The immunoglobulin molecule is a perfect template for the de novo generation of biocatalytic functions. Catalytic antibodies, or abzymes, obtained by the structural mimicking of enzyme active sites have been shown to catalyze numerous chemical reactions. Natural enzyme analogs for some of these reactions have not yet been found or possibly do not exist at all. Nowadays, the dramatic breakthrough in antibody engineering and expression technologies has promoted a considerable expansion of immunoglobulin's medical applications and is offering abzymes a (...) unique chance to become a promising source of high‐precision “catalytic vaccines.” At the same time, the discovery of natural abzymes on the background of autoimmune disease revealed their beneficial and pathogenic roles in the disease progression. Thus, the conflicting Dr. Jekyll and Mr. Hyde protective and destructive essences of catalytic antibodies should be carefully considered in the development of therapeutic abzyme applications. (shrink)

An innovative approach to the production of anti‐receptor antibodies is now being fully exploited for a number of different cell receptors. This approach employs the concept that antibodies directed against pharmacologically active ligands have a three‐dimensional binding site which is somewhat analogous to the natural receptor. Consequently, when anti‐idiotype antibodies are produced against these anti‐ligand antibodies, some of the anti‐idiotypes will comprise a positive three‐dimensional shape which mimics the original ligand. The anti‐idiotypic antibodies generated in (...) this fashion are able to bind to cell surface receptors. This approach has now been successfully applied to peptide hormones, small bio‐active peptides, interferon, viral hemagglutinins, and a number of small neurotransmitter ligands. So far, the boundaries for this working ‘molecular engineering’ concept have not been reached. This concept may also shed light on the processes which take place in the generation of anti‐receptor antibodies in several autoimmune diseases. (shrink)

Niels Kaj Jerne has proposed the “immune network theory” of interactions among anti‐idiotypic antibodies, able to interfere with humoral responses to certain antigens. After the occurrence of the primary generation of antibodies, against an antigenic epitope, idiotypes of these antibodies induce anti‐idiotypic antibodies that modulate the intensity of the first response, and so on. Adverse effects following SARS‐COV‐2 COVID‐19 vaccines are occasionally similar to the symptoms of COVID‐19 infection. Rare events linked to SARS‐CoV‐2 vaccines also resemble (...) some rarely reported COVID‐19 complications. Safety data from product information by European Medicines Agency suggest that spectra do overlap for four main vaccines. The proposition is that vaccine events and COVID‐19 complications are related to anti‐idiotypic antibodies whose spatial shape can lead to interactions with ACE2 molecules, in individuals with a prolonged Spike protein synthesis. The vaccines target cells by their affinity to the vaccine vector, or to engulf lipid nanoparticles. Anti‐idiotypic antibodies shaped similarly to the Spike protein possibly interact with ACE2 molecules and cause diverse signs and symptoms. (shrink)

Antibodies that are specific for DNA provide an excellent system for studying the protein‐nucleic acid interactions that allow proteins to recognize specific DNA structures or sequences.

Mutations in DNA topoisomerase II are often correlated with drug‐resistance in tumor cell lines. Studies of topoisomerase II‐mediated drug‐resistance in various model systems, as well as the sequencing of such mutations from drug‐resistant tumors, have shed light on the functional domains of topoisomerase II, on how it interacts with inhibitors, and on the different mechanisms by which cells avoid the toxic effects of many clinically important anti‐tumor drugs.

DNA topoisomerases, capable of manipulating DNA topology, are ubiquitous and indispensable for cellular survival due to the numerous roles they play during DNA metabolism. As we review here, current structural approaches have revealed unprecedented insights into the complex DNA‐topoisomerase interaction and strand passage mechanism, helping to advance our understanding of their activities in vivo. This has been complemented by single‐molecule techniques, which have facilitated the detailed dissection of the various topoisomerase reactions. Recent work has also revealed the importance of topoisomerase (...) interactions with accessory proteins and other DNA‐associated proteins, supporting the idea that they often function as part of multi‐enzyme assemblies in vivo. In addition, novel topoisomerases have been identified and explored, such as topo VIII and Mini‐A. These new findings are advancing our understanding of DNA‐related processes and the vital functions topos fulfil, demonstrating their indispensability in virtually every aspect of DNA metabolism. (shrink)

