bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions
Authors: Petkantchin Remy , Rousseau Alexandre , Eker Omer , Boudjeltia Karim Zouaoui , Raynaud Franck , Chopard Bastien ,   the INSIST investigators
Published: May 2023

ABSTRACTOne of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conductedin vitroflow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.
Pseudorabies virus hijacks DDX3X, initiating an addictive “mad itch” and immune suppression, to facilitate viral spread
Authors: Cronin Shane J. F. , Tejada Miguel A. , Song Ren , Laval Kathlyn , Cikes Domagoj , Ji Ming , Brai Annalaura , Stadlmann Johannes , Novatchikova Maria , Perlot Thomas , Ali Omar Hasan , Botta Lorenzo , Decker Thomas , Lazovic Jelena , Hagelkruys Astrid , Enquist Lynn , Rao Shuan , Koyuncu Orkide O. , Penninger Josef M. 
Published: May 2023

AbstractInfections with defined Herpesviruses, such as Pseudorabies virus (PRV) and Varicella zoster virus (VZV) can cause neuropathic itch, referred to as “mad itch” in multiple species. The underlying mechanisms involved in neuropathic “mad itch” are poorly understood. Here, we show that PRV infections hijack the RNA helicase DDX3X in sensory neurons to facilitate anterograde transport of the virus along axons. PRV induces re-localization of DDX3X from the cell body to the axons which ultimately leads to death of the infected sensory neurons. Inducible genetic ablation ofDdx3xin sensory neurons results in neuronal death and “mad itch” in mice. This neuropathic “mad itch” is propagated through activation of the opioid system making the animals “addicted to itch”. Moreover, we show that PRV co-opts and diverts T cell development in the thymus via a sensory neuron-IL-6-hypothalamus-corticosterone stress pathway. Our data reveal how PRV, through regulation of DDX3X in sensory neurons, travels along axons and triggers neuropathic itch and immune deviations to initiate pathophysiological programs which facilitate its spread to enhance infectivity.
Ectopically expressedAirnlncRNA deposits Polycomb with a potency that rivalsXist
Authors: Trotman Jackson B. , Braceros Aki K. , Bischoff Steven R. , Murvin McKenzie M. , Boyson Samuel P. , Cherney Rachel E. , Eberhard Quinn E. , Abrash Elizabeth W. , Cowley Dale O. , Calabrese J. Mauro 
Published: May 2023

AbstractWe report that when expressed at similar levels from an isogenic locus, theAirnlncRNA induces Polycomb deposition with a potency that rivalsXist. However, when subject to the same degree of promoter activation,Xistis more abundant and more potent thanAirn. Our data definitively demonstrate that theAirnlncRNA is functional and suggest thatXistachieved extreme potency in part by evolving mechanisms to promote its own abundance.
CASCADE-Cas3 Enables Highly Efficient Genome Engineering inStreptomycesSpecies
Authors: Whitford Christopher M. , Gockel Peter , Faurdal David , Gren Tetiana , Sigrist Renata , Weber Tilmann 
Published: May 2023

AbstractType I CRISPR systems are widespread in bacteria and archaea. The main differences compared to more widely applied type II systems are multi-effector CASCADE needed for crRNA processing and target recognition, as well as the processive nature of the hallmark nuclease Cas3. Given the widespread nature of type I systems, the processive nature of Cas3, as well as the recombinogenic overhangs created by Cas3, we hypothesized that Cas3 would be uniquely positioned to enable efficient genome engineering in streptomycetes. Here, we report a new type I based CRISPR genome engineering tool for streptomycetes. The plasmid system, called pCRISPR-Cas3, utilizes a compact type I-C CRISPR system and enables highly efficient genome engineering. pCRISPR-Cas3, outperforms pCRISPR-Cas9 and facilitates targeted and random sized deletions, as well as substitutions of large genomic regions such as biosynthetic gene clusters. Without additional modifications, pCRISPR-Cas3 enabled genome engineering in severalStreptomycesspecies at high efficiencies.
Systematic characterization of a non-transgenic Aβ1–42amyloidosis model: synaptic plasticity and memory deficits in female and male mice
Authors: Jiménez-Herrera Raquel , Contreras Ana , Iborra-Lázaro Guillermo , Jeremic Danko , Djebari Souhail , Navarro-López Juan , Jiménez-Díaz Lydia 
Published: May 2023

