146 research outputs found
Synthesis and Evaluation of Novel Modulators of the Ceramide Transfer Protein
Das Ceramid Transfer Protein (CERT) ist einer der geschwindigkeitsbestimmenden Proteine in der de novo Biosynthese von Sphingomyelin. Es ist verantwortlich fĂŒr den nicht-vesikulĂ€ren Transfer von Ceramid vom Endoplasmatischen Retikulum zum Golgi-Apparat. Die Inhibition von CERT wird als potenzielle Behandlung fĂŒr Krankheiten wie Infektionen, Krebs oder Gain-of-Function-Mutationen des CERT Gens diskutiert. KĂŒrzlich, wurde Lomitapide als potenter Inhibitor des CERT-vermittelten intermembran-Transfers identifiziert.
Im ersten Teil dieser Arbeit wird die Synthese von Lomitapide Derivaten mit verbesserter Wirksamkeit und SelektivitĂ€t prĂ€sentiert. Die synthetisierten Analoga wurden in vitro mithilfe eines liposomalen Transferassays auf ihre Inhibition der CERT-TransferaktivitĂ€t getestet. ZusĂ€tzlich konnte durch die Messung des Ceramid-Sphingomyelin-VerhĂ€ltnisses nach Inhibitor Behandlung die AktivitĂ€t in cellulo bestĂ€tigt werden. Die SelektivitĂ€t gegenĂŒber dem Mikrosomalen Triglycerid Transfer Protein (MTP) wurde durch Messung der MTP-vermittelten Sekretion von apoB ermittelt. Unter den synthetisierten Analoga zeigten einige verbesserte CERT-Transfer Inhibition und niedrigere Inhibition der apoB Sekretion, sogar bei fĂŒnffacher Konzentration verglichen mit Lomitapide. Obwohl die Bewertung der biologischen AktivitĂ€t noch im Gange ist, wurde eine vorlĂ€ufige Struktur-AktivitĂ€ts-Beziehung etabliert. Es wurden strukturelle Bestandteile identifiziert, die wichtig fĂŒr die CERT-Inhibition sind und andere welche variabel sind, um die Wirksamkeit und SelektivitĂ€t in Zukunft noch weiter zu steigern.
Der zweite Teil dieser Arbeit beschreibt die Synthese von Lomitapide-basierten proteolysis targeting chimeras (PROTACs) fĂŒr CERT. PROTACs haben sich im letzten Jahrzehnt zu einem vielversprechenden therapeutischen Ansatz entwickelt und mehrere potenzielle Wirkstoffe hervorgebracht. PROTACs sind heterobifunktionale MolekĂŒle, die sich den zellulĂ€ren Weg der Proteinzersetzung zunutze machen, indem sie das gewĂŒnschte Protein zur Zersetzung markieren. Es wurde eine erste Serie von CERT PROTACs mit vielversprechender Abbauwirkung synthetisiert, welche eine bevorzugte Zersetzung von CERT aber nicht CERTL andeuten. CERTL ist eine lĂ€ngere SpleiĂ-Variante, welche vornehmlich im Herz, Gehirn und den Skelettmuskeln exprimiert wird. Eine zweite Serie von PROTACs mit variierter Linker KettenlĂ€nge wurde synthetisiert. Untersuchung des Einflusses auf die apoB Sekretion aus HepG2 Zellen zeigte sogar bei 50-facher Konzentration einen niedrigeren Einfluss auf diese als Lomitapide.The ceramide transfer protein (CERT) is one of the rate-limiting proteins in the de novo biosynthesis of sphingomyelin, facilitating the non-vesicular transfer of ceramide from the Endoplasmic Reticulum to the Golgi-apparatus. Inhibition of CERT has been proposed as a potential treatment for pathogenesis like infectious diseases, cancer, or disease-causing gain-of-function mutations within the CERT gene. Recently Lomitapide has been identified as a potent inhibitor of CERT-mediated intermembrane transfer.
