bluuebunny/crossref_metadata_2025_split huggingface dataset:
Projections and fractional dynamics of COVID-19 with optimal control analysis
Authors: Nabi Khondoker Nazmoon , Kumar Pushpendra , Erturk Vedat Suat 
Published: November 2020

AbstractWhen the entire world is eagerly waiting for a safe, effective and widely available COVID-19 vaccine, un-precedented spikes of new cases are evident in numerous countries. To gain a deeper understanding about the future dynamics of COVID-19, a compartmental mathematical model has been proposed in this paper incorporating all possible non-pharmaceutical intervention policies. Model parameters have been calibrated using sophisticated trust-region-reflective algorithm and short-term projection results have been illustrated for Argentina, Bangladesh, Brazil, Colombia and India. Control reproduction numbers (ℛc) have been calculated in order to get insights about the current epidemic scenario in the above-mentioned countries. Forecasting results depict that the aforesaid countries are having downward trends in daily COVID-19 cases. However, it is highly recommended to use efficacious face coverings and maintain strict physical distancing, as the pandemic is not over in any country. Global sensitivity analysis enlightens the fact that efficacy of face coverings is the most significant parameter, which could significantly control the transmission dynamics of the novel coronavirus compared to other non-pharmaceutical measures. In addition, reduction in effective contact rate with isolated patients is also essential in bringing down the epidemic threshold (ℛc) below unity. All necessary graphical simulations have been performed with the help of Caputo-Fabrizio fractional derivatives. In addition, optimal control problem for fractional system has been designed and the existence of unique solution has also been showed by using Picard-Lindelof technique. Finally, the unconditionally stability of the given fractional numerical technique has been proved.
High content Image Analysis to study phenotypic heterogeneity in endothelial cell monolayers
Authors: Chesnais Francois , Hue Jonas , Roy Errin , Branco Marco , Stokes Ruby , Pellon Aize , Le Caillec Juliette , Elbahtety Eyad , Battilocchi Matteo , Danovi Davide , Veschini Lorenzo 
Published: November 2020

AbstractEndothelial cells (EC) are heterogeneous across and within tissues, reflecting distinct, specialised functions. EC heterogeneity has been proposed to underpin EC plasticity independently from vessel microenvironments. However, heterogeneity driven by contact-dependent or short-range cell-cell crosstalk cannot be evaluated with single cell transcriptomic approaches as spatial and contextual information is lost. Nonetheless, quantification of EC heterogeneity and understanding of its molecular drivers is key to developing novel therapeutics for cancer, cardiovascular diseases and for revascularisation in regenerative medicine.Here, we developed an EC profiling tool (ECPT) to examine individual cells within intact monolayers. We used ECPT to characterise different phenotypes in arterial, venous and microvascular EC populations. In line with other studies, we measured heterogeneity in terms of cell cycle, proliferation, and junction organisation. ECPT uncovered a previously under-appreciated single-cell heterogeneity in NOTCH activation. We correlated cell proliferation with different NOTCH activation states at the single cell and population levels. The positional and relational information extracted with our novel approach is key to elucidating the molecular mechanisms underpinning EC heterogeneity.Summary statementEndothelial cells heterogeneity is key to complex collective functions and cell behaviour. We developed a novel image based endothelial cell profiling tool and quantified heterogeneity in NOTCH signalling in monolayers.
Immunogenicity and protective efficacy of one- and two-dose regimens of the Ad26.COV2.S COVID-19 vaccine candidate in adult and aged rhesus macaques
Authors: Solforosi Laura , Kuipers Harmjan , Huber Sietske K. Rosendahl , van der Lubbe Joan E.M. , Dekking Liesbeth , Czapska-Casey Dominika N. , Gil Ana Izquierdo , Baert Miranda R.M. , Drijver Joke , Vaneman Joost , van Huizen Ella , Choi Ying , Vreugdenhil Jessica , Kroos Sanne , de Wilde Adriaan H. , Kourkouta Eleni , Custers Jerome , Dalebout Tim J. , Myeni Sebenzile K. , Kikkert Marjolein , Snijder Eric J. , Barouch Dan H. , Böszörményi Kinga P. , Stammes Marieke A. , Kondova Ivanela , Verschoor Ernst J. , Verstrepen Babs E. , Koopman Gerrit , Mooij Petra , Bogers Willy M.J.M. , van Heerden Marjolein , Muchene Leacky , Tolboom Jeroen T.B.M. , Roozendaal Ramon , Schuitemaker Hanneke , Wegmann Frank , Zahn Roland C. 
Published: November 2020