The many genetic complementation groups of DNA excision‐repair defective mammalian cells indicate the considerable complexity of the excision repair process. The cloning of several repair genes is taking the field a step closer to mechanistic studies of the actions and interactions of repair proteins. Early biochemical studies of mammalian DNA repair in vitro are now at hand. Repair synthesis in damaged DNA can be monitored by following the incorporation of radiolabelled nucleotides. Synthesis is carried out by mammalian cell extracts and (...) is defective in extracts from cell lines derived from individuals with the excisionrepair disorder xeroderma pigmentosum. Biochemical complementation of the defective extracts can be used to purify repair proteins. Repair of damage caused by agents including ultraviolet irradiation, psoralens, and platinating compounds has been observed. Neutralising antibodies against the human single‐stranded DNA binding protein (HSSB) have demonstrated a requirement for this protein in DNA excision repair as well as in DNA replication. (shrink)

Topoisomerase enzymes – found in prokaryotes to human cells – control conformational changes in DNA and aid the orderly progression of DNA replication, gene transcription and the separation of daughter chromosomes at cell division. Several classes of anti‐cancer drugs are now recognised as topoisomerase poisons because of their ability to trap topoisomerase molecules on DNA as ‘cleavable complexes’. Understanding how drugs generate such complexes and why they are toxic to actively growing cancer cells is a major challenge for the development (...) of modern approaches to chemotherapy. (shrink)

Human monoclonal antibodies are extremely difficult to obtain by hybridoma technology. As an alternative, ‘human‐like’ antibodies have been produced by recombinant DNA technology. The first such engineered antibodies consisted of chimaeric proteins, in which murine variable regions were linked to human constant regions. More recently ‘human’ antibodies have been ‘reshaped’ by transplanting the binding site of a murine antibody into a human antibody. Further‐more antibodies have been dissected into groups of domains (Fab's, Fc's) and for (...) example, Fab's have been joined to enzymes resulting in antibody‐enzyme chimaeras. In addition to their potential clinical applications, engineered antibodies will prove invaluable in studies of structure/function relationships of variable and constant regions. (shrink)

In ordinary language, in the medical sciences, and in the overlap between them, we frequently make claims which imply that we might have had different gametic origins from the ones we actually have. Such statements seem intuitively true and coherent. But they counterfactually ascribe different DNA to their referents and therefore contradict material-origin essentialism, which Kripke and his followers argue is intuitively obvious. In this paper I argue, using examples from ordinary language and from philosophy of medicine and bioethics, that (...) statements which attribute alternative material origins to their referents are useful, common in political and medical reasoning, and in many cases best interpreted literally. So we must replace the doctrine of material-origin essentialism with one that can make sense of ordinary discourse and the language of the medical sciences. I propose an anti-essentialist account of such counterfactuals according to which individuals’ modal properties are relative to a given inquiry. (shrink)

High‐precision tumor targeting with conventional therapeutics is based on the concept of the ideal drug as a “magic bullet”; this became possible after techniques were developed for production of monoclonal antibodies (mAbs). Innovative DNA technologies have revolutionized this area and enhanced clinical efficiency of mAbs. The experience of applying small‐size recombinant antibodies (monovalent binding fragments and their derivatives) to cancer targeting showed that even high‐affinity monovalent interactions provide fast blood clearance but only modest retention time on the target (...) antigen. Conversion of recombinant antibodies into multivalent format increases their functional affinity, decreases dissociation rates for cell‐surface and optimizes biodistribution. In addition, it allows the creation of bispecific antibody molecules that can target two different antigens simultaneously and do not exist in nature. Different multimerization strategies used now in antibody engineering make it possible to optimize biodistribution and tumor targeting of recombinant antibody constructs for cancer diagnostics and therapy. BioEssays 30:904–918, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A large proportion of tumour‐associated antigens seem to be determined by carbohydrate structures. Advances in the study of the antigenicity of cell‐surface carbohydrates have been hampered by the absence of advanced monoclonal hybridoma technology comparable to that available for the study of protein antigens. Monoclonal antibodies have been raised against a carbohydrate epitope (43–9F) that is associated with the proliferative features of squamous lung carcinomas. These were used in turn to generate anti‐idiotype antibodies with homology to 43–9F. The (...) method and its possible applications are described, together with a procedure to detect rare cell membrane variants within large populations. (shrink)

