416 research outputs found

    Vitalism and Its Legacy in Twentieth Century Life Sciences and Philosophy

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    This Open Access book combines philosophical and historical analysis of various forms of alternatives to mechanism and mechanistic explanation, focusing on the 19th century to the present. It addresses vitalism, organicism and responses to materialism and its relevance to current biological science. In doing so, it promotes dialogue and discussion about the historical and philosophical importance of vitalism and other non-mechanistic conceptions of life. It points towards the integration of genomic science into the broader history of biology. It details a broad engagement with a variety of nineteenth, twentieth and twenty-first century vitalisms and conceptions of life. In addition, it discusses important threads in the history of concepts in the United States and Europe, including charting new reception histories in eastern and south-eastern Europe. While vitalism, organicism and similar epistemologies are often the concern of specialists in the history and philosophy of biology and of historians of ideas, the range of the contributions as well as the geographical and temporal scope of the volume allows for it to appeal to the historian of science and the historian of biology generally

    Agency and Organisation: The Dialectics of Nature and Life

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    In recent decades, there have been major theoretical changes within evolutionary biology. In this dissertation, I critically reconstruct these developments through philosophy to assess how it may inform these debates. The overall aim is to show the mutual relevance between current trends in biology and the dialectical approach to nature. I argue that the repetition of the neglected tradition of organicism is anticipated both by a dialectical tradition within science and by Hegel’s philosophy – and that these theories may together inform the ongoing shift within evolutionary biology called the Extended Evolutionary Synthesis (EES). I stage the discussion by outlining the tenets and history of the modern synthesis (MS) and the alternative: the extended evolutionary synthesis (EES). It takes us into topics such as autonomy, organisation, reduction, and autopoiesis. Based on these discussions, I make the case that the most promising alternative to the MS is the so-called organisational approach formulated within theoretical biology and apply dialectics to strengthen this claim. In my view, they share a fundamental premise: Biology must surpass the physical worldview and adopt a more complex model to comprehend life as an ongoing regeneration of organisation and an expression of self-determination. To bring out the philosophical stakes of this shift, I take on Hegel’s writings on nature, life, and purposiveness and relate them to contemporary thinkers. The main contribution of this work lies not in a particularly novel reading of any of the theories I examine but in bringing them together – both within philosophy and biology and between them – and systematically mapping how philosophy and the humanities should deal with the natural sciences. The new kind of naturalism suggested here, which places life at its core, also calls for another scientific ideal which strives for unification without subsumption or eradication of differences

    New computational methods for structural modeling protein-protein and protein-nucleic acid interactions

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    Programa de Doctorat en Biomedicina[eng] The study of the 3D structural details of protein-protein and protein-DNA interactions is essential to understand biomolecular functions at the molecular level. Given the difficulty of the structural determination of these complexes by experimental techniques, computational tools are becoming a powerful to increase the actual structural coverage of protein-protein and protein-DNA interactions. pyDock is one of these tools, which uses its scoring function to determine the quality of models generated by other tools. pyDock is usually combined with the model sampling methods FTDOCK or ZDOCK. This combination has shown a consistently good prediction performance in community-wide assessment experiments like CAPRI or CASP and has provided biological insights and insightful interpretation of experiments by modeling many biomolecular interactions of biomedical and biotechnological interest. This software combination has demonstrated good predictive performance in the blinded evaluation experiments CAPRI and CASP. It has provided biological insights by modeling many biomolecular interactions of biomedical and biotechnological interest. Here, we describe a pyDock software update, which includes its adaptation to the newest python code, the capability of including cofactor and other small molecules, and an internal parallelization to use the computational resources more efficiently. A strategy was designed to integrate the template-based docking and ab initio docking approaches by creating a new scoring function based on the pyDock scoring energy basis function and the TM-score measure of structural similarity of protein structures. This strategy was partially used for our participation in the 7th CAPRI, the 3rd CASP-CAPRI and the 4th CASP-CAPRI joint experiments. These experiments were challenging, as we needed to model protein-protein complexes, multimeric oligomerization proteins, protein-peptide, and protein-oligosaccharide interactions. Many proposed targets required the efficient integration of rigid-body docking, template-based modeling, flexible optimization, multi- parametric scoring, and experimental restraints. This was especially relevant for the multi- molecular assemblies proposed in the 3er and 4th CASP-CAPRI joint experiments. In addition, a case study, in which electron transfer protein complexes were modelled to test the software new capabilities. Good results were achieved as the structural models obtained help explaining the differences in photosynthetic efficiency between red and green algae

