bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors
Authors: Cwetsch Andrzej W , Narducci Roberto , Bolla Maria , Pinto Bruno , Perlini Laura , Bassani Silvia , Passafaro Maria , Cancedda Laura
Published: June 2020

PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9) is an infantile onset epilepsy syndrome characterized by psychiatric (including autistic) sensory and cognitive impairment of varying degrees. EIEE9 is caused by X-linked PCDH19 protein loss of function. Due to random X-chromosome inactivation, EIEE9-affected females present a mosaic population of healthy and Pcdh19-mutant cells. Unfortunately, no mouse models recapitulate to date both the brain histological and behavioural deficits present in people with EIEE9. Thus, the search for a proper understanding of the disease, and possible future treatment is hampered. By inducing a focal mosaicism of Pcdh19 expression usingin uteroelectroporation in rat, we found here that Pcdh19 signaling in specific brain areas is implicated in neuronal migration, as well as in core behaviors related to autism and cognitive function.
Co-occupancy analysis reveals novel transcriptional synergies for axon growth
Authors: Venkatesh Ishwariya , Mehra Vatsal , Wang Zimei , Simpson Matthew T. , Eastwood Erik , Chakraborty Advaita , Beine Zac , Gross Derek , Cabahug Michael , Olson Greta , Blackmore Murray G.
Published: June 2020

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a novel bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in an animal model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify novel TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics roadmap to detect TF synergy.
Longitudinal isolation of potent near-germline SARS-CoV-2-neutralizing antibodies from COVID-19 patients
Authors: Kreer Christoph , Zehner Matthias , Weber Timm , Rohde Cornelius , Halwe Sandro , Ercanoglu Meryem S. , Gieselmann Lutz , Korenkov Michael , Gruell Henning , Schommers Philipp , Vanshylla Kanika , Di Cristanziano Veronica , Janicki Hanna , Brinker Reinhild , Ashurov Artem , Krähling Verena , Kupke Alexandra , Cohen-Dvashi Hadas , Koch Manuel , Lederer Simone , Pfeifer Nico , Wolf Timo , Vehreschild Maria J.G.T. , Wendtner Clemens , Diskin Ron , Becker Stephan , Klein Florian
Published: June 2020

The SARS-CoV-2 pandemic has unprecedented implications for public health, social life, and world economy. Since approved drugs and vaccines are not available, new options for COVID-19 treatment and prevention are highly demanded. To identify SARS-CoV-2 neutralizing antibodies, we analysed the antibody response of 12 COVID-19 patients from 8 to 69 days post diagnosis. By screening 4,313 SARS-CoV-2-reactive B cells, we isolated 255 antibodies from different time points as early as 8 days post diagnosis. Among these, 28 potently neutralized authentic SARS-CoV-2 (IC100as low as 0.04 μg/ml), showing a broad spectrum of V genes and low levels of somatic mutations. Interestingly, potential precursors were identified in naïve B cell repertoires from 48 healthy individuals that were sampled before the COVID-19 pandemic. Our results demonstrate that SARS-CoV-2 neutralizing antibodies are readily generated from a diverse pool of precursors, fostering the hope of rapid induction of a protective immune response upon vaccination.
DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)
Authors: Simon Tincy , Riemer Pamela , Detjen Katharina , Di Domenico Annunziata , Bormann Felix , Menne Andrea , Khouja Slim , Monjé Nanna , Childs Liam H. , Lenze Dido , Leser Ulf , Jarosch Armin , Rossner Florian , Morkel Markus , Blüthgen Nils , Pavel Marianne , Horst David , Capper David , Marinoni Ilaria , Perren Aurel , Mamlouk Soulafa , Sers Christine
Published: June 2020

Pancreatic Neuroendocrine Carcinomas (PanNECs) are high-grade, poorly-differentiated tumors grouped together with Pancreatic Neuroendocrine Tumors (PanNETs) and placed within the Pancreatic Neuroendocrine Neoplasms (PanNENs) WHO tumor classification. Despite recent studies suggesting the endocrine origin of low-grade PanNETs, high-grade PanNEC origin remains unknown. DNA methylation analysis using the Illumina 850K beadchip array was conducted on 57 PanNEN samples, including 14 PanNECs. Distinct methylation profiles separated PanNEN samples into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA mutations, copy number changes and Immunohistochemistry of pancreatic cell-type markers PDX1, ARX and SOX9 were utilized to further characterize PanNECs and their hierarchical cell of origin in the pancreas. Phylo-epigenetic and cell-type signature features using methylation data from normal alpha, beta, acinar and ductal adult cells indicate an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Our study provides a robust and clinically relevant method relying on methylation profiles to clearly distinguish PanNECs from PanNETG3s to improve patient stratification and treatment.
The alternative sigma factor σXmediates competence shut-off at the cell pole inStreptococcus pneumoniae
Authors: Johnston Calum , Soulet Anne-Lise , Berge Matthieu , Prudhomme Marc , De Lemos David , Polard Patrice
Published: June 2020

