cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.4123185
title: Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins

description: The nuclear lamina mechanically integrates the nucleus with the cytoskeleton and extracellular environment and regulates gene expression. These functions are exerted through direct and indirect interactions with the lamina's major constituent proteins, the A-type lamins, which are encoded by the <i>LMNA</i> gene. Using quantitative stable isotope labeling-based shotgun proteomics we have analyzed the proteome of human dermal fibroblasts in which we have depleted A-type lamins by means of a sustained siRNA-mediated <i>LMNA</i> knockdown. Gene ontology analysis revealed that the largest fraction of differentially produced proteins was involved in actin cytoskeleton organization, in particular proteins involved in focal adhesion dynamics, such as actin-related protein 2 and 3 (ACTR2/3), subunits of the ARP2/3 complex, and fascin actin-bundling protein 1 (FSCN1). Functional validation using quantitative immunofluorescence showed a significant reduction in the size of focal adhesion points in A-type lamin depleted cells, which correlated with a reduction in early cell adhesion capacity and an increased cell motility. At the same time, loss of A-type lamins led to more pronounced stress fibers and higher traction forces. This phenotype could not be mimicked or reversed by experimental modulation of the STAT3-IL6 pathway, but it was partly recapitulated by chemical inhibition of the ARP2/3 complex. Thus, our data suggest that the loss of A-type lamins perturbs the balance between focal adhesions and cytoskeletal tension. This imbalance may contribute to mechanosensing defects observed in certain laminopathies.
DOI: 10.7910/dvn/v1rjpf/3yrsny
title: cbb20170221_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123182.v1
title: Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

description: Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrow-derived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing <i>Atg7</i> or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca<sup>2+</sup> concentration. Either Ca<sup>2+</sup> chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular re-endothelialization in patients with hypercholesterolemia.
DOI: 10.6084/m9.figshare.4123185.v2
title: Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins

description: The nuclear lamina mechanically integrates the nucleus with the cytoskeleton and extracellular environment and regulates gene expression. These functions are exerted through direct and indirect interactions with the lamina's major constituent proteins, the A-type lamins, which are encoded by the <i>LMNA</i> gene. Using quantitative stable isotope labeling-based shotgun proteomics we have analyzed the proteome of human dermal fibroblasts in which we have depleted A-type lamins by means of a sustained siRNA-mediated <i>LMNA</i> knockdown. Gene ontology analysis revealed that the largest fraction of differentially produced proteins was involved in actin cytoskeleton organization, in particular proteins involved in focal adhesion dynamics, such as actin-related protein 2 and 3 (ACTR2/3), subunits of the ARP2/3 complex, and fascin actin-bundling protein 1 (FSCN1). Functional validation using quantitative immunofluorescence showed a significant reduction in the size of focal adhesion points in A-type lamin depleted cells, which correlated with a reduction in early cell adhesion capacity and an increased cell motility. At the same time, loss of A-type lamins led to more pronounced stress fibers and higher traction forces. This phenotype could not be mimicked or reversed by experimental modulation of the STAT3-IL6 pathway, but it was partly recapitulated by chemical inhibition of the ARP2/3 complex. Thus, our data suggest that the loss of A-type lamins perturbs the balance between focal adhesions and cytoskeletal tension. This imbalance may contribute to mechanosensing defects observed in certain laminopathies.
DOI: 10.6084/m9.figshare.4123185.v1
title: Uncoordinated regulation of focal adhesions and cytoskeletal tension due to the loss of a-type lamins

description: The nuclear lamina mechanically integrates the nucleus with the cytoskeleton and extracellular environment and regulates gene expression. These functions are exerted through direct and indirect interactions with the lamina's major constituent proteins, the A-type lamins, which are encoded by the <i>LMNA</i> gene. Using quantitative stable isotope labeling-based shotgun proteomics we have analyzed the proteome of human dermal fibroblasts in which we have depleted A-type lamins by means of a sustained siRNA-mediated <i>LMNA</i> knockdown. Gene ontology analysis revealed that the largest fraction of differentially produced proteins was involved in actin cytoskeleton organization, in particular proteins involved in focal adhesion dynamics, such as actin-related protein 2 and 3 (ACTR2/3), subunits of the ARP2/3 complex, and fascin actin-bundling protein 1 (FSCN1). Functional validation using quantitative immunofluorescence showed a significant reduction in the size of focal adhesion points in A-type lamin depleted cells, which correlated with a reduction in early cell adhesion capacity and an increased cell motility. At the same time, loss of A-type lamins led to more pronounced stress fibers and higher traction forces in cells undergoing enzymatic detachment. This phenotype could not be mimicked or reversed by experimental modulation of the STAT3-IL6 pathway, but it was partly recapitulated by chemical inhibition of the ARP2/3 complex. Thus, our data suggest that the loss of A-type lamins perturbs the balance between focal adhesions and cytoskeletal tension. This imbalance may contribute to mechanosensing defects observed in certain laminopathies.
DOI: 10.7910/dvn/v1rjpf/lz8ypl
title: cbb20170811_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123179
title: The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes

