bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Functional Data Analysis Approach to RuBisCO Engineering
Authors: McCormack Adam C. 
Published: June 2023

AbstractMitigating and adapting to climate change requires carbon emission control and effective technologies for drawing greenhouse gases from the atmosphere. Here we propose an effective strategy for guiding the rubisco engineering problem, which seeks to improve photosynthesis and carbon sequestration in crops by minimizing photorespiration, a major impediment to crop yields. Photorespiration occurs when rubisco oxygenates rather than carboxylates, thus reducing carbohydrate synthesis to eliminate toxic byproducts. Most plants, including most agricultural crops, exhibit a C3 photosynthetic pathway and have not developed adaptive mechanisms to combat rubisco’s tradeoff. The span of low activity rubiscos opens the possibility of engineering less productive crops to express higher activity enzymes. The main experimental challenges in bypassing rubisco’s biochemical limitations include its molecular size and complexity, lack of empirical data, and costs of acquiring new data, but recent advances in machine learning and data analytics could allow us to overcome these challenges. In particular, we propose a novel computational approach to inform experimental research into rubisco engineering by employing recently developed techniques from functional data analysis. We show that the separation between high and low activity enzymes can be modeled within the sequence space of rubisco’s primary structure, and we further discuss how our approach can guide deeper investigation into the rubisco engineering problem. Future empirical success would simultaneously address major global issues such as rising atmospheric CO2levels and food insecurity.
NG2 Glia Reprogramming Induces Robust Axonal Regeneration After Spinal Cord Injury
Authors: Tai Wenjiao , Du Xiaolong , Chen Chen , Xu Xiao-Ming , Zhang Chun-Li , Wu Wei 
Published: June 2023

ABSTRACTSpinal cord injury (SCI) often leads to neuronal loss, axonal degeneration and behavioral dysfunction. We recently show that in vivo reprogramming of NG2 glia produces new neurons, reduces glial scaring, and ultimately leads to improved function after SCI. By examining endogenous neurons, we here unexpectedly uncover that NG2 glia reprogramming also induces robust axonal regeneration of the corticospinal tract and serotonergic neurons. Such reprogramming-induced axonal regeneration may contribute to the reconstruction of neural networks essential for behavioral recovery.
Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
Authors: Koo Junghui , Seong Chang-Soo , Parker Rebecca E. , Dwivedi Bhakti , Arthur Robert A. , Dinasarapu Ashok Reddy , Johnston H. Richard , Claussen Henry , Tucker-Burden Carol , Ramalingam Suresh S. , Fu Haian , Zhou Wei , Marcus Adam I. , Gilbert-Ross Melissa 
Published: June 2023

AbstractThe acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the ‘gas’ and ‘breaks’ to finely tune iron-regulated tumor progression.
UniSpec: A Deep Learning Approach for Predicting Energy-Sensitive Peptide Tandem Mass Spectra and Generating Proteomics-Wide In-Silico Spectral Libraries
Authors: Lapin Joel , Yan Xinjian , Dong Qian 
Published: June 2023

