatially structured environment, such as villi and crypts in the gut or in tortuous pores within soil and filters.
TheEscherichia colismall heat shock protein IbpA plays a role in regulating the heat shock response by controlling the translation of σ32
Authors: Miwa Tsukumi , Taguchi Hideki 
Published: March 2023

AbstractSmall heat shock proteins (sHsps) act as ATP-independent chaperones that prevent irreversible aggregate formation by sequestering denatured proteins. IbpA, anEscherichia colisHsp, functions not only as a chaperone but also as a suppressor of its own expression through posttranscriptional regulation, contributing to negative feedback regulation. IbpA also regulates the expression of its paralog, IbpB, in a similar manner, but the extent to which IbpA regulates other protein expressions is unclear. We have discovered that IbpA downregulates the expression of many Hsps by repressing the translation of the heat shock transcription factor σ32. The IbpA regulation not only controls the σ32level but also contributes to the shut-off of the heat shock response. These results revealed an unexplored role of IbpA to regulate heat shock response at a translational level, which adds a new layer for tightly controlled and rapid expression of σ32on demand.Significance StatementTo survive during heat shock, cells have a mechanism to induce the synthesis of Hsps and to restore normal levels when the stress subsides. The molecular mechanisms of the heat shock response inE. colihave been extensively studied over the years. The master heat shock transcriptional regulator, σ32, which is normally at low levels due to chaperone-mediated degradation, is increased upon heat shock. Our study has identified a previously unknown factor, IbpA, that regulates the level of σ32by suppressing its expression at a translational level, thereby contributing to the heat shock response regulation.
Delta-dependent Notch activation closes the early neuroblast temporal program to promote lineage progression and neurogenesis termination inDrosophila
Authors: Sood Chhavi , Nahid Md Ausrafuggaman , Branham Kendall R. , Pahl Matthew C. , Doyle Susan E. , Siegrist Sarah E. 
Published: March 2023

SummaryNeuroblasts inDrosophiladivide asymmetrically, sequentially expressing a series of intrinsic factors to generate a diversity of neuron types. These intrinsic factors known as temporal factors dictate timing of neuroblast transitions in response to steroid hormone signaling and specify early versus late temporal fates in neuroblast neuron progeny. After completing their temporal programs, neuroblasts differentiate or die, finalizing both neuron number and type within each neuroblast lineage. From a screen aimed at identifying genes required to terminate neuroblast divisions, we identified Notch and Notch pathway components. When Notch is knocked down, neuroblasts maintain early temporal factor expression longer, delay late temporal factor expression, and continue dividing into adulthood. We find that Delta, expressed in cortex glia, neuroblasts, and after division, their GMC progeny, regulates neuroblast Notch activity. We also find that Delta in neuroblasts is expressed high early, low late, and is controlled by the intrinsic temporal program: early factor Imp promotes Delta, late factors Syp/E93 reduce Delta. Thus, in addition to systemic steroid hormone cues, forward lineage progression is controlled by local cell-cell signaling between neuroblasts and their cortex glia/GMC neighbors: Delta transactivates Notch in neuroblasts bringing the early temporal program and early temporal factor expression to a close.
Fungal melanin suppresses airway epithelial chemokine secretion through blockade of calcium fluxing
Authors: Reedy Jennifer L. , Jensen Kirstine Nolling , Crossen Arianne J. , Basham Kyle J. , Ward Rebecca A. , Reardon Christopher M. , Harding Hannah Brown , Hepworth Olivia W. , Simaku Patricia , Kwaku Geneva N. , Tone Kazuya , Willment Janet A. , Reid Delyth M. , Stappers Mark H.T. , Brown Gordon D. , Rajagopal Jayaraj , Vyas Jatin M. 
Published: March 2023

SummaryRespiratory infections caused by the human fungal pathogenAspergillus fumigatusare a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway bothin vitroandin vivo.Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.
Learning transcriptional and regulatory dynamics driving cancer cell plasticity using neural ODE-based optimal transport
Authors: Tong Alexander , Kuchroo Manik , Gupta Shabarni , Venkat Aarthi , San Juan Beatriz P. , Rangel Laura , Zhu Brandon , Lock John G. , Chaffer Christine L. , Krishnaswamy Smita 
Published: March 2023

