bluuebunny/crossref_metadata_2025_split huggingface dataset:
preon: Fast and accurate entity normalization for drug names and cancer types in precision oncology
Authors: Ermshaus Arik , Piechotta Michael , Rüter Gina , Keilholz Ulrich , Leser Ulf , Benary Manuela 
Published: May 2023

AbstractMotivationIn precision oncology, clinicians are aiming to find the best treatment for any patient based on their molecular characterization. A major bottleneck is the annotation and evaluation of individual variants, for which usually a range of knowledge bases are manually screened. To incorporate and integrate the vast information of different databases, fast and accurate methods for harmonization are necessary.Summarypreon is a fast and accurate library for the normalization of drug names and cancer types in large-scale data integration.Availability and Implementationpreon is implemented in Python and freely available via the PyPI repository. Source code and gold standard data sets are available athttps://github.com/ermshaua/preon/.Contactmanuela.benary@bih-charite.deSupplementary informationSupplementary data are available online.
Shigellagenerates distinct IAM subpopulations during epithelial cell invasion to promote efficient intracellular niche formation
Authors: Sanchez Lisa , Connor Michael G. , Hamon Mélanie , Valenzuela Camila , Enninga Jost 
Published: May 2023

AbstractThe facultative intracellular pathogenShigella flexneriinvades non-phagocytic epithelial gut cells. Through a syringe-like apparatus called type 3 secretion system, it injects effector proteins into the host cell triggering actin rearrangements leading to its uptake within a tight vacuole, termed the bacterial-containing vacuole (BCV). Simultaneously,Shigellainduces the formation of large vesicles around the entry site, which we refer to as infection- associated macropinosomes (IAMs). After entry,Shigellaruptures the BCV and escapes into the host cytosol by disassembling the BCV remnants. Previously, IAM formation has been shown to be required for efficient BCV escape, but the molecular events associated with BCV disassembly have remained unclear. To identify host components required for BCV disassembly, we performed a microscopy-based screen to monitor the recruitment of BAR domain-containing proteins, which are a family of host proteins involved in membrane shaping and sensing (e.g. endocytosis and recycling) duringShigellaepithelial cell invasion. We identified endosomal recycling BAR protein Sorting Nexin-8 (SNX8) localized to IAMs in a PI(3)P-dependent manner before BCV disassembly. At least two distinct IAM subpopulations around the BCV were found, either being recycled back to cellular compartments such as the plasma membrane or transitioning to become RAB11A positive “contact-IAMs” involved in promoting BCV rupture. The IAM subpopulation duality was marked by the exclusive recruitment of either SNX8 or RAB11A. Finally, hindering PI(3)P production at the IAMs led to an inhibition of SNX8 recruitment at these compartments and delayed both, the step of BCV rupture time and successive BCV disassembly. Overall, our work sheds light on howShigellaestablishes its intracellular niche through the subversion of a specific set of IAMs.
Nanoparticle-induced biomembrane fusion: unraveling the effect of core size on stalk formation
Authors: Brosio Giorgia , Rossi Giulia , Bochicchio Davide 
Published: May 2023

Membrane fusionin vitrois a strategy to load model or cell-derived vesicles with proteins, drugs, and genetic materials for theranostic applications. It is thus crucial to develop strategies to control the fusion process, also through synthetic fusogenic agents. Ligand-protected, membrane-penetrating gold nanoparticles (Au NPs) can facilitate membrane fusion, but the molecular mechanisms remain unresolved. Here, we tackle NP-induced stalk formation using a coarse-grained Molecular Dynamics approach and enhanced sampling techniques. We show that smaller (2 nm in diameter) NPs lead to a lower free energy barrier and higher stalk stability than larger NPs (4 nm). We demonstrate that this difference is due to a different ligand conformational freedom, which in turn depends on the Au core curvature. Our study provides precious insights into the mechanisms underlying NP-mediated membrane fusion, while our computational approach is general and applicable to studying stalk formation caused by other fusogenic agents.TOC GRAPHICS
The cell walls of differentCharaspecies (Charophyceae) are characterized by branched galactans rich in 3-O-methylgalactose and absence of arabinogalactan-proteins
Authors: Pfeifer Lukas , Mueller Kim-Kristine , Utermöhlen Jon , Erdt Felicitas , Zehge Jean Bastian Just , Schubert Hendrik , Classen Birgit 
Published: May 2023