AbstractIn this report, we present UniSpec, an attention-based deep neural network designed to predict complete collision-induced fragmentation of tryptic peptides, aimed at enhancing peptide and protein identification in shotgun proteomics studies. We preprocessed spectral data from peptide tandem mass spectral libraries, compiled by the National Institute of Standards and Technology (NIST), utilizing a data approach tailored for model development, resulting in high-quality, energy-consistent spectral datasets. By analyzing all the annotated fragment ions present in these libraries, we constructed an extensive peptide fragment dictionary containing 7919 isotopic ions from sequence ions, neutral loss, internal, iminium, and amino acid fragment ions. The streamlined dictionary-based spectral training data enables UniSpec to efficiently learn the complex intensity patterns of various product ions, resulting in reliable spectral predictions for a wide range of unmodified and modified peptides. We evaluated the model’s accuracy by comparing its performance across training and testing data, considering diverse peptide characteristics like peptide classes, charge states, and sequence lengths. Our model attained a median cosine similarity score of 0.951 and 0.923 on the training and test data respectively. Contrary to existing deep learning models that often overlook a substantial part of peptide tandem mass spectra beyond the sequence b and y ion series, UniSpec can predict up to 75% of all measured fragment intensities (including unknown signals) in the raw experimental spectra. This represents a marked advancement from the 43.5% coverage achieved solely by b and y sequence ions in the NIST library spectra. For the evaluation of our model’s practical utility in predicting proteome-wide in-silico spectral libraries, we executed a benchmark test using a dataset of HeLa cells. UniSpec displayed a significant overlap of peptide identifications with the widely used search engine MS-GF+ and the NIST experimental spectral library, demonstrating its robust performance as a standalone peptide identification tool.
Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by minor groove anchor competition
Authors: Kobayashi Wataru , Sappler Anna , Bollschweiler Daniel , Kümmecke Maximilian , Basquin Jérôme , Arslantas Eda Nur , Ruangroengkulrith Siwat , Hornberger Renate , Duderstadt Karl , Tachibana Kikuë 
Published: June 2023

AbstractGene expression during natural and induced reprogramming is controlled by pioneer transcription factors, which bind nucleosomal DNA and initiate gene expression from closed chromatin. How pioneer factors perform this function is poorly understood. Nr5a2 is a pioneer factor that is critical for zygotic genome activation (ZGA) in totipotent embryos, pluripotency in embryonic stem cells and metabolic regulation in adult tissues. To study how Nr5a2 functions as a pioneer factor, we used cryo-electron microscopy to determine a structure of human NR5A2 bound to a nucleosome. The structure shows that the conserved C-terminal extension (CTE) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome and releases entry-exit site DNA at a ∼50° angle. Residue aspartic acid 159 of the CTE loop induces the rearrangement by shifting a histone H2A α2 helix towards the nucleosome center. Mutational analysis showed that NR5A2 D159 is largely dispensable for DNA binding but required for stable nucleosome association and persistent DNA unwrapping. These findings suggest that NR5A2 belongs to a previously unknown class of pioneer factors that can use minor groove anchor competition to destabilize nucleosomes and facilitate gene expression changes during reprogramming.
Comparison of genomic diversity between single and pooledStaphylococcus aureuscolonies isolated from human colonisation cultures
Authors: Raghuram Vishnu , Gunoskey Jessica J. , Hofstetter Katrina S. , Jacko Natasia F. , Shumaker Margot J. , Hu Yi-Juan , Read Timothy D. , David Michael Z. 
Published: June 2023

AbstractThe most common approach to sampling the bacterial populations within an infected or colonised host is to sequence genomes from a single colony obtained from a culture plate. However, it is recognized that this method does not capture the genetic diversity in the population. An alternative is to sequence a mixture containing multiple colonies (“pool-seq”), but this has the disadvantage that it is a non-homogeneous sample, making it difficult to perform specific experiments. We compared differences in measures of genetic diversity between eight single-colony isolates (singles) and pool-seq on a set of 2286S. aureusculture samples. The samples were obtained by swabbing three body sites on 85 human participants quarterly for a year, who initially presented with a methicillin-resistantS. aureusskin and soft-tissue infection (SSTI). We compared parameters such as sequence quality, contamination, allele frequency, nucleotide diversity and pangenome diversity in each pool to the corresponding singles. Comparing singles from the same culture plate, we found that 18% of sample collections contained mixtures of multiple Multilocus sequence types (MLSTs or STs). We showed that pool-seq data alone could predict the presence of multi-ST populations with 95% accuracy. We also showed that pool-seq could be used to estimate the number of polymorphic sites in the population. Additionally, we found that the pool may contain clinically relevant genes such as antimicrobial resistance markers that may be missed when only examining singles. These results highlight the potential advantage of analysing genome sequences of total populations obtained from clinical cultures rather than single colonies.Graphical Abstract
Subgenome dominance shapes novel gene evolution in the decaploid pitcher plantNepenthes gracilis
Authors: Saul Franziska , Scharmann Mathias , Wakatake Takanori , Rajaraman Sitaram , Marques André , Freund Matthias , Bringmann Gerhard , Channon Louisa , Becker Dirk , Carroll Emily , Low Yee Wen , Lindqvist Charlotte , Gilbert Kadeem J. , Renner Tanya , Masuda Sachiko , Richter Michaela , Vogg Gerd , Shirasu Ken , Michael Todd P. , Hedrich Rainer , Albert Victor A. , Fukushima Kenji 
Published: June 2023