In the first part of this thesis, the synthesis of Lomitapide derivatives with improved potency and selectivity is presented. The synthesized analogs were tested in vitro for their inhibition of CERT-transfer using a liposomal transfer assay. Additionally, the activity could be confirmed in cellulo by monitoring the ceramide-sphingomyelin-ratio after inhibitor treatment. Selectivity against the microsomal triglyceride transfer protein (MTP) has been determined by monitoring the MTP-mediated cellular secretion of apoB. Among the synthesized analogs, several showed improved CERT-transfer inhibition and lower inhibition of apoB secretion even at five-fold higher concentrations compared to Lomitapide. Although the biological evaluation is still underway, a preliminary structure-activity-relationship has been established and identified structural motifs important for CERT inhibition and modifiable moieties to increase potency and selectivity even further in the future. The second part of the thesis describes the synthesis of Lomitapide-based proteolysis targeting chimeras (PROTACs) for CERT. PROTACs have evolved in the last decade as a promising therapeutic technique and resulted in the development of several drugs which are currently in clinical trials. PROTACs are heterobifunctional small molecules that mediate the degradation of the target protein by hijacking the cellular proteasomal pathway. A first series of synthesized CERT PROTACs showed promising preliminary results for CERT degrader activity and indicated a preferred degradation of CERT over CERTL, a longer splicing variant expressed in the heart, brain, and skeletal muscles. Motivated by this a second generation of PROTACs with varying linker chain lengths was synthesized. Investigation of their inhibition of apoB secretion from HepG2 cells revealed lower activity on secretion than Lomitapide even at 50-fold concentrations for a set of CERT PROTACs
Semantic Enrichment of a Multilingual Archive with Linked Open Data
This paper introduces MERCKX, a Multilingual Entity/Resource Combiner & Knowledge eXtractor. A case study involving the semantic enrichment of a multilingual archive is presented with the aim of assessing the relevance of natural language processing techniques such as named-entity recognition and entity linking for cultural heritage material. In order to improve the indexing of historical collections, we map entities to the Linked Open Data cloud using a language-independent method. Our evaluation shows that MERCKX outperforms similar tools on the task of place disambiguation and linking, achieving over 80% precision despite lower recall scores. These results are encouraging for small and medium-size cultural institutions since they demonstrate that semantic enrichment can be achieved with limited resources.Peer reviewe
Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets
The understanding of the role of sphingolipid metabolism in cancer has tremendously increased in the past ten years. Many tumors are characterized by imbalances in sphingolipid metabolism. In many cases, disorders of sphingolipid metabolism are also likely to cause or at least promote cancer. In this review, sphingolipid transport proteins and the processes catalyzed by them are regarded as essential components of sphingolipid metabolism. There is much to suggest that these processes are often rate-limiting steps for metabolism of individual sphingolipid species and thus represent potential target structures for pharmaceutical anticancer research. Here, we summarize empirical and biochemical data on different proteins with key roles in sphingolipid transport and their potential role in cancer.Peer Reviewe
How hot is .brussels? Analysis of the uptake of the .brussels top-level domain name extension