AbstractSafe and effective coronavirus disease (COVID)-19 vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged non-human primates (NHP). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared to a single dose. In one-dose regimens neutralizing antibody responses were stable for at least 14 weeks, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and Th1 skewed cellular responses in aged NHP that were comparable to adult animals. Importantly, aged Ad26.COV2.S-vaccinated animals challenged 3 months post -dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. These are the first NHP data showing COVID-19 vaccine protection against the SARS-CoV-2 spike G614 variant and support ongoing clinical Ad26.COV2.S development.SummaryCOVID-19 vaccines are urgently needed and while single-dose vaccines are preferred, two-dose regimens may improve efficacy. We show improved Ad26.COV2.S immunogenicity in non-human primates after a second vaccine dose, while both regimens protected aged animals against SARS-CoV-2 disease.
USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma
Authors: Ruiz E. Josue , Pinto-Fernandez Adan , Turnbull Andrew P. , Lan Linxiang , Charlton Thomas M. , Scott Hannah Claire , Damianou Andreas , Vere George , Riising Eva M. , Da Costa Clive , Krajewski Wojciech W. , Guerin David , Kearns Jeffrey , Ioannidis Stephanos , Katz Marie , McKinnon Crystal , O’Connell Jonathan C. , Moncaut Natalia , Rosewell Ian , Nye Emma , Jones Neil , Heride Claire , Gersch Malte , Wu Min , Dinsmore Christopher J. , Hammonds Tim R. , Kim Sunkyu , Komander David , Urbé Sylvie , Clague Michael J. , Kessler Benedikt M. , Behrens Axel 
Published: November 2020

AbstractLung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoprotein c-MYC. Here, we show that genetic inactivation ofUsp28induced regression of established murine LSCC lung tumors. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-Myc proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.
Development of a mass-spectrometry based method for the identification of thein vivowhole blood and plasma ADP-ribosylomes
Authors: Lüthi Stephanie C. , Howald Anna , Nowak Kathrin , Graage Robert , Bartolomei Giody , Neupert Christine , Sidler Xaver , Pedrioli Deena M. Leslie , Hottiger Michael O. 
Published: November 2020

ABSTRACTBlood and plasma proteins are heavily investigated as biomarkers for different diseases. However, the post-translational modification states of these proteins are rarely analyzed since blood contains many enzymes that rapidly remove these modification after sampling. In contrast to the well-described role of protein ADP-ribosylation in cells and organs, its role in blood remains mostly uncharacterized. Here, we discovered that plasma phosphodiesterases and/or ADP-ribosylhydrolases rapidly demodify in vitro ADP-ribosylated proteins. Thus, to identify the in vivo whole blood and plasma ADP-ribosylomes, we established a novel mass-spectrometry based workflow that was applied to blood samples collected from LPS-treated pigs (Sus scrofa), which serves as a model for human systemic inflammatory response syndrome. These analyses identified 60 ADP-ribosylated proteins, 17 of which were ADP-ribosylated plasma proteins. This new protocol provides an important step forward for the rapidly developing field of ADP-ribosylation and defines the blood and plasma ADP-ribosylomes under both healthy and disease conditions.
Shifting gradients of macroscale cortical organization mark the transition from childhood to adolescence
Authors: Dong Hao-Ming , Margulies Daniel S. , Zuo Xi-Nian , Holmes Avram J. 
Published: November 2020

