Dragon09/odtu_chatbot huggingface dataset:
towards highaffinity ligands for orphan receptors gpr3 gpr6 gpr12

the family of g proteincoupled receptors gpcrs comprises more than 800 human cell surface receptors that perceive and transmit extracellular stimuli into the cell interior due to their involvement in numerous biochemical processes gpcrs represent prime targets for the treatment of various diseases and are modulated by more than 30 of approved drugs today however a large proportion of the druggable gpcrome remains pharmacologically untapped including the socalled orphan gpcrs ogpcrs receptors for which the endogenous ligands remain unknowngpr3 6 and 12 constitute a cluster of orphan gpcrs that is involved in numerous pathophysiological processes including neurodegenerative disorders such as parkinsons and alzheimers dementia gpr3 and gpr12 further mediate meiotic arrest in oocytes and suppress the development of metabolic diseases other physiological processes and diseases associated with gpr3612 are neuropathic pain perception addiction and different forms of cancer although these receptors represent promising pharmacological targets and researchers have been trying to discover molecules targeting these receptors for more than two decades only a limited set of five ligands is currently available modern gpr3612targeted drug discovery is still hampered by the lack of verified endogenous ligands our poor understanding of their structural organization and signalling cascades promoted by these receptors and a limited panel of assays revealing gpr3612 activity in living cellshere i propose to implement an interdisciplinary research approach combining computational methodologies with advanced biosensor technology in order to discover advanced ligands for these attractive drug targets these novel compounds will aid in developing advanced therapeutics tackling severe human diseases and our reseach will highlight the power of interdisciplinary drug discovery approaches promoting their implementation in the gpcr field and beyond
inclusive aligned innovation agendas across europe

innaxe aims at strengthening the interconnection and fostering the dialog among european life sciences and healthtech innovation ecosystems to increase their efficiency and innovation capacities with the focus on the twin transformation that ecosystems stakeholders are already experiencing innaxe intends to define and prepare a joint actionable plan towards more interconnected inclusive sustainable dynamic and competitive life sciences and healthcare innovation ecosystems across the eu and associated countries to overcome the current fragmentation when it comes to innovation capabilities the consortium is composed of 6 leading cluster organisations that bring together connect coordinate dynamise and accelerate the life sciences and healthtech innovation ecosystems community at regional level in catalonia biocat es le de france medicen fr rhineneckar biorn de at national level in bulgaria hlsc bg and denmark dlsc dk and at eu level and associated countries cebr be the regionalnational ecosystems in this consortium cover all the innovation levels of the european innovation scoreboard eis and regional innovation scoreboard ris from emerging innovators to innovation leaders the joint action plan will specifically address performance gaps of emerging and moderate innovator regions with the help of strong innovator and innovation leader regions the project will broaden its scope to include ecosystems from other eu and associated countries through the council of european bioregions cebr a partner in this project innaxe intends to align the project outcomes to the diverse policies in the eu agenda for innovation ec work programs and regional local and national agendas as well as other eufunded projects exploring complementarities and synergies to draft an optimal joint action plan jap
mechanistic models of leukemianiche interaction using multimodal single cell profiling

the bone marrow is one of the most dynamic adult stem cell niches containing hematopoietic stem cells and nonhematopoietic mesenchymal stem and stromal cells which make up the bone marrow niche the niche regulates the immune system and constitutes a major determinant of chemoresistance in hematological malignancies including acute myeloid leukemia aml identifying the mechanisms by which aml interacts with its niche will open novel therapeutic avenuesaml is driven and maintained by leukemic stem cells lscs and failure to eradicate them will result in relapsing of the disease yet despite decades of research on lscs none of the therapies aiming at eradicating them reached clinical practice recent studies suggest an important role for bone marrow stromal and immune cells in driving aml together with our preliminary data that show lscsinduced upregulation of metastasisrelated genes in stromal cells this leads to the hypothesis that aml remodels its niche in ways that favours its survival and represses healthy hematopoiesis most studies in aml focus on lscintrinsic stromal niche or immune mediated mechanisms separately thus we currently lack a comprehensive view of the complexity of the human bone marrow and its interaction with aml to close these gaps we propose an ambitious experimental design including multimodal single cell sequencing of an aml cohort followed by innovative computational approaches integrating these data into predictive celltype specific models to generate mechanistic hypotheses about amlniche interactions that we then test using patientderived xenograft and in vitro culture models our ambitious project will provide fundamental insights into stem cellniche interactions and may lead to a paradigmshift in treating hematological malignancies away from eradicating malignant cells towards reconstituting a healthy niche that generates a healthy immune environment
connecting random conformal geometry and teichmüller theory