AbstractWhile single-cell technologies have allowed scientists to characterize cell states that emerge during cancer progression through temporal sampling, connecting these samples over time and inferring gene-gene relationships that promote cancer plasticity remains a challenge. To address these challenges, we developed TrajectoryNet, a neural ordinary differential equation network that learns continuous dynamics via interpolation of population flows between sampled timepoints. By running causality analysis on the output of TrajectoryNet, we compute rich and complex gene-gene networks that drive pathogenic trajectories forward. Applying this pipeline to scRNAseq data generated fromin vitromodels of breast cancer, we identify and validate a refined CD44hiEPCAM+CAV1+marker profile that improves the identification and isolation of cancer stem cells (CSCs) from bulk cell populations. Studying the cell plasticity trajectories emerging from this population, we identify comprehensive temporal regulatory networks that drive cell fate decisions between an epithelial-to-mesenchymal (EMT) trajectory, and a mesenchymal-to-epithelial (MET) trajectory. Through these studies, we identify and validate estrogen related receptor alpha as a critical mediator of CSC plasticity. We further apply TrajectoryNet to anin vivoxenograft model and demonstrate it’s ability to elucidate trajectories governing primary tumor metastasis to the lung, identifying a dominant EMT trajectory that includes elements of our newly-defined temporal EMT regulatory network. Demonstrated here in cancer, the TrajectoryNet pipeline is a transformative approach to uncovering temporal molecular programs operating in dynamic cell systems from static single-cell data.
Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities
Authors: Garg Vidur , Yang Yang , Nowotschin Sonja , Setty Manu , Kuo Ying-Yi , Sharma Roshan , Polyzos Alexander , Salataj Eralda , Murphy Dylan , Jang Amy , Pe’er Dana , Apostolou Effie , Hadjantonakis Anna-Katerina 
Published: March 2023

SUMMARYTwo distinct fates, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common progenitor cells, the inner cell mass (ICM), in mammalian embryos. To study how these sister identities are forged, we leveraged embryonic (ES) and eXtraembryonicENdoderm (XEN) stem cells –in vitrocounterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses uncovered distinct rates, efficiencies and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4, KLF4 and SOX2-induced XEN-to-iPS reprogramming progressed with diminished efficiency and kinetics. The dominant PrE transcriptional program, safeguarded byGata4, and globally elevated chromatin accessibility of EPI underscored the differential plasticities of the two states. Mappingin vitrotrajectories to embryos revealed reprogramming in either direction tracked along, and toggled between, EPI and PrEin vivostates without transitioning through the ICM.
Nightmare or delight: taxonomic circumscription meets reticulate evolution in the phylogenomic era
Authors: Jin Ze-Tao , Hodel Richard G.J. , Ma Dai-Kun , Wang Hui , Liu Guang-Ning , Ren Chen , Ge Bin-Jie , Fan Qiang , Jin Shui-Hu , Xu Chao , Wu Jun , Liu Bin-Bin 
Published: March 2023

AbstractPhylogenetic studies in the phylogenomics era have demonstrated that reticulate evolution greatly impedes the accuracy of phylogenetic inference, and consequently can obscure taxonomic treatments. However, the systematics community lacks a broadly applicable strategy for taxonomic delimitation in groups identified to have pervasive reticulate evolution. The red-fruit genus,Stranvaesia, provides an ideal model for testing the effect of reticulation on generic circumscription when hybridization and allopolyploidy define a group’s evolutionary history. Here, we conducted phylogenomic analyses integrating data from hundreds of single-copy nuclear (SCN) genes and plastomes, and interrogated nuclear paralogs to clarify the inter/intra-generic relationship ofStranvaesiaand its allies in the framework of Maleae. Analyses of phylogenomic discord and phylogenetic networks showed that allopolyploidization and introgression promoted the origin and diversification of theStranvaesiaclade, a conclusion further bolstered by cytonuclear and gene tree discordance. The well-inferred phylogenetic backbone revealed an updated generic delimitation ofStranvaesiaand a new genus,Weniomeles, characterized by purple-black fruits, trunk and/or branches with thorns, and fruit core with multilocular separated by a layer of sclereids and a cluster of sclereids at the top of the locules. Here, we highlight a broadly-applicable workflow for inferring how analyses of reticulate evolution in phylogenomic data can directly shape taxonomic revisions.
simpleaf: A simple, flexible, and scalable framework for single-cell transcriptomics data processing using alevin-fry
Authors: He Dongze , Patro Rob 
Published: March 2023

AbstractSummaryThealevin-fryecosystem provides a robust and growing suite of programs for single-cell data processing. However, as new single-cell technologies are introduced, as the community continues to adjust best practices for data processing, and as thealevin-fryecosystem itself expands and grows, it is becoming increasingly important to manage the complexity ofalevin-fry’s single-cell preprocessing workflows while retaining the performance and flexibility that make these tools enticing. We introducesimpleaf, a program that simplifies the processing of single-cell data using tools from thealevin-fryecosystem, and adds new functionality and capabilities, while retaining the flexibility and performance of the underlying tools.Availability and implementationSimpleafis written in Rust and released under a BSD 3-Clause license. It is freely available from its GitHub repositoryhttps://github.com/COMBINE-lab/simpleaf, and via bioconda. Documentation forsimpleafis available athttps://simpleaf.readthedocs.io/en/latest/and tutorials forsimpleafare being developed that can be accessed athttps://combine-lab.github.io/alevin-fry-tutorials.
Metabolic Multireactor: practical considerations for using simple oxygen sensing optodes for high-throughput batch reactor metabolism experiments
Authors: Kaufman M.H. , Torgeson J. , Stegen J. C. 
Published: March 2023