AbstractThe transition from childhood to adolescence is marked by pronounced shifts in brain structure and function that coincide with the development of physical, cognitive, and social abilities. Prior work in adult populations has characterized the topographical organization of cortex, revealing macroscale functional gradients that extend from unimodal (somato/motor and visual) regions through the cortical association areas that underpin complex cognition in humans. However, the presence of these core functional gradients across development as well as their maturational course have yet to be established. Here, leveraging 378 resting-state fMRI scans from 190 healthy individuals aged 6-17 years, we demonstrate that the transition from childhood to adolescence is reflected in the gradual maturation of gradient patterns across the cortical sheet. In children, the overarching organizational gradient is anchored within unimodal cortex, between somato/motor and visual territories. Conversely, in adolescence the principal gradient of connectivity transitions into an adult-like spatial framework, with the default network at the opposite end of a spectrum from primary sensory and motor regions. The observed gradient transitions are gradually refined with age, reaching a sharp inflection point in 13- and 14-year-olds. Functional maturation was nonuniformly distributed across cortical networks. Unimodal networks reached their mature positions early in development, while association regions, in particular medial prefrontal cortex, reached a later peak during adolescence. These data reveal age-dependent changes in the macroscale organization of cortex and suggest the scheduled maturation of functional gradient patterns may be critically important for understanding how cognitive and behavioral capabilities are refined across development.SignificanceHuman abilities and behavior change dramatically across development, emerging from a cascade of hierarchical changes in brain circuitry. Here, we describe age-dependent shifts in the macroscale functional organization of cortex in childhood and adolescence. The characterization of functional connectivity patterns in children revealed an overarching organizational framework anchored within unimodal cortex, between somato/motor and visual regions. Conversely, in adolescents we observed a transition into an adult-like gradient that situates the default network at the opposite end of a spectrum from primary sensory and motor regions. This spatial framework emerged gradually with age, reaching a sharp inflection point at the transition from childhood to adolescence. These data reveal the presence of a developmental change from a functional motif first dominated by the distinction between sensory and motor systems, and then balanced through interactions with later-maturing aspects of association cortex that support more abstract cognitive functions.
Multiplexed single-cell profiling of chromatin states at genomic loci by expansion microscopy
Authors: Woodworth Marcus A. , Ng Kenneth K.H. , Halpern Aaron R. , Pease Nicholas A. , Nguyen Phuc H.B. , Kueh Hao Yuan , Vaughan Joshua C. 
Published: November 2020

AbstractProper regulation of genome architecture and activity is essential for the development and function of multicellular organisms. Histone modifications, acting in combination, specify these activity states at individual genomic loci. However, the methods used to study these modifications often require either a large number of cells or are limited to targeting one histone mark at a time. Here, we developed a new method called Single Cell Evaluation of Post-TRanslational Epigenetic Encoding (SCEPTRE) that uses Expansion Microscopy (ExM) to visualize and quantify multiple histone modifications at non-repetitive genomic regions in single cells at a spatial resolution of ~75 nm. Using SCEPTRE, we distinguished multiple histone modifications at a single housekeeping gene, quantified histone modification levels at multiple developmentally-regulated genes in individual cells, and identified a relationship between histone H3K4 trimethylation and the loading of paused RNA polymerase II at individual loci. Thus, SCEPTRE enables multiplexed detection of combinatorial chromatin states at single genomic loci in single cells.
Neuroglian regulatesDrosophilaintestinal stem cell proliferation through enhanced signaling via the Epidermal Growth Factor Receptor
Authors: Resnik-Docampo Martin , Cunningham Kathleen M. , Ruvalcaba S. Mateo , Choi Charles , Sauer Vivien , Jones D. Leanne 
Published: November 2020