ABSTRACTStreptophyte algae are the closest relatives of land plants and their latest common ancestor performed the most drastic adaptation that happened in plant evolution around 500 million years ago: the conquest of land. Beside other adaptations, this step required changes in cell wall composition. Today knowledge on cell walls of streptophyte algae and especially presence of arabinogalactan-proteins (AGPs), which are important signaling molecules of all land plants, is limited. To get deeper insights in cell walls of streptophyte algae, especially of the Charophyceae, we performed sequential cell wall extractions of fourCharaspecies. The three speciesChara globularis,Chara subspinosaandChara tomentosarevealed comparable cell wall compositions with pectins, xylans and xyloglucans, whereasChara asperawas outstanding with higher amounts of uronic acids in the pectic fractions and lack of reactivity with antibodies binding to xylan- and xyloglucan epitopes. Search for AGPs in the fourCharaspecies and alsoNitellopsis obtusarevealed presence of galactans with pyranosidic galactose in 1,3-, 1,6- and 1,3,6-linkage, which are typical galactan motifs of land plant AGPs. A unique feature of these branched galactans were high portions of 3-O-methylgalactose. OnlyNitellopsiscontained substantial amounts of Ara. Bioinformatic search for prolyl-4-hydroxylase necessary for biosynthesis of AGPs revealed one possible functional sequence in the genome ofChara braunii, but no hydroxyproline could be detected in the fourCharaspecies andNitellopsis obtusa. We conclude that AGPs typical for land plants are absent at least in these members of the Charophyceae.
Phytocystatin 6 is a context-dependent, tight-binding inhibitor ofArabidopsis thalianalegumain isoform β
Authors: Santos Naiá P. , Soh Wai T. , Demir Fatih , Tenhaken Raimund , Briza Peter , Huesgen Pitter F. , Brandstetter Hans , Dall Elfriede 
Published: May 2023

AbstractPlant legumains are crucial for processing seed storage proteins and are critical regulators of plant programmed cell death. Although research on legumains boosted recently, little is known about their activity regulation. In our study, we used pull-down experiments to identify AtCYT6 as a natural inhibitor of legumain isoform β (AtLEGβ) inArabidopsis thaliana. Biochemical analysis revealed that AtCYT6 inhibits both AtLEGβ and papain-like cysteine proteases through two cystatin domains. The N-terminal domain inhibits papain-like proteases, while the C-terminal domain inhibits AtLEGβ. Furthermore, we showed that AtCYT6 interacts with legumain in a substrate-like manner, facilitated by a conserved asparagine residue in its reactive center loop. Complex formation was additionally stabilized by charged exosite interactions, contributing to pH-dependent inhibition. Processing of AtCYT6 by AtLEGβ suggests a context-specific regulatory mechanism with implications for plant physiology, development, and programmed cell death. These findings enhance our understanding of AtLEGβ regulation and its broader physiological significance.
Extracellular G-quadruplex and Z-DNA protect biofilms from DNase I and forms a DNAzyme with peroxidase activity
Authors: Minero Gabriel Antonio S. , Møllebjerg Andreas , Thiesen Celine , Johansen Mikkel Illemann , Jørgensen Nis Pedersen , Birkedal Victoria , Otzen Daniel , Meyer Rikke L. 
Published: May 2023

