bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 disease severity
Authors: Inde Zintis , Yapp Clarence , Joshi Gaurav N. , Spetz Johan , Fraser Cameron , Deskin Brian , Ghelfi Elisa , Sodhi Chhinder , Hackam David J. , Kobzik Lester , Croker Ben A. , Brownfield Douglas , Jia Hongpeng , Sarosiek Kristopher A. 
Published: September 2020

ABSTRACTAngiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19)1. COVID-19 disease severity, while highly variable, is typically lower in pediatric patients than adults (particularly the elderly), but increased rates of hospitalizations requiring intensive care are observed in infants than in older children. The reasons for these differences are unknown. To detect potential age-based correlates of disease severity, we measured ACE2 protein expression at the single cell level in human lung tissue specimens from over 100 donors from ∼4 months to 75 years of age. We found that expression of ACE2 in distal lung epithelial cells generally increases with advancing age but exhibits extreme intra- and inter-individual heterogeneity. Notably, we also detected ACE2 expression on neonatal airway epithelial cells and within the lung parenchyma. Similar patterns were found at the transcript level:ACE2mRNA is expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood in alveolar epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is also dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in juveniles, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells – this may limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for potential translation of apoptosis modulating drugs as novel treatments for COVID-19.
Stable colony stimulating factor 1 fusion protein treatment increases HSC pool and enhances their mobilisation in mice
Authors: Kaur Simranpreet , Sehgal Anuj , Wu Andy C. , Millard Susan M , Batoon Lena , Ferrari-Cestari Michelle , Levesque Jean-Pierre , Hume David A. , Raggatt Liza J. , Pettit Allison R. 
Published: September 2020

AbstractPrior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with colony stimulating factor-1 (CSF1) to modify the BM niche and expand the potential HSC pool for autologous transplantation. We administrated CSF1 Fc fusion protein (CSF1-Fc) to naive C57Bl/6 mice and assessed the impacts on HSC number and function and overall haematopoiesis. Outcomes were assessed byin situimaging andex vivoflow cytometry with functional validation by colony formation and competitive transplantation assay. CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of haematopoiesis was accompanied by an increase in the total available HSPC pool. In the spleen, increased HSC was associated with expression of the BM niche marker CD169 in red pulp macrophages. Pre-treatment with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of granulocyte colony stimulating factor (G-CSF) treatment. These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve autologous or heterologous HSC transplantation outcomes.Key points1) Recovery from Fc-modified colony stimulating factor-1 (CSF1-Fc) treatment was accompanied by an increase in total haematopoietic stem cells. 2) Pre-conditioning with CSF1-Fc increased the reconstitution potential of blood after haematopoietic stem cell mobilisation.
Enzymatic synthesis of fatty acid amides using microbial lipids as acyl group-donors and their biological activities
Authors: El-Baz Hatim A. , Elazzazy Ahmed M. , Saleh Tamer S. , Dritsas Panagiotis , Mahyoub Jazem A. , Baeshen Mohammed N. , Madian Hekmat R. , Alkhaled Mohammed , Aggelis George 
Published: September 2020

AbstractFatty acid amides (FAAs) are of great interest due to their broad industrial applications. They can be synthesized enzymatically with many advantages over chemical synthesis. In this study, the fatty acid moieties of lipids ofCunninghamella echinulataATHUM 4411,Umbelopsis isabellinaATHUM 2935,Nannochloropsis gaditanaCCAP 849/5, Olive oil and an eicosapentaenoic acid (EPA) concentrate were converted into their fatty acid methyl esters and used in the FAA (i.e. ethylene diamine amides) enzymatic synthesis, using lipases as biocatalysts. The FAA synthesis, monitored usingin situNMR, FT-IR and thin-layer chromatography, was catalyzed efficiently by the immobilizedCandida rugosalipase. The synthesized FAAs exhibited a significant antimicrobial activity, especially those containing oleic acid in high proportions (i.e. derived from Olive oil andU. isabellinaoil), against several human pathogenic microorganisms, insecticidal activity against yellow fever mosquito, especially those ofC. echinulatacontaining gamma linolenic acid, and anti-cancer properties against SKOV-3 ovarian cancer cell line, especially those containing EPA in their structures (i.e. EPA concentrate andN. gaditanaoil). We conclude that FAAs can be efficiently synthesized using microbial oils of different fatty acid composition and used in specific biological applications.
Endothelial-to-hematopoietic transition is induced by Notch glycosylation and upregulation of Mycn
Authors: Laruy Briane , Garcia-Gonzalez Irene , Casquero-Garcia Veronica , Benedito Rui 
Published: September 2020