    Predicting and Understanding Binding Affinities of Synthetic Anion Receptors

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    Anion receptors are molecules that can recognise and bind anions. They have applications in organocatalysis, anion sensing and the removal of anions from wastewater. Some anion receptors are also able to transport anions across cell membranes and show promise for the treatment of diseases such as cystic fibrosis and cancer. As such, it is of interest to develop computational methods that can reliably predict the physicochemical properties and anion binding affinities of these molecules. However, efforts to computationally model these molecules are hampered by the sheer size of typical receptors, making them too expensive to treat using accurate quantum chemical methods. Whilst efficient approximations such as local-correlation methods have been developed, the broader accuracy of these methods, particularly in their application to ionic non-covalent systems remains unclear. To address this gap, this thesis has carried out an extensive validation of local-correlation methods, and economical density functional theory (DFT) methods for receptors with different binding motifs. Additionally, multiscale models have also been examined with the view to extending the scope of these methods to model very large anion receptors. DFT methods giving good agreement with highly accurate calculations at a fraction of the cost were identified. The use of semiempirical methods combined with DFT in a multiscale model for calculating anion binding affinities lead to unexpectedly large errors with modest savings of computational time, while some "three-fold corrected" methods show promise in reducing the cost of geometry optimisations of large receptors. These validated protocols were subsequently applied to investigate the structure-binding relationships of a wide range of dual-hydrogen bonding receptors. Notably, different receptor motifs were found to have different conformational preferences, which could explain why experimentally, thioureas, thiosquaramides and croconamides show weaker chloride binding affinities than would be expected based on their acidity. The results suggest that pre-organising anion receptors in the conformer that facilitates hydrogen bond formation could be a promising strategy for the development of anion receptors. It is envisaged that these findings will aid in the design and screening of novel anion receptors with increased binding affinity and selectivity

    Elucidating the Structure and Regulatory Interactions of the HOTAIR Non-Coding RNA and the Bacterial RNase P. Holoenzyme

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    RNA structures and RNA-protein interactions are studied as potential drug targets, biomarkers in cancer, and can be administered as vaccines. The cancer associated HOTAIR (HOX transcript antisense RNA) exists in higher vertebrates and interacts with chromatin remodeling enzymes. We examined the thermodynamic folding properties and structural propensity of the exonic regions of HOTAIR using biophysical methods and NMR spectroscopy. Different exons of HOTAIR contain variable degrees of structural heterogeneity. We identify one exonic region, exon 4, that adopts a stable and compact fold under low magnesium concentrations. Close agreement of NMR spectroscopy and chemical probing confirm conserved base pair interactions within helix 10 of exon 4 of the human HOTAIR long non-coding RNA (lncRNA). Unlike HOTAIR, the ribonuclease P (RNase P) exists in bacteria, archaea and eukarya. RNase P is a universal RNA-protein endonuclease that catalyzes 5â€Č precursor-tRNA (ptRNA) processing. Protein concentration and temperature dependent NMR studies were performed on a thermostable RNase P protein from Thermatoga maritima to understand its oligomerization properties. The identification of a monomeric P protein conformer from NMR relaxation data and chemical shift information provided new insight into the conformational dynamics of the P protein. Taken together, local structural changes of the P protein and the 5â€Č leader RNA facilitate optimal substrate alignment and catalytic activation of the RNase P holoenzyme. As RNase P is an essential enzyme in life, knowledge of the structural differences between pathogenic bacterial and human RNase P may help in the development of new antibiotic therapeutics that target RNase P. The enzyme activity of Mycobacterium tuberculosis RNase P was examined through 32P radioactivity assays, and multidimensional 2D/3D NMR spectroscopy was implemented to study the solution structure of the M. tuberculosis RNase P protein. A comparative analysis of the pathogenic and non-pathogenic RNase P proteins brings important structural insight into the development of antibiotics that target tuberculosis RNase P