Bacterial competence for genetic transformation is a well-known species-specific differentiation program driving genome plasticity, antibiotic resistance and virulence in many pathogens. How competence regulation is spatiotemporally integrated in the cell is ill-defined. Here, we unraveled the localization dynamics of the key regulators that master the two intertwined transcription waves controlling competence inStreptococcus pneumoniae. The first wave relies on a stress-inducible phosphorelay system, made up of the ComD and ComE proteins, and the second is directed by an alternative sigma factor, σX, which includes in its regulon the DprA protein that turns off competence through interaction with phosphorylated ComE. Remarkably, we found that ComD, σXand DprA stably co-localize at a single cell pole over the competence period. In contrast, ComE assembles into dynamic patches in the cell periphery, colocalizing temporarily with DprA and ComD at the pole. Furthermore, we provide evidence that σXdirectly conveys DprA polar anchoring. Through this protein targeting function, σXis shown to be actively involved in the timely shut-off of the competence cycle, hence preserving cell fitness. Altogether, this study unveils an unprecedented role for a bacterial transcription σ factor in spatially coordinating the negative feedback loop of its own genetic circuit.
Hierarchical Model for the Role of J-Domain Proteins in Distinct Cellular Functions
Authors: Sugimoto Shinya , Yamanaka Kunitoshi , Niwa Tatsuya , Kinjo Yuki , Mizunoe Yoshimitsu , Ogura Teru
Published: June 2020

InEscherichia coli, the major bacterial Hsp70 system consists of DnaK, three J-domain proteins (JDPs: DnaJ, CbpA, and DjlA), and one nucleotide exchange factor (NEF: GrpE). JDPs determine substrate specificity for the Hsp70 system; however, knowledge on their specific role in bacterial cellular functions is limited. In this study, we demonstrated the role of JDPs in bacterial survival during heat stress and the DnaK-regulated formation of curli—extracellular amyloid fibers involved inE. colibiofilm formation. Genetic analysis with a complete set of JDP-null mutant strains demonstrated that only DnaJ is essential for survival at high temperature, while DnaJ and CbpA are indispensable in DnaK regulation of curli production. Additionally, we found that DnaJ and CbpA are involved in the expression of the master regulator CsgD through the folding of MlrA; this keeps CsgA in a translocation-competent state by preventing its aggregation in the cytoplasm. Our findings support a hierarchical model wherein the role of JDPs in the Hsp70 system differs according to individual cellular functions.
Cancer exosomes harbor diverse hypoxia-targeted mRNAs and contribute toward tumor angiogenesis
Authors: Zhang Pan , Lim Su Bin , Jiang Kuan , Chew Ti Weng , Low Boon Chuan , Lim Chwee Teck
Published: June 2020

Exosomes are extracellular vesicles of endosome origin secreted by various cells. The exosomal cargo, especially proteins and microRNAs, have been extensively investigated for their roles in intercellular communication and as biomarkers for clinical applications. However, the understanding of types and functions of exosomal mRNAs remains limited. Here, we evaluated the mRNAs of 61 hypoxia-targeted genes in exosomes by quantitative reverse transcription PCR (RT-qPCR). Among these 61 mRNAs, 14.8% of them were detected in the MCF10A-derived exosomes, 42.6% in the MCF7-derived exosomes, and 49.2% in the MDA-MB-231-derived exosomes, many of which are differentially regulated in response to hypoxic stress in a cell-line dependent manner. Consequently, 30 exosomal mRNAs are identified as cancer related biomarkers as they are present in cancer cell-derived exosomes and absent in MCF10A-derived exosomes. Co-culture of MDA-MB-231 cells with HUVECs shows uptake of MDA-MB-231 secreted exosomes by the Human umbilical vein endothelial cells (HUVECs). Subsequently, the cancer exosomal VEGFA mRNAs were translated within the HUVECs into proteins that promoted VEGFR-dependent angiogenesis. This finding provides novel insights into how cancer cells can directly contribute towards angiogenesis. RNA-seq also shows that cancer exosomes can upregulate epithelial-mesenchymal transition-related and metabolism-related genes. The transcripts of these genes are found present in the cancer exosomes, suggesting that the uptake of exosomal mRNAs at least partially contributed to the upregulation of the corresponding mRNAs. This study shows that cancer exosomes harbor diverse mRNAs, some of which can act as promising biomarkers as well as contribute towards reprogramming of recipient cells.
Molecular switch architecture drives response properties
Authors: Ghusinga Khem Raj , Jones Roger D. , Jones Alan M. , Elston Timothy C.
Published: June 2020