SummaryTheDrosophila melanogasterintestine is an excellent system for elucidating mechanisms regulating stem cell behavior under homeostatic conditions or in response to injury, stress, or ageing. Here we show that the septate junction (SJ) protein Neuroglian (Nrg) is expressed in intestinal stem cells (ISCs) and daughter enteroblasts (EBs) within the fly midgut, the equivalent of the mammalian small intestine. Although Nrg localizes to the plasma membrane, SJs are not present between ISC/EBs, suggesting Nrg plays a different role in this tissue. Generation of ISCs homozygous for a null allele ofNrgrevealed that Nrg is required for ISC proliferation in young flies, and depletion of Nrg from ISCs/EBs was able to suppress the increase in ISC proliferation with age. Conversely, overexpression ofNrgin ISC/EBs was sufficient to drive ISC proliferation, leading to an increase in cells expressing ISC/EB markers. In addition, we observed an increase in EGFR activation. Genetic epistasis experiments revealed that Nrg acts upstream of EGFR in the midgut to regulate ISC proliferation. As Nrg function is highly conserved in mammalian systems, our work characterizing the role of Nrg in the intestine has implications for the etiology and treatment of intestinal disorders due to altered ISC behavior.
The RAS GTPase RIT1 compromises mitotic fidelity through spindle assembly checkpoint suppression
Authors: Cuevas-Navarro Antonio , Van Richard , Cheng Alice , Urisman Anatoly , Castel Pau , McCormick Frank 
Published: November 2020

SUMMARYThe spindle assembly checkpoint (SAC) is an evolutionarily conserved safety mechanism that maintains genomic stability. However, despite the understanding of the fundamental mechanisms that control the SAC, it remains unknown how signaling pathways directly interact with and regulate the mitotic checkpoint activity. In response to extracellular stimuli, a diverse network of signaling pathways involved in cell growth, survival, and differentiation are activated and this process is prominently regulated by the Ras family of GTPases. Here we show that RIT1, a Ras-related GTPase, is essential for timely progression through mitosis and proper chromosome segregation. Furthermore, pathogenic levels of RIT1 silence the SAC, accelerate transit through mitosis, and promote chromosome segregation errors through direct association with SAC proteins MAD2 and p31comet. Our results highlight a unique function of RIT1 compared to other Ras GTPases and elucidate a direct link between a signaling pathway and the SAC through a novel regulatory mechanism.Graphical Abstract
Random Forest Regression models for Lactation and Successful Insemination in Holstein Friesian cows
Authors: Oluoch Lillian , Stachó László , Viharos László , Viharos Andor , Mikó Edit 
Published: November 2020

AbstractTo overcome well-known difficulties in establishing reliable models based on large data sets, the Random Forest Regression (RFR) method is applied to study economical breeding and milk production of dairy cows. As for the features of RFR, there are several positive experiences in various areas of applications supporting that with RFR one can achieve reliable model predictions for industrial production of any product providing a useful base for decisions. In this study, a data set of a period of ten years including about eighty thousand cows was analysed by means of RFR. Ranking of production control parameters is obtained, the most important explanatory variables are found by computing the variances of the target variable on the sets created during the training phases of the RFR. Predictions are made for the milk production and the conception of the calves with high accuracy on given data and simulations are used to investigate prediction accuracy. This paper is primarily concerned with the mathematical aspects of a forthcoming work focused on the agricultural viewpoints. As for future mathematical research plans, the results will be compared with models based on factor analysis and linear regression.
Newborns’ sensitivity to speed changes as a building block for animacy perception
Authors: Di Giorgio Elisa , Lunghi Marco , Vallortigara Giorgio , Simion Francesca 
Published: November 2020

