bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-function analysis of distant diphtheria toxin homologs reveals insights into host adaptation
Authors: Sugiman-Marangos Seiji N. , Gill Shivneet K. , Mansfield Michael J. , Orrell Kathleen E. , Doxey Andrew C. , Melnyk Roman A. 
Published: August 2021

AbstractDiphtheria toxin (DT) is the archetype of bacterial exotoxins implicated in human diseases and has played a central role in defining the field of toxinology since its discovery in 1888. Despite being one of the most extensively characterized bacterial toxins, the origins and molecular evolution of DT host specialization remain unknown. Here, we determined high-resolution structures of two recently discovered distant homologs of DT. These DT-like proteins from non-human associatedStreptomyces albireticuli(17% identity to DT) andSeinonella peptonophila(20% identity to DT) display remarkable structural similarity to DT enabling a comparative investigation into DT’s unique toxicity toward mammalian cells. We find that the individual domains of DT-like toxins retain two critical features of DT’s activity: full catalytic function and ability to translocate across mammalian cell membranes. However, we show that receptor-binding, pH-dependent pore-formation and proteolytic release of the cytotoxic enzyme into the cytosol are not optimized for human cell physiology and thus unable to efficiently deliver the cytotoxic cargo into human hosts. Our work provides structural insights into DT’s evolutionary history, and implies key transitions required for the emergence of human-specificity of a major bacterial exotoxin with an important history in human disease.
TSC2-extracellular matrix crosstalk controls pulmonary vascular proliferation and pulmonary hypertension
Authors: Shen Yuanjun , Goncharov Dmitry A. , Pena Andressa , Baust Jeffery , Barragan Andres Chavez , Ray Arnab , Rode Analise , Bachman Timothy N. , Chang Baojun , Rojas Mauricio , DeLisser Horace , Mora Ana L. , Kudryashova Tatiana V. , Goncharova Elena. A. 
Published: August 2021

AbstractIncreased proliferation and survival of resident cells in small pulmonary arteries (PA) are important drivers of pulmonary hypertension (PH). Tuberous sclerosis complex 2 (TSC2) is a negative regulator of mTOR complex 1 and cell growth. Here we show that TSC2 is deficient in small remodeled PA/PA vascular smooth muscle cells (PAVSMC) from human PAH and experimental PH lungs. TSC2 deficiency was reproducedin vitroby maintaining PAVSMC on pathologically stiff substrates and was required for stiffness-induced proliferation, accumulation of transcriptional co-activators YAP/TAZ and up-regulation of mTOR. Depletion of TSC2 reproduced PH featuresin vitroin human PAVSMC andin vivoin SM22-Tsc2+/− mice. TSC2 loss in PAVSMC was supported by YAP and led to the up-regulation of YAP/TAZ and mTOR via modulating the extracellular matrix (ECM) composition. ECM, produced by TSC2-deficient PAVSMC, promoted growth of non-diseased PA adventitial fibroblasts and PAVSMC, which, in turn, was prevented by α5β1 integrin receptor antagonist ATN161.In vitro, molecular and pharmacological (SRT2104) restoration of TSC2 down-regulated YAP/TAZ, mTOR, and ECM production, inhibited proliferation and induced apoptosis in human PAH PAVSMC.In vivo, orally administrated SRT2104 restored TSC2, resolved pulmonary vascular remodeling, PH, and improved right heart in two rodent models of PH. Thus, PAVSMC TSC2 is a critical integrator of ECM composition and stiffness with pro-proliferative signaling and PH, and the restoration of functional TSC2 could be an attractive therapeutic option to treat PH.One Sentence SummaryTSC2 acts as mechanosensor and mechanotransducer, integrating ECM composition and stiffness with pro-proliferative signaling in pulmonary vasculature; its deficiency in PA vascular smooth muscle cells results in ECM remodeling, hyper-proliferation and pulmonary hypertension, which could be reversed by pharmacological restoration of functional TSC2.
Stress-dependent inhibition of cell polarity through unbalancing the GEF/GAP regulation of Cdc42
Authors: Salat-Canela Clàudia , Carmona Mercè , Martín-García Rebeca , Pérez Pilar , Ayté José , Hidalgo Elena 
Published: August 2021

