bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of environment on the evolution and proliferation of protocells of increasing complexity
Authors: Roy Suvam , Sengupta Supratim 
Published: July 2022

AbstractThe formation, growth, division and proliferation of protocells containing RNA strands is an important step in ensuring the viability of a mixed RNA-lipid world. Experiments and computer simulations indicate that RNA encapsulated inside protocells can favour the protocell promoting its growth while protecting the system from being over-run by parasites. Recent work has also shown the rolling-circle replication mechanism can be harnessed to ensure rapid growth of RNA strands and probabilistic emergence and proliferation of protocells with functionally diverse ribozymes. Despite these advances in our understanding of a primordial RNA-lipid world, key questions remain about the ideal environment for formation of protocells and its role in regulating the proliferation of functionally complex protocells. The hot spring hypothesis suggests that mineral-rich regions near hot-springs, subject to dry-wet cycles provide an ideal environment for the origin of primitive protocells. We develop a computational model to study protocellular evolution in such environments that are distinguished by the occurrence of three distinct phases, a wet phase, followed by a gel phase, and subsequently by a dry phase. We determine the conditions under which protocells containing multiple types of ribozymes can evolve and proliferate in such regions. We find that diffusion in the gel-phase can inhibit the proliferation of complex protocells with the extent of inhibition being most significant when a small fraction of protocells is eliminated during environmental cycling. Our work clarifies how the environment can shape the evolution and proliferation of complex protocells.
Myeloid mechano-metabolic programming restricts anti-tumor immunity
Authors: Tharp K.M. , Kersten K. , Maller O.M. , Timblin G.A. , Stashko C. , Canale F.P. , Hayward M-K. , Berestjuk I. , ten Hoeve-Scott J. , Samad B. , Ironside A.J. , Geiger R. , Combes A.J. , Weaver V.M. 
Published: July 2022

AbstractTumor progression is accompanied by fibrosis, which is associated with diminished anti-tumor immune infiltrate. Here, we demonstrate that tumor infiltrating myeloid cells respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a TGF-beta (TGFβ)-directed, collagen biosynthesis program. A collateral effect of this programming is an untenable metabolic milieu for productive CD8 T cell anti-tumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline, and secrete ornithine that compromises CD8+T cell function. Thus, a stiff and fibrotic TME may impede anti-tumor immunity not only by direct physical exclusion of CD8+T cells, but also via secondary effects of a myeloid mechano-metabolic programming we identified that creates an inhospitable metabolic milieu for CD8+T cells.
Telomere dysfunction impairs intestinal differentiation and predisposes to diet-induced colitis
Authors: Engevik Mindy , Guo Lei , Song Won-Suk , Chronowski Christopher G , Akhanov Viktor , Bosquez Navish , Engevik Amy C. , Oezguen Numan , Coarfa Cristian , Putluri Nagireddy , Catic Andre , Baur Joseph A. , Finegold Milton , Shroyer Noah , Gu Jianhua , Ferraris Ronaldo P. , Halliday Jennifer A , Herman Christophe , Colla Simona , Dierick Herman , Jang Cholsoon , Sahin Ergun 
Published: July 2022

AbstractIntestinal epithelium dysfunction causes barrier defects, malabsorption and dysbiosis, predicting local and systemic disease, morbidity and mortality in humans. However, the underlying causes are not well understood. Here we show that telomere shortening is a host intrinsic factor that impairs enterocyte differentiation. The presence of such undifferentiated enterocytes is associated with barrier disruption and malabsorption of nutrients, such as fructose. A fructose-rich diet causes increased fructose spillover to the colon and induces colitis in a microbiome-dependent manner. The microbiome uses fructose to synthesize essential metabolites, including NAD precursors, that complement the host’s low NAD pool in the inflamed colon. Thus, telomere shortening drives enterocyte dysfunction and predisposes to diet-induced colitis through barrier disruption, increased nutrient flux to the colon and modulation of the microbiome. This differerentiation defect expands the canonical stem cell failure-centered view of how telomere shortening impacts the intestine and predisposes to intestinal disease in conditions associated with short telomeres.
AlphaPeptDeep: A modular deep learning framework to predict peptide properties for proteomics
Authors: Zeng Wen-Feng , Zhou Xie-Xuan , Willems Sander , Ammar Constantin , Wahle Maria , Bludau Isabell , Voytik Eugenia , Strauss Maximillian T. , Mann Matthias 
Published: July 2022