Many intracellular signaling pathways are composed of molecular switches, proteins that transition between two states—onandoff. Typically, signaling is initiated when an external stimulus activates its cognate receptor that in turn causes downstream switches to transition fromofftoonusing one of the following mechanisms: activation, in which the transition rate from theoffstate to theonstate increases; derepression, in which the transition rate from theonstate to theoffstate decreases; and concerted, in which activation and derepression operate simultaneously. We use mathematical modeling to compare these signaling mechanisms in terms of their dose-response curves, response times, and abilities to process upstream fluctuations. Our analysis elucidates several general principles. First, activation increases the sensitivity of the pathway, whereas derepression decreases sensitivity. Second, activation generates response times that decrease with signal strength, whereas derepression causes response times to increase with signal strength. These opposing features allow the concerted mechanism to not only show dose-response alignment, but also to decouple the response time from stimulus strength. However, these potentially beneficial properties come at the expense of increased susceptibility to up-stream fluctuations. In addition to above response metrics, we also examine the effect of receptor removal on switches governed by activation and derepression. We find that if inactive (active) receptors are preferentially removed then activation (derepression) exhibits a sustained response whereas derepression (activation) adapts. In total, we show how the architecture of molecular switches govern their response properties. We also discuss the biological implications of our findings.
Molecular diversity of glutamatergic and GABAergic synapses from multiplexed fluorescence imaging
Authors: Danielson Eric , de Arce Karen Perez , Cimini Beth , Wamhoff Eike-Christian , Singh Shantanu , Cottrell Jeffrey R , Carpenter Anne E. , Bathe Mark
Published: June 2020

Neuronal synapses contain hundreds of different protein species important for regulating signal transmission. Characterizing differential expression profiles of proteins within synapses in distinct regions of the brain has revealed a high degree of synaptic diversity defined by unique molecular organization. Multiplexed imaging ofin vitroneuronal culture models at single synapse resolution offers new opportunities for exploring synaptic reorganization in response to chemical and genetic perturbations. Here, we combine 12-color multiplexed fluorescence imaging with quantitative image analysis and machine learning to identify novel synaptic subtypes within excitatory and inhibitory synapses based on the expression profiles of major synaptic components. We characterize differences in the correlated expression of proteins within these subtypes and we examine how the distribution of these synapses is modified following induction of synaptic plasticity. Under chronic suppression of neuronal activity, phenotypic characterization revealed coordinated increases in both excitatory and inhibitory protein levels without changes in the distribution of synaptic subtypes, suggesting concerted events targeting glutamatergic and GABAergic synapses. Our results offer molecular insight into the mechanisms of synaptic plasticity.
Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity
Authors: Miller Jessica M. , Meki Moustafa H. , Ou Qinghui , George Sharon A. , Gams Anna , Abouleisa Riham R. E. , Tang Xian-Liang , Ahern Brooke M. , Giridharan Guruprasad A. , El-Baz Ayman , Hill Bradford G. , Satin Jonathan , Conklin Daniel J. , Moslehi Javid , Bolli Roberto , Ribeiro Alexandre J. S. , Efimov Igor R. , Mohamed Tamer M. A.
Published: June 2020

The limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity and understanding mechanism. Recently, we developed a functional human and pig heart slice biomimetic culture system that fully preserves the viability and functionality of 300 µm heart slices for 6 days. Here, we tested the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) associated with different mechanisms leading to cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and transcriptome. Slices incubated with any of these drugs for 48 h showed significant loss in viability, cardiomyocyte structure and functionality. Mechanistically, RNA sequencing demonstrated a significant downregulation of cardiac genes and upregulation of oxidative response in doxorubicin-treated tissues. Trastuzumab treatment caused major downregulation in cardiac muscle contraction-related genes, consistent with its clinically known direct effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes in line with its mechanism of action. Heart slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes; they are superior in detecting sunitinib cardiotoxicity phenotypes and mechanism in the clinically relevant concentration range, 100 nM – 1 µM. These results indicate that heart slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanism of action.
Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation
Authors: Vásquez-Trincado César , Patel Monika , Sivaramakrishnan Aishwarya , Bekeová Carmen , Anderson-Pullinger Lauren , Wang Nadan , Tang Hsin-Yao , Seifert Erin L.
Published: June 2020

