bluuebunny/crossref_metadata_2025_split huggingface dataset:
First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia
Authors: Temesgen Zelalem , Assi Mariam , Vergidis Paschalis , Rizza Stacey A. , Bauer Philippe R. , Pickering Brian W. , Razonable Raymund R. , Libertin Claudia R. , Burger Charles D. , Orenstein Robert , Vargas Hugo E. , Varatharaj Palraj Bharath Raj , Dababneh Ala S. , Chappell Gabrielle , Chappell Dale , Ahmed Omar , Sakemura Reona , Durrant Cameron , Kenderian Saad S. , Badley Andrew D. 
Published: June 2020

ABSTRACTBackgroundIn COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe and critical COVID-19 pneumonia.MethodsHospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.ResultsTwelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe and critical COVID-19 pneumonia.ConclusionsIn high-risk COVID-19 patients with severe and critical pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.
Covid-19 vs BCG: Statistical Significance Analysis
Authors: Dolgikh Serge 
Published: June 2020

AbstractWe present an updated time-adjusted dataset and conclusions at Covid-19 Time Zero + 5 month (04.06.2020). The conclusions of the original analysis reviewed and mostly maintained at this time point. With the data accumulated to date a statistical significance of the BCG immunization correlation hypothesis is evaluated with the conclusion that it has achieved the level of confidence. Several specific cases are discussed with respect to the induced immunity hypothesis.
Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression
Authors: Zhang Haolin , Karisetty Bhanu Chandra , Bhatnagar Akanksha , Armour Ellen M. , Beaver Mariah , Roach Tiffany V. , Mortazavi Sina , Mandloi Shreya , Elefant Felice 
Published: June 2020

ABSTRACTAlzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in theDrosophilabrain produced solely by human amyloid-β42. We show that early Aβ42induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterationsviadistinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.
Single cell transfection of human induced pluripotent stem cells using a droplet-based microfluidic system
Authors: Pérez C. , Sanluis-Verdes A. , Waisman A. , Lombardi A. , Rosero G. , La Greca A. , Bhansali S. , Bourguignon N. , Luzzani C. , Pérez M.S. , Miriuka S. , Lerner B. 
Published: June 2020

ABSTRACTMicrofluidic tools have recently made possible many advances in biological and biomedical research. Research fields such as Physics, Engineering, Chemistry and Biology have combined to produce innovation in Microfluidics which has positively impacted on areas as diverse as nucleotide sequence, functional genomics, single-cell studies, single molecules assays, and biomedical diagnostics. Among these areas regenerative medicine and stem cells have benefited from Microfluidics due to these tools have had a profound impact on their applications. In the study, we present a high-performance droplet-based system for transfecting individual human-induced pluripotent stem cells. We show that this system has great efficiency in single cells and captured droplets, similar to other microfluidic methods and lower cost. We demonstrate that this microfluidic approach can be associated with the PiggyBac transposase-based system to increase its transfection efficiency. Our results provide a starting point for subsequent applications in more complex transfection systems, single-cell differentiation interactions, cell subpopulations, cell therapy, among other potential applications.
Toxoplasma gondiiAP2XII-2 contributes to proper progression through S-phase of the cell cycle
Authors: Srivastava Sandeep , White Michael W. , Sullivan William J. 
Published: June 2020

