bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathological Tau transmission initiated by binding lymphocyte-activation gene 3
Authors: Chen Chan , Kumbhar Ramhari , Wang Hu , Yang Xiuli , Gadhave Kundlik , Rastegar Cyrus , Kimura Yasuyoshi , Behensky Adam , Katakam Sruthi , Jeong Deok , Wang Liang , Wang Anthony , Chen Rong , Zhang Shu , Jin Lingtao , Workman Creg J. , Vignali Dario A.A. , Pletinkova Olga , Nauen David W. , Wong Philip C. , Troncoso Juan C. , Ying Mingyao , Dawson Valina L. , Dawson Ted M. , Mao Xiaobo 
Published: May 2023

AbstractThe spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer’s disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1, 2. Clinical observation combined with complementary experimental studies3, 4have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion ofLag3or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lackingLag3selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target.One Sentence SummaryLag3 is a neuronal receptor specific for Tau PFF, and is required for uptake, propagation and transmission of Tau pathology.
The AMP deaminase of the molluskHelix pomatiais an unexpected member of the adenosine deaminase-related growth factor (ADGF) family
Authors: Tzertzinis George , Ganatra Mehul B. , Ruse Cristian , Taron Christopher H. , Causey Bryce , Wang Liang , Schildkraut Ira 
Published: May 2023

AbstractWe report here the first occurrence of an adenosine deaminase-related growth factor (ADGF) that deaminates adenosine 5’ monophosphate (AMP) in preference to adenosine. The ADGFs are a group of secreted deaminases found throughout the animal kingdom that affect the extracellular concentration of adenosine by converting it to inosine. The AMP deaminase studied here was first isolated and biochemically characterized from the roman snailHelix pomatiain 1983. Determination of the amino acid sequence of the AMP deaminase enabled sequence comparisons to protein databases and revealed it as a member of the ADGF family. Cloning and expression of its cDNA inPichia pastorisallowed the comparison of the biochemical characteristics of the native and recombinant forms of the enzyme and confirmed they correspond to the previously reported activity. Uncharacteristically, theH. pomatiaAMP deaminase was determined to be dissimilar to the AMP deaminase family by sequence comparison while demonstrating similarity to the ADGFs despite having AMP as its preferred substrate rather than adenosine.
Visible-Light Optical Coherence Tomography Fibergraphy of the Tree Shrew Retinal Ganglion Cell Axon Bundles
Authors: Miller David A. , Grannonico Marta , Liu Mingna , Savier Elise , McHaney Kara , Erisir Alev , Netland Peter A. , Cang Jianhua , Liu Xiaorong , Zhang Hao F. 
Published: May 2023

AbstractWe seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.
Infection-induced epilepsy is caused by increased expression of chondroitin sulfate proteoglycans in hippocampus and amygdala
Authors: Patel Dipan C. , Swift Nathaniel , Tewari Bhanu P. , Browning Jack L. , Prim Courtney , Chaunsali Lata , Kimbrough Ian , Olsen Michelle L. , Sontheimer Harald 
Published: May 2023

AbstractAlterations in the extracellular matrix (ECM) are common in epilepsy, yet whether they are cause or consequence of disease is unknow. Using Theiler’s virus infection model of acquired epilepsy we findde novoexpression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was normalized by aggrecan deletion.In situexperiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations (K+, Ca2+) on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. We show similar changes in CSPGs in pilocarpine-induced epilepsy suggesting enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and novel therapeutic potential.
Curiosity satisfaction increases event-related potentials sensitive to reward
Authors: Rueterbories Tim , Mecklinger Axel , Eschmann Kathrin C. J. , Crivelli-Decker Jordan , Ranganath Charan , Gruber Matthias J. 
Published: May 2023