AbstractSubgenome dominance after whole-genome duplication generates distinction in gene number and expression at the level of chromosome sets, but it remains unclear how this process may be involved in evolutionary novelty. Here, we generated a chromosome-scale genome assembly of the Asian pitcher plantNepenthes gracilisto analyze how its novel traits (dioecy and carnivorous pitcher leaves) are linked to genomic evolution. We found a decaploid karyotype with five complete sets of syntenic chromosomes (2n= 10x= 80) yet with a clear indication of subgenome dominance and highly diploidized gene contents. The male-linked and pericentromerically located region on the putative sex chromosome was identified in a recessive subgenome and was found to harbor three transcription factors involved in flower and pollen development, including a likely neofunctionalizedLEAFYduplicate. Transcriptomic and syntenic analyses of carnivory-related genes suggested that the paleopolyploidization events seeded genes that subsequently formed tandem clusters in recessive subgenomes with specific expression in the digestive zone of the pitcher, where specialized cells digest prey and absorb derived nutrients. Novel gene evolution in recessive subgenomes is likely to be prevalent because duplicates were enriched withNepenthes-specific genes with tissue-specific expression, including those expressed in trapping pitchers. Thus, subgenome dominance likely contributed to evolutionary novelty by allowing recessive subgenomes experiencing relaxed purifying selection to serve as a preferred host of novel tissue-specific duplicates. Our results provide insight into how polyploids, which may frequently be evolutionary dead-ends, have given rise to novel traits in exceptionally thriving high-ploidy lineages.
Temporal segmentation and ‘look ahead’ simulation: Physical events structure visual perception of intuitive physics
Authors: Yates Tristan S. , Yasuda Shannon , Yildirim Ilker 
Published: June 2023

AbstractHow we perceive the physical world is not only organized in terms of objects, but also structured in time as sequences of events. This is especially evident in intuitive physics, with temporally bounded dynamics such as falling, occlusion, and bouncing demarcating the continuous flow of sensory inputs. While the spatial structure and attentional consequences of physical objects have been well-studied, much less is known about the temporal structure and attentional consequences of physical events in visual perception. Previous work has recognized physical events as units in the mind, and used pre-segmented object interactions to explore physical representations. However, these studies did not address whether and how perception imposes the kind of temporal structure that carves these physical events to begin with, and the attentional consequences of such segmentation during intuitive physics. Here, we use performance-based tasks to address this gap. In Experiment 1, we find that perception not only spontaneously separates visual input in time into physical events, but also, this segmentation occurs in a nonlinear manner within a few hundred milliseconds at the moment of the event boundary. In Experiment 2, we find that event representations, once formed, use coarse ‘look ahead’ simulations to selectively prioritize those objects that are predictively part of the unfolding dynamics. This rich temporal and predictive structure of physical events, formed during vision, should inform models of intuitive physics.
Mechanisms of cilia regeneration inXenopusmulticiliated epitheliumin vivo
Authors: Rao Venkatramanan G. , Subramanianbalachandar Vignesharavind , Magaj Magdalena M. , Redemann Stefanie , Kulkarni Saurabh S. 
Published: June 2023