AbstractToxoplasma gondiiis a protozoan parasite that causes lifelong chronic infection that can reactivate in immunocompromised individuals. Upon infection, the replicative stage (tachyzoite) converts into a latent tissue cyst stage (bradyzoite). Like other apicomplexans,T. gondiipossesses an extensive linage of proteins called ApiAP2s that contain plant-like DNA-binding domains. The function of most ApiAP2s is unknown. We previously found that AP2IX-4 is a cell cycle-regulated ApiAP2 expressed only in dividing parasites as a putative transcriptional repressor. In this study, we purified proteins interacting with AP2IX-4, finding it to be a component of the recently characterized microrchidia (MORC) transcriptional repressor complex. We further analyzed AP2XII-2, another cell cycle-regulated factor that associates with AP2IX-4. We monitored parallel expression of AP2IX-4 and AP2XII-2 proteins in tachyzoites, detecting peak expression during S/M phase. Unlike AP2IX-4, which is dispensable in tachyzoites, loss of AP2XII-2 resulted in a slowed tachyzoite growth due to a delay in S-phase progression. We also found that AP2XII-2 depletion increased the frequency of bradyzoite differentiation in vitro. These results suggest that multiple AP2 factors collaborate to ensure proper cell cycle progression and tissue cyst formation inT. gondii.ImportanceToxoplasma gondiiis a single-celled parasite that causes opportunistic infection due to its ability to convert into a latent cyst stage. This work describes a new transcriptional factor called AP2XII-2 that plays a role in properly maintaining the growth rate of replicating parasites, which contributes to signals required for development into its dormant stage. Without AP2XII-2,Toxoplasmaparasites experience a delay in their cell cycle that increases the frequency of latent cyst formation. In addition, we found that AP2XII-2 operates in a multi-subunit complex with other AP2 factors and chromatin remodeling machinery that represses gene expression. These findings add to our understanding of howToxoplasmaparasites balance replication and dormancy, revealing novel points of potential therapeutic intervention to disrupt this clinically relevant process.
Retarded Logistic Equation as a Universal Dynamic Model for the Spread of COVID-19
Authors: Shayak B , Sharma Mohit M 
Published: June 2020

ABSTRACTIn this work we propose the retarded logistic equation as a dynamic model for the spread of COVID-19 all over the world. This equation accounts for asymptomatic transmission, pre-symptomatic or latent transmission as well as contact tracing and isolation, and leads to a transparent definition of the instantaneous reproduction number R. For different parameter values, the model equation admits different classes of solutions. These solution classes correspond to, inter alia, containment of the outbreak via public health measures, exponential growth despite public health measures, containment despite reopening and second wave following reopening. We believe that the spread of COVID in every localized area such as a city, district or county can be accounted for by one of our solution classes. In regions where R > 1 initially despite aggressive epidemic management efforts, we find that if the mitigation measures are sustained, then it is still possible for R to dip below unity when far less than the region’s entire population is affected, and from that point onwards the outbreak can be driven to extinction in time. We call this phenomenon partial herd immunity. Our analysis indicates that COVID-19 is an extremely vicious and unpredictable disease which poses unique challenges for public health authorities, on account of which “case races” among various countries and states do not serve any purpose and present delusive appearances while ignoring significant determinants.
Beyond forest succession: a gap model to study ecosystem functioning and tree community composition under climate change
Authors: Morin Xavier , de Coligny François , Martin-StPaul Nicolas , Bugmann Harald , Cailleret Maxime , Limousin Jean-Marc , Ourcival Jean-Marc , Prevosto Bernard , Simioni Guillaume , Vennetier Michel , Guillemot Joannès 
Published: June 2020

ABSTRACTClimate change impacts forest functioning and dynamics, and large uncertainties remain regarding the interactions between species composition, demographic processes, and environmental drivers. There are few robust tools available to link these processes, which precludes accurate projections and recommendations for long-term forest management. Forest gap-models present a balance between complexity and generality and are widely used in predictive forest ecology. However, their relevance to tackle questions about the links between species composition, climate and forest functioning is unclear. In this regard, demonstrating the ability of gap-models to predict the growth of forest stands at the annual time scale – representing a sensitive and integrated signal of tree functioning and mortality risk - appears as a fundamental step.In this study, we aimed at assessing the ability of a gap-model to accurately predict forest growth in the short-term and potential community composition in the long-term, across a wide range of species and environmental conditions. To do so, we present the gap-model ForCEEPS, calibrated using an original parameterization procedure for the main tree species in France. ForCEEPS was shown to satisfactorily predict forest annual growth (averaged over a few years) at the plot level from mountain to Mediterranean climates, regardless the species. Such an accuracy was not gained at the cost of losing precision for long-term predictions, as the model showed a strong ability to predict potential community composition along a gradient of sites with contrasted conditions. The mechanistic relevance of ForCEEPS parameterization was explored by showing the congruence between the values of key model parameter and species functional traits. We further showed that accounting for the spatial configuration of crowns within forest stands, the effects of climatic constraints and the variability of shade tolerances in the species community are all crucial to better predict short-term productivity with gap-models.The dual ability of predicting short-term functioning and long-term community composition, as well as the balance between generality and realism (i.e., predicting accuracy) of the new generation of gap-models may open great perspectives for the exploration of the biodiversity-ecosystem functioning relationships, species coexistence mechanisms, and the impacts of climate change on forest ecosystems.
Patch-clamp recordings in slices of telencephalon, diencephalon and rhombencephalon of salamanders
Authors: Flaive Aurélie , Ryczko Dimitri 
Published: June 2020