random conformal geometry deals with the analysis of conformally invariant systems using probabilistic methods random geometric objects such as the random fractal sle curves arise from statistical mechanics models and are of central interest in modern probability theory and mathematical physics teichmüller theory as originally introduced studies complex structures on a surface teichmüller spaces carry a rich geometric structure and have been an important research topic since the midtwentieth century these two fields are traditionally far apart however via the introduction of the loewner energy the pi showed surprisingly that sle is closely related to weilpetersson teichmüller space and made the first contact between sle theory and teichmüller theory further developments exploring the link and recent progress in probabilistic liouville conformal field theory also suggest that the connection between the two areas is stronger than currently known and we believe exploring the connection is of major scientific interest the ambition of this project is to break new ground in establishing links between fundamental concepts in random conformal geometry and teichmüller theory by combining in a pioneering way techniques from probability complex analysis geometric analysis khler geometry spectral theory and representation theory we focus on three objectives 1 advance the understanding of the deep reason behind the link between sle and the khler geometry of weilpetersson universal teichmüller space 2 establish the link between liouville actions and projective structures in a systematic way 3 identify the holography of loewner energy and explore the uncharted territory of holographic principles of random conformal geometry the successful completion of this program will substantially reshape our understanding of both areas and has the potential to bring revolutionary development to them both
expanding the genome editing toolbox by rational reprogramming of tyrosine recombinase dna specificities

gene therapies aim to cure genetic diseases by modifying the dna blueprint an ideal gene therapy should be durable safe and efficient which often requires integration of large therapeutic dna cargo at precise genomic locations advanced dna editors with programmable specificities such as the crispr technology are limited by the nucleasebased mechanism and poor efficiency of large dna insertions increased efficiency specificity and precision of large edits are required to address a broad therapeutic spacetyrosine recombinases yrs efficiently rearrange large dna segments without the pitfalls of nucleasebased editors but with an important caveat rational reprogramming of their specificities for binding nonnative dna targets is an unsolved problem edityr ambitiously aims to develop a rationally programmable tyrosine recombinase platform for efficient integration of large dna cargo into precise genomic locations edityr will expand recombinase engineering capabilities by exploiting the recent advances in large scale dna synthesis and sequencing coupled with bioinformatics and innovative protein design objective 1 will engineer tyrosine recombinase dna specificities and extract a comprehensive dna recognition code objective 2 will modify their oligomerization properties to enable binding nonpalindromic targets allowing targeting any desired nucleotide sequence objective 3 will investigate requirements for irreversible recombination to maximize integration efficiencies and unlock the full therapeutic potential of these enzymes finally objective 4 will validate engineered enzymes by identification of targetable sequences in therapeutically relevant genomic regions and integration of therapeutic dna cargo in various human cell types for different disease casesedityr will establish tyrosine recombinases as advanced tools for genome editing creating a dna editing technology that will elevate the capabilities of gene therapies to unprecedented levels
political elites and regime change in the middle east and north africa accommodation or exclusion

whether political elites accommodate or exclude their rivals during regime crises can be a matter of life and death following the 2011 uprisings in the middle east and north africa mena elite compromise sustained a democratic transition in tunisia while elite conflict triggered a coup in egypt tunisia has since seen three democratic elections while thousands of egyptians were jailed or killed by the new military regime why do elites in some cases pursue accommodation while they push for excluding their rivals in others menaperc proposes an answer to this puzzle the degrees of asymmetry and polarization between regime coalitions and their challengers shape elite preferences for accommodation or exclusion these preferences in turn determine the type of regime emerging from crisis regime coalitions comprise elites who provide crucial links to social constituencies and whose collective support stabilizes the regime the project theorizes the role of these actors linking macrolevel outcomes in terms of regime types to evidence on the microlevel of individual elites the project draws on evidence on 12 regime spells in three mena countries across more than a century regime coalitions are identified by focusing on members of parliament in egypt 1882present tunisia 1907present and turkey 1908present observing processes of elite change empirically based on individuallevel data on these elite members and leveraging these data in a mixedmethods design second the project traces causal mechanism through elite surveys and indepth fieldwork examining authoritarian consolidation in contemporary egypt democratization in tunisia and democratic backsliding in turkey the project makes three contributions it theorizes why elites accommodate or exclude during regime crises it pioneers an innovative way of testing this model by observing elite change over time and it traces the models causal mechanisms in ongoing processes of regime change
competition in the digital era technology and geopolitics in the xxi century

