bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interplay between neoantigens and immune cells in sarcomas treated with checkpoint inhibition
Authors: Anzar Irantzu , Malone Brandon , Samarakoon Pubudu , Vardaxis Ioannis , Simovski Boris , Fontenelle Hugues , Meza-Zepeda Leonardo A , Stratford Richard , Keung Emily Z , Burgess Melissa , Tawbi Hussein A. , Myklebost Ola , Clancy Trevor 
Published: May 2023

AbstractSarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes. To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME). A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important. The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.
Endodermal BRD4 mediates epithelial-mesenchymal crosstalk during lung development
Authors: Liberti Derek C. , Wen Hongbo , Quansah Kwaku K. , Chandrasekaran Prashant , Pankin Josh , Michki Nigel S. , Jin Annabelle , Lu MinQi , Nieuwburgh Maureen Peers De , Young Lisa R. , Jain Rajan , Frank David B. 
Published: May 2023

SUMMARYLung morphogenesis relies on diverse cell intrinsic and extrinsic mechanisms to ensure proper cellular differentiation and compartmentalization. Using genetic mouse models, tissue explants, and transcriptomic analysis, we demonstrate that the epigenetic reader Bromodomain Containing Protein 4 (BRD4) is required for lung morphogenesis and perinatal survival. Endodermal BRD4 deletion impairs epithelial-mesenchymal crosstalk, leading to disrupted proximal-distal patterning and branching morphogenesis. These early defects result in dilated airways and the formation of cystic distal airway structures, containing both airway and alveolar features. Moreover, BRD4 deficient lungs exhibit abnormal airway and alveolar epithelial cell lineage allocation and differentiation. Restoration of SHH signaling partially rescues defects due to loss of BRD4, suggesting a role for BRD4 in regulating the SHH-FGF signaling axis. Together, these data identify the essential role of Brd4 in lung development to ensure proper intercellular crosstalk to enable proper lineage specification, identity, and maturation.
Dependent variable selection in phylogenetic generalized least squares regression analysis under Pagel’s lambda model
Authors: Chen Zheng-Lin , Guo Hong-Ji , Niu Deng-Ke 
Published: May 2023

AbstractPhylogenetic generalized least squares (PGLS) regression is widely used to analyze evolutionary relationships between two traits. In contrast to the equal treatment of analyzed traits in conventional correlation methods such as Pearson and Spearman’s rank tests, we must designate one trait as the independent variable and the other as the dependent variable.We retrieved an empirical dataset containing the optimal growth temperature, minimal doubling time, CRISPR-Cas, and prophage contents of 262 bacteria from a recent publication and conducted 16000 simulations of the evolution of two traits along a binary tree with 100 terminal nodes, using different models and variances. Correlations in these two datasets were examined by PGLS regression using Pagel’sλmodel.By examining correlations in the empirical dataset, we found that switching independent and dependent variables resulted in conflicting results in 26.3% of cases. PGLS regression analysis of the 16000 simulated data showed that the frequency of conflicting outcomes from switching dependent and independent variables depends on the strength of the relationship between the two analyzed traits. Switching dependent and independent variables would strongly affect the parameter estimation of the PGLS regressions if the two variables differ significantly in their phylogenetic signals. To assess correlations in each simulation, we established a gold standard by analyzing changes in traits along phylogenetic branches. Next, we tested seven potential criteria for dependent variable selection: log-likelihood, Akaike information criterion,R2,p-value, Pagel’sλ, Blomberg et al.’sK, and the estimatedλin Pagel’sλmodel. We determined that the last three criteria performed equally well in selecting the dependent variable and were superior to the other four.Since Pagel’sλand Blomberg et al.’sKvalues are indicators of phylogenetic signals, which are commonly calculated at the beginning of phylogenetic comparative studies, we suggest using the trait with a higherλorKvalue as the dependent variable for practicality in future PGLS regressions. In analyzing the evolutionary relationship between two traits, we should designate the trait with a stronger phylogenetic signal as the dependent variable even if it could logically assume the cause in the relationship.
Bearskin2 mediates the coordinated secretion of xylogalacturonan and root cap polygalacturonase in Arabidopsis border-like cells
Authors: Liu Zhongyuan , Wang Pengfei , Goh Tatsuaki , Nakajima Keiji , Kang Byung-Ho 
Published: May 2023