AbstractThe salamander is a key limbed vertebrate from which many major scientific questions can be addressed in the fields of motor control, evolutionary biology, and regeneration biology. An important gap of knowledge is the description of the electrophysiological properties of the neurons constituting their central nervous system. To our knowledge, some patch-clamp electrophysiological recordings were done in the spinal cord and recently in hindbrain slices, but not in any higher brain region. Here, we present a method to obtain patch-clamp recordings in slices of the telencephalon, diencephalon and rhombencephalon of salamanders. The method includes dissection of the brain, brain slice preparation, visual identification of neurons and patch-clamp recordings. We provide single cell recordings in the rhombencephalon, diencephalon and telencephalon of salamanders. This method should open new avenues to dissect the operation of salamander brain circuits at the cellular level.Highlights- Salamander brain slices of telencephalon, diencephalon, and rhombencephalon- Patch-clamp recordings in salamander brain slices- The salamander as a model to decipher tetrapod neural microcircuits
Detection of uncoupled circadian rhythms in individual cells ofLemna minorusing a dual-color bioluminescence monitoring system
Authors: Watanabe Emiri , Isoda Minako , Muranaka Tomoaki , Ito Shogo , Oyama Tokitaka 
Published: June 2020

SummaryThe plant circadian oscillation system is based on the circadian clock of individual cells and coordinates the circadian behavior of the plant body. To observe the cellular circadian behavior of both the oscillator and its output in plants, we developed the dual-color bioluminescence monitoring system that automatically measured the luminescence of two luciferase reporters simultaneously at a single-cell level. We selected a yellow-green-emitting firefly luciferase (LUC+) and a red-emitting luciferase (PtRLUC) that is a mutant form of Brazilian click beetle ELUC. We usedAtCCA1::LUC+ andCaMV35S::PtRLUCto observe the cellular behavior of the oscillator and output, respectively. These bioluminescent reporters were introduced into the cells of a duckweed,Lemna minor, by particle bombardment. Time series of the bioluminescence of individual cells in a frond were obtained using a dual-color bioluminescence monitoring system with a green-pass- and red-pass filter. Luminescence intensities from the LUC+ and PtRLUC of each cell were calculated from the filtered luminescence intensities. We succeeded in reconstructing the bioluminescence behaviors ofAtCCA1::LUC+ andCaMV35S::PtRLUCin the same cells. Under prolonged constant light conditions,AtCCA1::LUC+ showed a robust circadian rhythm in individual cells in an asynchronous state in the frond, as previously reported in studies using other plants. In contrast,CaMV35S::PtRLUCstochastically showed circadian rhythms in a synchronous state. Thus, we clearly demonstrated the uncoupling between the oscillator and output in individual cells. This dual-color bioluminescence monitoring system is a powerful tool to analyze various stochastic phenomena accompanying large cell-to-cell variation in gene expression.Significance statementWe succeeded in establishing the world’s first dual-color bioluminescence monitoring system at a single-cell level that enables simultaneous measurement of the luminescence activities of two reporter genes in plants. This system is a strong tool to analyze stochastic phenomena, and we clearly demonstrated the uncoupling of rhythmic behavior between two bioluminescent reporters in individual cells that stochastically occurred in the same plant.
Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation
Authors: Rannikmae Helena , Peel Samantha , Barry Simon , Sur Inderpreet , Taipale Jussi , Senda Takao , de la Roche Marc 
Published: June 2020

AbstractThe tumour suppressor adenomatous polyposis coli (Apc) regulates diverse effector pathways essential for cellular homeostasis. Truncating mutations in Apc, leading to the loss of its Wnt pathway and microtubule regulatory domains, are oncogenic in human and murine intestinal epithelia and drive malignant transformation. Whereas uncontrolled proliferation via Wnt pathway deregulation is an unequivocal consequence of oncogenic Apc mutations, it is not known whether loss of its other control systems contribute to tumorigenesis. Here we employin vitromodels of tumorigenesis to unmask the molecular barriers erected by Apc that maintain normal epithelial homeostasis in the murine intestinal epithelia. We determine that (i) enterocyte proliferation, (ii) microtubule dynamics and (iii) epithelial morphology are controlled by three independent molecular pathways, each corrupted by oncogenic Apc mutations. The key result of the study is to establish that Apc regulates three individual biological fates in the intestinal epithelia, through three distinct effector pathways, a significant advance to our understanding of normal tissue homeostasis, the molecular architecture of epithelial tissue and the aetiology of intestinal cancer.
Responsiveness variability during anaesthesia relates to inherent differences in brain structure and function of the fronto-parietal networks
Authors: Deng Feng , Taylor Nicola , Owen Adrian M. , Cusack Rhodri , Naci Lorina 
Published: June 2020

