bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the quorum sensing systems in Pseudomonas aeruginosa can involve both loss of regulon function and network modulation
Authors: Jayakumar Priyanikha , Figueiredo Alexandre R. T. , Kümmerli Rolf 
Published: May 2022

AbstractPseudomonas aeruginosa populations evolving in cystic fibrosis (CF) lungs, animal infection models, natural environments or in vitro undergo extensive genetic adaption and diversification. A common mutational target is the quorum sensing (QS) regulon, a three-unit regulatory system that controls the expression of a suite of virulence factors and secreted public goods. Three scenarios have been advocated to explain selection for QS mutants, which include (I) disuse of the regulon, (II) cheating on public goods, or (III) modulation of the network. Here, we test these scenarios by examining a set of 61 QS mutants from an experimental evolution study. We observed non-synonymous mutations in all three QS systems – Las, Rhl and PQS. Most Las mutants carried large deletions, resulting in loss of QS function, and the inability to produce QS-regulated traits (scenario I or II). Conversely, phenotypic and gene expression analyses of Rhl mutants support network modulation (scenario III), as these mutants overexpressed the Las and Rhl regulators and showed an altered QS-regulated trait production portfolio. PQS mutants also showed patterns of network modulation (scenario III), spurring strain diversification and phenotypic trade-offs, where the upregulation of certain QS traits is associated with the downregulation of others. Overall, our results indicate that mutations in different QS systems lead to diverging effects on the social portfolio of bacterial populations. These mutations might not only affect the plasticity and diversity of evolved populations but could also impact bacterial fitness and virulence in infections.ImportancePseudomonas aeruginosa uses quorum sensing (QS), a three-unit multi-layered network, to coordinate expression of traits for growth and virulence in the context of infections. Despite its importance for bacterial fitness, the QS regulon appears to be a common mutational target during long-term adaptation of P. aeruginosa in the host, natural environments and experimental evolutions. This raises the questions why such an important regulatory system is under selection and how mutations change the portfolio of QS-regulated traits. Here, we examine a set of 61 naturally evolved mutants to address these questions. We found that mutations involving the master regulator, LasR, resulted in an almost complete breakdown of QS, while mutations in RhlR and PqsR resulted in modulations of the QS regulon, where both the QS regulon structure and the QS-regulated trait portfolio changed. Our work reveals that natural selection drives diversification in QS activity patterns in evolving populations.
Perfusion Quantification in the Human Brain Using DSC MRI – Simulations and Validations at 3T
Authors: Schulman J. , Sayin E.S. , Manalac A. , Poublanc J. , Sobczyk O. , Duffin J. , Fisher J.A. , Mikulis D.J. , Uludağ K. 
Published: May 2022

AbstractGadolinium (Gd) and deoxyhemoglobin (dOHb) are paramagnetic contrast agents capable of inducing changes in T2*-weighted MRI signal, utilized in dynamic susceptibility contrast (DSC) MRI. With multiple contrast agents and analysis choices, there are a variety of questions as to its capability to accurately quantify perfusion values. To address these questions, we developed a novel signal model for DSC MRI that incorporates signal contributions from intravascular and extravascular water proton spins at 3T for arterial, venous, and cerebral tissue voxels. This framework allowed us to model the MRI signal in response to changes in Gd and dOHb concentrations, and the effects that various experimental and tissue parameters have on perfusion quantification. We compared the predictions of the numerical simulations with those obtained from experimental data at 3T on six healthy human subjects using Gd and dOHb boluses as contrast agents. Using standard DSC analysis, we identified perfusion quantification dependencies in the experimental results that were in close agreement with the simulations. We found that a reduced baseline oxygen saturation (base-SaO2), greater susceptibility of applied contrast agent (Gd vs dOHb), and larger magnitude of the hypoxic drop (ΔSaO2) reduces overestimation of the cerebral blood volume (rCBV) and flow (rCBF). Furthermore, shortening the bolus duration increases the accuracy and reduces the calculated values of mean transit time (MTT). This study demonstrates that changes in Gd and dOHb can be described by the same unifying theoretical framework, as validated by the experimental results. Based on our work, we suggest practices in DSC MRI that increase accuracy and reduce inter- and intra-subject variability. In uncovering a wide array of quantification dependencies, we argue that caution must be exercised when comparing perfusion values obtained from a standard DSC MRI analysis when employing different experimental paradigms.
Cortex-wide fast activation of VIP-expressing inhibitory neurons by reward and punishment
Authors: Szadai Zoltán , Pi Hyun-Jae , Chevy Quentin , Ócsai Katalin , Albeanu Florin , Chiovini Balázs , Szalay Gergely , Katona Gergely , Kepecs Adam , Rózsa Balázs 
Published: April 2022