AbstractBackgroundOne of the neuropathological hallmarks of Alzheimer’s disease (AD) is amyloid-β(Aβ) accumulation in the hippocampus that causes its dysfunction. This disruption includes excitatory/inhibitory imbalance, synaptic plasticity and oscillatory activity impairments, and memory deficits. Although AD prevalence is higher in women than men, the possible sex difference is scarcely explored and information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data of the early amyloidosis stages in females, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of Aβ1–42on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse, in both male and female mice.MethodsTo do so, we evaluated long term potentiation (LTP) withex vivoelectrophysiological recordings and spatial (working, short- and long-term) and exploratory habituation memory using Barnes maze or open field habituation tasks respectively.ResultsWe found that Aβ1–42administration impairs all forms of memory evaluated, regardless the sex, in a long-lasting manner (up to 17 days post-injection). Furthermore, LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underly memory deficits.ConclusionsIn conclusion, our results provide further evidence of the shifting of LTP/LTD threshold due to a singleicv. Aβ1-42injection, which underly cognitive deficits in early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.
MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation
Authors: Pantier Raphaël , Brown Megan , Han Sicheng , Paton Katie , Meek Stephen , Montavon Thomas , McHugh Toni , Kelly David A. , Hochepied Tino , Libert Claude , Jenuwein Thomas , Burdon Tom , Bird Adrian 
Published: May 2023

AbstractCorrelative evidence has suggested that DNA methylation promotes the formation of transcriptionally silent heterochromatin. Accordingly, the methyl-CpG binding domain protein MeCP2 is often portrayed as a constituent of heterochromatin. This interpretation has been reinforced by the use of mouse cells as an experimental system for studying the mammalian epigenome, as heterochromatin, DNA methylation and MeCP2 colocalise in prominent foci. The findings presented here revise this view. We show that focal localisation of MeCP2 in mice is independent of heterochromatin, as DNA methylation-dependent MeCP2 foci persist even when the signature heterochromatin histone mark H3K9me3 is absent and heterochromatin protein HP1 is diffuse. Contrary to the proposal that MeCP2 forms condensates at mouse heterochromatic foci via liquid-liquid phase transition, the short methyl-CpG binding domain, which lacks the disordered domains thought to be required for condensation, is sufficient to target foci in mouse cells. Importantly, we find that the formation of MeCP2 foci in mice is highly atypical, as they are indetectable in 14 out of 16 other mammalian species, including humans. Notably, MeCP2 foci are absent inMus spretuswhich can interbreed withMus musculusbut lacks its highly methylated pericentric satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form nuclear condensates and its localisation is independent of heterochromatin formation. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns and is typically euchromatic.
Flexible control of vocal timing inCarollia perspicillatabats enables escape from acoustic interference
Authors: Kiai Ava , Clemens Jan , Kössl Manfred , Poeppel David , Hechavarría Julio 
Published: May 2023

AbstractIn natural environments, background noise can degrade the integrity of acoustic signals, posing a problem for animals that rely on their vocalizations for communication and navigation. A simple behavioral strategy to combat acoustic interference would be to restrict call emissions to periods of low-amplitude or no noise. Using audio playback and computational tools for the automated detection of over 2.5 million vocalizations from groups of freely vocalizing bats, we show that bats (Carollia perspicillata) can dynamically adapt the timing of their calls to avoid acoustic jamming in both predictably and unpredictably patterned noise. This study demonstrates that bats spontaneously seek out temporal windows of opportunity for vocalizing in acoustically crowded environments, providing a mechanism for efficient echolocation and communication in cluttered acoustic landscapes.One Sentence SummaryBats avoid acoustic interference by rapidly adjusting the timing of vocalizations to the temporal pattern of varying noise.
A tubulin-binding protein that preferentially binds to GDP-tubulin and promotes GTP exchange
Authors: Yon Wesley J. , Ha Taekjip , Zheng Yixian , Pedersen Ross T.A. 
Published: May 2023

Abstractα- and β-tubulin form heterodimers, with GTPase activity, that assemble into microtubules. Like other GTPases, the nucleotide-bound state of tubulin heterodimers controls whether the molecules are in a biologically active or inactive state. While α-tubulin in the heterodimer is constitutively bound to GTP, β-tubulin can be bound to either GDP (GDP-tubulin) or GTP (GTP-tubulin). GTP-tubulin hydrolyzes its GTP to GDP following assembly into a microtubule and, upon disassembly, must exchange its bound GDP for GTP to participate in subsequent microtubule polymerization. Tubulin dimers have been shown to exhibit rapid intrinsic nucleotide exchange in vitro, leading to a commonly accepted belief that a tubulin guanine nucleotide exchange factor (GEF) may be unnecessary in cells. Here, we use quantitative binding assays to show that BuGZ, a spindle assembly factor, binds tightly to GDP-tubulin, less tightly to GTP-tubulin, and weakly to microtubules. We further show that BuGZ promotes the incorporation of GTP into tubulin using a nucleotide exchange assay. The discovery of a tubulin GEF suggests a mechanism that may aid rapid microtubule assembly dynamics in cells.
Limited Expression ofNrf2in Neurons Across the Central Nervous System
Authors: Levings Daniel C. , Pathak Salil Saurav , Yang Yi-Mei , Slattery Matthew 
Published: May 2023