AbstractSuccessful learning depends on various factors such as depth of processing, motivation, or curiosity about information. A strong drive to learn something or the expectation of receiving a reward can be crucial to enhance learning. However, the influence of curiosity on the processing of new information and its similarity with reward processing is not well understood. This study examined whether states of curiosity influence specific event-related-potentials (ERPs) associated with reward processing and whether these ERPs are related with later memory benefits. In an initial screening phase, participants indicated their curiosity and confidence in prior knowledge about answers to various trivia questions. In a subsequent study phase, we targeted different time windows related to reward processing during the presentation of trivia answers containing the Reward-Positivity (RewP; 250 - 350 ms), the P3 (250 - 500 ms), and the Late-Positive-Potential (LPP; 600 - 1000 ms). In a following surprise memory test, we found that participants recalled more high- than low-curiosity answers. The RewP, P3 and LPP showed greater positive mean amplitudes for high compared to low curiosity, reflecting increased reward processing. In addition, we found that the RewP and the P3 showed more positive mean amplitudes for later recalled compared to later forgotten answers, but curiosity did not modulate this encoding-related results. These findings support the view that the satisfaction of curiosity resembles reward processing, indicated by event-related-potentials.
Genomic surveillance of antimicrobial-resistantEscherichia coliin fecal sludge and sewage in Uganda
Authors: Gomi Ryota , Matsumura Yasufumi , Yamamoto Masaki , Tanaka Mai , Komakech Allan John , Matsuda Tomonari , Harada Hidenori 
Published: May 2023

ABSTRACTThe global increase of antimicrobial resistance (AMR) is a major public health concern. An effective AMR surveillance tool is needed to track the emergence and spread of AMR. Wastewater surveillance has been proposed as a resource-efficient tool for monitoring AMR carriage in the community. Here, we performed genomic surveillance of antimicrobial-resistantEscherichia coliobtained from fecal sludge and sewage in Uganda to gain insights intoE. coliepidemiology and AMR burden in the underlying population. Selective media containing different antibiotic combinations (cefotaxime, ciprofloxacin, cefotaxime + ciprofloxacin + gentamicin) were used to obtain antimicrobial-resistantE. colifrom fecal sludge and sewage. Short-read sequencing was performed for the obtained isolates, and a subset of isolates (selected from predominant sequence types (STs)) was also subjected to long-read sequencing. Genomic analysis of the obtainedE. coliisolates (n = 181) revealed the prevalence of clonal complex 10, including ST167 (n = 43), ST10 (n = 28), ST1284 (n = 17), and ST617 (n = 4), in both fecal sludge and sewage, irrespective of antibiotics used for selection. We also detected global high-risk clones ST1193 (n = 10) and ST131 (n = 2 clade A, n = 3 subclade C1-M27, and n = 1 subclade C2). Diverse AMR determinants, including extended-spectrum β-lactamase genes (mostlyblaCTX-M-15) and mutations ingyrAandparC, were identified. Analysis of the completed genomes revealed that diverse IncF plasmids and chromosomal integration were the major contributors to the spread of AMR genes in the predominant STs. This study showed that a combination of sewage surveillance (or fecal sludge surveillance) and whole-genome sequencing can be a powerful tool for monitoring AMR carriage in the underlying population.
Unraveling cellular complexity with unlimited multiplexed super-resolution imaging
Authors: Schueder Florian , Rivera-Molina Felix , Su Maohan , Kidd Phylicia , Rothman James E. , Toomre Derek , Bewersdorf Joerg 
Published: May 2023

SummaryMapping the intricate spatial relationships between the many different molecules inside a cell is essential to understanding cellular functions in all their complexity. Super-resolution fluorescence microscopy offers the required spatial resolution but struggles to reveal more than four different targets simultaneously. Exchanging labels in subsequent imaging rounds for multiplexed imaging extends this number but is limited by its low throughput. Here we present a novel imaging method for rapid multiplexed super-resolution microscopy of a nearly unlimited number of molecular targets by leveraging fluorogenic labeling in conjunction with Transient Adapter-mediated switching for high-throughput DNA-PAINT (FLASH-PAINT). We demonstrate the cell biological versatility of FLASH-PAINT in mammalian cells in four applications: i) mapping nine proteins in a single mammalian cell, ii) elucidating the functional organization of primary cilia by nine-target imaging, iii) revealing the changes in proximity of twelve different targets in unperturbed and dissociated Golgi stacks and iv) investigating inter-organelle contacts at 3D super-resolution.
A novel mitochondrial regulon for Ferroptosis during fungal pathogenesis
Authors: Shen Qing , Yang Fan , Naqvi Naweed I. 
Published: May 2023

AbstractFerroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human- and plant-diseases and to immunity thereof. Here, we utilized a range of chemical biological tools, genetic mutants and biochemical analyses to gain insights into how the fungal pathogenMagnaporthe oryzaeundergoes Ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a functional dependency between such intrinsic Ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the Ferroptosis defects therein. Graded inhibition of mitochondrial Coenzyme Q (CoQ) biosynthesis with or without ferroptosis inhibitor Liproxstation-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of Aconitase in the Tricarboxylic acid cycle in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to Ferroptosis. Lastly, we present an important mitochondrial bioenergetics and redox-regulatory network regulon essential for intrinsic Ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.
Prolonged stalling of RNA Polymerase II at DNA damage explains phenotypical differences between Cockayne and UV-sensitive syndromes
Authors: Hansen Camila Gonzalo , Steurer Barbara , Janssens Roel C. , Zhou Di , van Sluis Marjolein , Lans Hannes , Marteijn Jurgen A. 
Published: May 2023

AbstractFaithful transcription of eukaryotic genes by RNA polymerase II (Pol II) is essential for proper cell function. Nevertheless, the integrity of the DNA template of Pol II is continuously challenged by different sources of DNA damage, such as UV-light, that impede transcription. When unresolved, these transcription-blocking lesions (TBLs) can cause cellular dysfunction, senescence and apoptosis, eventually resulting in DNA damage-induced aging. Cells counteract these deleterious effects by Transcription-Coupled Nucleotide Excision Repair (TC-NER), which specifically removes TBLs, thereby safeguarding transcription. TC-NER initiation relies on the concerted actions of the CSB, CSA and UVSSA proteins, and loss of either of these factors results in a complete TC-NER deficiency. Although their TC-NER defect is similar, UVSSA loss results in UV-Sensitive Syndrome (UVSS), with only mild phenotypes like freckling and photosensitivity, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by premature aging, progressive neurodegeneration and mental retardation. Thus far the underlying mechanism for these striking differences in phenotypes remains unclear. Using live-cell imaging approaches, here we show that in TC-NER proficient cells lesion-stalled Pol II is swiftly resolved by repair of the TBL. However, in CSA and CSB knockout (KO) cells, elongating Pol II remains chromatin-bound. This lesion-stalled Pol II will obstruct other DNA transacting processes and will also shield the damage from repair by alternative pathways. In contrast, in UVSSA KO cells, Pol II is removed from the TBL by VCP-mediated proteasomal degradation, thereby, allowing alternative repair mechanisms to remove the TBL.
Single-cycle SARS-CoV-2 vaccine elicits high protection and sterilizing immunity in hamsters
Authors: Lett Martin Joseph , Otte Fabian , Hauser David , Schön Jacob , Kipfer Enja Tatjana , Hoffmann Donata , Halwe Nico J. , Ulrich Lorenz , Zhang Yuepeng , Cmiljanovic Vladimir , Wylezich Claudia , Urda Lorena , Lang Christopher , Beer Martin , Mittelholzer Christian , Klimkait Thomas 
Published: May 2023

AbstractVaccines have been central in ending the COVID-19 pandemic, but newly emerging SARS-CoV-2 variants increasingly escape first-generation vaccine protection. To fill this gap, live particle-based vaccines mimicking natural infection aim at protecting against a broader spectrum of virus variants. We designed “single-cycle SARS-CoV-2 viruses” (SCVs) that lack essential viral genes, possess superior immune-modulatory features and provide an excellent safety profile in the Syrian hamster model. Full protection of all intranasally vaccinated animals was achieved against an autologous challenge with SARS-CoV-2 virus using an Envelope-gene-deleted vaccine candidate. By deleting key immune-downregulating genes, sterilizing immunity was achieved with an advanced candidate without virus spread to contact animals. Hence, SCVs have the potential to induce a broad and durable protection against COVID-19 superior to a natural infection.
“Ghost” fragment ions in structure and site-specific glycoproteomics analysis
Authors: Campos Diana , Girgis Michael , Yang Qiang , Zong Guanghui , Goldman Radoslav , Wang Lai-Xi , Sanda Miloslav 
Published: May 2023