ABSTRACTCdc42 rules cell polarity and growth in fission yeast. It is negatively and positively regulated by GTPase-activating proteins (GAPs) and by Guanine nucleotide Exchange factors (GEFs), respectively. Active Cdc42-GTP localizes to the poles, where it associates with numerous proteins constituting the polarity module. However, little is known about its down-regulation. We describe here that oxidative stress causes Sty1 kinase-dependent Cdc42 inactivation at cell poles. Both the amount of active Cdc42 at poles and cell length inversely correlate with Sty1 activity, explaining the elongated morphology of Δsty1 cells. We have created stress-blinded cell poles by either eliminating two Cdc42 GAPs or through the constitutive tethering of a GEF to the cell tips, and biochemically demonstrate that Rga3 is a direct substrate of Sty1. We propose that stress-activated Sty1 promotes GTP hydrolysis and prevents GEF activity at the cell tips, thus leading to the inhibition of Cdc42 and polarized growth cessation.
Evolutionary divergence of anaphase spindle mechanics in nematode embryos constrained by antagonistic pulling and viscous forces
Authors: Khatri Dhruv , Brugière Thibault , Athale Chaitanya A. , Delattre Marie 
Published: August 2021

AbstractCells are the basic unit of biological organization, and their division is remarkably conserved across phyla. However from an evolutionary perspective, it remains unclear how much cellular parameters can diverge, without altering the basic function they sustain. We address the mechanics of asymmetric mitotic spindle positioning during the first embryonic division of six nematode species. We propose a viscoelastic model of spindle positioning and mobility that can provide a physical explanation of why in C. elegans it undergoes oscillations during elongation, whereas most others lack oscillations. To test this model, we measured the pulling forces and opposing cytoplasmic drag by a combination of laser ablation of the anaphase spindle and tracking of intracellular granules. While centrosomes of all species recoil on spindle cutting, quantitative differences correlate with the cytoplasmic viscosity. In fact, increased viscosity correlates with decreased oscillation speeds of intact spindles across species. However, the absence of oscillations despite low viscosity in some species, can only be explained by smaller pulling forces. Consequently, we find that spindle mobility across the species analyzed here is characterized by a tradeoff between cytoplasmic viscosity and pulling forces. Our work provides a framework for understanding mechanical constraints on evolutionary diversification of spindle mobility.
Unusually slow spike frequency adaptation in deep cerebellar nuclei neurons preserves linear transformations on the sub-second time scale
Authors: Khan Mehak M. , Chen Christopher H. , Regehr Wade G. 
Published: August 2021

AbstractPurkinje cells (PCs) are spontaneously active neurons of the cerebellar cortex that inhibit glutamatergic projection neurons within the deep cerebellar nuclei (DCN) that in turn provide the primary cerebellar output. Brief reductions in PC firing rapidly increase DCN neuron firing. However, prolonged reductions in PC inhibition, as seen in some disease states, certain types of transgenic mice, and in acute slices of the cerebellum, do not evoke large sustained increases in DCN firing. Here we test whether there is a mechanism of spike-frequency adaptation in DCN neurons that could account for these properties. We find that prolonged optogenetic suppression of PC synapsesin vivotransiently elevates PC firing that strongly adapts within ten seconds. We perform current-clamp recordings at near physiological temperature in acute brain slices to examine how DCN neurons respond to prolonged depolarizations. Adaptation in DCN neurons is exceptionally slow and bidirectional. A depolarizing current step evokes large initial increases in firing that decay to less than 20% of the initial increase within approximately ten seconds. Such slow adaptation could allow DCN neurons to adapt to prolonged changes in PC firing while maintaining their linear firing frequency-current relationship on subsecond time scales.
Neural stem cell expressed vascular endothelial growth factor maintains the neurogenic vascular niche of the adult mouse hippocampus
Authors: Dause Tyler J. , Denninger Jiyeon K. , Osap Robert , Walters Ashley E. , Rieskamp Joshua D. , Kuwahara Akela A. , Kirby Elizabeth D. 
Published: August 2021