The opening up of the top-level domain name market in 2012 has offered new perspectives for companies, administrations and individuals to include a geographic component within the domain name of their website. Little to no research has been carried out since then to analyse the uptake of the new top-level domain names (TLDNs). Based on the specific case of the TLDN .brussels, this article proposes an empirical study of how the opening up of the top-level domain name market actually impacts registration practices. By making use of freely available software tools such as OpenRefine and Natural Language Processing (NLP) methods, the entire corpus of the .brussels domain names (6 300) was analysed from a quantitative perspective. Based on a statistically representative sample (592 domain names), a qualitative interpretation allowed a more fine-grained analysis of how the new TLDN is being used in practice. By doing so, the article gives detailed insight into the impact of the recent changes to the rules concerning domain name registration. Through this analysis, researchers, policy makers, investors and anyone concerned about the identity of Brussels in the digital realm may have a better understanding of the state of play of the .brussels TLDN.En 2012, la libĂ©ralisation du marchĂ© des noms de domaine de premier niveau a ouvert de nouvelles perspectives aux entreprises, aux administrations et aux particuliers, en leur permettant dâinclure un Ă©lĂ©ment gĂ©ographique dans le nom de domaine de leurs sites web. Depuis lors, trĂšs peu dâĂ©tudes, pour autant quâil en existe, ont Ă©tĂ© menĂ©es sur lâutilisation des nouveaux noms de domaine de premier niveau (top-level domain names, TLDN). Ă partir du cas spĂ©cifique du TLDN « .brussels », le prĂ©sent article propose une analyse empirique de lâimpact rĂ©el de lâouverture de ce marchĂ© sur les pratiques en matiĂšre dâenregistrement de noms de domaine. Au moyen de logiciels en accĂšs gratuit, tels quâOpenRefine, et de mĂ©thodes de traitement du langage naturel (TLN), lâensemble des 6 300 noms de domaine finissant par « .brussels » a pu ĂȘtre examinĂ© du point de vue quantitatif. LâinterprĂ©tation qualitative dâun Ă©chantillon statistiquement reprĂ©sentatif (592 noms de domaine) a permis dâaffiner lâanalyse pour voir comment ce nouveau TLDN est utilisĂ© dans la pratique. Ainsi, lâarticle apporte des informations dĂ©taillĂ©es sur lâincidence des rĂ©centes modifications rĂ©glementaires relatives Ă lâenregistrement des noms de domaine. VoilĂ qui devrait Ă©clairer chercheurs, dĂ©cideurs, investisseurs et quiconque se souciant de lâidentitĂ© de Bruxelles dans le monde numĂ©rique quant Ă la situation du TLDN « .brussels ».De openstelling van de markt van de top level domeinnamen in 2012 bood nieuwe perspectieven voor bedrijven, overheden en privĂ©personen om een geografisch component op te nemen in de domeinnaam van hun website. Sindsdien werd er weinig tot geen onderzoek verricht om de introductie van de nieuwe top level domeinnamen (TLDN) te analyseren. Op basis van het specifieke geval van de TLDN .brussels, bespreekt dit artikel het empirisch onderzoek naar de mate waarin de openstelling van de markt van de top level domeinnamen de registratiepraktijken daadwerkelijk heeft beĂŻnvloed. Door gebruik te maken van vrij beschikbare softwaretools, zoals OpenRefine en Natural Language Processing (NLP) methodes, werd het volledige corpus van de .brussels domeinnamen (6 300) vanuit kwantitatief oogpunt geanalyseerd. Op basis van een statistisch representatieve steekproef (592 domeinnamen), maakte een kwalitatieve interpretatie een verfijndere analyse mogelijk van de manier waarop de nieuwe TLDN in de praktijk wordt gebruikt. Op die manier geeft het artikel een gedetailleerd inzicht in de gevolgen van de recente wijzigingen van de regels inzake registratie van de domeinnamen. Dankzij deze analyse kunnen onderzoekers, beleidsmakers, investeerders en al wie om de identiteit van Brussel in de digitale wereld geeft, een beter inzicht krijgen van de stand van zaken van de .brussels TLDN
Hoe hot is .brussels? Analyse van de introductie van de top level domeinnaam .brussels
De openstelling van de markt van de top level domeinnamen in 2012 bood nieuwe perspectieven voor bedrijven, overheden en privĂ©personen om een geografisch component op te nemen in de domeinnaam van hun website. Sindsdien werd er weinig tot geen onderzoek verricht om de introductie van de nieuwe top level domeinnamen (TLDN) te analyseren. Op basis van het specifieke geval van de TLDN .brussels, bespreekt dit artikel het empirisch onderzoek naar de mate waarin de openstelling van de markt van de top level domeinnamen de registratiepraktijken daadwerkelijk heeft beĂŻnvloed. Door gebruik te maken van vrij beschikbare softwaretools, zoals OpenRefine en Natural Language Processing (NLP) methodes, werd het volledige corpus van de .brussels domeinnamen (6 300) vanuit kwantitatief oogpunt geanalyseerd. Op basis van een statistisch representatieve steekproef (592 domeinnamen), maakte een kwalitatieve