Friedreich’s ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron-sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood, though are expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at FXN levels < 20% of normal, without heart failure. We investigated substrate-specific bioenergetics and nutrient and stress signaling in the heart, to evaluate how this model responds to FXN depletion. After > 8 weeks with FXN levels < 20% of normal, TG hearts did not display overt hypertrophy and were in fact smaller; global protein translation was lower, while protein degradative pathways were unaltered. Cardiac contractility was maintained, likely due to preserved β-oxidation, though oxidative phosphorylation capacity for pyruvate was lower. Bioenergetics alterations matched mitochondrial proteomics changes, including a non-uniform decrease in abundance of ISC-containing proteins. In parallel, both mTORC1 signaling and the integrated stress response (ISR) were activated. The lack of overt cardiac hypertrophy, consistent with lower global protein translation, suggests that ISR predominated over mTORC1 activation. Suppression of a major ATP demanding process could benefit the FXN-depleted heart, at least short term. Thus, the FXN-depleted heart may enter a protective state, not necessarily linked to a major energy deficit. Finally, we propose the model used here as a pre-clinical model of cardiomyopathy in FRDA.
Prediction of non-canonical routes for SARS-CoV-2 infection in human placenta cells
Authors: Constantino F. B. , Cury S. S. , Nogueira C. R. , Carvalho R. F. , Justulin L. A.
Published: June 2020

The SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The data available about COVID-19 during pregnancy have demonstrated placental infection; however, the intrauterine transmission of SARS-CoV-2 is still debated. Intriguingly, while canonical SARS-CoV-2 cell entry mediators are expressed at low levels in placental cells, the receptors for viruses that cause congenital infections such as the cytomegalovirus and Zika virus are highly expressed in these cells. Here we analyzed the transcriptional profile (microarray and single-cell RNA-Seq) of proteins potentially interacting with coronaviruses to identify non-canonical mediators of SARS-CoV-2 infection and replication in the placenta. We show that, despite low levels of the canonical cell entry mediatorsACE2andTMPRSS2, cells of the syncytiotrophoblast, villous cytotrophoblast, and extravillous trophoblast co-express high levels of the potential non-canonical cell-entry mediatorsDPP4andCTSL. We also found changes in the expression ofDAAM1andPAICSgenes during pregnancy, which are translated into proteins also predicted to interact with coronaviruses proteins. These results provide new insight into the interaction between SARS-CoV-2 and host proteins that may act as non-canonical routes for SARS-CoV-2 infection and replication in the placenta cells.
Autoencoder based local T cell repertoire density can be used to classify samples and T cell receptors
Authors: Dvorkin Shirit , Levi Reut , Louzoun Yoram
Published: June 2020

Recent advances in T cell repertoire (TCR) sequencing allow for characterization of repertoire properties, as well as the frequency and sharing of specific TCR. However, there is no efficient measure for the local density of a given TCR. TCRs are often described either through their Complementary Determining region 3 (CDR3) sequences, or theirV/J usage or their clone size. We here show that the local repertoire density can be estimated using a combined representation of these components through distance conserving autoencoders and Kernel Density Estimates (KDE).

We present ELATE – an Encoder based LocAl Tcr dEnsity and show that the resulting density of a sample can be used as a novel measure to study repertoire properties. The cross-density between two samples can be used as a similarity matrix to fully characterize samples from the same host. Finally, the same projection in combination with machine learning algorithms can be used to predict TCR-peptide binding through the local density of known TCRs binding a specific target.

Code availability-https://github.com/louzounlab/Autoencoder
Application of Good Agricultural Practices (GAP) by the Banana Farmers of Chitwan, Nepal
Authors: Joshi Arati , Kalauni Dharmendra , Tiwari Ujjal
Published: June 2020

The study was conducted to identify the cultivation practices followed by the banana growers and compares it with the framework of Good Agricultural Practices as recommended by the World Banana Forum. Both qualitative and quantitative approach was used for data collection. The scheduled interview was carried out from 103 banana growers, two focused group discussion was carried out with the banana growers, and two key informant interview was carried out; one with the President of Banana Growers Association, Chitwan and another with Executive Director of Chamber of Commerce and Industry, Chitwan. The findings revealed that GAP related to soil management and fertilization (87.4%) and harvesting and on-farm processing (94.2%) is adopted at a low level. Only 36% of farmers apply an appropriate dose of chemical fertilizer, 28% follow crop rotation and 7.8% perform mulching/ intercropping. About 38% of the respondents do not have any source of irrigation. About 98% of the farmers do not perform any processing, cleaning, storing, and packaging of banana. Further, 55% of farmers do not use appropriate personal protective equipment while applying pesticides. The results showed that there is low awareness regarding GAP among the banana farmers in the Chitwan district. Therefore, the conduction of awareness programs and training related to GAP is recommended. By far, no study has been carried out to analyze the good agricultural practices applied by banana growers in Nepal. This study identified the prevailing gap in farmer’s practices and good agricultural practices.
A systematic review of European farmer and non-farmer attitudes towards landscapes, ecosystem services, and agricultural management practices: Implications for permanent grassland management
Authors: Tindale Sophie J. , Elliott John , Elings Marjolein , Gallardo-Cobos Rosa , Hunter Erik , Lieberherr Eva , Miškolci Simona , Price Paul Newell , Quatrini Simone , Sánchez-Zamora Pedro , Schlueter Hannah , Frewer Lynn J.
Published: June 2020