description: Macroautophagy/autophagy plays a critical role in immunity by directly degrading invading pathogens such as Group A <i>Streptococcus</i> (GAS), through a process that has been named xenophagy. We previously demonstrated that autophagic vacuoles directed against GAS, termed GAS-containing autophagosome-like vacuoles (GcAVs), use recycling endosomes (REs) as a membrane source. However, the precise molecular mechanism that facilitates the fusion between GcAVs and REs remains unclear. Here, we demonstrate that STX6 (syntaxin 6) is recruited to GcAVs and forms a complex with VTI1B and VAMP3 to regulate the GcAV-RE fusion that is required for xenophagy. STX6 targets the GcAV membrane through its tyrosine-based sorting motif and transmembrane domain, and localizes to TFRC (transferrin receptor)-positive punctate structures on GcAVs through its H2 SNARE domain. Knockdown and knockout experiments revealed that STX6 is required for the fusion between GcAVs and REs to promote clearance of intracellular GAS by autophagy. Moreover, VAMP3 and VTI1B interact with STX6 and localize on the TFRC-positive puncta on GcAVs, and are also involved in the RE-GcAV fusion. Furthermore, knockout of <i>RABGEF1</i> impairs the RE-GcAV fusion and STX6-VAMP3 interaction. These findings demonstrate that RABGEF1 mediates RE fusion with GcAVs through the STX6-VAMP3-VTI1B complex, and reveal the SNARE dynamics involved in autophagosome formation in response to bacterial infection.
DOI: 10.6084/m9.figshare.4123179.v1
title: The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes

description: Macroautophagy/autophagy plays a critical role in immunity by directly degrading invading pathogens such as Group A <i>Streptococcus</i> (GAS), through a process that has been named xenophagy. We previously demonstrated that autophagic vacuoles directed against GAS, termed GAS-containing autophagosome-like vacuoles (GcAVs), use recycling endosomes (REs) as a membrane source. However, the precise molecular mechanism that facilitates the fusion between GcAVs and REs remains unclear. Here, we demonstrate that STX6 (syntaxin 6) is recruited to GcAVs and forms a complex with VTI1B and VAMP3 to regulate the GcAV-RE fusion that is required for xenophagy. STX6 targets the GcAV membrane through its tyrosine-based sorting motif and transmembrane domain, and localizes to TFRC (transferrin receptor)-positive punctate structures on GcAVs through its H2 SNARE domain. Knockdown and knockout experiments revealed that STX6 is required for the fusion between GcAVs and REs to promote clearance of intracellular GAS by autophagy. Moreover, VAMP3 and VTI1B interact with STX6 and localize on the TFRC-positive puncta on GcAVs, and are also involved in the RE-GcAV fusion. Furthermore, knockout of <i>RABGEF1</i> impairs the RE-GcAV fusion and STX6-VAMP3 interaction. These findings demonstrate that RABGEF1 mediates RE fusion with GcAVs through the STX6-VAMP3-VTI1B complex, and reveal the SNARE dynamics involved in autophagosome formation in response to bacterial infection.
DOI: 10.7910/dvn/v1rjpf/asl812
title: cbb20170502_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123167
title: Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats

description: Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes <i>Bmal1</i> and <i>Per2</i> in the liver and in fat. In addition, the expression of g<i>lutamate aspartate transporter, glial fibrillary acidic protein</i> and <i>glutamate transporter-1</i>, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.
DOI: 10.6084/m9.figshare.4123170
title: Identification of natural products with neuronal and metabolic benefits through autophagy induction

description: Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.
DOI: 10.7910/dvn/v1rjpf/luqket
title: cbb20170731_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123158
title: Genome - Capsaspora owczarzaki (v3)

description: Capsaspora owczarzaki's genome assembly and annotation. VERSION 3–<strong>Arnau Sebé-Pedrós</strong>, Manuel Irimia, <strong>Javier del Campo</strong>, <strong>Helena Parra-Acero</strong><strong>,</strong> Carsten Russ, Chad Nusbaum, Benjamin J. Blencowe & <strong>Iñaki Ruiz-Trillo</strong>. (2013) <em>Regulated aggregative multicellularity in a close unicellular relative of Metazoa</em>. <em><strong>eLife</strong> 2013;2:e01287</em>www.multicellgenome.com<br>
DOI: 10.6084/m9.figshare.4123170.v1
title: Identification of natural products with neuronal and metabolic benefits through autophagy induction