interpretatie een verfijndere analyse mogelijk van de manier waarop de nieuwe TLDN in de praktijk wordt gebruikt. Op die manier geeft het artikel een gedetailleerd inzicht in de gevolgen van de recente wijzigingen van de regels inzake registratie van de domeinnamen. Dankzij deze analyse kunnen onderzoekers, beleidsmakers, investeerders en al wie om de identiteit van Brussel in de digitale wereld geeft, een beter inzicht krijgen van de stand van zaken van de .brussels TLDN.En 2012, la libĂ©ralisation du marchĂ© des noms de domaine de premier niveau a ouvert de nouvelles perspectives aux entreprises, aux administrations et aux particuliers, en leur permettant dâinclure un Ă©lĂ©ment gĂ©ographique dans le nom de domaine de leurs sites web. Depuis lors, trĂšs peu dâĂ©tudes, pour autant quâil en existe, ont Ă©tĂ© menĂ©es sur lâutilisation des nouveaux noms de domaine de premier niveau (top-level domain names, TLDN). Ă partir du cas spĂ©cifique du TLDN « .brussels », le prĂ©sent article propose une analyse empirique de lâimpact rĂ©el de lâouverture de ce marchĂ© sur les pratiques en matiĂšre dâenregistrement de noms de domaine. Au moyen de logiciels en accĂšs gratuit, tels quâOpenRefine, et de mĂ©thodes de traitement du langage naturel (TLN), lâensemble des 6 300 noms de domaine finissant par « .brussels » a pu ĂȘtre examinĂ© du point de vue quantitatif. LâinterprĂ©tation qualitative dâun Ă©chantillon statistiquement reprĂ©sentatif (592 noms de domaine) a permis dâaffiner lâanalyse pour voir comment ce nouveau TLDN est utilisĂ© dans la pratique. Ainsi, lâarticle apporte des informations dĂ©taillĂ©es sur lâincidence des rĂ©centes modifications rĂ©glementaires relatives Ă lâenregistrement des noms de domaine. VoilĂ qui devrait Ă©clairer chercheurs, dĂ©cideurs, investisseurs et quiconque se souciant de lâidentitĂ© de Bruxelles dans le monde numĂ©rique quant Ă la situation du TLDN « .brussels ».The opening up of the top-level domain name market in 2012 has offered new perspectives for companies, administrations and individuals to include a geographic component within the domain name of their website. Little to no research has been carried out since then to analyse the uptake of the new top-level domain names (TLDNs). Based on the specific case of the TLDN .brussels, this article proposes an empirical study of how the opening up of the top-level domain name market actually impacts registration practices. By making use of freely available software tools such as OpenRefine and Natural Language Processing (NLP) methods, the entire corpus of the .brussels domain names (6 300) was analysed from a quantitative perspective. Based on a statistically representative sample (592 domain names), a qualitative interpretation allowed a more fine-grained analysis of how the new TLDN is being used in practice. By doing so, the article gives detailed insight into the impact of the recent changes to the rules concerning domain name registration. Through this analysis, researchers, policy makers, investors and anyone concerned about the identity of Brussels in the digital realm may have a better understanding of the state of play of the .brussels TLDN
Methane flux from flowback operations at a shale gas site
We report measurements of methane (CH4) mixing ratios and emission fluxes derived from sampling at a monitoring station at an exploratory shale gas extraction facility in Lancashire, England. Elevated ambient CH4 mixing ratios were recorded in January 2019 during a period of cold-venting associated with a nitrogen lift process at the facility. These processes are used to clear the well to stimulate flow of natural gas from the target shale. Estimates of CH4 flux during the emission event were made using three independent modeling approaches: Gaussian plume dispersion (following both a simple Gaussian plume inversion and the US EPA OTM 33-A method), and a Lagrangian stochastic transport model (WindTrax). The three methods yielded an estimated peak CH4 flux during January 2019 of approximately 70 g sâ1. The total mass of CH4 emitted during the six-day venting period was calculated to be 2.9, 4.2 ± 1.4(1Ï) and 7.1 ± 2.1(1Ï) tonnes CH4 using the simple Gaussian plume model, WindTrax, and OTM-33A methods, respectively. Whilst the flux approaches all agreed within 1Ï uncertainty, an estimate of 4.2 (± 1.4) tonnes CH4 represents the most confident assessment due to the explicit modeling of