ABSTRACTMany bacteria form biofilms to protect themselves from predators or stressful environmental conditions. In the biofilm, bacteria are embedded in a protective extracellular matrix composed of polysaccharides, proteins and extracellular DNA (eDNA). eDNA most often arises from lysed cells, and it is the only matrix component most biofilms appear to have in common. However, little is known about the form DNA takes in the extracellular space, and how different non-canonical DNA structures such as Z-DNA or G-quadruplex formation might contribute to its function in the biofilm.The aim of this study was to determine if non-canonical DNA structures form in eDNA-rich staphylococcal biofilms, and if these structures protect the biofilm from degradation by nucleases. We grewStaphylococcus epidermidisbiofilms in laboratory media amended with hemin and NaCl to stabilize secondary DNA structures and visualized their location by immunolabelling and fluorescence microscopy. We furthermore visualized the macroscopic biofilm structure by optical coherence tomography. We developed assays to quantify degradation of Z-DNA and G-quadruplex DNA oligos by different nucleases, and subsequently investigated how these enzymes affected eDNA in the biofilms.Z-DNA and G-quadruplex DNA were abundant in the biofilm matrix, and were often present in a web-like structure in biofilms grownin vitroandin vivousing a murine implant-associated osteomyelitis model.In vitro, the structures did not form in the absence of NaCl or mechanical shaking during biofilm growth, or in bacterial strains deficient in eDNA or exopolysaccharide production. We thus infer that eDNA and polysaccharides interact, leading to non-canonical DNA structures under mechanical stress when stabilized by salt, and we confirmed that G-quadruplex DNA and Z-DNA was also present in biofilms from infected implants. Mammalian DNase I lacked activity against Z-DNA and G-quadruplex DNA, while Micrococcal nuclease could degrade G-quadruplex DNA and S1 Aspergillus nuclease could degrade Z-DNA. Micrococcal nuclease, which originates fromStaphylococcus aureus, may thus be key for dispersal of biofilm in staphylococci. In addition to its structural role, we show for the first time that the eDNA in biofilms forms a DNAzyme with peroxidase-like activity in the presence of hemin. While peroxidases are part of host defenses against pathogens, we now show that biofilms can possess intrinsic peroxidase activity in the extracellular matrix.Abstract Figure
Development of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic strategy for Alzheimer’s disease
Authors: Du Yuhong , Bradshaw William J. , Leisner Tina M. , Annor-Gyamfi Joel K. , Qian Kun , Bashore Frances M. , Sikdar Arunima , Nwogbo Felix O. , Ivanov Andrey A. , Frye Stephen V. , Gileadi Opher , Brennan Paul E. , Levey Allan I. ,   the Emory-Sage-SGC TREAT-AD Center, Axtman Alison D. , Pearce Kenneth H. , Fu Haian , Katis Vittorio L. 
Published: May 2023

AbstractRecent genome-wide association studies have revealed genetic risk factors for Alzheimer’s disease (AD) that are exclusively expressed in microglia within the brain. A proteomics approach identified moesin (MSN), a FERM (four-point-one ezrin radixin moesin) domain protein, and the receptor CD44 as hub proteins found within a co-expression module strongly linked to AD clinical and pathological traits as well as microglia. The FERM domain of MSN interacts with the phospholipid PIP2and the cytoplasmic tails of receptors such as CD44. This study explored the feasibility of developing protein-protein interaction inhibitors that target the MSN–CD44 interaction. Structural and mutational analyses revealed that the FERM domain of MSN binds to CD44 by incorporating a beta strand within the F3 lobe. Phage-display studies identified an allosteric site located close to the PIP2binding site in the FERM domain that affects CD44 binding within the F3 lobe. These findings support a model in which PIP2binding to the FERM domain stimulates receptor tail binding through an allosteric mechanism that causes the F3 lobe to adopt an open conformation permissive for binding. High-throughput screening of a chemical library identified two compounds that disrupt the MSN–CD44 interaction, and one compound series was further optimized for biochemical activity, specificity, and solubility. The results suggest that the FERM domain holds potential as a drug development target. The small molecule preliminary leads generated from the study could serve as a foundation for additional medicinal chemistry effort with the goal of controlling microglial activity in AD by modifying the MSN–CD44 interaction.
Distinct accessory roles of Arabidopsis VEL proteins in Polycomb silencing
Authors: Franco-Echevarría Elsa , Nielsen Mathias , Schulten Anna , Cheema Jitender , Morgan Tomos E , Bienz Mariann , Dean Caroline 
Published: May 2023