AbstractThe vasculature is a key component of adult brain neural stem cell (NSC) niches. In the adult mammalian hippocampus, NSCs reside in close contact with a dense capillary network. How this niche is maintained is unclear. We recently found that adult hippocampal NSCs express vascular endothelial growth factor (VEGF), a soluble factor with chemoattractive properties for vascular endothelia. Here, we show that NSC-specific VEGF loss led to dissociation of NSCs from local vasculature but surprisingly found no changes in vascular density. Instead, we found that NSC-derived VEGF supports the motility of NSCs themselves via a cell internal signaling loop. We further found that this internal autocrine loop also independently maintained NSC quiescence cell autonomously. Combined, our findings suggest that NSCs maintain their populations via 2 mechanisms that are dependent on cell internal VEGF signaling: self-stimulated motility towards vasculature and cell autonomous maintenance of quiescence programs.
A systematic data-driven approach to analyze sensor-level EEG connectivity: Identifying robust phase-synchronized network components using surface Laplacian with spectral-spatial PCA
Authors: Smith Ezra E. , Bel-Bahar Tarik S. , Kayser Jürgen 
Published: August 2021

AbstractAlthough conventional averaging across predefined frequency bands reduces the complexity of EEG functional connectivity (FC), it obscures the identification of resting-state brain networks (RSN) and impedes accurate estimation of FC reliability. Extending prior work, we combined scalp current source density (CSD; spherical spline surface Laplacian) and spectral-spatial PCA to identify FC components. Phase-based FC was estimated via debiased weighted phase-locking index from CSD-transformed resting EEGs (71 sensors, 8 min, eyes open/closed, 35 healthy adults, 1-week retest). Spectral PCA extracted 6 robust alpha and theta factors (86.6% variance). Subsequent spatial PCA for each spectral factor revealed seven robust regionally-focused (posterior, central, frontal) and long-range (posterior-anterior) alpha components (peaks at 8, 10 and 13 Hz) and a midfrontal theta (6 Hz) component, accounting for 37.0% of FC variance. These spatial FC components were consistent with well-known networks (e.g., default mode, visual, sensorimotor), and four were sensitive to eyes open/closed conditions. Most FC components had good-to-excellent internal consistency (odd/even epochs, eyes open/closed) and test-retest reliability (ICCs ≥ .8). Moreover, the FC component structure was generally present in subsamples (session × odd/even epoch, or smaller subgroups [n = 7-10]), as indicated by similarity of factor loadings across PCA solutions. Apart from systematically reducing FC dimensionality, our approach avoids arbitrary thresholds and allows quantification of meaningful and reliable network components that may prove to be of high relevance for basic and clinical research applications.
Long-term Transverse Imaging of the Hippocampus with Glass Microperiscopes
Authors: Redman William T , Wolcott Nora S , Montelisciani Luca , Luna Gabriel , Marks Tyler D , Sit Kevin K , Yu Che-Hang , Smith Spencer L , Goard Michael J 
Published: August 2021

ABSTRACTThe hippocampus consists of a stereotyped neuronal circuit repeated along the septal-temporal axis. This transverse circuit contains distinct subfields with stereotyped connectivity that support crucial cognitive processes, including episodic and spatial memory. However, comprehensive measurements across the transverse hippocampal circuit in vivo are intractable with existing techniques. Here, we developed an approach for two-photon imaging of the transverse hippocampal plane in awake mice via implanted glass microperiscopes, allowing optical access to the major hippocampal subfields and to the dendritic arbor of pyramidal neurons. Using this approach, we tracked dendritic morphological dynamics on CA1 apical dendrites and characterized spine turnover. We then used calcium imaging to quantify the prevalence of place and speed cells across subfields. Finally, we measured the anatomical distribution of spatial information, finding a non-uniform distribution of spatial selectivity along the DG-to-CA1 axis. This approach extends the existing toolbox for structural and functional measurements of hippocampal circuitry.
LACK OF EVIDENCE FOR A VIABLE MICROBIOTA IN MURINE AMNIOTIC FLUID
Authors: Winters Andrew D. , Romero Roberto , Greenberg Jonathan M. , Galaz Jose , Shaffer Zachary , Garcia-Flores Valeria , Kracht David J. , Gomez-Lopez Nardhy , Theis Kevin R. 
Published: August 2021