AbstractMachine learning and in particular deep learning (DL) are increasingly important in mass spectrometry (MS)-based proteomics. Recent DL models can predict the retention time, ion mobility and fragment intensities of a peptide just from the amino acid sequence with good accuracy. However, DL is a very rapidly developing field with new neural network architectures frequently appearing, which are challenging to incorporate for proteomics researchers. Here we introduce AlphaPeptDeep, a modular Python framework built on the PyTorch DL library that learns and predicts the properties of peptides (https://github.com/MannLabs/alphapeptdeep). It features a model shop that enables non-specialists to create models in just a few lines of code. AlphaPeptDeep represents post-translational modifications in a generic manner, even if only the chemical composition is known. Extensive use of transfer learning obviates the need for large data sets to refine models for particular experimental conditions. The AlphaPeptDeep models for predicting retention time, collisional cross sections and fragment intensities are at least on par with existing tools. Additional sequence-based properties can also be predicted by AlphaPeptDeep, as demonstrated with a novel HLA peptide prediction model to improve HLA peptide identification for data-independent acquisition.
In-line swimming dynamics revealed by fish interacting with a robotic mechanism
Authors: Thandiackal Robin , Lauder George V. 
Published: July 2022

ABSTRACTSchooling in fish is linked to a number of factors such as increased foraging success, predator avoidance, and social interactions. In addition, a prevailing hypothesis is that swimming in groups provides energetic benefits through hydrodynamic interactions. Thrust wakes are frequently occurring flow structures in fish schools as they are shed behind swimming fish. Despite increased flow speeds in these wakes, recent modelling work has suggested that swimming directly in-line behind an individual may lead to increased efficiency. However, no data are available on live fish interacting with thrust wakes. Here we designed a controlled experiment in which brook trout, Salvelinus fontinalis, interact with thrust wakes generated by a robotic mechanism that produces a fish-like wake. We show that trout swim in thrust wakes, reduce their tail-beat frequencies, and synchronize with the robotic flapping mechanism. Our flow and pressure field analysis revealed that the trout are interacting with oncoming vortices and that they exhibit reduced pressure drag at the head compared to swimming in isolation. Together, these experiments suggest that trout swim energetically more efficiently in thrust wakes and support the hypothesis that swimming in the wake of one another is an advantageous strategy to save energy in a school.
Arabidopsis uses a molecular grounding mechanism and a biophysical circuit breaker to limit floral abscission signaling
Authors: Taylor Isaiah W. , Patharkar O. Rahul , Mijar Medhavinee , Hsu Che-Wei , Baer John , Niederhuth Chad E. , Ohler Uwe , Benfey Philip N. , Walker John C. 
Published: July 2022

AbstractAbscission is the programmed separation of plant organs. It is widespread in the plant kingdom with important functions in development and environmental response. In Arabidopsis, abscission of floral organs (sepals, petals, and stamens) is controlled by two receptor-like protein kinases HAESA (HAE) and HAESA LIKE-2 (HSL2), which orchestrate the programmed dissolution of the abscission zone connecting floral organs to the developing fruit. In this work, we use single-cell RNA-Sequencing to characterize the coreHAE/HSL2abscission gene expression program. We identify theMAP KINASE PHOSPHATASE-1/MKP1gene as a negative regulator of this pathway. MKP1 acts prior to activation of HAE/HSL2 signaling to establish a signaling threshold required for the initiation of abscission. By analogy to electrical circuit control, we liken MKP1 to a molecular grounding mechanism that dissipates errant pathway activation absent HAE/HSL2 signaling. Furthermore, we use single-cell data to identify genes expressed in two sub-populations of abscission zone cells: those proximal and those distal to the plane of separation. We identifyINFLORESCENCE DEFICIENT IN ABSCISSION/IDA, encoding the activating ligand of HAE/HSL2, as one of the mRNAs most highly enriched in distal abscission zone cells at the base of the abscising organs. We show how this expression pattern forms a biophysical circuit breaker whereby, when the organ is shed, the source of the IDA peptide is removed, leading to cessation of HAE/HSL2 signaling. Overall, this work provides insight into the multiple control mechanisms acting on the abscission-signaling pathway.
Modulatory dynamics of periodic and aperiodic activity in respiration-brain coupling
Authors: Kluger Daniel S. , Forster Carina , Abbasi Omid , Chalas Nikos , Villringer Arno , Gross Joachim 
Published: July 2022

