cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.3706290.v1
title: Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

description: Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation of cytosolic proteins such as SNCA (synuclein α), a protein strongly implicated in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA and the consequences of CMA failure in the living brain remain elusive. Here we show that CMA inhibition in the adult rat substantia nigra via adeno-associated virus-mediated delivery of short hairpin RNAs targeting the LAMP2A receptor, involved in CMA's rate limiting step, was accompanied by intracellular accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. Strikingly, LAMP2A downregulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro- and microgliosis and relevant motor deficits. Thus, this study highlights for the first time the importance of the CMA pathway in the dopaminergic system and suggests that CMA impairment may underlie PD pathogenesis.
DOI: 10.5281/zenodo.3872735
title: Profiling the REACH-chemical space with Generative Topographic Mapping

description: The REACH (Registration Evaluation Authorization and restriction of Chemicals) regulation requires from industries the reporting of hazard data for substances placed on the market. Thanks to the registration procedure initiated in 2007, a large REACH database [1] of well defined (eco)toxicological properties has been created. The REACH-chemical space is defined by more than 21’500 compounds registered in the REACH database. Considering the high number of chemicals and endpoints for which experimental data is available, the ability to visualize this chemical space as well as to profile a compound integrating several key properties at once is a growing need. Here, the data distribution in REACH chemical space was visualized and analysed with the help of 2-dimensional Generative Topographic Map (GTM). Similarly to geographical map, on GTM, each object (compound) is visualized as a datapoint. Moreover, compounds possessing similar properties tend to be located in neighbourhood. The third dimension can be added in order to display a distribution of the given (eco)toxicological property (such-called “property landscape”), which can further be used for property assessment of new compounds projected on the map. We report the universal REACH map which accommodates 11 endpoints, covering environmental fate, and (eco)toxicological properties. This map is able to provide predictions for each property, and demonstrates acceptable predictive performance in cross-validation: balanced accuracy ranges from 0.60 to 0.78. Superposition of different property landscapes allows to delineate the “areas of interest” populated by molecules possessing desirable (eco)toxicological profile.
description: {"references": ["echem portal: global portal to information on chemical substances (OECD). https://www.echemportal.org/echemportal/", "K. Mansouri, A. Abdelaziz, A. Rybacka, A. Roncaglioni, A. Tropsha, A. Varnek et al., CERAPP: collaborative estrogen receptor activity prediction project, Environ. Health Perspect. 124 (2016), pp. 1023\u20131033.", "K. Mansouri, N. Kleinstreuer, A.M. Abdelaziz, D. Alberga, V.M. Alves, P.L. Andersson et al., Compara: collaborative modeling project for androgen receptor activity, Environ. Health Perspect. (2020).", "Kleinstreuer, Nicole C., et al. \"Predictive models for acute oral systemic toxicity: a workshop to bridge the gap from research to regulation.\" Computational Toxicology 8 (2018): 21-24.", "F. Lunghini, G. Marcou, P. Gantzer, P. Azam, D. Horvath, E. Van Miert and A. Varnek, Modelling of ready biodegradability based on combined public and industrial data sources, SAR QSAR Environ. Res. 31 (2020), pp. 171\u2013186.", "F. Lunghini, G. Marcou, P. Azam, D. Horvath, R. Patoux, E. Van Miert and A. Varnek, Consensus models to predict oral rat acute toxicity and validation on a dataset coming from the industrial context, SAR QSAR Environ. Res. 30 (2019), pp. 879\u2013897."]}
DOI: 10.6084/m9.figshare.3706254
title: Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

description: Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases.
DOI: 10.5281/zenodo.3872734
title: Profiling the REACH-chemical space with Generative Topographic Mapping

