bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of corticosteroid treatment on 1376 hospitalized COVID-19 patients. A cohort study.
Authors: Albani Filippo , Fusina Federica , Granato Enza , Capotosto Cristina , Ceracchi Claudia , Gargaruti Riccardo , Santangelo Giovanni , Schiavone Luca , Taranto Maria Salvatrice , Tosati Cinzia , Vavassori Elena , Natalini Giuseppe 
Published: July 2020

AbstractBackgroundSince the start of the novel coronavirus 2019 (COVID-19) pandemic, corticosteroid use has been the subject of debate. The available evidence is uncertain, and knowledge on the subject is evolving. The aim of our cohort study was to evaluate the association between corticosteroid therapy and hospital mortality, in patients hospitalized with COVID-19 after balancing for possible confounders.ResultsOne thousand four hundred forty four patients were admitted to our hospital with a positive RT-PCR test for SARS-CoV-2, 559 patients (39%) were exposed to corticosteroids during hospital stay, 844 (61%) were not exposed to corticosteroids.In the cohort of patients exposed to corticosteroids, 171 (30.6%) died. In the cohort of patients not exposed to corticosteroids, 183 (21.7%) died (unadjusted p <0.001). Nonetheless, exposure to corticosteroids was not associated with in-hospital mortality after balancing with overlap weight propensity score (adjusted p = 0.25). Patients in the corticosteroids cohort had reduced risk of ICU admission (adjusted p <0.001).ConclusionsTreatment with corticosteroids did not affect hospital mortality in patients with COVID-19 after balancing for confounders. A possible advantage of corticosteroid therapy was to reduce Intensive Care Unit admission, which could be useful in reducing pressure on the Intensive Care Units in times of limited resources, as during the COVID-19 pandemic.
HIGH VERSUS STANDARD DOSES OF CORTICOSTEROIDS IN COVID-19 PATIENTS WITH AN ACUTE RESPIRATORY DISTRESS SYNDROME: a controlled observational comparative study
Authors: Monreal Enric , de la Maza Susana Sainz , Natera-Villalba Elena , Beltrán-Corbellini Álvaro , Rodríguez-Jorge Fernando , Fernández-Velasco Jose Ignacio , Walo-Delgado Paulette , Muriel Alfonso , Zamora Javier , Alonso-Canovas Araceli , Fortún Jesús , Manzano Luis , Montero-Errasquín Beatriz , Costa-Frossard Lucienne , Masjuan Jaime , María Villar Luisa ,   for the COVID-HRC group
Published: July 2020

ABSTRACTINTRODUCTIONDespite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe Coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients.METHODSAll consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an acute respiratory distress syndrome (ARDS). Patients were allocated to the high doses (HD, ≥250mg/day of methylprednisolone) of corticosteroids or the standard doses (SD, ≤1.5mg/kg/day of methylprednisolone) at discretion of treating physician. The primary endpoint was the mortality between both cohorts and secondary endpoints were the risk of need for mechanical ventilation (MV) or death and the risk of developing a severe ARDS.RESULTS573 patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54–73) years. In HD cohort, a worse baseline respiratory situation was observed and male sex, older age and comorbidities were significantly more common. After adjusting by baseline characteristics, HD were associated with a higher mortality than SD (adjusted-OR 2.46, 95% CI 1.58 – 3.83, p<0.001) and with an increased risk of needing MV or death (adjusted-OR 2.50, p=0.001). Conversely, the risk of developing a severe ARDS was similar between groups. Interaction analysis showed that HD increased mortality exclusively in elderly patients.CONCLUSIONOur real-world experience advises against exceeding 1-1.5mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.SUMMARYIn patients with severe COVID-19, high doses of corticosteroids are associated with a higher mortality and risk of need for mechanical ventilation or death compared to standard doses. This deleterious effect is mainly observed in the elderly.
The regulatory landscape of Arabidopsis thaliana roots at single-cell resolution
Authors: Dorrity Michael W. , Alexandre Cristina M. , Hamm Morgan , Vigil Anna-Lena , Fields Stanley , Queitsch Christine , Cuperus Josh 
Published: July 2020