SUMMARYReward and punishment powerfully inform ongoing behaviors and drive learning throughout the brain, including neocortex. Yet it remains elusive how these global signals are represented and impact local cortical computations. Previously we found that in auditory cortex, VIP-expressing interneurons are recruited by reinforcement feedback. Here, we used 3D random-access two-photon microscopy and fiber photometry to monitor VIP neural activity in dozens of cortical areas while mice learned an auditory decision task. We show that reward and punishment evoke a rapid, cortex-wide activation of most VIP interneurons. This global recruitment mode of VIP interneurons showed variations in temporal dynamics in individual neurons and across areas. Neither their weak sensory tuning in visual cortex, nor their arousal state modulation was predictive of reinforcer responses of VIP interneurons. We suggest that VIP-expressing cortical inhibitory neurons transduce global reinforcement signals to provide disinhibitory control over local circuit computations and their plasticity.
Increasing transposase abundance with ocean depth correlates with a particle-associated lifestyle
Authors: Zhong Juntao , del Rosario Hernández Thais , Kyrysyuk Oleksandr , Tully Benjamin J. , Anderson Rika E. 
Published: May 2022

AbstractTransposases are mobile genetic elements (MGEs) that move within and between genomes, promoting genomic plasticity in microorganisms. In marine microbial communities, the abundance of transposases increases with depth, but the reasons behind this trend remain unclear. Our analysis of metagenomes from theTaraOceans and Malaspina Expeditions suggests that a particle-associated lifestyle is the main covariate for the high occurrence of transposases in the deep ocean. We observed a strong and depth-independent correlation between transposase abundance and the presence of biofilm-associated genes, as well as the prevalence of secretory enzymes. This suggests that mobile genetic elements readily propagate among microbial communities within crowded biofilms. Furthermore, we show that particle association positively correlates with larger genome size, which is in turn is associated with higher transposase abundance. Cassette sequences associated with transposons are enriched with genes related to defense mechanisms, which are more highly expressed in the deep sea. Thus, while transposons spread at the expense of their microbial hosts, they also introduce novel genes and potentially benefit the hosts in helping to compete for limited resources. Overall, our results suggest a new understanding of deep ocean particles as highways for gene sharing among defensively oriented microbial genomes.ImportanceGenes can move within and between microbial genomes via mobile genetic elements, which include transposases and transposons. In the oceans, there is a puzzling increase in transposase abundance in microbial genomes as depth increases. To gain insight into this trend, we conducted an extensive analysis of marine microbial metagenomes and metatranscriptomes. We found a significant correlation between transposase abundance and a particle-associated lifestyle among marine microbes. We also observed a link between transposase abundance and genes related to defense mechanisms. These results suggest that as microbes become densely packed into crowded particles, mobile genes are more likely to spread and carry genetic material that provides a competitive advantage in crowded habitats. This may enable deep sea microbes to effectively compete in such environments.
Intraoperative calculus or hemorrhage in transurethral seminal vesiculoscopy as a risk factor for recurrent hemospermia
Authors: Mei Cheng-En , Hu Ju-Chuan , Li Jian-Ri , Chiu Kun-Yuan , Wang Shian-Shiang , Chen Chuan-Shu 
Published: May 2022

AbstractWe summarized our experience regarding Transurethral Seminal Vesiculoscopy (TUSV) and analyzed both recurrence status and risk factors for recurrence. From January 2010 to December 2020, 48 patients with intractable hemospermia received successful TUSV at Taichung Invalids General Hospital. For the intraoperative findings, the five-year Disease-free Survival rates (DFS) were 74.1% in the no calculus group compared to 37.1% in the calculus group with a significant difference (log-rank p = 0.015), 75.0% in the no hemorrhage or no blood clot group compared to 43.2% in the hemorrhage or blood clot group with significant difference (log-rank p = 0.032). Univariate analysis showed intraoperative calculus (p = 0.040; HR: 2.94, 95% CI: 1.05–8.21) to be significantly associated with recurrence (p < 0.05). Patients with intractable hemospermia who were diagnosed with stones or blood clots found during TUSV experienced a higher rate of hemospermia recurrence.
Multi-scale phase separation by explosive percolation with single chromatin loop resolution
Authors: Sengupta Kaustav , Denkiewicz Michał , Chiliński Mateusz , Szczepińska Teresa , Mollah Ayatullah Faruk , Korsak Sevastianos , D’Souza Raissa , Ruan Yijun , Plewczynski Dariusz 
Published: May 2022