description: The REACH (Registration Evaluation Authorization and restriction of Chemicals) regulation requires from industries the reporting of hazard data for substances placed on the market. Thanks to the registration procedure initiated in 2007, a large REACH database [1] of well defined (eco)toxicological properties has been created. The REACH-chemical space is defined by more than 21’500 compounds registered in the REACH database. Considering the high number of chemicals and endpoints for which experimental data is available, the ability to visualize this chemical space as well as to profile a compound integrating several key properties at once is a growing need. Here, the data distribution in REACH chemical space was visualized and analysed with the help of 2-dimensional Generative Topographic Map (GTM). Similarly to geographical map, on GTM, each object (compound) is visualized as a datapoint. Moreover, compounds possessing similar properties tend to be located in neighbourhood. The third dimension can be added in order to display a distribution of the given (eco)toxicological property (such-called “property landscape”), which can further be used for property assessment of new compounds projected on the map. We report the universal REACH map which accommodates 11 endpoints, covering environmental fate, and (eco)toxicological properties. This map is able to provide predictions for each property, and demonstrates acceptable predictive performance in cross-validation: balanced accuracy ranges from 0.60 to 0.78. Superposition of different property landscapes allows to delineate the “areas of interest” populated by molecules possessing desirable (eco)toxicological profile.
description: {"references": ["echem portal: global portal to information on chemical substances (OECD). https://www.echemportal.org/echemportal/", "K. Mansouri, A. Abdelaziz, A. Rybacka, A. Roncaglioni, A. Tropsha, A. Varnek et al., CERAPP: collaborative estrogen receptor activity prediction project, Environ. Health Perspect. 124 (2016), pp. 1023\u20131033.", "K. Mansouri, N. Kleinstreuer, A.M. Abdelaziz, D. Alberga, V.M. Alves, P.L. Andersson et al., Compara: collaborative modeling project for androgen receptor activity, Environ. Health Perspect. (2020).", "Kleinstreuer, Nicole C., et al. \"Predictive models for acute oral systemic toxicity: a workshop to bridge the gap from research to regulation.\" Computational Toxicology 8 (2018): 21-24.", "F. Lunghini, G. Marcou, P. Gantzer, P. Azam, D. Horvath, E. Van Miert and A. Varnek, Modelling of ready biodegradability based on combined public and industrial data sources, SAR QSAR Environ. Res. 31 (2020), pp. 171\u2013186.", "F. Lunghini, G. Marcou, P. Azam, D. Horvath, R. Patoux, E. Van Miert and A. Varnek, Consensus models to predict oral rat acute toxicity and validation on a dataset coming from the industrial context, SAR QSAR Environ. Res. 30 (2019), pp. 879\u2013897."]}
DOI: 10.6084/m9.figshare.3706254.v2
title: Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

description: Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases.
DOI: 10.6084/m9.figshare.3706254.v1
title: Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

description: Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases.
DOI: 10.6084/m9.figshare.3706053
title: Elevated <i>Mirc1/Mir17-92</i> cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages

description: Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the <i>CF transmembrane conductance regulator (CFTR)</i> gene, resulting in defective CFTR function. Macroautophagy/autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. Autophagy clears pathogens and dysfunctional protein aggregates within macrophages. However, this process is impaired in CF patients and CF mice, as their macrophages exhibit limited autophagy activity. The study of microRNAs (<i>Mirs</i>), and other noncoding RNAs, continues to offer new therapeutic targets. The objective of this study was to elucidate the role of <i>Mirs</i> in dysregulated autophagy-related genes in CF macrophages, and then target them to restore this host-defense function and improve CFTR channel function. We identified the <i>Mirc1/Mir17-92</i> cluster as a potential negative regulator of autophagy as CF macrophages exhibit decreased autophagy protein expression and increased cluster expression when compared to wild-type (WT) counterparts. The absence or reduced expression of the cluster increases autophagy protein expression, suggesting the canonical inverse relationship between <i>Mirc1/Mir17-92</i> and autophagy gene expression. An <i>in silico</i> study for targets of <i>Mirs</i> that comprise the cluster suggested that the majority of the <i>Mirs</i> target autophagy mRNAs. Those targets were validated by luciferase assays. Notably, the ability of macrophages expressing mutant F508del CFTR to transport halide through their membranes is compromised and can be restored by downregulation of these inherently elevated <i>Mirs</i>, via restoration of autophagy. In vivo, downregulation of <i>Mir17</i> and <i>Mir20a</i> partially restored autophagy expression and hence improved the clearance of <i>Burkholderia cenocepacia</i>. Thus, these data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.
DOI: 10.6084/m9.figshare.3706053.v1
title: Elevated <i>Mirc1/Mir17-92</i> cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages

description: Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the <i>CF transmembrane conductance regulator (CFTR)</i> gene, resulting in defective CFTR function. Macroautophagy/autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. Autophagy clears pathogens and dysfunctional protein aggregates within macrophages. However, this process is impaired in CF patients and CF mice, as their macrophages exhibit limited autophagy activity. The study of microRNAs (<i>Mirs</i>), and other noncoding RNAs, continues to offer new therapeutic targets. The objective of this study was to elucidate the role of <i>Mirs</i> in dysregulated autophagy-related genes in CF macrophages, and then target them to restore this host-defense function and improve CFTR channel function. We identified the <i>Mirc1/Mir17-92</i> cluster as a potential negative regulator of autophagy as CF macrophages exhibit decreased autophagy protein expression and increased cluster expression when compared to wild-type (WT) counterparts. The absence or reduced expression of the cluster increases autophagy protein expression, suggesting the canonical inverse relationship between <i>Mirc1/Mir17-92</i> and autophagy gene expression. An <i>in silico</i> study for targets of <i>Mirs</i> that comprise the cluster suggested that the majority of the <i>Mirs</i> target autophagy mRNAs. Those targets were validated by luciferase assays. Notably, the ability of macrophages expressing mutant F508del CFTR to transport halide through their membranes is compromised and can be restored by downregulation of these inherently elevated <i>Mirs</i>, via restoration of autophagy. In vivo, downregulation of <i>Mir17</i> and <i>Mir20a</i> partially restored autophagy expression and hence improved the clearance of <i>Burkholderia cenocepacia</i>. Thus, these data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.
DOI: 10.6084/m9.figshare.3703629
title: Treatment of allergic rhinitis with CpG oligodeoxynucleotides alleviates the lower airway outcomes of combined allergic rhinitis and asthma syndrome via a mechanism that possibly involves in TSLP

description: <b>Purpose:</b> Thymic stromal lymphopoietin (TSLP) is a critical regulator of immune responses associated with Th2 cytokine-mediated inflammation. Intranasal administration of oligodeoxynucleotides with CpG motifs (CpG-ODNs) might improve lower airway outcomes of combined allergic rhinitis and asthma syndrome (CARAS), but the inherent mechanisms of CpG-ODNs are not well defined. This study investigated whether CpG-ODNs treated to upper airway could reduce lower airway TSLP expression as well as whether this reduction could contribute to the alleviation of lower allergic inflammation and airway hyper-reactivity (AHR) in CARAS mice. <b>Materials and Methods:</b> Ovalbumin (OVA)-sensitized BALB/c mice were intranasal OVA exposure three times a week for 3 weeks. CpG-ODNs or an anti-TSLP mAb was administered to a subset of these mice 1 hour after intranasal OVA challenge, followed by 5 days of OVA aerosol challenge. The resulting immunological variables, nasal symptoms, and nasal mucosa and lung tissues pathology were evaluated. TSLP production in the lung tissues and bronchoalveolar lavage fluid (BALF) were determined by RT-PCR, western blotting or enzyme-linked immunosorbent assay. <b>Results:</b> The CARAS mice exhibited overexpression of TSLP in the lung tissues and BALF, and also demonstrated significant increases in BALF and splenocyte Th2-associated cytokine production, serum OVA-specific IgE, nose and lung pathologies, and AHR. Intranasal administration of CpG-ODNs restored TSLP in the lower airway, and it significantly reduced the following parameters: Th2-type cytokine production levels; the percentage of eosinophils in the BALF; IL-4 and IL-5 concentrations in the supernatants of cultured splenic lymphocytes; serum OVA-specific IgE; peribronchial inflammation score in the lungs; and nose pathology and nasal symptoms. Similar results were obtained when the CARAS mice were treated with an anti-TSLP mAb to block intranasal TSLP activity. <b>Conclusions:</b> Treatment with intranasal CpG-ODNs improves lower airway immunological variable outcomes in the CARAS model via a mechanism that possibly involves in suppressing pulmonary TSLP-triggered allergic inflammation.
DOI: 10.6084/m9.figshare.3703629.v1
title: Treatment of allergic rhinitis with CpG oligodeoxynucleotides alleviates the lower airway outcomes of combined allergic rhinitis and asthma syndrome via a mechanism that possibly involves in TSLP