AbstractA better understanding of the molecular mechanisms driving hematopoietic stem cell (HSC) specification and expansion may enable better pharmacological strategies to produce them in sufficient numbers for transplantation. In the embryo, HSCs arise from a defined subset of arterial endothelial cells (ECs) located in the aorta–gonad–mesonephros (AGM) region that undergo endothelial-to-hematopoietic transition (EHT). Arterialization and HSC development are generally believed to require the action of Notch. Here we show that although Notch activity is initially required for arterialization, it is detrimental to subsequent EHT. Mechanistically, we show that effective EHT depends on a Mfng-induced decrease in Jag1-Notch signaling in hemogenic ECs. This causes upregulation of Mycn, an important metabolic and cell-cycle regulator that we found to be required for EHT. During the subsequent development of hematopoietic lineages,Mycnexpression decreases and its function is taken on by the homologousMycgene.
Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas
Authors: Wang Huabo , Lu Jie , Mandel Jordan A. , Zhang Weiqi , Schwalbe Marie , Gorka Joanna , Liu Ying , Marburger Brady , Wang Jinglin , Ranganathan Sarangarajan , Prochownik Edward V. 
Published: September 2020

AbstractBackground and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often bears β-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis.MethodsWe evaluated NFE2L2’s role in HB pathogenesis by co-expressing all combinations of mutant β-catenin, YAPS127Aand the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors.ResultsIn association with β-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2’s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant β-catenin, YAPS127Aand Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant β-catenin-YAPS127A-L30P/R34P tumors.ConclusionsOur findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.
Single-molecule spectroscopy reveals dynamic allostery mediated by the substrate-binding domain of a AAA+ machine
Authors: Iljina Marija , Mazal Hisham , Goloubinoff Pierre , Riven Inbal , Haran Gilad 
Published: September 2020

AbstractClpB is an ATP-dependent protein disaggregation machine that is activated on demand by co-chaperones and by aggregates caused by heat shock or mutations. The regulation of ClpB’s function is critical, since its persistent activation is toxicin vivo. Each ClpB molecule is composed of an auxiliary N-terminal domain (NTD), an essential regulatory middle domain (MD) that activates the machine by tilting, and two nucleotide-binding domains that are responsible for ATP-fuelled substrate threading. The NTD is generally thought to serve as a substrate-binding domain, which is commonly considered to be dispensable for ClpB’s activity, and is not well-characterized structurally due to its high mobility. Here we use single-molecule FRET spectroscopy to directly monitor the real-time dynamics of ClpB’s NTD and reveal its involvement in novel allosteric interactions. We find that the NTD fluctuates on a microsecond timescale and, unexpectedly, shows little change in conformational dynamics upon binding of a substrate protein. During its fast motion, the NTD makes crucial contacts with the regulatory MD, directly affecting its conformational state and thereby influencing the overall ATPase and unfolding activity of this machine. Moreover, we also show that the NTD mediates signal transduction to the nucleotide-binding domains through conserved residues. The two regulatory pathways revealed here enable the NTD to suppress the MD in the absence of protein substrate, and to limit ATPase and disaggregation activities of ClpB. The use of multiple parallel allosteric pathways involving ultrafast domain motions might be common to AAA+ molecular machines to ensure their fast and reversible activation.
Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect
Authors: Malhotra Angad , Walle Matthias , Paul Graeme R. , Kuhn Gisela A. , Müller Ralph 
Published: September 2020