SUMMARYCilia regeneration is a physiological event, and while studied extensively in unicellular organisms, it remains poorly understood in vertebrates. In this study, usingXenopusmulticiliated cells (MCCs) as a model, we demonstrate that, unlike unicellular organisms, deciliation removes the transition zone (TZ) and the ciliary axoneme. While MCCs immediately begin the regeneration of the ciliary axoneme, surprisingly, the assembly of TZ is delayed. However, ciliary tip proteins, Sentan and Clamp, localize to regenerating cilia without delay. Using cycloheximide (CHX) to block new protein synthesis, we show that the TZ protein B9d1 is not a component of the cilia precursor pool and requires new transcription/translation, providing insights into the delayed repair of TZ. Moreover, MCCs in CHX treatment assemble fewer (∼ 10 vs. ∼150 in controls) but near wild-type length (ranging between 60 to 90%) cilia by gradually concentrating ciliogenesis proteins like IFTs at a select few basal bodies. Using mathematical modeling, we show that cilia length compared to cilia number influences the force generated by MCCs more. In summary, our results question the requirement of TZ in motile cilia assembly and provide insights into how cells determine organelle size and number.
Structure Reveals Homology in Elevator Transporters
Authors: Trebesch Noah , Tajkhorshid Emad 
Published: June 2023

AbstractThe elevator transport mechanism is one of the handful of canonical mechanisms by which transporters shuttle their substrates across the semi-permeable membranes that surround cells and organelles. Studies of molecular function are naturally guided by evolutionary context, but until now this context has been limited for elevator transporters because established evolutionary classification methods have organized them into several apparently unrelated families. Through comprehensive examination of the pertinent structures available in the Protein Data Bank, we show that 62 elevator transporters from 18 families share a conserved architecture in their transport domains consisting of 10 helices connected in 8 topologies. Through quantitative analysis of the structural similarity, structural complexity, and topologically-corrected sequence similarity among the transport domains, we provide compelling evidence that these elevator transporters are all homologous. Using our analysis, we have constructed a phylogenetic tree to enable quantification and visualization of the evolutionary relationships among elevator transporters and their families. We also report several examples of functional features that are shared by elevator transporters from different families. Our findings shed new light on the elevator transport mechanism and allow us to understand it in a far deeper and more nuanced manner.
Discovery of Competent Chromatin Regions in Human Embryonic Stem Cells
Authors: Pulecio Julian , Tayyebi Zakieh , Liu Dingyu , Wong Wilfred , Luo Renhe , Damodaran Jeyaram R , Kaplan Samuel , Cho Hyunwoo , Yan Jielin , Murphy Dylan , Rickert Robert W. , Shukla Abhijit , Zhong Aaron , González Federico , Yang Dexin , Li Wenbo , Zhou Ting , Apostolou Effie , Leslie Christina S. , Huangfu Danwei 
Published: June 2023

ABSTRACTThe mechanisms underlying the ability of embryonic stem cells (ESCs) to rapidly activate lineage-specific genes during differentiation remain largely unknown. Through multiple CRISPR-activation screens, we discovered human ESCs have pre-established transcriptionally competent chromatin regions (CCRs) that support lineage-specific gene expression at levels comparable to differentiated cells. CCRs reside in the same topological domains as their target genes. They lack typical enhancer-associated histone modifications but show enriched occupancy of pluripotent transcription factors, DNA demethylation factors, and histone deacetylases. TET1 and QSER1 protect CCRs from excessive DNA methylation, while HDAC1 family members prevent premature activation. This “push and pull” feature resembles bivalent domains at developmental gene promoters but involves distinct molecular mechanisms. Our study provides new insights into pluripotency regulation and cellular plasticity in development and disease.One sentence summaryWe report a class of distal regulatory regions distinct from enhancers that confer human embryonic stem cells with the competence to rapidly activate the expression of lineage-specific genes.
Deconvolution reveals compositional differences in high-grade serous ovarian cancer subtypes
Authors: Hippen Ariel A. , Davidson Natalie R. , Barnard Mollie E. , Weber Lukas M. , Gertz Jason , Doherty Jennifer A. , Hicks Stephanie C. , Greene Casey S. 
Published: June 2023