AbstractThe 2m-long human DNA is tightly intertwined into the cell nucleus of the size of 10μm. The DNA packing is explained by folding of chromatin fiber. This folding leads to the formation of such hierarchical structures as: chromosomal territories, compartments; densely packed genomic regions known as Chromatin Contact Domains (CCDs), and loops. We propose models of dynamical genome folding into hierarchical components in human lymphoblastoid, stem cell, and fibroblast cell lines. Our models are based on explosive percolation theory. The chromosomes are modeled as graphs where CTCF chromatin loops are represented as edges. The folding trajectory is simulated by gradually introducing loops to the graph following various edge addition strategies that are based on topological network properties, chromatin loop frequencies, compartmentalization, or epigenomic features. Finally, we propose the genome folding model - a biophysical pseudo-time process guided by a single scalar order parameter. The parameter is calculated by Linear Discriminant Analysis. We simulate the loop formation by using Loop Extrusion Model (LEM) while adding them to the system. The chromatin phase separation, where fiber folds into topological domains and compartments, is observed when the critical number of contacts is reached. We also observe that 80% of the loops are needed for chromatin fiber to condense in 3D space, and this is constant through various cell lines. Overall, our in-silico model integrates the high-throughput 3D genome interaction experimental data with the novel theoretical concept of phase separation, which allows us to model event-based time dynamics of chromatin loop formation and folding trajectories.
Sweet taste receptor cells may participate in mucosal immune surveillance
Authors: Qin Yumei , Zheng Xin , Tian Shiyi , Margolskee Robert F. , Sukumaran Sunil K. 
Published: May 2022

AbstractThe oral microbiome is second only to its intestinal counterpart in diversity and abundance, but its effects on taste cells remains largely unexplored. Using single cell RNASeq, we found that mouse taste receptor cells (STRCs) have a gene expression signature reminiscent of Microfold (M) cells, a central player in immune surveillance in the mucosa associated lymphoid tissue (MALT) such as those in the Peyer’s patch and tonsils. Administration of Tumor Necrosis Factor Ligand Superfamily Member 11 (TNFSF11, also known as RANKL), a growth factor required for differentiation of M cells dramatically increased M cell proliferation and marker gene expression in the taste papillae and in cultured taste organoids from wild type (WT) mice. Taste papillae and organoids from knockout mice lacking Spib (SpibKO), a RANKL-regulated transcription factor required for M cell development and regeneration on the other hand, failed to respond to RANKL. Taste papillae from SpibKO mice also showed reduced expression of NF-κB signaling pathway components and proinflammatory cytokines and attracted fewer immune cells. However, lipopolysaccharide-induced expression of cytokines was strongly upregulated in SpibKO mice compared to their WT counterparts. Like M cells, STRCs from WT but not SpibKO mice readily took up fluorescently labeled microbeads, a proxy for microbial transcytosis. The proportion of STRCs and other taste cell subtypes are unaltered in SpibKO mice; however, they displayed increased attraction to sweet and umami taste stimuli. We propose that STRCs are involved in immune surveillance at the taste papillae and tune their taste responses to microbial signaling and infection.
Face Familiarity Revealed by Fixational Eye Movements and Fixation-Related Potentials in Free Viewing
Authors: Kadosh Oren , Bonneh Yoram 
Published: May 2022

AbstractEvent-related potentials (ERPs) and the oculomotor inhibition (OMI) in response to transient visual stimuli are known to be sensitive to different stimulus properties, including attention and expectation. In natural vision, transient stimulation of the visual cortex is generated primarily by saccades. Recent studies suggest that the core EEG components in free viewing, induced by saccades (fixation-related potentials, RPs), are similar to the ERP components with flashed stimuli. We have recently found that the OMI in response to flashed stimuli is sensitive to face familiarity. Here, we investigated whether fixation-related-potentials (FRPs) and microsaccade inhibition (OMI) in free viewing are sensitive to face familiarity. Observers (N=15) freely watched a slideshow of seven unfamiliar and one familiar world leader’s facial images presented randomly for 4-seconds periods, with multiple images per identity. We measured the occipital fixation-related N1 relative to the P1 magnitude as well as the associated fixation-triggered OMI. We found that the average N1 was significantly smaller and the OMI was shorter for the familiar face, compared with any of the 7 unfamiliar faces. Moreover, the P1 was suppressed across saccades for the familiar but not for the unfamiliar faces. Overall, the results indicate that the occipital FRP and the OMI in free viewing are sensitive to face familiarity; this could perhaps be used as a novel physiological measure for studying hidden suppressed memories.
Microglial ferroptotic stress causes non-cell autonomous neuronal death
Authors: Liddell Jeffrey R. , Hilton James B.W. , Kysenius Kai , Nikseresht Sara , McInnes Lachlan E. , Hare Dominic J. , Paul Bence , Trist Benjamin G. , Double Kay L. , Mercer Stephen W. , Ayton Scott , Roberts Blaine R. , Beckman Joseph S. , McLean Catriona A. , White Anthony R. , Donnelly Paul S. , Bush Ashley I. , Crouch Peter J. 
Published: May 2022

AbstractBackgroundFerroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.MethodsTo elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). Finally, we utilised the SOD1G37R mouse model of ALS and a novel CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.ResultsWe found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Moreover, a molecular correlation between ferroptosis and neurotoxic astrocytes evident in ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with the novel, CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective.ConclusionsBy showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.
C-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD
Authors: Sahana TG , Chase Katherine Johnson , Liu Feilin , Lloyd Thomas E. , Rossoll Wilfried , Zhang Ke 
Published: May 2022

AbstractStress granules (SGs), RNA/protein condensates assembled in cells under stress, are believed to play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how SG assembly is regulated and related to pathomechanism is incompletely understood. Here, we show that ER stress activates JNK via IRE1 in fly and cellular models of C9orf72-mediated ALS/FTD (c9ALS/FTD), the most common genetic form of ALS/FTD. Furthermore, activated JNK promotes SG assembly induced by poly(GR) and poly(PR), two toxic proteins implicated in c9ALS/FTD, by promoting the transcription of G3BP1, a key SG protein. Consistent with these findings, JNK or IRE1 inhibition reduced SG formation, G3BP1 mRNA and protein levels, and neurotoxicity in cells overexpressing poly(GR) and poly(PR) or neurons derived from c9ALS/FTD patient induced pluripotent stem cells (iPSCs). Our findings connect ER stress, JNK, and SG assembly in a unified pathway contributing to c9ALS/FTD neurodegeneration.
TAMPA: interpretable analysis and visualization of metagenomics-based taxon abundance profiles
Authors: Sarwal Varuni , Brito Jaqueline , Mangul Serghei , Koslicki David 
Published: May 2022

AbstractMetagenomic taxonomic profiling aims to predict the identity and relative abundance of taxa in a given whole genome sequencing metagenomic sample. A recent surge in computational methods that aim to accurately estimate taxonomic profiles, called taxonomic profilers, have motivated community driven efforts to create standardized benchmarking datasets and platforms, standardized taxonomic profile formats, as well as a benchmarking platform to assess tool performance. While this standardization is essential, there is currently a lack of tools to visualize the standardized output of the many existing taxonomic profilers, and benchmarking studies rely on a single value metrics to compare performance of tools and compare to benchmarking datasets. Here we report the development of TAMPA (Taxonomic metagenome profiling evaluation), a robust and easy-to-use method that allows scientists to easily interpret and interact with taxonomic profiles produced by the many different taxonomic profiler methods beyond the standard metrics used by the scientific community. We demonstrate the unique ability of TAMPA to provide important biological insights into the taxonomic differences between samples otherwise missed by commonly utilized metrics. Additionally, we show that TAMPA can help visualize the output of taxonomic profilers, enabling biologists to effectively choose the most appropriate profiling method to use on their metagenomics data. TAMPA is available on GitHub, Bioconda and Galaxy Toolshed at https://github.com/dkoslicki/TAMPA, and is released under the MIT license.
Immediate myeloid depot for SARS-CoV-2 in the human lung
Authors: Magnen Mélia , You Ran , Rao Arjun A. , Davis Ryan T. , Rodriguez Lauren , Simoneau Camille R. , Hysenaj Lisiena , Hu Kenneth H. ,   The UCSF COMET Consortium, Love Christina , Woodruff Prescott G. , Erle David J. , Hendrickson Carolyn M. , Calfee Carolyn S. , Matthay Michael A. , Roose Jeroen P. , Sil Anita , Ott Melanie , Langelier Charles R. , Krummel Matthew F. , Looney Mark R. 
Published: May 2022

AbstractIn the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, considerable focus has been placed on a model of viral entry into host epithelial populations, with a separate focus upon the responding immune system dysfunction that exacerbates or causes disease. We developed a precision-cut lung slice model to investigate very early host-viral pathogenesis and found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations in the human lung. Infection of alveolar macrophages was partially dependent upon their expression of ACE2, and the infections were productive for amplifying virus, both findings which were in contrast with their neutralization of another pandemic virus, Influenza A virus (IAV). Compared to IAV, SARS-CoV-2 was extremely poor at inducing interferon-stimulated genes in infected myeloid cells, providing a window of opportunity for modest titers to amplify within these cells. Endotracheal aspirate samples from humans with the acute respiratory distress syndrome (ARDS) from COVID-19 confirmed the lung slice findings, revealing a persistent myeloid depot. In the early phase of SARS-CoV-2 infection, myeloid cells may provide a safe harbor for the virus with minimal immune stimulatory cues being generated, resulting in effective viral colonization and quenching of the immune system.