AbstractMethods to repair bone defects arising from trauma, resection, or disease, continue to be sought after. Cyclic mechanical loading is well established to influence bone (re)modelling activity, in which bone formation and resorption are correlated to micro-scale strain. Based on this, the application of mechanical stimulation across a bone defect could improve healing. However, if ignoring the mechanical integrity of defected bone, loading regimes have a high potential to either cause damage or be ineffective. This study explores real-time finite element (rtFE) methods that use three-dimensional structural analyses from micro-computed tomography images to estimate effective peak cyclic loads in a subject-specific and time-dependent manner. It demonstrates the concept in a cyclically loaded mouse caudal vertebral bone defect model. Using rtFE analysis combined with adaptive mechanical loading, mouse bone healing was significantly improved over non-loaded controls, with no incidence of vertebral fractures. Such rtFE-driven adaptive loading regimes demonstrated here could be relevant to clinical bone defect healing scenarios, where mechanical loading can become patient-specific and more efficacious. This is achieved by accounting for initial bone defect conditions and spatio-temporal healing, both being factors that are always unique to the patient.
Differential expression of transposable elements in stem cell lineages of the preimplantation embryo
Authors: Dai Eddie , Alvarez Nehemiah S. , Rumi M. A. Karim 
Published: September 2020

ABSTRACTApproximately half of the human genome is comprised of transposable elements (TEs), which are genetic elements capable of amplifying themselves within the genome. Throughout the course of human life, TEs are expressed in germ cells, the preimplantation embryo, and the placenta but silenced elsewhere. However, the functions of TEs during embryonic development are poorly understood. Trophoblast stem (TS), embryonic stem (ES), and extraembryonic endoderm stem (XEN) cells are cell lineages derived from the preimplantation embryo and known to have different TE silencing mechanisms. Thus, it is likely distinct TEs are expressed in each lineage and that proteins coded by these TEs have lineage-specific functions. The purpose of this research was to determine which TEs are expressed in each of these stem cell lineages and to compare expression levels between lineages. Each lineage’s transcriptome was analyzed by quantifying TE expression in RNA-sequencing data from mouse stem cells. Expression data were then used for differential expression analyses performed between the cell types. It was found that certain families of TEs are distinctly expressed in certain lineages, suggesting expression of these families may be involved in the differentiation and development of each lineage, the understanding of which can lead to improved stem cell therapies and capacity to study human embryonic development.
scGCN: a Graph Convolutional Networks Algorithm for Knowledge Transfer in Single Cell Omics
Authors: Song Qianqian , Su Jing , Zhang Wei 
Published: September 2020

AbstractSingle-cell omics represent the fastest-growing genomics data type in the literature and the public genomics repositories. Leveraging the growing repository of labeled datasets and transferring labels from existing datasets to newly generated datasets will empower the exploration of the single-cell omics. The current label transfer methods have limited performance, largely due to the intrinsic heterogeneity and extrinsic differences between datasets. Here, we present a robust graph-based artificial intelligence model, single-cell Graph Convolutional Network (scGCN), to achieve effective knowledge transfer across disparate datasets. Benchmarked with other label transfer methods on totally 30 single cell omics datasets, scGCN has consistently demonstrated superior accuracy on leveraging cells from different tissues, platforms, and species, as well as cells profiled at different molecular layers. scGCN is implemented as an integrated workflow as a python software, which is available athttps://github.com/QSong-github/scGCN.
Sustained neural activity correlates with rapid perceptual learning of auditory patterns
Authors: Herrmann Björn , Araz Kurdo , Johnsrude Ingrid S. 
Published: September 2020