AbstractBorder-like cells (BLCs) are sheets of cells that are continuously sloughed off and replenished at the Arabidopsis root cap surface.ROOT CAP POLYGALACTURONASE (RCPG)encodes a putative pectinase involved in BLC shedding. Xylogalacturonan (XGA) is a pectic polysaccharide whose synthesis is associated with cell detachment and secreted separately from other cell wall polysaccharides.BEARSKIN1 (BRN1)andBRN2areArabidopsisNAC family transcription factors, andRCPGexpression is inhibited inbrn1/2. To explore the link between XGA and RCPG, we examined XGA synthesis inArabidopsislines with altered RCPG levels. We found that RCPG was contained in XGA-carrying vesicles budding from thetrans-Golgi, but XGA synthesis was not affected in thercpgmutant. XGA was absent in BLCs ofbrn2, but not ofbrn1, indicating thatBRN2is necessary for XGA synthesis. Overexpression of functional RCPG-GFP (oeRCPG-GFP) caused upregulation ofBRN2, ectopic XGA synthesis, overaccumulation of endogenous RCPG, and accelerated BLC turnover, suggesting a positive regulatory loop between RCPG and BRN2. Inactivation ofBRN2inoeRCPG-GFPsuppressed RCPG-GFP expression, excess RCPG, and XGA synthesis. Our data provide evidence that XGA and RCPG are secreted together and that BRN2 controls XGA synthesis, which facilitates RCPG export and BLC separation.
Staining and resin embedding of wholeDaphniamagna samples for micro-CT imaging enabling 3D visualization of cells, tissues, and organs of various thicknesses
Authors: Ngu Mee S. , Vanselow Daniel J. , Saint-Fort Rachelle A. , Sugarman Andrew L. , Zaino Carolyn R. , Yakovlev Maksim A. , Cheng Keith C. , Ang Khai C. 
Published: May 2023

AbstractMicro-CT imaging is a powerful tool for generating high resolution, isotropic three-dimensional datasets of whole, centimeter-scale model organisms that can be used for qualitative and quantitative analysis. The small size, global freshwater distribution, wide range of cell size and structures of micron scale, and common use ofD. magnain toxicological and environmental studies make it an ideal model for demonstrating the potential power of micro-CT-enabled whole-organism phenotyping. This protocol details the steps involved inD. magnasamples preparation for micro-CT: euthanasia, fixation, staining, and resin embedding. Micro-CT reconstructions of samples imaged using synchrotron micro-CT reveal histological (microanatomic) features of organ systems, tissues, and cells in the context of the entire organism at sub-micron resolution, and in 3 dimensionality. The enabled “3D histology” and 3D renderings can be used towards morphometric analyses across cells, tissues, and organ systems for both descriptive and hypothesis testing studies.
Signatures of heuristic-based directed exploration in two-step sequential decision task behaviour
Authors: Brands A. M. , Mathar D. , Peters J. 
Published: May 2023

AbstractProcesses formalized in classic Reinforcement Learning (RL) theory, such as model-based (MB) control and exploration strategies have proven fertile in cognitive and computational neuroscience, as well as computational psychiatry. Dysregulations in MB control and exploration and their neurocomputational underpinnings play a key role across several psychiatric disorders. Yet, computational accounts mostly study these processes in isolation. The current study extended standard hybrid models of a widely-used sequential RL-task (two-step task; TST) employed to measure MB control. We implemented and compared different computational model extensions for this task to quantify potential exploration mechanisms. In two independent data sets spanning two different variants of the task, an extension of a classical hybrid RL model with a heuristic-based exploration mechanism provided the best fit, and revealed a robust positive effect of directed exploration on choice probabilities in stage one of the task. Posterior predictive checks further showed that the extended model reproduced choice patterns present in both data sets. Results are discussed with respect to implications for computational psychiatry and the search for neurocognitive endophenotypes.
Rescue of proteotoxic stress and neurodegeneration by the Zn2+transporter ZIP7
Authors: Guo Xiaoran , Mutch Morgan , Torres Alba Yurani , Nano Maddalena , McDonald Drew , Chen Zijing , Montell Craig , Dai Wei , Montell Denise J. 
Published: May 2023