AbstractNrf2 is a broadly expressed transcription factor that regulates gene expression in response to reactive oxygen species (ROS) and oxidative stress. It is commonly referred to as a ubiquitous pathway, but this generalization overlooks work indicating that Nrf2 is essentially unexpressed in some neuronal populations. To explore whether this pattern extends throughout the central nervous system (CNS), we quantifiedNrf2expression and chromatin accessibility at theNrf2locus across multiple single cell datasets. In both the mouse and human CNS,Nrf2was repressed in almost all mature neurons, but highly expressed in non-neuronal support cells, and this pattern was robust across multiple human CNS diseases. A subset of key Nrf2 target genes, likeSlc7a11, also remained low in neurons. Thus, these data suggest that while most cells express Nrf2, with activity determined by ROS levels, neurons actively avoid Nrf2 activity by keepingNrf2expression low.
Stability of mpox (monkeypox) virus in bodily fluids and wastewater
Authors: Yinda Claude Kwe , Morris Dylan H. , Fischer Robert J , Gallogly Shane , Weishampel Zachary A. , Port Julia R. , Bushmaker Trenton , Schulz Jonathan E. , Bibby Kyle , van Doremalen Neeltje , Lloyd-Smith James O. , Munster Vincent J. 
Published: May 2023

AbstractImportanceSince May 2022, human monkeypox (mpox) infections have spread rapidly outside endemic countries. On July 23, 2023, WHO declared a Public Health Emergency of international Concern because of the unprecedented global spread of mpox. Whereas there is an incomplete understanding of transmission routes, the spread of monkeypox virus (MPXV) through sexual contact networks of men who have sex with men (MSM) highlights the potential of transmission during sexual activity, either via bodily fluids or via direct contact. This research assesses the potential for MPXV to remain infectious in the environment on surfaces and in fluids under different environmental conditions.ObjectiveTo investigate the stability of MPXV on various surfaces, at different environmental conditions and in different bodily fluids (human blood, semen, serum, saliva, urine, and feces), and to assess decontamination of MPXV-contaminated wastewater via chlorination.Design, Setting, and ExposuresAll experiments involving viable MPXV were performed at the Rocky Mountains Laboratory under high containment conditions using MPXV strain hMPXV/USA/MA001. Infectious MPXV was quantified via plaque assay. Environmental decay rates were estimated using a Bayesian statistical model, with a Poisson likelihood for plaque counts.ResultsMPXV showed surface dependent stability, with faster decay at higher temperatures. Decay rates varied considerably depending on the medium in which virus was suspended, both overall MPXV displayed considerable environmental stability in bodily fluids and in particular proteinaceous fluids, such as blood and semen, lead to greater persistence. Wastewater chlorination was an effective decontamination technique.Conclusions and RelevanceMPXV retains its infectivity in the environment when it is deposited in blood, semen, and serum; environmental decay is more rapid in less proteinaceous fluids, particularly once residual liquid has evaporated. The observed persistence of MPXV implies environmental contamination in healthcare setting, could serve as vehicles of transmission and dissemination in these environments. Chlorination was effective in decontamination of wastewater. Key findings and public health implications; these results suggest that MPXV can have prolonged stability in the environment and are therefore directly relevant for hospital hygiene practices to prevent nosocomial transmission.
The Regulator FleQ Post-Transcriptionally Regulates the Production of RTX Adhesins byPseudomonas fluorescens
Authors: Pastora Alexander B. , O’Toole George A. 
Published: May 2023