ABSTRACTMass spectrometry (MS) can unlock crucial insights into the intricate world of glycosylation analysis. Despite its immense potential, the qualitative and quantitative analysis of isobaric glycopeptide structures remains one of the most daunting hurdles in the field of glycoproteomics. The ability to distinguish between these complex glycan structures poses a significant challenge, hindering our ability to accurately measure and understand the role of glycoproteins in biological systems. A few recent publications described the use of collision energy (CE) modulation to improve structural elucidation, especially for qualitative purposes. Different linkages of glycan units usually demonstrate different stabilities under CID/HCD fragmentation conditions. Fragmentation of the glycan moiety produces low molecular weight ions (oxonium ions) that can serve as a structure-specific signature for specific glycan moieties, however, specificity of these fragments has never been examined closely. Here, we investigated fragmentation specificity using synthetic stable isotope-labelled glycopeptide standards. These standards were isotopically labelled at the reducing terminal GlcNAc, which allowed us to resolve fragments produced by oligomannose core moiety and fragments generated from outer antennary structures. Our research identified the potential for false positive structure assignments due to the occurrence of “Ghost” fragments resulting from single glyco unit rearrangement or mannose core fragmentation within the collision cell. To mitigate this issue, we have established a minimal intensity threshold for these fragments to prevent the misidentification of structure-specific fragments in glycoproteomics analysis. Our findings provide a crucial step forward in the quest for more accurate and reliable glycoproteomics measurements.Graphical abstract
Epigenome Editing Durability Varies Widely Across Cardiovascular Disease Target Genes
Authors: Whittaker Madelynn N. , Testa Lauren C. , Quigley Aidan , Jindal Ishaan , Cortez-Alvarado Saúl V. , Qu Ping , Yang Yifan , Alameh Mohamad-Gabriel , Musunuru Kiran , Wang Xiao 
Published: May 2023

ABSTRACTBackgroundHepatic knockdown of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or the angiopoietin-like 3 (ANGPTL3) gene has been demonstrated to reduce blood low-density lipoprotein cholesterol (LDL-C) levels, and hepatic knockdown of the angiotensinogen (AGT) gene has been demonstrated to reduce blood pressure. Genome editing can productively target each of these three genes in hepatocytes in the liver, offering the possibility of durable “one-and-done” therapies for hypercholesterolemia and hypertension. However, concerns around making permanent gene sequence changes via DNA strand breaks might hinder acceptance of these therapies. Epigenome editing offers an alternative approach to gene inactivation, via silencing of gene expression by methylation of the promoter region, but the long-term durability of epigenome editing remains to be established.MethodsWe assessed the ability of epigenome editing to durably reduce the expression of the humanPCSK9, ANGPTL3, andAGTgenes in HuH-7 hepatoma cells. Using the CRISPRoff epigenome editor, we identified guide RNAs that produced efficient gene knockdown immediately after transfection. We assessed the durability of gene expression and methylation changes through serial cell passages.ResultsCells treated with CRISPRoff andPCSK9guide RNAs were maintained for up to 124 cell doublings and demonstrated durable knockdown of gene expression and increased CpG dinucleotide methylation in the promoter, exon 1, and intron 1 regions. In contrast, cells treated with CRISPRoff andANGPTL3guide RNAs experienced only transient knockdown of gene expression. Cells treated with CRISPRoff andAGTguide RNAs also experienced transient knockdown of gene expression; although initially there was increased CpG methylation throughout the early part of the gene, this methylation was geographically heterogeneous—transient in the promoter, and stable in intron 1.ConclusionsThis work demonstrates precise and durable gene regulation via methylation, supporting a new therapeutic approach for protection against cardiovascular disease via knockdown of genes such asPCSK9. However, the durability of knockdown with methylation changes is not generalizable across target genes, likely limiting the therapeutic potential of epigenome editing compared to other modalities.
Environmental Persistence and Disinfection of Lassa Virus
Authors: Shaffer Marlee , Fischer Robert J. , Gallogly Shane , Ginn Olivia , Munster Vincent , Bibby Kyle 
Published: May 2023

AbstractLassa Fever, caused by Lassa virus (LASV), is endemic to West Africa, where approximately 300,000 illnesses and 5,000 deaths occur annually. LASV is primarily spread by infected multimammate rats via urine and fomites, highlighting the importance of understanding the environmental fate of LASV. This study evaluated the persistence of LASV strains on surfaces in aqueous solutions and with sodium hypochlorite disinfection. LASV strains (Josiah and Sauerwald) were more stable in DI water (k = 0.23 and 0.34 days-1) than primary influent wastewater (k = 1.3 and 1.9 days-1). The decay rates of LASV on HDPE (k = 4.3 and 2.3 days-1) and Stainless Steel (k = 5.3 and 2.7 days-1) were not significantly different for either strain. Sodium hypochlorite was highly effective at inactivating both strains of LASV. This work presents data for the environmental persistence of LASV to inform future risk assessment and management efforts.