AbstractAnaesthesia combined with functional neuroimaging provides a powerful approach for understanding the brain mechanisms of consciousness. Although propofol is used ubiquitously in clinical interventions that reversibly suppress consciousness, it shows large inter-individual variability, and the brain bases of this variability remain poorly understood. We asked whether three networks key to conscious cognition — the dorsal attention (DAN), executive control (ECN), and default mode (DMN) — underlie responsiveness variability under anaesthesia. Healthy participants (N=17) were moderately anaesthetized during narrative understanding and resting state conditions inside the Magnetic Resonance Imaging scanner. A target detection task measured behavioural responsiveness. An independent behavioural study (N=25) qualified the attention demands of narrative understanding. 30% of participants were unaffected in their response times, thus thwarting a key aim of anaesthesia — the suppression of behavioural responsiveness. Individuals with stronger functional connectivity within the DAN and ECN, between them, and to the DMN, and with larger grey matter volume in frontal regions were more resilient to anaesthesia. For the first time, we show that responsiveness variability during propofol anaesthesia relates to inherent differences in brain structure and function of the fronto-parietal networks, which can be predicted prior to sedation. Results highlight novel markers for improving awareness monitoring during clinical anaesthesia.Key pointsModerate propofol anaesthesia showed highly variable effects across individuals30% of healthy participants’ response times were unaffected by anaesthesia and 70% had significantly delayed, fragmented, or fully omitted responsesGrey matter volume in frontal cortex and functional connectivity of the fronto-parietal networks predicted resilience to anaesthesia
Nrf2 activator-encapsulating polymeric nanoparticles and LDL-like nanoparticles target atherosclerotic plaque
Authors: Maiocchi Sophie , Thai Sydney , Buglak Nicholas , Cartaya Ana , Anwar Arnida , Corbin Ian , Bahnson Edward 
Published: June 2020

AbstractAtherosclerotic vascular disease is the leading cause of death world-wide with few novel therapies available in spite of the ongoing health burden. Oxidative stress is a well-established driver of atherosclerotic progression; however the clinical translation of redox-based therapies is lacking. One of the challenges facing redox-based therapies is their targeted delivery to cellular domains of redox dysregulation. In the current study we sought to develop NPs encapsulating redox-based interventions that exploit passive means of targeting to selectively accumulate in atherosclerotic plaque with the aim of enhancing the intra-plaque bioavailability of interventions. Herein we present two types of nanoparticles (NPs): (i) We have employed flash nanoprecipitation to synthesize polymeric NPs encapsulating the hydrophobic Nrf2 activator drug, CDDO-Methyl, (ii) we have generated LDL-like NPs encapsulating the anti-inflammatory compound, oleic acid (OA). Nrf2-activators are a promising class of redox-active drug molecules whereby activation of Nrf2 results in the expression of several antioxidant and cyto-protective enzymes. Moreover, local activation of Nrf2 within the atherosclerotic plaque can be athero-protective. In this study we characterize the physiochemical properties of these NPs as well as confirm in vitro association of NPs with murine macrophages. In vitro drug release of CDDO-Me from polymeric NPs was determined by Nrf2-ARE-driven GFP fluorescence. In vivo localization was assessed through immunofluorescence of histological sections as well as whole-tissue light sheet fluorescence microscopy. We show that CDDO-Me-NPs and LDL-OA-NPs selectively accumulate in atherosclerotic plaque of two widely-used murine models of atherosclerosis: ApoE-/-and LDLr-/-mice. Overall, these studies underline that targeting of atherosclerotic plaque is an effective means to enhance delivery of redox-based interventions. Future work will assess the therapeutic efficacy of intra-plaque Nrf2 activation or anti-inflammatory actions with CDDO-Me-NPs or LDL-OA-NPs, respectively.