AbstractBiofilm formation by the Gram-negative gammaproteobacteriumPseudomonas fluorescensrelies on the production of the repeat-in-toxin (RTX) adhesins LapA and MapA in the cytoplasm, secretion of these adhesins through their respective type 1 secretion systems, and retention at the cell surface. Published work has shown that retention of the adhesins occurs via a post-translational mechanism involving the cyclic-di-GMP receptor LapD and the protease LapG. However, little is known about the underlying mechanisms that regulate the production of these adhesins. Here, we demonstrate that the master regulator FleQ modulates biofilm formation by post-transcriptionally regulating the production of LapA and MapA. We find that a ΔfleQmutant has a biofilm formation defect compared to the WT strain, which is attributed in part to a decrease in LapA and MapA production, despite the ΔfleQmutant having increased levels oflapAandmapAtranscripts compared to the WT strain. Through transposon mutagenesis and subsequent genetic analysis, we found that over-stimulation of the Gac/Rsm pathway partially rescues biofilm formation in the ΔfleQmutant background. Collectively, these findings provide evidence that FleQ regulates biofilm formation by post-transcriptionally regulating the production of LapA and MapA, and that activation of the Gac/Rsm pathway can enhance biofilm formation byP. fluorescens.ImportanceBiofilm formation is a highly coordinated process that bacteria undergo to colonize a variety of surfaces. ForPseudomonas fluorescens, biofilm formation requires the production and localization of RTX adhesins to the cell surface. To date, little is known about the underlying mechanisms that regulate biofilm formation byP. fluorescens. Here, we identify FleQ as a key regulator of biofilm formation that modulates the production of LapA and MapA through a post-transcriptional mechanism. We provide further evidence implicating activation of the Gac/Rsm system in FleQ-dependent regulation of biofilm formation. Together, our findings uncover evidence for a mechanism of post-transcriptional regulation of the LapA/MapA adhesins.
Host genetic background regulates the capacity for anti-tumor antibody-dependent phagocytosis
Authors: Glassbrook James E. , Hackett Justin B. , Muñiz Maria C. , Bross Madeline , Dyson Greg , Movahhedin Nasrin , Ullrich Alexander , Gibson Heather M. 
Published: May 2023

AbstractBackgroundAntitumor antibody, or targeted immunotherapy, has revolutionized cancer treatment and markedly improved patient outcomes. A prime example is the monoclonal antibody (mAb) trastuzumab, which targets human epidermal growth factor receptor 2 (HER2). However, like many targeted immunotherapies, only a subset of patients benefit from trastuzumab long-term. In addition to tumor-intrinsic factors, we hypothesize that host genetics may influence subsequent immune activation.MethodsTo model the human population, we produced F1 crosses of genetically heterogeneous Diversity Outbred (DO) mice with BALB/c mice (DOCF1). Distinct DOCF1 mice were orthotopically implanted with the BALB/c-syngeneic TUBO mammary tumor line, which expresses the HER2 ortholog rat neu. Treatment with anti-neu mAb clone 7.16.4 began once tumors reached ∼200 mm3. Genetic linkage and quantitative trait locus (QTL) effects analyses in R/qtl2 identified loci associated with tumor growth rates. Locus validation was performed with BALB/c F1 crosses with recombinant-inbred Collaborative Cross (CC) strains selected for therapy-associated driver genetics (CCxCF1). The respective roles of natural killer (NK) cells and macrophages were investigated by selective depletion in vivo. Ex vivo macrophage antibody-dependent phagocytosis (ADCP) assays were evaluated by confocal microscopy using 7.16.4-opsonized E2Crimson-expressing TUBO tumor cells.ResultsWe observed a divergent response to anti-tumor antibody therapy in DOCF1 mice. Genetic linkage analysis detected a locus on chromosome 10 that correlates to a robust response to therapy, which was validated in CCxCF1 models. Single-cell RNA sequencing of tumors from responder and non-responder models identified key differences in tumor immune infiltrate composition, particularly within macrophage (Mφ) subsets. This is further supported byex vivoanalysis showing Mφ ADCP capacity correlates toin vivotreatment outcomes in both DOCF1 and CCxCF1 models.ConclusionsHost genetics play a key regulatory role in targeted immunotherapy outcomes, and putative causal genes are identified in murine chromosome 10 which may govern Mφ function during ADCP.
Brief oxygen exposure after traumatic brain injury speeds recovery and promotes adaptive chronic endoplasmic reticulum stress responses
Authors: Torrens Jordyn N. , Hetzer Shelby M. , Evanson Nathan K. 
Published: May 2023

AbstractTraumatic brain injury (TBI) is a major public health concern particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post injury leading to higher mortality; so, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality. Adolescent male mice experienced a closed-head weight-drop TBI then were exposed to 100% O2until normal breathing returned or recovered in room air. We followed mice for 7- and 30-days and assessed their optokinetic response; retinal ganglion cell loss; axonal degeneration; glial reactivity; and retinal ER stress protein levels. O2reduced adolescent mortality by 40%, improved post-injury visual acuity, and reduced axonal degeneration and gliosis in optic projection regions. ER stress protein expression was altered in injured mice, and mice given O2utilized different ER-stress pathways in a time dependent manner. Finally, O2exposure may be mediating these ER stress responses through regulation of the redox-sensitive ER folding protein ERO1α, which has been linked to a reduction in the toxic effects of free radicals in other animal models of ER stress.