AbstractProteotoxic stress drives numerous degenerative diseases. In response to misfolded proteins, cells adapt by activating the unfolded protein response (UPR), including endoplasmic reticulum-associated protein degradation (ERAD). However persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. From plants to humans, loss of the Zn2+transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn2+is limiting for deubiquitination of client proteins by the Rpn11 Zn2+metalloproteinase as they enter the proteasome in Drosophila and human cells. ZIP7 overexpression rescues defective vision caused by misfolded rhodopsin in Drosophila. Thus ZIP7 overexpression may prevent diseases caused by proteotoxic stress, and existing ZIP inhibitors may be effective against proteasome-dependent cancers.One-Sentence SummaryZn2+transport from the ER to the cytosol promotes deubiquitination and proteasomal degradation of misfolded proteins and prevents blindness in a fly neurodegeneration model.
Higher-order assembly is a regulatory switch that promotes outer kinetochore recruitment
Authors: Sissoko Gunter B. , Tarasovetc Ekaterina V. , Grishchuk Ekaterina L. , Cheeseman Iain M. 
Published: May 2023

SummaryTo faithfully segregate chromosomes during vertebrate mitosis, kinetochore-microtubule interactions must be restricted to a single site on each chromosome. Prior work on pair-wise kinetochore protein interactions has been unable to identify the mechanisms that prevent kinetochore formation in regions with a low density of CENP-A nucleosomes. To investigate the impact of higher-order assembly on kinetochore formation, we generated defined oligomers of the inner kinetochore protein CENP-T using two distinct, genetically engineered systems in human cells. Although individual CENP-T molecules interact poorly with other kinetochore proteins, oligomers that mimic the centromeric density of CENP-T trigger the robust formation of functional, cytoplasmic kinetochore-like particles. Both in cells andin vitro, each molecule of oligomerized CENP-T recruits substantially higher levels of outer kinetochore components than monomeric CENP-T molecules. Thus, the density-dependence of CENP-T restricts outer kinetochore recruitment to centromeres, where densely packed CENP-A recruits a high local concentration of CENP-T.
One particle per residue is sufficient to describe all-atom protein structures
Authors: Heo Lim , Feig Michael 
Published: May 2023