AbstractPolycomb Repressive Complex 2 (PRC2) mediates epigenetic silencing of target genes in animals and plants. In Arabidopsis, PRC2 is required for the cold-induced epigenetic silencing of theFLCfloral repressor locus to align flowering with spring. During this process, PRC2 relies on VEL accessory factors, including the constitutively expressed VRN5 and the cold-induced VIN3. The VEL proteins are physically associated with PRC2, but their individual functions remain unclear. Here, we show an intimate association between recombinant VRN5 and multiple components within a reconstituted PRC2, dependent on a compact conformation of VRN5 central domains. Key residues mediating this compact conformation are conserved amongst VRN5 orthologs across the plant kingdom. By contrast, VIN3 interacts with VAL1, a transcriptional repressor that binds directly toFLC. These associations differentially affect their role in H3K27me deposition: both proteins are required for H3K27me3, but only VRN5 is necessary for H3K27me2. Although originally defined as vernalization regulators, VIN3 and VRN5 co-associate with many targets in the Arabidopsis genome that are modified with H3K27me3. Our work, therefore, reveals the distinct accessory roles for VEL proteins in conferring cold-induced silencing onFLC, with broad relevance for PRC2 targets generally.
Soybean-SCN duel: Novel insight into Soybean’s Resistant Responses toHeterodera glycines
Authors: Torabi Sepideh , Seifi Soren , Geddes-McAlister Jennifer , Tenuta Albert , Wally Owen , Torkamaneh Davoud , Eskandari Milad 
Published: May 2023

AbstractSoybean cyst nematodes (SCN,Heterodera glycinesIchinohe) are a significant threat to soybean production globally, causing severe yield losses and necessitating the development of effective strategies to combat this devastating nematode disease. This study presents dual RNA-seq analyses of the three most common SCN-resistant lines (Plant Introduction (PI) 437654, 548402, and 88788) and the susceptible line Lee74 against the SCN HG type 1.2.5.7 to identify the mechanisms of resistance and virulence genes involved in resistance breakdown. Transcriptomic and pathway analyses reveal the activation of the phenylpropanoid pathway, MAPK signaling pathway, plant hormone signal transduction, and secondary metabolite pathways in the resistance mechanisms. PI 437654, which exhibited robust resistance (female index, FI=0%), demonstrated unique gene expression associated with cell wall reinforcement, oxidative enzymes, ROS scavengers, and Ca+2 sensors governing the salicylic acid (SA) biosynthesis process, indicating its key defense mechanism. Moreover, using different hosts with varying levels of immunity and a susceptible line provided insights into SCN pathogenesis and howH. glycineovercomes different layers of host immunity by modulating its virulence genes. This research provides novel insights into the molecular mechanisms underlying soybean-SCN interactions and identifies potential targets for developing strategies to manage this devastating nematode disease.
Transcription start site heterogeneity and its role in RNA fate determination distinguish HIV-1 from other retroviruses and are mediated by core promoter elements
Authors: Kharytonchyk Siarhei , Burnett Cleo , GC Keshav , Telesnitsky Alice 
Published: May 2023

AbstractHIV-1 uses heterogeneous transcription start sites (TSSs) to generate two RNA 5’ isoforms that adopt radically different structures and perform distinct replication functions. Although these RNAs differ in length by only two bases, exclusively the shorter RNA is encapsidated while the longer RNA is excluded from virions and provides intracellular functions. The current study examined TSS usage and packaging selectivity for a broad range of retroviruses and found that heterogenous TSS usage was a conserved feature of all tested HIV-1 strains, but all other retroviruses examined displayed unique TSSs. Phylogenetic csomparisons and chimeric viruses’ properties provided evidence that this mechanism of RNA fate determination was an innovation of the HIV-1 lineage, with determinants mapping to core promoter elements. Fine-tuning differences between HIV-1 and HIV-2, which uses a unique TSS, implicated purine residue positioning plus a specific TSS-adjacent dinucleotide in specifying multiplicity of TSS usage. Based on these findings, HIV-1 expression constructs were generated that differed from the parental strain by only two point mutations yet each expressed only one of HIV-1’s two RNAs. Replication defects of the variant with only the presumptive founder TSS were less severe than those for the virus with only the secondary start site.
“Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity”
Authors: Diaz Antonio Cadiz , Cirrincione Anthony M , Schmidt Natalie A , Ugo Marie J , Amaya Sanchez Maria Celina , Reimonn Cassandra A. , Wuchty Stefan , Pellegrini Adriana D , Rude Leah RK , Pappalardo Leah G , Regan Daniel P , Howell Caitlin , Hrstka Sybil , Dasari Surendra , Lisse Thomas S , Harrison Benjamin J , Xu Mike Xiangxi , Staff Nathan P , Rieger Sandra 
Published: May 2023