the competition in the digital era code project investigates the competition between china europe and the united states us for access and control of three critical technological sectors semiconductors cloud computing and space these sectors are respectively the backbone the brain and the legs of the current wave of technological innovation and they have a fundamental impact on economic military and geopolitical hierarchiescode proposes a multidisciplinary theoretical framework and an original mixedmethod approach to study technology competition in these sectors the main hypothesis of the project is that the very technological characteristics of the industrial sectors are key to explain when and why china europe and the us succeed in some sectors and struggle in others specifically different combinations of cycle of technological change the speed at which technologies evolve in each industrial sector and the degree of modularity the possibility to divide complex technical systems into components and outsource them to external suppliers generate different hypotheses on the ability of china and europe to compete with the us in semiconductors cloud and spacecode is a highrisk project because investigates technologically complex and highly politicized sectors yet it is also a highgain project as simultaneously advances the debate on international relations uschina geopolitical transition europes role in the world political economy role of the state in technology innovation role of global value chains and management and innovation how technology competition unfolds in highly politicized sectors
flexible chemical looping combustion for combined heat and power production from biogenic residues with negative emission

chp plants are burdened with significant economic risks when investing in carbon capture and storage ccs due to the high cost and energy penalty of ccs switching the feedstock from fossil fuels to biomass can significantly reduce the overall co2 emission however it is essential to develop chp technologies that can utilize lowvalue biogenic residues and wastes to avoid an increase in the cost of utility in addition coupling a biochp plant with ccs results in negative co2 emissions which is fundamental to many scenarios to reach the net zero emission targetsthe bioflexclc project develops and demonstrates a novel flexible technology for chp plants at trl 5 to utilize lowvalue biogenic residues as feedstock for heat and power production with negative co2 emissions bioflexclc combines the breakthrough chemicallooping combustion clc technology with conventional circulating fluidized bed cfb boilers the concept is flexible to switch between clccfb modes bioflexclc operating in clc mode has inherent co2 capture at a low cost and without energy penalty bioflexclc utilizes biogenic residues and wastes improves conversion efficiencies achieves negative co2 emissions reduces sox and nox emissions enhances co2 capture efficiency at a considerably reduced cost has flexibility towards load demand fluctuations and the capacity to switch to cfb combustion if market conditions are not amiable for carbon capture or if there is difficulty in the operation to decreases the risk of implement bioflexclc is supported by an expert consortium to ensure the quality of research and appropriate exploitation the academic partners in the consortium are leading institutions in the areas of clc and cfb boilers the industrial partners are technology providers of boilers chemical looping technologies as well as gas cleaning and co2 liquefaction bioflexclc is also backed by utility companies in the consortium having chp plants on biomass and fossil fuel
computational scanning for responding clonotypes in immune repertoires

personalized medicine promises to exploit the diversity of human immune repertoires to design targeted t cell and b cellbased vaccines and therapeutics however even for mass vaccine design identifying responding clonotypes to new viruses is costly labor intensive and time consumingrespond turns existing algorithmic solutions for identifying responding immune clonotypes into a userfriendly platform to aid drug and therapeutics discovery respond combines different algorithmic solutions and finds the best computational approach to fit the users needs it is based on four methods developed during the erc cog struggle project alice noiset fstar and hlaguessr they are based on different properties of responding clonotypes from sequence similarity to abundance and publicness the idea of respond is to integrate these features in a userfriendly tool that exploits the strengths of all methods to find the best answer to the practitioners query respond will return lists of candidates for responding clonotypes and a statistical analysis of their occurrence in databssescollaborating with big pharma startups medical researchers and practitioners respond will develop computational solutions to reduce the costs of biotechnological discovery and significantly decrease the time to test new vaccines and treatments based on consulting and feedback we will aim to give the user what they need in an appealing interface the tool will be of use for everyone involved in exploiting immune repertoires for treatment and prophylactics from personalized medicine mass vaccine design to agriculture respond will pursue commercialization and market solutions both within academia the biotechnology and medical sectors
understanding the maintenance and heritability of hematopoietic stem cell memories highthroughput drug screening meets singlecell barcoding