Permanent grassland (PG) is an important agricultural land use for the delivery of multiple ecosystem services (ES), including carbon sequestration, water quality protection, food production, habitat provision, and cultural activities. However, PG environments are threatened by sub-optimal management, cultivation, and abandonment that are influenced by context, land manager’s attitudes and societal demand for ES. Therefore, the perceptions and attitudes of key decision-makers (farmers) and other stakeholders (non-farmers, including citizens and consumers of the products of permanent grasslands, and ES) need to be understood to ensure the sustainability of PGs and the ES they provide. A systematic review of the literature identified 135 scholarly articles. Application of thematic analysis, allowed the organization, and synthesis of current research related to (different) stakeholder attitudes, and how these influence PG management and the delivery of ES. The results suggest that different stakeholders hold different views towards permanent grassland, with farmers in particular having to balance economic with other (potentially conflicting) drivers. The types of knowledge held by different groups of stakeholders, access to sources of information, as well as the influence of knowledge on behaviour; and environmental values (for example in relation to aesthetics or conservation of biodiversity) explained why certain motivations for attitudes and behaviours are held. A major gap, however, was identified in relation to PG as opposed to other types of landscape.
Microtubules regulate pancreatic beta cell heterogeneity via spatiotemporal control of insulin secretion hot spots
Authors: Trogden Kathryn P. , McKinney Hudson , Zhu Xiaodong , Arpag Goker , Folland Thomas G. , Osipovich Anna B. , Magnuson Mark A , Zanic Marija , Gu Guoqiang , Holmes William R. , Kaverina Irina
Published: June 2020

Heterogeneity of glucose-stimulated insulin secretion (GSIS) in pancreatic islets is physiologically important but poorly understood. Here, we utilize whole mouse islets to determine how microtubules affect secretion toward the vascular extracellular matrix. Our data indicate that microtubule stability in the β-cell population is heterogenous, and that cells with more stable microtubules secrete less in response to a stimulus. Consistently, microtubule hyper-stabilization prevents, and microtubule depolymerization promotes β-cell activation. Analysis of spatiotemporal patterns of secretion events shows that microtubule depolymerization activates otherwise dormant β-cells via initiation of secretion clusters (hot spots). Microtubule depolymerization also enhances secretion from individual cells, introducing both additional clusters and scattered events. Interestingly, without microtubules, the timing of clustered secretion is dysregulated, extending the first phase of GSIS. Our findings uncover a novel microtubule function in tuning insulin secretion hot spots, which leads to accurately measured and timed response to glucose stimuli and promotes functional β-cell heterogeneity.
The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity
Authors: Zhang Lizhou , Jackson Cody B , Mou Huihui , Ojha Amrita , Rangarajan Erumbi S , Izard Tina , Farzan Michael , Choe Hyeryun
Published: June 2020

SARS coronavirus 2 (SARS-CoV-2) isolates encoding a D614G mutation in the viral spike (S) protein predominate over time in locales where it is found, implying that this change enhances viral transmission. We therefore compared the functional properties of the S proteins with aspartic acid (SD614) and glycine (SG614) at residue 614. We observed that retroviruses pseudotyped with SG614infected ACE2-expressing cells markedly more efficiently than those with SD614. This greater infectivity was correlated with less S1 shedding and greater incorporation of the S protein into the pseudovirion. Similar results were obtained using the virus-like particles produced with SARS-CoV-2 M, N, E, and S proteins. However, SG614did not bind ACE2 more efficiently than SD614, and the pseudoviruses containing these S proteins were neutralized with comparable efficiencies by convalescent plasma. These results show SG614is more stable than SD614, consistent with epidemiological data suggesting that viruses with SG614transmit more efficiently.
APP binds to the EGFR ligands HB-EGF and EGF, acting synergistically with EGF to promote ERK signaling and neuritogenesis
Authors: da Rocha Joana F. , Bastos Luísa , Domingues Sara C. , Bento Ana R. , Konietzko Uwe , da Cruz e Silva Odete A. B. , Vieira Sandra I.
Published: June 2020

