cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.7127366
title: Simulation code: spatial model from A spatio-temporal model reveals self-limiting Fc<i>ɛ</i>RI cross-linking by multivalent antigens

description: Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (Fc<i>ɛ</i>RI) in the plasma membrane of mast cells. However, understanding of the mechanisms of Fc<i>ɛ</i>RI aggregation remains incomplete. Experimental reports indicate that Fc<i>ɛ</i>RI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse Fc<i>ɛ</i>RI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.
DOI: 10.6084/m9.figshare.7127330
title: Supplementary Material for: Comparing Therapeutic Efficacy and Safety of Epoetin Beta and Epoetin Alfa in the Treatment of Anemia in End-Stage Renal Disease Hemodialysis Patients

description: <b><i>Background:</i></b> Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin® (epoetin beta, CinnaGen) with Eprex® (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients. <b><i>Methods:</i></b> In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin® or Eprex® for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10–12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints. <b><i>Results:</i></b> A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (<i>p</i> = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10–12 g/dL showed no statistically significant difference between treatment arms (<i>p</i> = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin® group. <b><i>Conclusion:</i></b> CinnaPoietin® was proved to be non-inferior to Eprex® in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639).
DOI: 10.6084/m9.figshare.7127366.v1
title: Simulation code: spatial model from A spatio-temporal model reveals self-limiting Fc<i>ɛ</i>RI cross-linking by multivalent antigens

description: Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (Fc<i>ɛ</i>RI) in the plasma membrane of mast cells. However, understanding of the mechanisms of Fc<i>ɛ</i>RI aggregation remains incomplete. Experimental reports indicate that Fc<i>ɛ</i>RI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse Fc<i>ɛ</i>RI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.
DOI: 10.6084/m9.figshare.7127279
title: Raw data of the specimens (1)

description: Raw data of the specimens in Insect Collection of Central South University of Forestry and Technology.
DOI: 10.6084/m9.figshare.7127267
title: Supplementary Material for: Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation

description: <b><i>Background/Aims:</i></b> We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation. <b><i>Methods:</i></b> The mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. <b><i>Results:</i></b> NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae. <b><i>Conclusion:</i></b> NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.
DOI: 10.6084/m9.figshare.7127279.v1
title: Raw data of the specimens (1)

description: Raw data of the specimens in Insect Collection of Central South University of Forestry and Technology.
DOI: 10.6084/m9.figshare.7127225
title: Controlling Rainwater Storage as a System

description: Globally, urban infill is stressing existing stormwater systems, necessitating costly infrastructure upgrades. Although household rainwater tanks provide significant distributed storage, they have virtually no impact on reducing peak flows for rare, long duration events. This study introduces an innovative “smart systems” approach to operating tanks to overcome this limitation. Smart tanks are operated as systems and tank opening/closing is optimised to reduce peak flows. To evaluate the proposed approach, we develop a simulation-optimization model by coupling SWMM with a multi-objective genetic algorithm. The results for a two allotment case study show a consistent reduction in peak flows for a 24 hour, 1 in 100-year storm for a range of rainfall patterns and tank sizes. For example, a system of 10 kL smart tanks reduced peak flows by 39%-48% compared with the same sized retention tanks. This smart systems approach provides an opportunity to reduce the cost of stormwater infrastructure.
DOI: 10.6084/m9.figshare.7127225.v1
title: Controlling Rainwater Storage as a System

description: Globally, urban infill is stressing existing stormwater systems, necessitating costly infrastructure upgrades. Although household rainwater tanks provide significant distributed storage, they have virtually no impact on reducing peak flows for rare, long duration events. This study introduces an innovative “smart systems” approach to operating tanks to overcome this limitation. Smart tanks are operated as systems and tank opening/closing is optimised to reduce peak flows. To evaluate the proposed approach, we develop a simulation-optimization model by coupling SWMM with a multi-objective genetic algorithm. The results for a two allotment case study show a consistent reduction in peak flows for a 24 hour, 1 in 100-year storm for a range of rainfall patterns and tank sizes. For example, a system of 10 kL smart tanks reduced peak flows by 39%-48% compared with the same sized retention tanks. This smart systems approach provides an opportunity to reduce the cost of stormwater infrastructure.
DOI: 10.6084/m9.figshare.7127189
title: Implementing a method for studying longitudinal DNA methylation variability in association with age

description: Interindividual variability of DNA methylation is a mechanism of the epigenetic drift in aging. Studies on cross-sectional data have discovered a change in methylation variability in association with age. However, thus far, no method explored DNA methylation variability in longitudinal data, which was the aim of this study. First, we performed a simulation study to explore methods for estimating methylation variability in longitudinal data. Second, an epigenome-wide association study (EWAS) on 1011 longitudinal samples (385 individuals followed up to 18 years) was performed to identify age-varying methylation sites using these methods. Following Breusch–Pagan test of heteroscedasticity, we showed that a linear regression model, where the residuals were used in a mixed effect model with a random intercept, properly estimated the change of interindividual variability over time. Our EWAS identified 570 CpG sites where methylation variability was significantly associated with age (<i>P </i>−7). Gene regions of identified loci were enriched in nervous system development functions. In conclusion, we provide a method for analyzing methylation variability in longitudinal data and further identified age-varying methylation loci in a longitudinal analysis using these methods.
DOI: 10.6084/m9.figshare.7127186
title: A possible role for fumagillin in cellular damage during host infection by <i>Aspergillus fumigatus</i>