ABSTRACTAtomistic resolution is considered the standard for high-resolution biomolecular structures, but coarse-grained models are often necessary to reflect limited experimental resolution or to achieve feasibility in computational studies. It is generally assumed that reduced representations involve a loss of detail, accuracy, and transferability. This study explores the use of advanced machine-learning networks to learn from known structures of proteins how to reconstruct atomistic models from reduced representations to assess how much information is lost when the vast knowledge about protein structures is taken into account. The main finding is that highly accurate and stereochemically realistic all-atom structures can be recovered with minimal loss of information from just a single bead per amino acid residue, especially when placed at the side chain center of mass. High-accuracy reconstructions with better than 1 Å heavy atom root-mean square deviations are still possible when only Cα coordinates are used as input. This suggests that lower-resolution representations are essentially sufficient to represent protein structures when combined with a machine-learning framework that encodes knowledge from known structures. Practical applications of this high-accuracy reconstruction scheme are illustrated for adding atomistic detail to low-resolution structures from experiment or coarse-grained models generated from computational modeling. Moreover, a rapid, deterministic all-atom reconstruction scheme allows the implementation of an efficient multi-scale framework. As a demonstration, the rapid refinement of accurate models against cryoEM densities is shown where sampling at the coarse-grained level is guided by map correlation functions applied at the atomistic level. With this approach, the accuracy of standard all-atom simulation based refinement schemes can be matched at a fraction of the computational cost.STATEMENT OF SIGNIFICANCEThe fundamental insight of this work is that atomistic detail of proteins can be recovered with minimal loss of information from highly reduced representations with just a single bead per amino acid residue. This is possible by encoding the existing knowledge about protein structures in a machine-learning model. This suggests that it is not strictly necessary to resolve structures in atomistic detail in experiments, computational modeling, or the generation of protein conformations via neural networks since atomistic details can inferred quickly via the neural network. This increases the relevance of experimental structures obtained at lower resolutions and broadens the impact of coarse-grained modeling.
Decryption of sequence, structure, and functional features of SINE repeat elements in SINEUP non-coding RNA–mediated post-transcriptional gene regulation
Authors: Sharma Harshita , Valentine Matthew N Z , Toki Naoko , Nishiyori Hiromi Sueki , Gustincich Stefano , Takahashi Hazuki , Carninci Piero 
Published: May 2023

AbstractRNA structure folding largely influences RNA regulation by providing flexibility and functional diversity. In silico and in vitro analyses are limited in their ability to capture the intricate relationships between dynamic RNA structure and RNA functional diversity present in the cell. Here, we investigate sequence, structure and functional features of mouse and human SINE-transcribed retrotransposons embedded in SINEUPs long non-coding RNAs, which positively regulate target gene expression post-transcriptionally. In-cell secondary structure probing reveals that functional SINEs-derived RNAs contain conserved short structure motifs essential for SINEUP-induced translation enhancement. We show that SINE RNA structure dynamically changes between the nucleus and cytoplasm and is associated with compartment-specific binding to RBP and related functions. Moreover, RNA–RNA interaction analysis shows that the SINE-derived RNAs interact directly with ribosomal RNAs, suggesting a mechanism of translation regulation. We further predict the architecture of 18 SINE RNAs in three dimensions guided by experimental secondary structure data. Overall, we demonstrate that the conservation of short key features involved in interactions with RBPs and ribosomal RNA drives the convergent function of evolutionarily distant SINE-transcribed RNAs.
Discovery of the apiosyltransferase, celery UGT94AX1 that catalyzes the biosynthesis of a flavone glycoside, apiin
Authors: Yamashita Maho , Fujimori Tae , An Song , Iguchi Sho , Takenaka Yuto , Kajiura Hiroyuki , Yoshizawa Takuya , Matsumura Hiroyoshi , Kobayashi Masaru , Ono Eiichiro , Ishimizu Takeshi 
Published: May 2023

AbstractApiose is a unique branched-chain pentose found in plant glycosides and a key component of the cell wall-polysaccharide pectin and other specialized metabolites. More than 1,200 plant-specialized metabolites contain apiose residues, represented by apiin, a distinctive flavone glycoside found in celery and parsley in the family Apiaceae. The physiological functions of apiin remain obscure, partly due to our lack of knowledge on apiosyltransferase during apiin biosynthesis. Here, we identified celery UGT94AX1 (AgApiT) as a novel apiosyltransferase, responsible for catalyzing the last sugar-modification step in apiin biosynthesis. AgApiT showed strict substrate specificity for the sugar donor, UDP-apiose, and moderate specificity for acceptor substrates, thereby producing various apiose-containing flavone glycosides in celery. Homology modeling of AgApiT with UDP-apiose, followed by site-directed mutagenesis experiments, identified unique Ile139, Phe140, and Leu356 residues in AgApiT, which are seemingly crucial for the recognition of UDP-apiose in the sugar donor pocket. Sequence comparison and molecular phylogenetic analysis of celery glycosyltransferases paralogous to AgApiT suggested thatAgApiTis the sole apiosyltransferase-encoding gene in the celery genome. This is the first report on the identification of a plant apiosyltransferase gene that will enhance our understanding of the physio-ecological functions of apiose and apiose-containing compounds.
Ventral pallidum projections to the ventral tegmental area reinforce but do not invigorate reward-seeking behavior
Authors: Palmer Dakota , Cayton Christelle A. , Scott Alexandra , Lin Iris , Newell Bailey , Weberg Morgan , Richard Jocelyn M. 
Published: May 2023