AbstractBodily rhythms such as respiration are increasingly acknowledged to modulate neural oscillations underlying human action, perception, and cognition. Conversely, the link between respiration and aperiodic brain activity – a non-oscillatory reflection of excitation-inhibition (E:I) balance – has remained unstudied. Aiming to disentangle potential respiration-related dynamics of periodic and aperiodic activity, we applied recently developed algorithms of time-resolved parameter estimation to resting-state MEG and EEG data from two labs (total N = 78 participants). We provide evidence that fluctuations of aperiodic brain activity (1/f slope) are phase-locked to the respiratory cycle, which suggests that spontaneous state shifts of excitation-inhibition balance are at least partly influenced by peripheral bodily signals. Moreover, differential temporal dynamics in their coupling to non-oscillatory and oscillatory activity raise the possibility of a functional distinction in the way each component is related to respiration. Our findings highlight the role of respiration as a physiological influence on brain signalling.
Trade-off between conservation of biological variation and batch effect removal in deep generative modeling for single-cell transcriptomics
Authors: Li Hui , McCarthy Davis J. , Shim Heejung , Wei Susan 
Published: July 2022

AbstractSingle-cell RNA sequencing (scRNA-seq) technology has contributed significantly to diverse research areas in biology, from cancer to development. Since scRNA-seq data is high-dimensional, a common strategy is to learn low-dimensional latent representations better to understand overall structure in the data. In this work, we build upon scVI, a powerful deep generative model which can learn biologically meaningful latent representations, but which has limited explicit control of batch effects. Rather than prioritizing batch effect removal over conservation of biological variation, or vice versa, our goal is to provide a bird’s eye view of the trade-offs between these two conflicting objectives. Specifically, using the well established concept of Pareto front from economics and engineering, we seek to learn the entire trade-off curve between conservation of biological variation and removal of batch effects.A multi-objective optimisation technique known as Pareto multi-task learning (Pareto MTL) is used to obtain the Pareto front between conservation of biological variation and batch effect removal. Our results indicate Pareto MTL can obtain a better Pareto front than the naive scalarization approach typically encountered in the literature. In addition, we propose to measure batch effect by applying a neural-network based estimator called Mutual Information Neural Estimation (MINE) and show benefits over the more standard Maximum Mean Discrepancy (MMD) measure. The Pareto front between conservation of biological variation and batch effect removal is a valuable tool for researchers in computational biology. Our results demonstrate the efficacy of applying Pareto MTL to estimate the Pareto front in conjunction with applying MINE to measure the batch effect.
Multisite gating in tonic sensory circuits integrates multimodal context to control persistent behavioral states
Authors: Thapliyal Saurabh , Beets Isabel , Glauser Dominique A. 
Published: July 2022

ABSTRACTMaintaining or shifting between behavioral states according to context is essential for animals to implement fitness-promoting strategies. How integration of internal state, past experience and sensory inputs orchestrate persistent multidimensional behavior changes remains poorly understood. Here, we show that C. elegans integrates food availability and environment temperature over different timescales to engage in persistent dwelling, scanning, global or glocal search strategies matching thermoregulatory and feeding needs. Transition between states, in each case, requires lifting multiple regulatory gates including AFD or FLP tonic sensory neurons activity, neuropeptide expression and downstream circuit responsiveness. State-specific FLP-6 or FLP-5 neuropeptide signaling acts on a distributed set of inhibitory receptors to promote scanning or glocal search, respectively, bypassing dopamine and glutamate-dependent behavioral state control. Multisite gating-dependent behavioral switch by GPCRs in tonic sensory circuits might represent a conserved regulatory logic for persistent behavioral state transitions enabling a flexible prioritization on the valance of multiple inputs.
Early Path Dominance as a Principle for Neurodevelopment
Authors: Razban Rostam M , Pachter Jonathan Asher , Dill Ken A , Mujica-Parodi Lilianne R 
Published: July 2022