    ATHENA Research Book, Volume 2

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    ATHENA European University is an association of nine higher education institutions with the mission of promoting excellence in research and innovation by enabling international cooperation. The acronym ATHENA stands for Association of Advanced Technologies in Higher Education. Partner institutions are from France, Germany, Greece, Italy, Lithuania, Portugal and Slovenia: University of OrlĂ©ans, University of Siegen, Hellenic Mediterranean University, NiccolĂČ Cusano University, Vilnius Gediminas Technical University, Polytechnic Institute of Porto and University of Maribor. In 2022, two institutions joined the alliance: the Maria Curie-SkƂodowska University from Poland and the University of Vigo from Spain. Also in 2022, an institution from Austria joined the alliance as an associate member: Carinthia University of Applied Sciences. This research book presents a selection of the research activities of ATHENA University's partners. It contains an overview of the research activities of individual members, a selection of the most important bibliographic works of members, peer-reviewed student theses, a descriptive list of ATHENA lectures and reports from individual working sections of the ATHENA project. The ATHENA Research Book provides a platform that encourages collaborative and interdisciplinary research projects by advanced and early career researchers

    Telomeres, Sex and Epigenetics: The role of mouse HP1Îł on telomere stability and sexual dimorphism

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    Heterochromatin Protein 1 (HP1) is a protein family of epigenetic modifiers that are integral units of heterochromatin establishment with three mammalian isoforms HP1α, HP1ÎČ and HP1Îł. All three isoforms are found in heterochromatic regions where they assist with chromatin compaction and gene silencing, yet, HP1Îł is also enriched on euchromatic regions with a suggestive gene activating role. In mice, HP1Îł has been shown to influence genes that differ between the sexes, nonetheless, the implications of this sexual dimorphism and the molecular mechanisms underlying it are poorly understood. Here, I show that HP1Îł is important for male cell proliferation and its absence causes earlier onset of cellular senescence in both sexes. The effect of HP1Îł loss is further reflected in male embryo growth rate. Cleavage under targets and release using nuclease (CUT & RUN) analysis revealed that HP1Îł is binding on genes differentially expressed among the sexes affecting their expression. Preliminary data using Super-Low Input Carrier Cap analysis of gene expression (SLIC-CAGE) suggests that HP1Îł most likely does not regulate cryptic transcription in mice. HP1Îł was also enriched on repetitive DNA sequences at the end of chromosomes termed telomeres. Given the recruitment of HP1Îł at telomeres for heterochromatin formation and the direct link between senescence and telomere length, we examined the role of this factor on telomere maintenance. Loss of mouse HP1Îł leads to a downregulation of various telomere and telomere-accessory transcripts, including shelterin protein TRF1. This transcriptional and protein downregulation is associated with increased telomere replication stress and DNA damage, both effects more profound in females. My analysis suggests that the source of the impaired telomere replication is the increase in telomeric DNA:RNA hybrids due to the upregulation of TElomeric Repeatcontaining RNA (TERRA) arising from mouse chromosome 18 and chromosome X. Overall, this PhD thesis showcases the important role of HP1Îł on sexual dimorphism and telomere stability during early mouse development.Open Acces