AbstractThe human visual system can discriminate between animate beingsvs. inanimate objects on the basis of some kinematic cues, such as starting from rest and speed changes by self-propulsion. The ontogenetic origin of such capability is still under debate. Here we investigate for the first time whether newborns manifest an attentional bias toward objects that abruptly change their speed along a trajectory as contrasted with objects that move at a constant speed. To this end, we systematically manipulated the motion speed of two objects. An object that moves with a constant speed was contrasted with an object that suddenly increases (Experiment 1) or with one that suddenly decreases its speed (Experiment 2). When presented with a single speed change, newborns did not show any visual preference. However, newborns preferred an object that abruptly increases and then decreases its speed (Experiment 3), but they did not show any visual preference for the reverse sequence pattern (Experiment 4). Overall, results are discussed in line with the hypothesis of the existence of attentional biases in newborns that trigger their attention towards some visual cues of motion that characterized animate perception in adults.
The histone deacetylase HDA15 interacts with MAC3A and MAC3B to regulate intron retention of ABA-responsive genes
Authors: Tu Yi-Tsung , Chen Chia-Yang , Huang Yi-Sui , Yen Ming-Ren , Hsieh Jo-Wei Allison , Chen Pao-Yang , Wu Keqiang 
Published: November 2020

AbstractHistone deacetylases (HDAs) play an important role in transcriptional regulation involved in multiple biological processes. In this study, we investigate the function of HDA15 in abscisic acid (ABA) responses. Immunopurification coupled with mass spectrometry-based proteomics was used to identify the HDA15 interacting proteins. We found that HDA15 can interact with the core subunits of MOS4-Associated Complex (MAC), MAC3A and MAC3B. In addition, ABA enhances the interaction of HDA15 with MAC3B.hda15andmac3a/mac3bmutants are ABA-insensitive in seed germination and hyposensitive to salinity. RNA sequencing (RNA-seq) analysis demonstrate that HDA15 and MAC3A/MAC3B not only affect the expression of ABA-related genes, but also regulate ABA-responsive intron retention (IR). Furthermore, HDA15 and MAC3A/MAC3B reduce the histone acetylation level of the genomic regions near ABA-responsive IRs. Our studies uncovered the role of histone deacetylation in ABA-mediated splicing regulation and identified that HDA15-MAC3A/MAC3B acts as an important regulation module to mediate splicing of introns in ABA responses.One Sentence SummaryHDA15 and MAC3A/MAC3B coregulate intron retention and reduce the histone acetylation level of the genomic regions near ABA-responsive retained introns.
Targeting G protein-coupled receptor-17 (GPR17) upregulation in paediatric diffuse midbrain gliomas leads to altered phenotype and susceptibility to therapies
Authors: Loveson Katie F. , Fillmore Helen L. 
Published: November 2020

AbstractPaediatric diffuse midline glioma (pDMG) also known as Diffuse intrinsic pontine gliomas (DIPG) is an incurable, aggressive childhood brain malignancy, that arises in a region- and age-specific nature. The underlying pathophysiology suggests dysregulation of postnatal neurodevelopmental processes causing aborted cell differentiation. The cell of origin is unclear, but data suggests an oligodendrocytic lineage (OPC), supported by the over-expression of transcription factors such as Olig1 and Olig2 in 80% of DIPG cases.In-depth bioinformatics and principal component analyses (PCA) of genes involved in brain development and pDMG support reports of OPC gene dysregulation and led to the identification of the G-protein coupled receptor 17 (GPR17) and its association with pDMG. GPR17 mRNA and protein expression was confirmed in all pDMG cell lines tested. Using a well-characterised agonist (MDL 299,51) and antagonist (HAMI3379) to modulate GPR17 function in pDMG cell lines resulted in phenotypic and genomic changes as well as in cell growth and migration. HAMI3379, a GPR17 specific antagonist resulted in a significant reduction in GPR17 mRNA and protein expression (p<0.006) and a significant reduction in migration (p<0.0025). When pDMG cells were pre-treatment with HAMI3379 in combination with known cytotoxic agents (Bleomycin, a radiation mimic, Panobinostat or Vincristine), there was a decrease in cell viability compare to cytotoxic agent alone. There are no current effective therapies for pDMG patients and the ability of blocking GPR17 function to enhance sensitivity to standard therapies is appealing and warrants further investigation.