ABSTRACTReward-predictive cues acquire motivating and reinforcing properties that contribute to the escalation and relapse of drug use in addiction. The ventral pallidum (VP) and ventral tegmental area (VTA) are two key nodes in brain reward circuitry implicated in addiction and necessary for the performance of cue-driven behavior. Evidence suggests that VP neurons projecting to the VTA (VP→VTA) promote cue-induced reinstatement of drug-seeking, but the mechanisms by which these neurons do so are undefined. In addition, the role of these neurons in the pursuit of non-drug reward is not known. In the current study, we usedin vivofiber photometry and optogenetics to record from and manipulate VP→VTA in rats performing a discriminative stimulus task (DS task) with sucrose reward to determine the fundamental role these neurons play in invigoration and reinforcement by reward and associated discriminative cues. We find that VP→VTA neurons are selectively active during reward consumption, that optogenetic stimulation of these neurons paired with reward consumption biases choice, and that VP→VTA optogenetic stimulation is reinforcing. Critically, we found no significant encoding of cue-elicited reward-seeking vigor and acute optogenetic stimulation of these neurons paired with cue onset did not enhance the probability or vigor of reward-seeking. Our results suggest that VP→VTA neurons are active during the consumption of natural reward and that this activity reinforces seeking behavior.
Changes in Active Site Loop Conformation Relate to the Transition toward a Novel Enzymatic Activity
Authors: Jacquet Pauline , Billot Raphaël , Shimon Amir , Hoekstra Nathan , Bergonzi Céline , Jenks Anthony , Chabrière Eric , Daudé David , Elias Mikael H. 
Published: May 2023

ABSTRACTEnzymatic promiscuity, the ability of enzymes to catalyze multiple, distinct chemical reactions, has been well documented and is hypothesized to be a major driver for the emergence of new enzymatic functions. Yet, the molecular mechanisms involved in the transition from one activity to another remain debated and elusive. Here, we evaluated the redesign of the active site binding cleft of the lactonaseSsoPox using structure-based design and combinatorial libraries. We created variants with largely improved catalytic abilities against phosphotriesters, the best ones being > 1,000-fold better compared to the wild-type enzyme. The observed shifts in activity specificity are large, ∼1,000,000-fold and beyond, since some variants completely lost their initial activity. The selected combinations of mutations have considerably reshaped the active site cavityviaside chain changes but mostly through large rearrangements of the active site loops, as revealed by a suite of crystal structures. This suggests that specific active site loop configuration is critical to the lactonase activity. Interestingly, analysis of high-resolution structures hints at the potential role of conformational sampling and its directionality in defining an enzyme activity profile.
A power law of cortical adaptation
Authors: Tring Elaine , Dipoppa Mario , Ringach Dario L. 
Published: May 2023

AbstractHow do neural populations adapt to the time-varying statistics of sensory input? To investigate, we measured the activity of neurons in primary visual cortex adapted to different environments, each associated with a distinct probability distribution over a stimulus set. Within each environment, a stimulus sequence was generated by independently sampling form its distribution. We find that two properties of adaptation capture how the population responses to a given stimulus, viewed as vectors, are linked across environments. First, the ratio between the response magnitudes is a power law of the ratio between the stimulus probabilities. Second, the response directions are largely invariant. These rules can be used to predict how cortical populations adapt to novel, sensory environments. Finally, we show how the power law enables the cortex to preferentially signal unexpected stimuli and to adjust the metabolic cost of its sensory representation to the entropy of the environment.