description: Virulence mechanisms of the pathogenic fungus <i>Aspergillus fumigatus</i> are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an <i>in vitro</i> pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that <i>A. fumigatus</i> progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.
DOI: 10.6084/m9.figshare.7127189.v2
title: Implementing a method for studying longitudinal DNA methylation variability in association with age

description: Interindividual variability of DNA methylation is a mechanism of the epigenetic drift in aging. Studies on cross-sectional data have discovered a change in methylation variability in association with age. However, thus far, no method explored DNA methylation variability in longitudinal data, which was the aim of this study. First, we performed a simulation study to explore methods for estimating methylation variability in longitudinal data. Second, an epigenome-wide association study (EWAS) on 1011 longitudinal samples (385 individuals followed up to 18 years) was performed to identify age-varying methylation sites using these methods. Following Breusch–Pagan test of heteroscedasticity, we showed that a linear regression model, where the residuals were used in a mixed effect model with a random intercept, properly estimated the change of interindividual variability over time. Our EWAS identified 570 CpG sites where methylation variability was significantly associated with age (<i>P </i>−7). Gene regions of identified loci were enriched in nervous system development functions. In conclusion, we provide a method for analyzing methylation variability in longitudinal data and further identified age-varying methylation loci in a longitudinal analysis using these methods.
DOI: 10.6084/m9.figshare.7127186.v2
title: A possible role for fumagillin in cellular damage during host infection by <i>Aspergillus fumigatus</i>

description: Virulence mechanisms of the pathogenic fungus <i>Aspergillus fumigatus</i> are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an <i>in vitro</i> pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that <i>A. fumigatus</i> progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.
DOI: 10.6084/m9.figshare.7127189.v1
title: Implementing a method for studying longitudinal DNA methylation variability in association with age

description: Interindividual variability of DNA methylation is a mechanism of the epigenetic drift in aging. Studies on cross-sectional data have discovered a change in methylation variability in association with age. However, thus far, no method explored DNA methylation variability in longitudinal data, which was the aim of this study. First, we performed a simulation study to explore methods for estimating methylation variability in longitudinal data. Second, an epigenome-wide association study (EWAS) on 1011 longitudinal samples (385 individuals followed up to 18 years) was performed to identify age-varying methylation sites using these methods. Following Breusch–Pagan test of heteroscedasticity, we showed that a linear regression model, where the residuals were used in a mixed effect model with a random intercept, properly estimated the change of interindividual variability over time. Our EWAS identified 570 CpG sites where methylation variability was significantly associated with age (<i>P </i>−7). Gene regions of identified loci were enriched in nervous system development functions. In conclusion, we provide a method for analyzing methylation variability in longitudinal data and further identified age-varying methylation loci in a longitudinal analysis using these methods.
DOI: 10.6084/m9.figshare.7127186.v1
title: A possible role for fumagillin in cellular damage during host infection by <i>Aspergillus fumigatus</i>

description: Virulence mechanisms of the pathogenic fungus <i>Aspergillus fumigatus</i> are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an <i>in vitro</i> pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that <i>A. fumigatus</i> progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.
DOI: 10.6084/m9.figshare.7127168
title: Ancient Fictionality Moses, Exodus and Conversion Theory.docx

description: The symbolic nature of the Moses and Exodus narratives, indicating conversion to a law-based society at the time of Persian rule.
DOI: 10.6084/m9.figshare.7127120
title: Mitochondrial and glycolysis-regulatory gene expression profiles are associated with intrauterine growth restriction

description: <b>Introduction:</b> Intrauterine growth restriction (IUGR) is a major pregnancy complication with significant postnatal implications. IUGR is characterized by high placental oxidative stress (OS) and increased mitochondrial DNA (mtDNA) abundance that altogether alter the placental metabolism. Such alterations may be captured by changes in the expression of mitochondrial-encoded oxidative phosphorylation genes and glycolysis-regulatory genes. <b>Study design:</b> We aimed here to determine the association between the placental expression of all 13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis-regulatory genes, <i>PDK1</i>, <i>PDK2</i>, <i>PDK3</i>, <i>PDK4</i>, <i>PKLR</i>, <i>PKM</i>, <i>OGT</i>, with IUGR, within a case-control study including 50 IUGR and 100 control pregnancies. We additionally assessed placental mtDNA abundance and OS. <b>Results:</b> Three mitochondrial genes, <i>MT-ND5</i>, <i>MT-ND6</i>, and <i>MT-ATP6</i> were found negatively associated with IUGR, while one glycolysis-regulatory gene, <i>PDK1</i> was positively associated with IUGR. mtDNA abundance and OS were positively associated with IUGR. Our study confirmed the existing data on IUGR inducing increased placental OS and mtDNA abundance. Further, our data highlighted the significant involvement of mitochondria and glucose metabolism in the OS-challenged IUGR placentas, which might modulate the placental expression of genes affecting the OXPHOS and promoting glycolysis. <b>Brief rationale:</b> By using banked placenta samples available at Icahn School of Medicine at Mount Sinai, this study aims at laying the foundation for the characterization of the role of mitochondria epi/genetics in IUGR. IUGR is a highly prevalent pregnancy outcome with long-term effects on the progeny that, at present, has limited tools that can be used for its diagnosis and characterization, thus limiting the efficacy of both clinical and public health interventions. The alterations of mitochondrial copy number, OS and mitochondrial and glycolysis-regulatory gene expression that we detected, together, provide the first evidence that these phenomena are playing an important role in the pathophysiology of IUGR. These findings suggest possible new research paths for the full characterization of mitochondrial biomarkers of IUGR.