AbstractWe performtargeted attack, a systematic computational unlinking of the network, to analyze its effects on global communication across the network through itsgiant cluster. Across diffusion magnetic resonance images from individuals in the UK Biobank, Adolescent Brain Cognitive Development Study and Developing Human Connectome Project, we find that targeted attack procedures on increasing white matter tract lengths and densities are remarkably invariant to aging and disease. Time-reversing the attack computation suggests a mechanism for how brains develop, for which we derive an analytical equation using percolation theory. Based on a close match between theory and experiment, our results demonstrate that tracts are limited to emanate from regions already in the giant cluster and tracts that appear earliest in neurodevelopment are those that become the longest and densest.SignificanceAs brains develop through neural growth and specialization, what mechanism ensures that new neurons are integrated into a fully connected brain, avoiding “bridges to nowhere”? Here, we study brain structure development from the perspective of percolation, a global measure of communication. Analyzing over 35,000 diffusion MRI scans on human individuals, from newborns to adults, we identify the following rules of brain neurogenesis through percolation theory: earlier tracts become longer and denser while maintaining a giant cluster. This signature, invariant to age or mental health, suggests a fundamental condition for the brain to function as an emergent whole.
Inflammatory Signaling in Pancreatic Cancer Transfers Between a Single-cell RNA Sequencing Atlas and Co-Culture
Authors: Kinny-Köster Benedict , Guinn Samantha , Tandurella Joseph A. , Mitchell Jacob T. , Sidiropoulos Dimitrios N. , Loth Melanie , Lyman Melissa R. , Pucsek Alexandra B. , Seppälä Toni T. , Cherry Christopher , Suri Reecha , Zlomke Haley , He Jin , Wolfgang Christopher L. , Yu Jun , Zheng Lei , Ryan David P. , Ting David T. , Kimmelman Alec , Gupta Anuj , Danilova Ludmila , Elisseeff Jennifer H. , Wood Laura D. , Stein-O’Brien Genevieve , Kagohara Luciane T. , Jaffee Elizabeth M. , Burkhart Richard A. , Fertig Elana J. , Zimmerman Jacquelyn W. 
Published: July 2022

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a heterogeneous tumor microenvironment (TME) that is enriched with cancer associated fibroblasts (CAFs)1. Cell-cell interactions involving these CAFs promote an immunosuppressive phenotype with altered inflammatory gene expression. While single-cell transcriptomics provides a tool to dissect the complex intercellular pathways that regulate cancer-associated inflammation in human tumors, complementary experimental systems for mechanistic validation remain limited. This study integrated single-cell data from human tumors and novel organoid co-cultures to study the PDAC TME. We derived a comprehensive atlas of PDAC gene expression from six published human single-cell RNA sequencing (scRNA-seq) datasets2–7to characterize intercellular signaling pathways between epithelial tumor cells and CAFs that regulate the inflammatory TME. Analysis of the epithelial cell compartment identified global gene expression pathways that modulate inflammatory signaling and are correlated with CAF composition. We then generated patient-derived organoid-CAF co-cultures to serve as a biological model of the cellular interactions learned from human tissue in the atlas. Transfer learning analysis to additional scRNA-seq data of this co-culture system and mechanistic experiments confirmed the epithelial response to fibroblast signaling. This bidirectional approach of complementary computational andin vitroapplications provides a framework for future studies identifying important mechanisms of intercellular interactions in PDAC.
High-Throughput Functional Assay in Cystic Fibrosis Patient-Derived Organoids Allows Drug Repurposing
Authors: Spelier S. , de Poel E. , Ithakisiou G.N. , Suen S.W.F. , Hagemeijer M.C. , Muilwijk D. , Vonk A.M. , Brunsveld J.E. , Kruisselbrink E. , van der Ent C.K. , Beekman J.M. 
Published: July 2022