AbstractIn plants, chromatin accessibility – the primary mark of regulatory DNA – is relatively static across tissues and conditions. This scarcity of accessible sites that are dynamic or tissue-specific may be due in part to tissue heterogeneity in previous bulk studies. To assess the effects of tissue heterogeneity, we apply single-cell ATAC-seq to A. thaliana roots and identify thousands of differentially accessible sites, sufficient to resolve all major cell types of the root. However, even this vast increase relative to bulk studies in the number of dynamic sites does not resolve the poor correlation at individual loci between accessibility and expression. Instead, we find that the entirety of a cell’s regulatory landscape and its transcriptome each capture cell type identity independently. We leverage this shared information on cell identity to integrate accessibility and transcriptome data in order to characterize developmental progression, endoreduplication and cell division in the root. We further use the combined data to characterize cell type-specific motif enrichments of large transcription factor families and to link the expression of individual family members to changing accessibility at specific loci, taking the first steps toward resolving the direct and indirect effects that shape gene expression. Our approach provides an analytical framework to infer the gene regulatory networks that execute plant development.
Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis
Authors: Ducimetière Laura , Lucchiari Giulia , Litscher Gioana , Nater Marc , Heeb Laura , Nuñez Nicolás Gonzalo , Wyss Laura , Burri Dominik , Vermeer Marijne , Gschwend Julia , Moor Andreas E. , Becher Burkhard , van den Broek Maries , Tugues Sonia 
Published: July 2020

SUMMARYThe liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and non-redundant action of two innate lymphocyte subpopulations, conventional NK cells (cNKs) and tissue-resident type I Innate Lymphoid Cells (trILC1s), is essential for anti-metastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 control metastatic seeding, whereas cNKs restrain outgrowth. The antimetastatic activity of cNKs is regulated in a tumor type-specific fashion. Thereby, individual cancer cell lines orchestrate the emergence of cNK subsets with unique phenotypic and functional traits. Understanding cancer-cell- as well as innate-cell-intrinsic factors will allow the exploitation of hepatic innate cells for development of novel cancer therapies.SignificanceInnate lymphoid cells hold great promise for the treatment of metastases. Development of effective therapies based on these versatile immune cells, however, is hampered by our limited knowledge of their behavior in the metastatic niche. Here, we describe that defense against liver metastasis requires the collaboration between two innate lymphocyte subsets, conventional NK cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s). We show that different cancers generate their own particular metastatic niche inducing specific changes in cNKs and trILC1s. Further, we uncover specific cNK subsets that can be manipulated to improve their anti-metastatic potential. Our work contributes to understanding how cancer-specific factors and hepatic innate lymphocytes exert mutual influence and how this can be exploited for therapeutic purposes.HighlightscNKs and trILC1s collaborate to control hepatic metastasistrILC1s restrict seeding and cNKs control outgrowth of cancer cells in the liverIndividual cancer cell lines orchestrate a distinct metastatic nicheThe metastatic niche dictates the phenotype and function of cNKs
Skill acquisition and gaze behavior during laparoscopic surgical simulation
Authors: Liu Sicong , Donaldson Rachel , Subramaniam Ashwin , Palmer Hannah , Champion Cosette , Cox Morgan L. , Appelbaum L. Gregory 
Published: July 2020

AbstractBackgroundExperts consistently exhibit more efficient gaze behaviors than non-experts during motor tasks. In surgery, experts have been shown to gaze more at surgical targets than surgical tools during simple simulations and when watching surgical recordings, suggesting a proactive control strategy with greater use of feedforward visual sampling. To investigate such expert gaze behaviors in a more dynamic and complex laparoscopic surgery simulation, the current study measured and compared gaze patterns between surgeons and novices who practiced extensively with laparoscopic simulation.MethodsThree surgeons were assessed in a testing visit and five novices were trained and assessed (at pre-, mid-, and post-training points) in a 5-visit protocol on the Fundamentals of Laparoscopic Surgery peg transfer task. The task was adjusted to have a fixed action sequence to allow recordings of dwell durations based on pre-defined areas of interest (AOIs). Novices’ individualized learning curves were analyzed using an inverse function model, and group-level differences were tested using analysis of variance on both behavioral performance and dwell duration measures.ResultsTrained novices were shown to reach more than 98% (M= 98.62%,SD= 1.06%) of their behavioral learning plateaus, leading to equivalent behavioral performance to that of surgeons. Despite this equivalence in behavioral performance, surgeons continued to show significantly shorter dwell durations at visual targets of current actions and longer dwell durations at future steps in the action sequence than trained novices (ps≤ .03, Cohen’sds> 2).ConclusionThis study demonstrates that, whereas novices can train to match surgeons on behavioral performance, their gaze pattern is still less efficient than that of surgeons, suggesting that eye-tracking metrics might be more sensitive than behavioral performance in detecting surgical expertise. Such insight can be applied to develop training protocols so non-experts can internalize experts’ “gaze templates” to accelerate learning.Article SummaryGaze pattern differences persist between laparoscopic surgery experts and novices who have been trained to reach over 98% of individualized behavioral learning plateaus in the Fundamentals of Laparoscopic Surgery (FLS) peg transfer task.The importance of this finding lies in motivating the decision and method of including gaze behaviors via eyetracking technology in the present surgical training programs.
Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening
Authors: Zhu Wei , Xu Miao , Chen Catherine Z. , Guo Hui , Shen Min , Hu Xin , Shinn Paul , Klumpp-Thomas Carleen , Michael Samuel G. , Zheng Wei 
Published: July 2020

AbstractThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C like protease (3CLpro), or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high throughput screening (qHTS) of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CLproassay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLprohave been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC50= 0.26 µM), Hydroxocobalamin (IC50= 3.29 µM), Suramin sodium (IC50= 6.5 µM), Z-DEVD-FMK (IC50= 6.81 µM), LLL-12 (IC50= 9.84 µM), and Z-FA-FMK (IC50= 11.39 µM) are the most potent 3CLproinhibitors. The activities of anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CLproinhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients, and as starting points for chemistry optimization for new drug development.
TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation
Authors: Pradhan P. , Toy R. , Jhita N. , Blanchard E. L. , Atalis A. , Pandey B. , Santangelo P. J. , Shayakhmetov D. M. , Roy K. 
Published: July 2020

AbstractInnate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). PAMPs and PAMP-analogs are also used as immune-adjuvants to enhance vaccine efficacy by activating various Pattern Recognition Receptors (PRRs), like Toll-like receptors (TLRs). Various combinations of PAMP adjuvants can trigger synergistic immune responses, but the underlying molecular mechanisms driving that synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with MPLA (TLR4-adjuvant) and CpG (TLR9-adjuvant) as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for the integrated, dual-adjuvant immune response. PLP-based co-presentation of MPLA and CpG to mouse bone marrow derived antigen-presenting cells (BM-APCs) elicited synergistic Type-I Interferon (IFN-β) and IL-12p70 responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that the adapter protein MyD88 and the Interferon-Regulatory-Factor-5 (IRF-5), but not the canonical factors IRF-3 or IRF-7, were necessary for production of both IFN-β and IL12p70. TRIF signaling was required to elicit the synergistic response; the absence of TRIF abolished synergy. Importantly, both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling (TRIF-TRAF-IRF5 pathway kinetics) drove the observed synergy. These results identify not only the key signaling mechanism that cooperates to generate a combinatorial response to MPLA-CpG dual engagement in BM-APCs, but they also underscore the critical role that signaling kinetics and biophysical presentation plays in integrated responses to combination adjuvants.
Actin bundle architecture and mechanics regulate myosin II force generation
Authors: Weirich Kimberly L. , Stam Samantha , Munro Ed , Gardel Margaret L. 
Published: July 2020

AbstractThe actin cytoskeleton is a soft, structural material that underlies biological processes such as cell division, motility, and cargo transport. The cross-linked actin filaments self-organize into a myriad of architectures, from disordered meshworks to ordered bundles, which are hypothesized to control the actomyosin force generation that regulates cell migration, shape, and adhesion. Here, we use fluorescence microscopy and simulations to investigate how actin bundle architectures with varying polarity, spacing, and rigidity impact myosin II dynamics and force generation. Microscopy reveals that mixed polarity bundles formed by rigid cross-linkers support slow, bidirectional myosin II filament motion, punctuated by periods of stalled motion. Simulations reveal that these locations of stalled myosin motion correspond to sustained, high forces in regions of balanced actin filament polarity. By contrast, mixed polarity bundles formed by compliant, large cross-linkers support fast, bidirectional motion with no traps. Simulations indicate that trap duration is directly related to force magnitude, and that the observed increased velocity corresponds to lower forces resulting from both the increased bundle compliance and filament spacing. Our results indicate that the properties of actin structures regulate the dynamics and magnitude of myosin II forces, highlighting the importance of architecture and mechanics in regulating forces in biological materials.
TLR7 and RIG-I dual-adjuvant loaded nanoparticles drive broadened and synergistic responses in dendritic cellsin vitroand generate unique cellular immune responses in influenza vaccination
Authors: Toy Randall , Keenum M. Cole , Pradhan Pallab , Phang Katelynn , Chen Patrick , Chukwu Chinwendu , Nguyen Anh , Liu Jiaying , Jain Sambhav , Kozlowski Gabrielle , Hosten Justin , Suthar Mehul S. , Roy Krishnendu 
Published: July 2020