ABSTRACTThe existence of an amniotic fluid microbiota (i.e., a viable microbial community) in mammals is controversial. Its existence would require a fundamental reconsideration of the role of intra-amniotic microbes in fetal development and pregnancy outcomes. In this study, we determined whether the amniotic fluid of mice harbors a microbiota in late gestation. Bacterial profiles of amniotic fluids located proximally or distally to the cervix were characterized through quantitative real-time PCR, 16S rRNA gene sequencing, and culture (N = 21 mice). These profiles were compared to those of technical controls for background DNA contamination. The load of 16S rDNA in the amniotic fluid exceeded that in controls. Additionally, the 16S rDNA profiles of the amniotic fluid differed from those of controls, withCorynebacterium tuberculostearicumbeing differentially more abundant in amniotic fluid profiles; however, this bacterium was not cultured. Of the 42 total bacterial cultures of amniotic fluids, only one yielded bacterial growth –Lactobacillus murinus. The 16S rRNA gene of this common murine-associated bacterium was not detected in any amniotic fluid sample, suggesting it did not originate from the amniotic fluid. No differences in 16S rDNA load, 16S rDNA profile, or bacterial culture were observed between amniotic fluids located proximal and distal to the cervix. Collectively, these data show that, although there is a modest DNA signal of bacteria in murine amniotic fluid, there is no evidence that this signal represents a viable microbiota. These findings refute the proposed role of amniotic fluid as a source of microorganisms forin uterocolonization.IMPORTANCEThe prevailing paradigm in obstetrics has been the sterile womb hypothesis, which posits that fetuses are first colonized by microorganisms during labor and/or the vaginal delivery process. However, it has been suggested that fetuses are consistently colonizedin utero. One proposed source of colonizers is the amniotic fluid surrounding the fetus. This concept has been derived primarily from investigations that relied on DNA sequencing. Due to the low microbial biomass of amniotic fluid, such studies are susceptible to influences of background DNA contamination. Additionally, even if there is a microbial DNA signature in amniotic fluid, this is not necessarily reflective of a resident microbiota that could colonize the mammalian fetus. In the current study, using multiple microbiologic approaches and incorporating technical controls for DNA contamination, we show that, although there is a low abundance bacterial DNA signal in amniotic fluid, this does not translate to the presence of viable bacteria.
Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: an observational longitudinal study over 12 months
Authors: Steinbeis Fridolin , Thibeault Charlotte , Doellinger Felix , Ring Raphaela Maria , Mittermaier Mirja , Ruwwe-Glösenkamp Christoph , Alius Florian , Knape Philipp , Meyer Hans-Jakob , Lippert Lena Johanna , Helbig Elisa Theresa , Grund Daniel , Temmesfeld-Wollbrück Bettina , Suttorp Norbert , Sander Leif Erik , Kurth Florian , Penzkofer Tobias , Witzenrath Martin , Zoller Thomas 
Published: August 2021

AbstractBackgroundProspective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse.Research questionWith this study, we aim to investigate pulmonary outcome following SARS-CoV-2 infection including pulmonary function, computed chest tomography, respiratory symptoms and quality of life over 12 months.Study design and Methods180 patients after acute COVID-19 were enrolled into a single-centre, prospective observational study and examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate objective and subjective respiratory limitations. Patients were stratified according to acute COVID-19 disease severity.ResultsOf 180 patients enrolled, 42/180 were not hospitalized during acute SARS-CoV-2 infection, 29/180 were hospitalized without need for oxygen, 43/180 with need for low-flow and 24/180 with high-flow oxygen, 26/180 required invasive mechanical ventilation and 16/180 were treated with ECMO. After acute COVID-19, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity after the acute phase and improved over 12 months except for those requiring ECMO treatment. Patients with milder disease showed a predominant reduction of ventilated area instead of simple restriction. The CT score of lung involvement in the acute phase increased significantly with COVID-19 severity and was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with mild initially disease.InterpretationSeverity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection. Patients with mild vs. severe disease show different patterns of lung involvement and symptom resolution.Clinical Trial RegistrationThe study is registered at the German registry for clinical studies (DRKS00021688)
Stress-induced collective behavior leads to the formation of multicellular structures and the survival of the unicellular alga Chlamydomonas
Authors: de Carpentier Félix , Maes Alexandre , Marchand Christophe H. , Chung Céline , Durand Cyrielle , Crozet Pierre , Lemaire Stéphane D. , Danon Antoine 
Published: August 2021