advection and meteorological stability permitted using the WindTrax model. This mass is consistent with fluxes calculated by the Environment Agency (in the range 2.7 to 6.8 tonnes CH4), using emission data provided by the shale site operator to the regulator. This study provides the first CH4 emission estimate for a nitrogen lift process and the first-reported flux monitoring of a UK shale gas site, and contributes to the evaluation of the environmental impacts of shale gas operations worldwide. This study also provides forward guidance on future monitoring applications and flux calculation in transient emission events. Implications: This manuscript discusses atmospheric measurements near to the UKâs first hydraulic fracturing facility, which has very high UK public, media, and policy interest. The focus of this manuscript is on a single week of data in which a large venting event at the shale gas site saw emissions of ~4 tonnes of methane to atmosphere, in breach of environmental permits. These results are likely to beresults are likely to be reported by the media and may influence future policy decisions concerning the UK hydraulic fracturing industry
The ENIGMA sports injury working group - an international collaboration to further our understanding of sport-related brain injury
Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor
Facility level measurement of offshore oil and gas installations from a medium-sized airborne platform : method development for quantification and source identification of methane emissions
Emissions of methane (CH4) from offshore oil and gas installations are poorly ground-truthed, and quantification relies heavily on the use of emission factors and activity data. As part of the United Nations Climate & Clean Air Coalition (UN CCAC) objective to study and reduce short-lived climate pollutants (SLCPs), a Twin Otter aircraft was used to survey CH4 emissions from UK and Dutch offshore oil and gas installations. The aims of the surveys were to (i) identify installations that are significant CH4 emitters, (ii) separate installation emissions from other emissions using carbon-isotopic fingerprinting and other chemical proxies, (iii) estimate CH4 emission rates, and (iv) improve flux estimation (and sampling) methodologies for rapid quantification of major gas leaks. In this paper, we detail the instrument and aircraft set-up for two campaigns flown in the springs of 2018 and 2019 over the southern North Sea and describe the developments made in both the planning and sampling methodology to maximise the quality and value of the data collected. We present example data collected from both campaigns to demonstrate the challenges encountered during offshore surveys, focussing on the complex meteorology of the marine boundary layer and sampling discrete plumes from an airborne platform. The uncertainties of CH4 flux calculations from measurements under varying boundary layer conditions are considered, as well as recommendations for attribution of sources through either spot sampling for volatile organic compounds (VOCs) /ÎŽ 13CCH4 or using in situ instrumental data to determine C2H6-CH4 ratios. A series of recommendations for both planning and measurement techniques for future offshore work within marine boundary layers is provided
Linking Symptom Inventories using Semantic Textual Similarity
An extensive library of symptom inventories has been developed over time to
measure clinical symptoms, but this variety has led to several long standing
issues. Most notably, results drawn from different settings and studies are not
comparable, which limits reproducibility. Here, we present an artificial
intelligence (AI) approach using semantic textual similarity (STS) to link
symptoms and scores across previously incongruous symptom inventories. We
tested the ability of four pre-trained STS models to screen thousands of
symptom description pairs for related content - a challenging task typically
requiring expert panels. Models were tasked to predict symptom severity across
four different inventories for 6,607 participants drawn from 16 international
data sources. The STS approach achieved 74.8% accuracy across five tasks,
outperforming other models tested. This work suggests that incorporating
contextual, semantic information can assist expert decision-making processes,
yielding gains for both general and disease-specific clinical assessment
- âŠ