The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer’s disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are well described neurotrophic and neuromodulator EGFR ligands, both implicated in neurological disorders like Schizophrenia and AD. Here we show that APP interacts with these two EGFR ligands and characterize the effects of APP-EGF interaction in ERK activation and neuritogenesis. HB-EGF was identified as a novel APP interactor in a yeast two-hybrid screen of a human brain cDNA library. Yeast co-transformation and co-immunoprecipitation assays confirmed APP interaction with HB-EGF. Moreover, co-immunoprecipitation also revealed that APP binds to cellular pro-EGF. Overexpression of HB-EGF in HeLa cells, or exposure of SH-SY5Y cells to EGF, both resulted in increased APP protein levels. EGF and APP were also observed to synergistically activate the ERK signaling pathway, crucial for early neuronal differentiation. Immunofluorescence analysis of cellular neuritogenesis in conditions of APP overexpression and EGF exposure, confirmed a synergistic effect in promoting the number and the mean length of neurite-like processes per cell. Synergistic ERK activation and neuritogenic effects were completely blocked by the EGFR inhibitor PD 168393, implying EGF-induced activation of EGFR as part of the mechanism. This work shows novel APP protein interactors and provides a major insight into the APP-driven mechanisms underlying neurite outgrowth and neuronal differentiation, with potential relevance for AD and for adult neuroregeneration.
Spatiotemporal Dynamics of Sound Representations reveal a Hierarchical Progression of Category Selectivity
Authors: Lowe Matthew X. , Mohsenzadeh Yalda , Lahner Benjamin , Charest Ian , Oliva Aude , Teng Santani
Published: June 2020

As the human brain transforms incoming sounds, it remains unclear whether semantic meaning is assigned via distributed, domain-general architectures or specialized hierarchical streams. Here we show that the spatiotemporal progression from acoustic to semantically dominated representations is consistent with a hierarchical processing scheme. Combining magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) patterns, we found superior temporal responses beginning ~80 ms post-stimulus onset, spreading to extratemporal cortices by ~130 ms. Early acoustically-dominated representations trended systematically toward semantic category dominance over time (after ~200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: vocalizations were preferentially distinguished in temporal and frontal voice-selective regions and the fusiform face area; scene and object sounds were distinguished in parahippocampal and medial place areas. Our results are consistent with an extended auditory processing hierarchy in which acoustic representations give rise to multiple streams specialized by category, including areas typically considered visual cortex.
Temporal clinical and laboratory response to interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia
Authors: Fomina Daria S. , Lysenko Mar’yana A. , Beloglazova Irina P. , Mutovina Zinaida Yu. , Poteshkina Nataliya G. , Samsonova Inna V. , Kruglova Tat’yana S. , Chernov Anton A. , Karaulov Alexander V. , Lederman Michael M.
Published: June 2020

Background

Emerging evidence links morbidity and mortality of pandemic COVID-19 pneumonia to an inflammatory cytokine storm.

Methods

Eighty nine patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) were treated with Tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor.

Results

Clinical and laboratory improvement was seen comparing baseline and 1-2 day post-infusion indices. Among 72 patients not receiving mechanical ventilation, NEWS2 scores fell from 5 to 2 (p < 0.001) C reactive protein levels fell from 95 to 14 mg/L (p < 0.001) and lymphocyte counts rose from 900 to 1000/uL (p = 0.036). Sixty three of 72 patients were discharged from hospital, one patient died, and 8 remained in hospital at time of writing. Among 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (p = 0.014) and early improvements in NEWS2 scores in 10 of 17, ten patients died and seven remain in hospital at time of writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (< 1000/uL) before TCZ administration.

Conclusions

Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of Tocilizumab, an anti IL-6 receptor antibody is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.
Numerical and experimental study of the laminar separation bubble over SS007 airfoil for micro aerial vehicles
Authors: V. Somashekar , A. Immanuel Selwyn Raj
Published: June 2020

Purpose

This paper aims to deal with the numerical investigation of laminar separation bubble (LSB) characteristics (length and height of the bubble) of SS007 airfoil at the chord Reynolds number of Rec = 0.68 × 105 to 10.28 × 105.

Design/methodology/approach

The numerical simulations of the flow around SS007 airfoil were carried out by using the commercial fluid dynamics (CFD) software, ANalysis system (ANSYS) 15. To solve the governing equations of the flow, a cell-centred control volume space discretisation approach is used. Wind tunnel experiments were conducted at the chord-based Reynolds number of Rec = 1.6 × 105 to validate the aerodynamic characteristics over SS007 airfoil.