SummaryDepending on their nature, living organisms use various strategies to adapt to environmental stress conditions. Multicellular organisms implement a set of reactions involving signaling and cooperation between different types of cells. Unicellular organisms on the other hand must activate defense systems, which involve collective behaviors between individual organisms. In the unicellular model algaChlamydomonas reinhardtii, the existence and the function of collective behavior mechanisms in response to stress remain largely unknown. Here we report the discovery of a mechanism of abiotic stress response that Chlamydomonas can trigger to form large multicellular structures that can comprise several thousand cells. We show that these aggregates constitute an effective bulwark within which the cells are efficiently protected from the toxic environment. We have generated the first family of mutants that aggregate spontaneously, thesocializermutants (saz), of which we describe here in detailsaz1. We took advantage of thesazmutants to implement a large scale multiomics approach that allowed us to show that aggregation is not the result of passive agglutination, but rather genetic reprogramming and substantial modification of the secretome. The reverse genetic analysis we conducted on some of the most promising candidates allowed us to identify the first positive and negative regulators of aggregation and to make hypotheses on how this process is controlled in Chlamydomonas.
Dynamics of cortical contrast adaptation predict perception of signals in noise
Authors: Angeloni Christopher F. , Młynarski Wiktor , Piasini Eugenio , Williams Aaron M. , Wood Katherine C. , Garami Linda , Hermundstad Ann M. , Geffen Maria N. 
Published: August 2021

AbstractNeurons throughout the sensory pathway adapt their responses depending on the statistical structure of the sensory environment. Contrast gain control is a form of adaptation in the auditory cortex, but it is unclear whether the dynamics of gain control reflect efficient adaptation, and whether they shape behavioral perception. Here, we trained mice to detect a target presented in background noise shortly after a change in the contrast of the background. The observed changes in cortical gain and behavioral detection followed the dynamics of a normative model of efficient contrast gain control; specifically, target detection and sensitivity improved slowly in low contrast, but degraded rapidly in high contrast. Auditory cortex was required for this task, and cortical responses were not only similarly affected by contrast but predicted variability in behavioral performance. Combined, our results demonstrate that dynamic gain adaptation supports efficient coding in auditory cortex and predicts the perception of sounds in noise.
Value capture in open innovation markets: the role of patent rights for innovation appropriation
Authors: Holgersson Marcus , Granstrand Ove 
Published: August 2021

PurposeThe role of patents for appropriating (capturing) value from innovation investments has for decades been of major interest to both practitioners and academics in innovation management. Many studies have implicitly assumed that firms appropriate value through in-house creation and marketing of innovative products and services, and that the main function of patents is to protect the exclusive sales in product and service markets. We challenge this assumption in light of the variety of business models, strategies and markets now being available, including different organizational and market forms of open innovation.Design/methodology/approachA conceptual framework and typology of open innovation markets is developed, and the role of patents for appropriation is investigated in these markets among 172 Swedish technology-based firms.FindingsThe results show that the importance of patents has a skewed distribution with some firms rating patents very important and with a fat tail of firms rating patents less important. Most importantly, the results indicate that patents are enabling exchange and technology trade in various types of open innovation markets rather than only supporting vertically integrated business models. Thus patents were found to help rather than hinder the use of open innovation markets.Originality/valueThe paper makes two main contributions. First a theoretical reinterpretation of open innovation with a conceptualization of open innovation markets for appropriation of innovation values. Second an empirical illustration of new roles of patents for appropriating innovation values in these markets. The paper in addition illustrates the use of a counterfactual approach to questionnaire surveys, as well as the complementarities between patents and other means of appropriation.