description: Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.
DOI: 10.6084/m9.figshare.4123167.v1
title: Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats

description: Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes <i>Bmal1</i> and <i>Per2</i> in the liver and in fat. In addition, the expression of g<i>lutamate aspartate transporter, glial fibrillary acidic protein</i> and <i>glutamate transporter-1</i>, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.
DOI: 10.7910/dvn/v1rjpf/jexpw5
title: cbb20170618_03.txt.gz

description: :unav
DOI: 10.7910/dvn/v1rjpf/wobw3r
title: cbb20171225_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123158.v1
title: Genome - Capsaspora owczarzaki (v3)

description: Capsaspora owczarzaki's genome assembly and annotation. VERSION 3–<strong>Arnau Sebé-Pedrós</strong>, Manuel Irimia, <strong>Javier del Campo</strong>, <strong>Helena Parra-Acero</strong><strong>,</strong> Carsten Russ, Chad Nusbaum, Benjamin J. Blencowe & <strong>Iñaki Ruiz-Trillo</strong>. (2013) <em>Regulated aggregative multicellularity in a close unicellular relative of Metazoa</em>. <em><strong>eLife</strong> 2013;2:e01287</em>www.multicellgenome.com<br>
DOI: 10.7910/dvn/v1rjpf/tbuh8k
title: cbb20170105_03.txt.gz

description: :unav
DOI: 10.6084/m9.figshare.4123107
title: Nutrition of infants and young children (one to three years) and its effect on later health: A systematic review of current recommendations (EarlyNutrition project)

description: <b>Background</b>. EarlyNutrition (www.project-earlynutrition.eu) is an international research project investigating the effects of early nutrition on metabolic programming. <b>Objective</b>. To summarize, by performing a systematic review, current standards, recommendations, guidelines, and regulations (hereafter, referred to as documents) on the nutrition of children up to three years of age. Special emphasis was placed on long-term effects of early nutrition, such as the risk of cardiovascular disease, hypertension, overweight, obesity, metabolic syndrome, diabetes, or glucose intolerance. <b>Methods</b>. MEDLINE, selected databases, and websites were searched for documents published between 2008 and January 2013. <b>Results</b>. Forty two documents met the inclusion criteria. The strongest and most consistent evidence for a protective, long-term effect was documented for breastfeeding. Also, limiting the intake of sodium and rapidly absorbed carbohydrates, use of a specific meal pattern, reducing the consumption of saturated fatty acids by replacing them with polyunsaturated fatty acids, and lowering the intake of trans fatty acids, seems beneficial. Many documents did not evaluate long-term outcomes of interest to us, or reported insufficient or imprecise data. Inconsistency in recommendations for some outcomes and research gaps were identified. <b>Conclusions</b>. Our findings may serve as a helpful tool in planning further research, preventive actions against important diet-related diseases, and guidelines improvement.
DOI: 10.6084/m9.figshare.4123110
title: The Discrete Regime of Flame Propagation in Metal Particulate Clouds

description: Flame propagation in lean suspensions of nonvolatile fuels (aluminum and iron) in oxidizing atmospheres is experimentally investigated. Suspensions of micron-sized fuel particles were dispersed in glass tubes using a flow of oxygen/argon mixture, and flame propagation into a quiescent mixture was observed via a variety of techniques. An independence of flame speed on oxygen concentration (from 15% to 30% oxygen in argon) was observed for the suspensions of aluminum particulates. This result is found to be consistent with theoretical estimations of the relative magnitudes of the particle combustion time and the inter-particle heat diffusion time, suggesting that flame propagation through the aluminum suspensions occurs in a regime controlled by the spatial discreteness of the multiphase medium. Experiments with iron exhibited the expected square root dependence of flame speed on oxygen concentration (from 15% to 60% oxygen in argon), demonstrating that propagation in this mixture is in the classical, continuum regime of thermal flames. The aluminum mixtures also exhibited an array of flame instabilities, including a pulsating oscillation that is theoretically predicted for mixtures with a high Lewis number, although acoustic interactions with the flame tube could not be ruled out in influencing the pulsations. The result that lean aluminum flames propagate in a discrete regime suggests that the statistical nature of the particulate suspensions will have a significant influence on flame propagation, giving rise to percolation-like behavior seen in previous computational simulations of reactive waves in discrete media.