during the development of multicellular organisms cells from the same niche can be stochastically exposed to different signals and stimuli and this variability has the potential to create epigenetic heterogeneity across cell populations importantly this heterogeneity can confer individual cells different functional properties or different capacities to respond to the same stimuli during the last decade multiple laboratories have reported the existence of hematopoietic stem cell hsc clones with different functional behaviors that are transmitted to daughter cells very interestingly these behaviors are transmitted to their progeny even after transplantation suggesting that heritable epigenetic components are required to establish and maintain them in this regard some questions arise which epigenetic regulators are involved in the maintenance of these memories which regions associate with specific hsc fate memories and how heritable are different chromatin states in dividing hscs until recently we were very limited by the current technologies to answer these questions now recent advances in singlecell lineage tracing singlecell multiomics and exvivo hsc expansion cultures can be leveraged to provide a robust mechanistic understanding of clonal heritability of hsc fates and states consequently this proposal aims to combine new lineage tracing techniques multimodal singlecell sequencing and functional assays to 1 create an atlas of clonallyheritable epigenetic states associated to specific functional hsc behaviors and 2 to identify epigenetic regulators that are required to maintain and transmit hsc memories associated with specific hsc fates
the first nonsurgical repair for pelvic organ prolapse

pelvic organ prolapse pop affects nearly 50 of women over 40 years old globally 89 of the cases seek treatment for symptomatic early stage prolapse despite the high prevalence and the progression of pop over time patients currently cannot be offered a repair solution until the condition worsens enough for surgical intervention however the surgical interventions of prolapse have several side effects like prolonged recovery pelvic pain and relapses of pop escala medical has developed a minimally invasive and incisionfree repair intervention for earlystage pop repair apyx apyx is the first medical device for treating early stage prolapse regaining quality of life and prevention of prolapse deterioration for the vast majority currently unaddressed pop sufferers the eic project will finalize the development of apyx conduct clinical trials and support scaleup and commercialization activities
a complete transformation path for cc backboned plastic wastes to highvalue chemicals and materials

plastic pollution has become a clear threat to many environmental niches and ecosystems due to rapidly increasing use of plastic products and leakage to the environment polyethylene pe is the most widely used and the largestvolume plastic ca 30 of total plastics due to the absence of reactive groups the cc backboned plastics are often categorized as nondegradable generally disposed by incineration or landfill 67 about 12 plastic wastes are recycled as the goods with inferior quality and performance the real catalytic route for upcycling of pe wastes into valueadded products is 1 it is clear that there is an urgent need to develop new routes for innovative upcycling of plastic wastes towards a paradigm shift in the plastic economy actpac proposes a complete valueadded industryviable path to convert pe firstly into alkanes then into highvalue chemicals monomers and finally into pelike but fully biodegradable polyesters beyond the stateofthe art technologies actpac will design and deploy new catalysts and crossmetathesis modes for highly active and selective metathesis of pe into linear alkanes with a narrow distribution range c6c18 90 two separate systems multienzyme machinery assembled in the recombinant cells and metabolic engineered yeast system dedicated to the transformation of alkanes into monomers will be developed monomers of diversified chainlengths will be used for the synthesis of polyesters presenting different properties and polymer performances assignable for various applications a zerowaste solution to the plastic waste management is thus created to keep them out of the environment and reclaim their values the new properties and specific applications of the new polyester plastics produced from upcycling of pe waste will bring up the smes with new business opportunities by scalable flexible and robust multiproduct manufacturing processes for ondemand and smallvolume output production
overcoming the curse of dimensionality through nonlinear stochastic algorithms

in a series of relevant real world problems it is of fundamental importance to approximatively compute evaluations of highdimensional functions such highdimensional approximation problems appear eg in stochastic optimal control problems in operations research eg in supervised learning problems eg in financial engineering where partial differential equations pdes and forward backward stochastic differential equations fbsdes are used to approximatively price financial products and eg in nonlinear filtering problems where stochastic pdes are used to approximatively describe the state of a given physical system with only partial information available standard approximation methods for such approximation problems suffer from the socalled curse of dimensionality in the sense that the number of computational operations of the approximation method grows at least exponentially in the problem dimension it is the key objective of this project to design and analyze approximation algorithms which provably overcome the curse of dimensionality in the case of stochastic optimal control problem nonlinear pdes nonlinear fbsdes certain spdes and certain supervised learning problems we intend to solve many of the above named approximation problems by combining different types of multilevel monte carlo approximation methods in particular multilevel picard approximation methods with stochastic gradient descent sgd optimization methods another chief objective of this project is to prove the conjecture that the sgd optimization method converges in the training of anns with relu activation we expect that the outcome of this project will have a significant impact on the way how highdimensional pdes fbsdes and stochastic optimal control problems are solved in engineering and operations research and on the mathematical understanding of the training of anns by means of the sgd optimization methods