description: <b>Purpose:</b> Thymic stromal lymphopoietin (TSLP) is a critical regulator of immune responses associated with Th2 cytokine-mediated inflammation. Intranasal administration of oligodeoxynucleotides with CpG motifs (CpG-ODNs) might improve lower airway outcomes of combined allergic rhinitis and asthma syndrome (CARAS), but the inherent mechanisms of CpG-ODNs are not well defined. This study investigated whether CpG-ODNs treated to upper airway could reduce lower airway TSLP expression as well as whether this reduction could contribute to the alleviation of lower allergic inflammation and airway hyper-reactivity (AHR) in CARAS mice. <b>Materials and Methods:</b> Ovalbumin (OVA)-sensitized BALB/c mice were intranasal OVA exposure three times a week for 3 weeks. CpG-ODNs or an anti-TSLP mAb was administered to a subset of these mice 1 hour after intranasal OVA challenge, followed by 5 days of OVA aerosol challenge. The resulting immunological variables, nasal symptoms, and nasal mucosa and lung tissues pathology were evaluated. TSLP production in the lung tissues and bronchoalveolar lavage fluid (BALF) were determined by RT-PCR, western blotting or enzyme-linked immunosorbent assay. <b>Results:</b> The CARAS mice exhibited overexpression of TSLP in the lung tissues and BALF, and also demonstrated significant increases in BALF and splenocyte Th2-associated cytokine production, serum OVA-specific IgE, nose and lung pathologies, and AHR. Intranasal administration of CpG-ODNs restored TSLP in the lower airway, and it significantly reduced the following parameters: Th2-type cytokine production levels; the percentage of eosinophils in the BALF; IL-4 and IL-5 concentrations in the supernatants of cultured splenic lymphocytes; serum OVA-specific IgE; peribronchial inflammation score in the lungs; and nose pathology and nasal symptoms. Similar results were obtained when the CARAS mice were treated with an anti-TSLP mAb to block intranasal TSLP activity. <b>Conclusions:</b> Treatment with intranasal CpG-ODNs improves lower airway immunological variable outcomes in the CARAS model via a mechanism that possibly involves in suppressing pulmonary TSLP-triggered allergic inflammation.
DOI: 10.6084/m9.figshare.3702861
title: VivoPoster2016v4_JO.pdf

description: Using data from research studies and clinical trials to enrich researcher profiles.<br>
DOI: 10.6084/m9.figshare.3702861.v1
title: VivoPoster2016v4_JO.pdf

description: Using data from research studies and clinical trials to enrich researcher profiles.<br>
DOI: 10.6084/m9.figshare.3702570
title: Microplastic Field Survey of Charleston Harbor and Winyah Bay, South Carolina

description: A field survey of microplastic pollution in Charleston Harbor and Winyah Bay was conducted in the summer of 2013 and 2014. Microplastic abundance was quantified in intertidal sediment, subtidal sediment, and the sea surface microlayer. Collected microplastics were categorized as fibers, foam, fragments, or spheres. Collected microplastic size fractions were 63, 150, and 500 microns.<br>In Figure 1, amount of plastic per square meter is depicted as a red gradient, with darker colors indicating greater microplastic abundance. Amount of plastic per 4 L collected in the sea surface microlayer is depicted as a purple gradient with darker colors indicating greater microplastic abundance.