AbstractWe present a system for carrying out small batch reactor microbial metabolism experiments on water and sediment samples for environmental questions. In general, it provides several advantages that can help researchers achieve impactful experiments at relatively low costs and high data quality. In particular, it allows for multiple reactors to be operated and their oxygen concentrations to be measured simultaneously, providing high throughput and high time-resolution data, which can be advantageous. Most existing literature on similar small batch-reactor metabolic studies is limited to either only a few samples, or only a few time points per sample, which can restrict the ability for researchers to learn from their experiments.The oxygen sensing system is based very directly on the work of Larsen, et al. [2011], and similar oxygen sensing technology is widely used in the literature. As such we do not delve deeply into the specifics of the fluorescent dye sensing mechanism. Instead, we focus on practical considerations. We describe the construction and operation of the calibration and experimental systems, and answer many of the questions likely to come up when other researchers choose to build and operate a similar system themselves (questions we ourselves had when we first built the system). In this way, we hope to provide an approachable and easy to use research article that can help other researchers construct and operate a similar system that can be tailored to ask their own research questions, with a minimum of confusion and missteps along the way.
AWC mediated behavioral plasticity inC. elegansagainstSalmonellaTyphimurium infection
Authors: Mallick Swarupa , Pradhan Jasmin , Negi Vidya Devi 
Published: March 2023

AbstractSoil-dwelling nematodeCaenorhabditis elegans(C. elegans) is widely found in close vicinity with different types of microbes, including bacteria, fungus, viruses, etc. However, sensing environmental stress, they often undergo a dormant state called dauer for better survival. Our current study aims to decipher chemosensory responses of worms underSalmonellaTyphimurium (WT-STM) infection and how bacterial gene modulating worms’ chemosensory system to mediate dauer larvae development. We initially observed the olfactory preference ofC. eleganstoward the pathogenic WT-STM. Although prolonged exposure showed enhanced lawn occupancy of worms infepBmutantSalmonellastrain with better associative learning response compared to WT-STM counterpart. We also found strong participation of AWC neuron for sensing ΔfepBstrain and mediating worms’ behavioral plasticity. Overall out study implying a relationship between chemosensory neurons and bacteria emitted signals alter worms’ behavioral plasticity which help us to understand complex scenario of host-pathogen interaction.
Accurate long-read sequencing identified GBA variants as a major genetic risk factor in the Luxembourg Parkinson’s study
Authors: Peiris Sinthuja Pachchek , Landoulsi Zied , Pavelka Lukas , Schulte Claudia , Buena-Atienza Elena , Gross Caspar , Hauser Ann-Kathrin , Bobbili Dheeraj Reddy , Casadei Nicolas , May Patrick , Krüger Rejko 
Published: March 2023

AbstractHeterozygous variants in the glucocerebrosidaseGBAgene are an increasingly recognized risk factor for Parkinson’s disease (PD). Due to the pseudogeneGBAP1that shares 96% sequence homology with theGBAcoding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape ofGBA-related PD. We established a novel long-read sequencing technology for assessing the full length of theGBAgene. We used subsequent regression models for genotype-phenotype analyses. We sequenced 752 patients with parkinsonism and 806 healthy controls of the Luxembourg Parkinson’s study. AllGBAvariants identified showed a 100% true positive rate by Sanger validation. We found 12% of unrelated PD patients carryingGBAvariants. Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape ofGBA-related parkinsonism in Luxembourg, showing a high prevalence ofGBAvariants as the major genetic risk for PD. Our approach provides an important advancement for highly accurateGBAvariant calling, which is essential for providing access to emerging causative therapies forGBAcarriers.
Comparison of the classification of HER2 from whole-slide images between pathologists and a deep learning model
Authors: Tsuneki Masayuki , Abe Makoto , Kanavati Fahdi 
Published: March 2023

AbstractHER2 (human epidermal growth factor receptor 2) is a protein that is found on the surface of some cells, including breast cells. HER2 plays a role in cell growth, division, and repair, and when it is overexpressed, it can contribute to the development of certain types of cancer, particularly breast cancer. HER2 overexpression occurs in approximately 20% of cases, and it is associated with more aggressive tumor phenotypes and poorer prognosis. This makes its status an important factor in determining treatment options for breast cancer. While HER2 expression is typically diagnosed through a combination of immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) testing on breast cancer tissue samples, we sought to determine to what extent it is possible to diagnose from H&E-stained specimens. To this effect we trained a deep learning model to classify HER2-positive image patches using a dataset of 10 whole-slide images (5 HER2-positive, 5 HER2-negative). We evaluated the model on a different test set consisting of patches extracted from 10 WSIs (5 HER2-positive, 5 HER2-negative), and we compared the performance against two pathologists on 100 512×512 patches (50 HER2-positive, 50 HER2-negative). Overall, the model achieved an accuracy of 73% while the pathologists achieved 58% and 47%, respectively.