    Insights into the function of DNA repair factors MRN and ATM

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    DNA double strand breaks (DSB) are a particularly deleterious threat to genomic integrity throughout all domains of life. DSBs can cause chromosomal aberrations, tumorigenesis and cell death if left unre-paired and are caused by either endogenous or exogenous sources. Cells rely on efficient detection, repair and response upon occurrence of DSBs. In eukaryotes, DSBs are mostly repaired by either end joining pathways or homologous recombination (HR). HR, in contrast to the end joining pathways, en-ables error-free DSB repair in presence of a template sister chromatid. The Mre11-Rad50-Nbs1 (MRN) complex recognizes and tethers DNA ends, even if they are obstructed by proteins to initiate HR. In order to respond to DSBs, the MRN complex recruits and activates the signaling kinase Ataxia-telangiectasia mutated (ATM), that belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. Activated ATM in turn initiates the cellular DNA damage response (DDR). Mre11 and Rad50 are highly conserved and form a topology-specific, ATP-dependent nuclease complex that pro-cesses DNA ends but leaves genomic DNA intact. The eukaryote specific Nbs1 subunit finetunes MRN’s endonuclease activity by providing interaction with proteins (e.g. CtIP). Apart from its nucleo-lytic activity, MRN has a scaffolding function that promotes DNA end tethering, repair foci formation and possibly signal amplification. Although the complex has been studied for more than two decades, a model that integrates both MRN’s enzymatic and scaffolding functions has not yet been established. In the first part of the thesis, such a model was elaborated by combining both structural and biochemical data from this and previ-ous studies. A cryo-electron microscopy (cryo-EM) structure of the Chaetomium thermophilum (Ct)MRN catalytic head domain in its ATPγS-bound state not only clarifies its atomic architecture but also reveals how a core part of Nbs1 stabilizes and possibly locks the Mre11 dimer. In this structure significant parts of the Rad50 coiled-coils were resolved in a rod configuration, stabilized by several interaction points. A previously uncharacterized C-terminal Mre11 domain, denoted bridge could fur-ther stabilize the rod configuration. The rod configuration and the bridge domain restrict access to the Rad50 DNA binding site. Biochemical analysis revealed the Rad50 DNA binding site is extremely specific for DNA ends. However, an additional, eukaryote-specific DNA binding site at the C-terminus of Mre11 enables binding to internal DNA. The Rad50 coiled-coil domains are linked at the apex via a zinc hook dimerization motif to form a large proteinaceous ring/rod. Cryo-EM data and crystal structures ex-plained how two MRN complexes can tether DNA ends via dimerization of these apical domains. In vivo assays indicate that mutation of the apex tethering element negatively impacts DSB repair. Mutations in DDR pathways allow cancer cells to cope with increased replication and genotoxic stress. For this reason, proteins involved in DDR were described to be promising targets in cancer therapy. Due to its central role in DSB induced DDR, ATM is an auspicious target for drug development. Howev-er, lack of ATM high-resolution structures, as well as atomic details of small molecule inhibitor binding modalities hampered the application of structure-based drug design. In the second part of the thesis, the binding modalities of two ATP-competitive ATM-inhibitors were described. This project was a col-laborative work with Merck KGaA, that provided a novel inhibitor (M4076) with improved pharmacoki-netics. Comparison of the inhibitor-bound kinase active sites with the likewise resolved ATPγS-bound active site explains the high affinities that were determined in biochemical assays. Superposition and sequence alignment of the ATM kinase active site with other PIKK active sites enables to rationalize the molecular reasons for selectivity. In biochemical assays, IC50 values of the inhibitors for ATM, PIKKs and CHK2 showed high selectivity towards ATM. The binding of the inhibitors stabilized the N-terminal solenoid domain of ATM, this enabled the generation of a high-resolution structure of the entire ATM protein. The quality of the map allowed the identification of two zinc binding sites that possibly stabi-lize loops and the generation of a near-complete ATM structure. Taken together, the structural data provides the framework for structure-based ATM inhibitor design and allows mapping of cancer muta-tion as well as functionally important protein interaction sites
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