Findings

The numerical results revealed that the LSB characteristics of a SS007 airfoil, and the aerodynamic performances are validated with experimental results. The lift and drag coefficients for both numerical and experimental results show very good correlation at Reynolds number 1.6 × 105. The lift coefficient linearly increases with the increasing angle of attack (AOA) is relatively small. The corresponding drag coefficient was found to be very small. After the formation of LSB which leads to burst to cause airfoil stall, the lift coefficient decreases and increases the drag coefficient.

Practical implications

Low Reynolds number and LSB characteristics concept in aerodynamics is predominant for both civilian and military applications. These include high altitude devices, wind turbines, human powered vehicles, remotely piloted vehicles, sailplanes, unmanned aerial vehicle and micro aerial vehicle. In this paper, the micro aerial vehicle flight conditions considered and investigated the LSB characteristics for different Reynolds number. To have better aerodynamic performances, it is strongly recommended to micro aerial vehicle (MAV) design engineers that the MAV is to fly at 12 m/s (cruise speed).

Social implications

MAVs and unmanned aerial vehicles seem to give some of the technical challenges of nature conservation monitoring and law enforcement a versatile, reliable and inexpensive solution.

Originality/value

The SS007 airfoil delays the flow separation and improves the aerodynamic efficiency by increasing the lift and decreasing the drag. The maximum increase in aerodynamic efficiency is 12.5% at stall angle of attack compared to the reference airfoil at Re = 2 × 105. The results are encouraging and this airfoil could have better aerodynamic performance for the development of MAV.
The revitalization of service orientation: a business services model
Authors: Plugge Albert , Nikou Shahrokh , Bouwman Harry
Published: June 2020

Purpose

Due to the convergence of rapid business developments and digitization challenges, service orientation is back on the research agenda as a concept to improve firms’ business services. Yet, little is known about the type of determinants that are relevant and to what degree they affect a firm’s service-oriented strategy.

Design/methodology/approach

Building on structural equation modeling (SEM) and a unique data set of 131 international firms from different continents, the authors identify and analyze the key determinants in the context of a firm’s service-oriented strategy.

Findings

The findings show that in order to cater for changes, organizations have to manage and adapt the coherence of the determinants’ business services, business processes and knowledge sharing continuously. Moreover, the results show that a service-oriented strategy is not only influenced by business services as such, but business services mediate the relationships between business processes, governance and process-aware information systems to a service-oriented strategy.

Research limitations/implications

A limitation is imposed by the limited sample size and the unbalanced response of participants (executive management). In future research, a more extensive survey among a broader group of participants will help the authors to develop their model further in order to generalize the results, as well as more finely grained research related to geography and size might be pursued. Future empirical research is necessary to identify and test the relationships between other constructs and study their effect on a firm’s service-oriented strategy.

Practical implications

On a practical level, the authors postulate that an organization’s executive management should pay attention to invest in an organizational entity (department) that manages business services continuously. This organizational entity has to ensure that related processes and knowledge sharing are in place to establish and maintain a service-oriented strategy.

Originality/value

This research contributes to service-oriented literature by operationalizing the implementation of an organization’s service-oriented strategy. The authors’ insights go beyond the findings of Aier et al. (2011). The authors found that a service-oriented strategy influences service-oriented project success positively. The authors extended these findings, based on a unique data set, by studying business services and influencing determinants (i.e. business processes, governance, PAIS and knowledge sharing) within the context of service orientation. The renewed attention to the concept of service orientation provides insights into critical determinants that influence the implementation of a service-oriented strategy.
New cubic B-spline approximation technique for numerical solutions of coupled viscous Burgers equations
Authors: Nazir Tahir , Abbas Muhammad , Iqbal Muhammad Kashif
Published: June 2020

Purpose

The purpose of this paper is to present a new cubic B-spline (CBS) approximation technique for the numerical treatment of coupled viscous Burgers’ equations arising in the study of fluid dynamics, continuous stochastic processes, acoustic transmissions and aerofoil flow theory.

Design/methodology/approach

The system of partial differential equations is discretized in time direction using the finite difference formulation, and the new CBS approximations have been used to interpolate the solution curves in the spatial direction. The theoretical estimation of stability and uniform convergence of the proposed numerical algorithm has been derived rigorously.

Findings

A different scheme based on the new approximation in CBS functions is proposed which is quite different from the existing methods developed (Mittal and Jiwari, 2012; Mittal and Arora, 2011; Mittal and Tripathi, 2014; Raslan et al., 2017; Shallal et al., 2019). Some numerical examples are presented to validate the performance and accuracy of the proposed technique. The simulation results have guaranteed the superior performance of the presented algorithm over the existing numerical techniques on approximate solutions of coupled viscous Burgers’ equations.