AbstractTaxanes are chemotherapeutic agents that induce microtubule modifications in cancer cells, resulting in cell cycle modifications and tumor remission. Here we show that paclitaxel, a widely used taxane, also induces microtubule modifications in healthy epidermal keratinocytes leading to chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel activates the cell cycle regulator, Kinesin-5 (Eg5), which promotes microtubule detyrosination and fasciculation (dfMT). Eg5 loss protects neurons from paclitaxel neurotoxicity, whereas keratinocyte-specific overexpression promotes axon degeneration.In vivoimaging and 3D reconstructions of dfMTs and nuclei, combined with mechanotransduction studies further show that dfMTs constrict keratinocyte nuclei, leading to nuclear Nox-dependent reactive oxygen species (X-ROS) formation upstream of MMP-13 and cutaneous sensory axon degeneration. This new insight facilitates our understanding of chemotherapy side effects and highlights the need for targeted therapies.
SLC12A9 is a lysosome-detoxifying ammonium – chloride co-transporter
Authors: Levin-Konigsberg Roni , Mitra Koushambi , Nigam AkshatKumar , Spees Kaitlyn , Hivare Pravin , Liu Katherine , Kundaje Anshul , Krishnan Yamuna , Bassik Michael C. 
Published: May 2023

AbstractAmmonia is a ubiquitous, toxic by-product of cell metabolism. Its high membrane permeability and proton affinity causes ammonia to accumulate inside acidic lysosomes in its poorly membrane-permeant form: ammonium (NH4+). Ammonium buildup compromises lysosomal function, suggesting the existence of mechanisms that protect cells from ammonium toxicity. Here, we identified SLC12A9 as a lysosomal ammonium exporter that preserves lysosomal homeostasis. SLC12A9 knockout cells showed grossly enlarged lysosomes and elevated ammonium content. These phenotypes were reversed upon removal of the metabolic source of ammonium or dissipation of the lysosomal pH gradient. Lysosomal chloride increased in SLC12A9 knockout cells and chloride binding by SLC12A9 was required for ammonium transport. Our data indicate that SLC12A9 is a chloride-driven ammonium co-transporter that is central in an unappreciated, fundamental mechanism of lysosomal physiology that may have special relevance in tissues with elevated ammonia, such as tumors.
Reinforcement-based option competition in human dorsal stream during exploration/exploitation of a continuous space
Authors: Hallquist Michael N. , Hwang Kai , Luna Beatriz , Dombrovski Alexandre Y. 
Published: May 2023

AbstractPrimates exploring and exploiting a continuous sensorimotor space rely on maps in the dorsal stream that guide visual search, locomotion, and grasp. For example, an animal swinging from one tree limb to the next uses rapidly evolving sensorimotor representations to decide when to harvest a reward. We show that such exploration/exploitation depends on dynamic maps of competing option values in the human dorsal stream. Using a reinforcement learning (RL) model capable of rapid learning and efficient exploration and exploitation, we show that preferred options are selectively maintained on the map while the values of spatiotemporally distant alternatives are compressed. Consistent with biophysical models of cortical option competition, dorsal stream BOLD signal increased and posterior cortical β1/α oscillations desynchronized as the number of potentially valuable options grew, matching predictions of information-compressing RL rather than traditional RL that caches long-term values. BOLD and β1/α responses were correlated and predicted the successful transition from exploration to exploitation. These option competition dynamics were observed across parietal and frontal dorsal stream regions, but not in the occipito-temporal MT+ sensitive to the average reward rate. Our results also illustrate that models’ diverging predictions about information dynamics can help to adjudicate between them based on population activity.Graphical abstract