AbstractRepeating structures forming regular patterns are common in sounds. Learning such patterns may enable accurate perceptual organization. In five experiments, we investigated the behavioral and neural signatures of rapid perceptual learning of regular sound patterns. We show that recurring (compared to novel) patterns are detected more quickly and increase sensitivity to pattern deviations and to the temporal order of pattern onset relative to a visual stimulus. Sustained neural activity reflected perceptual learning in two ways. Firstly, sustained activity increased earlier for recurring than novel patterns when participants attended to sounds, but not when they ignored them; this earlier increase mirrored the rapid perceptual learning we observed behaviorally. Secondly, the magnitude of sustained activity was generally lower for recurring than novel patterns, but only for trials later in the experiment, and independent of whether participants attended to or ignored sounds. The late manifestation of sustained activity reduction suggests that it is not directly related to rapid perceptual learning, but to a mechanism that does not require attention to sound. In sum, we demonstrate that the latency of sustained activity reflects rapid perceptual learning of auditory patterns, while the magnitude may reflect a result of learning, such as better prediction of learned auditory patterns.
Suppression of amyloid-β secretion from neurons bycis-9,trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid
Authors: Hata Saori , Kikuchi Kazunori , Kano Kuniyuki , Saito Haruka , Sobu Yuriko , Kinoshita Shoichi , Saito Takashi , Saido Takaomi C. , Sano Yoshitake , Taru Hidenori , Aoki Junken , Komano Hiroto , Tomita Taisuke , Natori Shunji , Suzuki Toshiharu 
Published: September 2020

AbstractConjugated linoleic acid (CLA) comprises several geometric and positional isomers of the parental linoleic acid (LA). Two of the isomers, cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA) exert various biological activities. However, the effect of CLA on generation of neurotoxic amyloid-β (Aβ) protein remains unclear. We found that c9,t11CLA significantly suppressed generation of Aβ in primary cultures of mouse neurons. CLA treatment did not affect the levels of β-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment (PS1 NTF), or Aβ protein precursor (APP) in cultured neurons. BACE1 activity in lysate of neurons treated with c9,t11 CLA, but not t10,c12 CLA, decreased slightly, although c9,t11 CLA did not directly affect the activity of recombinant BACE1. Interestingly, localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, where APP is predominantly cleaved by BACE1. c9,t11 CLA and t10,c12 CLA appeared to be incorporated into membrane phospholipids, as the level of CLA-containing lysophosphatidylcholine (CLA-LPC) increased dramatically in neurons incubated with CLA. Taken together, our findings indicate that accumulation of c9,t11 CLA-LPC, but not t10,c12 CLA-LPC, in neuronal membranes suppresses amyloidogenic cleavage of APP, thereby contributing to preservation of brain neurons by suppressing neurotoxic Aβ production in aged subjects.
Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling
Authors: Thakore Pratish , Alvarado Michael G. , Ali Sher , Mughal Amreen , Pires Paulo W. , Yamasaki Evan , Pritchard Harry A. T. , Isakson Brant E. , Tran Cam Ha T. , Earley Scott 
Published: September 2020

AbstractBlood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrativeex vivoandin vivoapproach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occursin vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.
Syringeal vocal folds do not have a voice in zebra finch vocal development
Authors: Maxwell Alyssa , Adam Iris , Larsen Pernille S. , Sørensen Peter G. , Elemans Coen P.H. 
Published: September 2020

AbstractVocal behaviour can be dramatically changed by both neural circuit development and postnatal maturation of the body. During song learning in songbirds, both the song system and syringeal muscles are functionally changing, but it is unknown if maturation of sound generators within the syrinx contributes to vocal development. Here we densely sample the respiratory pressure control space of the zebra finch syrinxin vitro. We show that the syrinx produces sound very efficiently and that key acoustic parameters, minimal fundamental frequency, entropy and source level, do not change over development in both sexes. Thus, our data suggests that the observed acoustic changes in vocal development must be attributed to changes in the motor control pathway, from song system circuitry to muscle force, and not by material property changes in the avian analog of the vocal folds. We propose that in songbirds, muscle use and training driven by the sexually dimorphic song system are the crucial drivers that lead to sexual dimorphism of the syringeal skeleton and musculature. The size and properties of the instrument are thus not changing, while its player is.