Originality/value

The current approach based on new CBS approximations is novel for the numerical study of coupled Burgers’ equations, and as far as we are aware, it has never been used for this purpose before.
Compensating employees in micro-sized social enterprises with innovative HR practices
Authors: Black Nicholas David
Published: June 2020

Purpose

The purpose of this paper is to understand how micro-sized social enterprises can compensate their employees equitably, despite encountering resource scarcity and prioritising their social mission.

Design/methodology/approach

The researcher interviewed the founders of micro-sized social enterprises from around the East Midlands and asked about the innovative human resource (HR) practices they used to compensate their employees. The eight interviews were semi-structured, in-depth and analysed thematically.

Findings

The findings and discussion demonstrate that the founders recognised the importance of compensating their employees equitably, but also acknowledged how paying them according to their contribution conflicted with prioritising their social mission as they never had sufficient resources to do everything. Alternatively, these founders used innovative HR practices to establish transactional relations, which primarily consisted of training, experience and references. This was perceived as equitable, despite paying their employees less than their contribution merited, as it allowed them to improve their future career prospects. These HR practices also benefitted these micro-social enterprises by increasing their human capital without increasing their costs.

Originality/value

The paper could be beneficial for academics and practitioners as it explores how the characteristics associated with being a micro-sized social enterprise impacted their HR practices.
Digital transformation in entrepreneurship education centres: preliminary evidence from the Italian Contamination Labs network
Authors: Secundo Giustina , Rippa Pierluigi , Meoli Michele
Published: June 2020

Purpose

This paper analyses whether the entrepreneurship education centres introduced by the Italian Ministry of Higher Education and Research in 2012 (the Italian Contamination Labs – CLabs) are effectively adopting the emergent digital technologies for nurturing their entrepreneurship education activities and dissemination of knowledge contamination practices among university students.

Design/methodology/approach

An in-depth analysis of italian entrepreneurship education centres provides evidence about the direct role played by digital technologies in supporting and enhancing the entrepreneurial processes, as well as on their indirect role in stimulating entrepreneurship activities of nascent student entrepreneurs.

Findings

Findings provide some insights into the strategic role of some categories of digital technologies inside the CLabs. The main results show still a weak use of digital technologies in CLabs except for social media and digital platforms, mainly used for promotion scope and communication of the entrepreneurial outputs achieved by the students.

Research limitations/implications

Limitations of the study consist of the need to expand the study to all the other CLabs belonging to the CLabs Italian Network and to derive a set of “invariance” among the cases in terms of digital technologies support for student entrepreneurship.

Practical implications

New ways of managing entrepreneurship centres will involve a more massive adoption of digital technologies to support and transform some processes realized inside the CLabs, even if the governance of such centres must develop new digital skills.

Originality/value

The originality of the work regards the contribution to the emerging role of digital technologies on the student's entrepreneurship.
A tool to assess the quality perception of healthcare employees
Authors: Kamalasanan Ajayan , Sathiyamurthi Gurumoorthy , Subbarayalu Arun Vijay
Published: June 2020

Purpose

The purpose of this project was to determine the validity and reliability of the Healthcare Quality Perception (HQP) questionnaire tool designed to capture employees' perceptions of healthcare quality in Indian hospitals.

Design/methodology/approach

Two hundred employees in private and public sector hospitals in India were randomly selected and given the HQP tool. It consisted of 38 Likert-scale items and six different subscales: (1) Planning and Documentation (n = 7); (2) Employee Participation in Quality Management Activities (n = 5); (3) Existence of Policies/Procedures/Guidelines (n = 5); (4) Quality and Patient Safety Management (n = 9); (5) Perceived Effect of Quality Improvement (n = 7) and (6) Training and Development Opportunities (n = 5). 156 completed questionnaires were received, demonstrating a 78% response rate. HQP tool subjected to statistical analysis to measure its reliability and validity. A p-value of less than 0.05 was considered as “significant.”

Findings

Factor analysis pulled out six factors that conjointly demonstrated 66.4 % of the variance in healthcare professionals' (HCPs') perception of healthcare service quality in selected Indian hospitals. The overall Cronbach's alpha coefficient was measured at 0.959 for internal consistency reliability. This study demonstrates that the identified six critical factors are important determinants influencing HCPs' perception of the quality of healthcare services in private and public sector hospitals in India.

Originality/value

This study provides evidence for the reliability and validity of the newly developed HCP Scale for the assessment of employee perception of the quality of services offered in selected hospitals in India, with potential applications in other contexts.