ABSTRACTCystic fibrosis (CF) is a rare hereditary disease caused by mutations in the CFTR gene. Recent therapies enable effective restoration of CFTR function of the most common F508del CFTR mutation. This shifts the unmet clinical need towards people with rare CFTR mutations such as nonsense mutations, of which G542X and W1282X are most prevalent. CFTR function measurements in patient-derived cell-based assays played a critical role in preclinical drug development for CF and may play an important role to identify new drugs for people with rare CFTR mutations.Here, we miniaturized the previously described forskolin induced swelling (FIS) assay in intestinal organoids from a 96-wells to a 384-wells plate screening format. Using this novel assay, we tested CFTR increasing potential of a 1400-compound FDA-approved drug library in organoids from donors with W1282X/W1282X CFTR nonsense mutations.The 384-wells FIS-assay demonstrated uniformity and robustness based on CV and Z’-factor calculations. In the primary screen, the top 5 compound combinations that increased CFTR function all contained at least one statin. In the secondary screen, we indeed verified that four out of the five statins, Mevastatin; Lovastatin; Simvastatin and Fluvastatin increased CFTR function when combined with CFTR modulators. Statin-induced CFTR rescue was W1282X specific, as increased CFTR function was not shown for patient-derived organoids harbouring R334W/R334W and F508del/F508del mutations.Future studies should focus on elucidating genotype specificity and mode-of-action of statins into more detail. This study exemplifies proof-of-principle of large-scale compound screening in a functional assay using patient derived organoids.Graphical abstract
Peptidoglycan recycling mediated by an ABC transporter in the plant pathogenAgrobacterium tumefaciens
Authors: Gilmore Michael C. , Cava Felipe 
Published: July 2022

AbstractDuring growth and division, the bacterial cell wall peptidoglycan (PG) is remodelled, resulting in the liberation of PG muropeptides which are typically reinternalized and recycled. Bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lack the canonical muropeptide transporter AmpG, despite having other key PG recycling enzymes. Here, we show that an alternative transporter, YejBEF-YepA, takes over this role in the Rhizobiales phytopathogenAgrobacterium tumefaciens. Muropeptide import by YejBEF-YepA governs expression of the β-lactamase AmpC inA. tumefaciens, contributing to β-lactam resistance. However, we show that the absence of YejBEF-YepA causes severe cell wall defects that go far beyond lowered AmpC activity. Thus, contrary to previously established Gram-negative models, PG recycling is vital for cell wall integrity inA. tumefaciens. YepA is widespread in the Rhizobiales and Rhodobacterales, suggesting that YejBEF-YepA-mediated PG recycling could represent an important but overlooked aspect of cell wall biology in these bacteria.
Indirect CRISPR screening with photoconversion revealed key factors of drug resistance with cell–cell interactions
Authors: Sugita Keisuke , Onishi Iichiroh , Nakayama Ran , Ishibashi Sachiko , Ikeda Masumi , Inoue Miori , Narita Rina , Oshima Shiori , Shimizu Kaho , Saito Shinichiro , Sato Shingo , Moriarity Branden S. , Yamamoto Kouhei , Largaespada David A. , Kitagawa Masanobu , Kurata Morito 
Published: July 2022

AbstractComprehensive screenings to clarify indirect cell–cell interactions, such as those in the tumor microenvironment, especially comprehensive assessments of supporting cells’ effects, are challenging. Therefore, in this study, indirect CRISPR screening for drug resistance with cell–cell interactions was invented. The photoconvertible fluorescent protein Dendra2 was inducted to determine the drug resistance responsible factors of supporting cells with CRISPR screenings. Random mutated supporting cells co-cultured with leukemic cells induced drug resistance with cell– cell interactions. Supporting cells responsible for drug resistance were isolated with green-to-red photoconversion, and 39 candidate genes were identified. Knocking out C9orf89, MAGI2, MLPH, or RHBDD2 in supporting cells reduced the ratio of apoptosis of cancer cells. In addition, the low expression of RHBDD2 in supporting cells, specifically fibroblasts, of clinical pancreatic cancer showed a shortened prognosis, and a negative correlation with CXCL12 was observed. Indirect CRISPR screening was established to isolate the responsible elements of cell–cell interactions. This screening method could reveal new mechanisms in all kinds of cell–cell interactions by revealing live phenotype-inducible cells, and it could be a new platform for discovering new targets of drugs for conventional chemotherapies.