AbstractOvarian cancer is a deadly disease with few effective therapies. The most common form is high-grade serous ovarian cancer (HGSOC). Transcriptomic subtypes of HGSOC have shown promise in characterizing tumor heterogeneity and are associated with survival. Gene expression signatures for the subtypes suggest variation in stromal cell types in the tumor microenvironment (TME). Here, we characterize the TME composition of HGSOC on a population scale by performing deconvolution on bulk transcriptomic data. We use comprehensive cell type profiles from 164 HGSOC tumor samples from two independent reference datasets, in order to compare cell type proportions across and within bulk transcriptomic datasets, and assess their alignment to the subtypes proposed by The Cancer Genome Atlas. We also assess the relationship between tumor composition and clinical outcomes. Our results suggest that HGSOC transcriptomic subtypes are driven by TME composition, specifically fibroblast and immune cell content, and we propose a modified HGSOC subtype model informed by cell composition.
JMnorm: a novel Joint Multi-feature normalization method for integrative and comparative epigenomics
Authors: Xiang Guanjue , Guo Yuchun , Bumcrot David , Sigova Alla 
Published: June 2023

ABSTRACTCombinatorial patterns of epigenetic features reflect transcriptional states and functions of genomic regions. While many epigenetic features have correlated relationships, most existing data normalization approaches analyze each feature independently. Such strategies may distort relationships between functionally correlated epigenetic features and hinder biological interpretation. We present a novel approach named JMnorm that simultaneously normalizes multiple epigenetic features across cell types, species, and experimental conditions by leveraging information from partially correlated epigenetic features. We demonstrate that JMnorm-normalized data can better preserve cross-epigenetic-feature correlations across different cell types and enhance consistency between biological replicates than data normalized by other methods. Additionally, we show that JMnorm-normalized data can consistently improve the performance of various downstream analyses, which include candidate cis-regulatory element clustering, cross-cell-type gene expression prediction, detection of transcription factor binding and changes upon perturbations. These findings suggest that JMnorm effectively minimizes technical noise while preserving true biologically significant relationships between epigenetic datasets. We anticipate that JMnorm will enhance integrative and comparative epigenomics.GRAPHICAL ABSTRACTJMnorm can jointly normalize multiple epigenetic features between the target sample and the reference.
BGCFlow: Systematic pangenome workflow for the analysis of biosynthetic gene clusters across large genomic datasets
Authors: Nuhamunada Matin , Mohite Omkar S. , Phaneuf Patrick V. , Palsson Bernhard O. , Weber Tilmann 
Published: June 2023

ABSTRACTGenome mining is revolutionizing natural products discovery efforts. The rapid increase in available genomes demands comprehensive computational platforms to effectively extract biosynthetic knowledge encoded across bacterial pangenomes. Here, we present BGCFlow, a novel systematic workflow integrating analytics for large-scale genome mining of bacterial pangenomes. BGCFlow incorporates several genome analytics and mining tools grouped into five common stages of analysis such as; i) data selection, ii) functional annotation, iii) phylogenetic analysis, iv) genome mining, and v) comparative analysis. Furthermore, BGCFlow provides easy configuration of different projects, parallel distribution, scheduled job monitoring, an interactive database to visualize tables, exploratory Jupyter notebooks, and customized reports. Here, we demonstrate the application of BGCFlow by investigating the phylogenetic distribution of various biosynthetic gene clusters detected across 42 genomes of theSaccharopolysporagenus, known to produce industrially important secondary/specialized metabolites. The BGCFlow-guided analysis predicted more accurate dereplication of BGCs and guided the targeted comparative analysis of selected RiPPs. The scalable, interoperable, adaptable, re-entrant, and reproducible nature of the BGCFlow will provide an effective novel way to extract the biosynthetic knowledge in the ever-growing genomic datasets of biotechnologically relevant bacterial species. BGCFlow is available for downloading athttps://github.com/NBChub/bgcflow.