ABSTRACTAlthough the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection – partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of combination adjuvants, mirroring the flu-virus related innate signaling pathways, could elicit strong cellular immunity. Here, we show that the small molecule adjuvant R848 and the RNA adjuvant PUUC, targeting endosomal TLR7s and cytoplasmic RLRs respectively, when delivered together in polymer nanoparticles (NP), elicits a broadened immune responses in mouse bone marrow-derived dendritic cells (mBMDCs) and a synergistic response in both mouse and human plasmacytoid dendritic cells (pDCs). In mBMDCs, NP-R848-PUUC induced both NF-κB and interferon signaling. Interferon responses to co-delivered R848 and PUUC were additive in human peripheral blood mononuclear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs. Vaccination with NPs loaded with H1N1 Flu antigen, R848, and PUUC increased percentage of CD8+ T-cells in the lungs, percentage of antigen-specific CD4+T-cells in the spleen, and enhanced overall cytokine-secreting T cell percentages upon antigen restimulation. Also in the spleen, T lymphopenia, especially after in vitro restimulation, was observed. Our results demonstrate that simultaneous engagement of TLR7 and RIG-I pathways using particulate carriers is a potential approach to improve cellular immunity in flu vaccination.GRAPHICAL ABSTRACT
Brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in theSORL1gene implicated in early onset familial Alzheimer’s disease
Authors: Barthelson Karissa , Pederson Stephen Martin , Newman Morgan , Lardelli Michael 
Published: July 2020

AbstractBackgroundTo prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role ofSORL1mutations in AD pathogenesis is unclear.MethodsTo understand the molecular consequences ofSORL1mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations insorl1display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations insorl1or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions.ResultsWe identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due tosorl1haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild typesorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish.ConclusionsOur results provide insight into the possible early brain molecular effects of an EOfAD mutation in humanSORL1. Differential effects of heterozygosity and complete loss of normalSORL1expression are revealed.
Fibroblast growth factor 9 stimulates neurite outgrowth through NF-kB signaling in striatal cell Huntington’s disease models
Authors: Yusuf Issa Olakunle , Chen Hsiu-Mei , Cheng Pei-Hsun , Chang Chih-Yi , Tsai Shaw-Jenq , Chuang Jih-Ing , Wu Chia-Ching , Huang Bu-Miin , Sun H. Sunny , Chen Chuan-Mu , Yang Shang-Hsun 
Published: July 2020

AbstractProper development of neuronal cells is important for brain functions, and impairment of neuronal development may lead to neuronal disorders, implying that improvement in neuronal development may be a therapeutic direction for these diseases. Huntington’s disease (HD) is a neurodegenerative disease characterized by impairment of neuronal structures, ultimately leading to neuronal death and dysfunctions of the central nervous system. Based on previous studies, fibroblast growth factor 9 (FGF9) may provide neuroprotective functions in HD, and FGFs may enhance neuronal development and neurite outgrowth. However, whether FGF9 can provide neuronal protective functions through improvement of neuronal morphology in HD is still unclear. Here, we study the effects of FGF9 on neuronal morphology in HD and attempt to understand the related working mechanisms. Taking advantage of striatal cell lines from HD knock-in mice, we found that FGF9 increases neurite outgrowth and upregulates several structural and synaptic proteins under HD conditions. In addition, activation of nuclear factor kappa B (NF-kB) signaling by FGF9 was observed to be significant in HD cells, and blockage of NF-kB leads to suppression of these structural and synaptic proteins induced by FGF9, suggesting the involvement of NF-kB signaling in these effects of FGF9. Taken these results together, FGF9 may enhance neurite outgrowth through upregulation of NF-kB signaling, and this mechanism could serve as an important mechanism for neuroprotective functions of FGF9 in HD.