The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour (...) cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity. (shrink)

Watson and Crick’s discovery of the structure of DNA led to developments that transformed many biological sciences. But what were the relevant developments and how did they transform biology? Much of the philosophical discussion concerning this question can be organized around two opposing views: theoretical reductionism and layer-cake antireductionism. Theoretical reductionist and their anti-reductionist foes hold two assumptions in common. First, both hold that biological knowledge is structured like a layer cake, with some biological sciences, such as molecular biology cast (...) at lower levels of organization, and others, such as classical genetics, cast at higher levels. Second, both assume that scientific knowledge is structured by theory and that the productivity of scientific research depends on whether the underlying theory identifies the fundamentals upon which the phenomena to be explained and investigated depend. In the first part of this paper, I challenge these assumptions. In the second part, I show how recasting the basic theory of classical genetics made it possible to retool the methodologies of genetics. It was the investigative power of these retooled methodologies, and not the explanatory power of a gene-based theory, that transformed biology. (shrink)

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress‐induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress‐induced mutation that are being revealed experimentally in laboratory settings provide (...) compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double‐strand‐break‐dependent stress‐induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti‐evolvability therapeutics for infectious disease and cancer. (shrink)

In response to DNA‐damage, cells have to decide between different cell fate programmes. Activation of the tumour suppressor HIPK2 specifies the DNA damage response (DDR) and tips the cell fate balance towards an apoptotic response. HIPK2 is activated by the checkpoint kinase ATM, and triggers apoptosis through regulatory phosphorylation of a set of cellular key molecules including the tumour suppressor p53 and the anti‐apoptotic corepressor CtBP. Recent work has identified HIPK2 as a regulator of the ultimate step in cytokinesis: the (...) abscission of the mother and daughter cells. Since proper cytokinesis is essential for genome stability and maintenance of correct ploidy, this finding sheds new light on the tumour suppressor function of HIPK2. Here we highlight the molecular mechanisms coordinating HIPK2 function and discuss its emerging role as a tumour suppressor. (shrink)

In 1956, I decided to apply my experience in microbial genetics to developing analogous systems for human cell lines, including the selection of mutants with either a loss or gain of a biochemical function. For instance, mutants resistant to azahypoxanthine showed a loss of the HPRT enzyme (hypoxanthine phosphoribosyl transferase), whereas gain of the same enzyme was accomplished by blocking de novo purine biosynthesis with aminopterin, while supplying hypoxanthine and thymine (HAT selection). Using HAT selection, we: (i) genetically transformed HPRT− (...) mutant cells to HPRT+ wild type by using DNA extracted from HPRT+ cells, and (ii) selected HPRT+ hybrid cells by fusing HPRT− D98/AH2 cells with skin cells. These approaches, which we dubbed in 1962 as a [first step toward gene therapy], contributed to the later development of (i) cell fusion techniques, (ii) the development of monoclonal antibodies, (iii) routine transformation of mammalian cells with cloned genes, and (iv) methods for creating transgenic organisms. (shrink)

ArgumentThis paper brings together the history of risk and the history of DNA repair, a biological phenomenon that emerged as a research field in between molecular biology, genetics, and radiation research in the 1960s. The case of xeroderma pigmentosum (XP), an inherited hypersensitivity to UV light and, hence, a disposition to skin cancer will be the starting point to argue that, in the 1970s and 1980s, DNA repair became entangled in the creation of new models of the human body at (...) risk – what is here conceptually referred to as the vulnerability aspect of body history – and new attempts at cancer prevention and enhancement of the body associated with the new flourishing research areas of antimutagenesis and anticarcinogenesis. The aim will be to demonstrate that DNA repair created special attempts at disease prevention: molecular enhancement, seeking to identify means to increase the self-repair abilities of the body at the molecular level. Prevention in this sense meant enhancing the body's ability to cope with the environmental hazards of an already toxic world. This strategy has recently been adopted by the beauty industry, which introduced DNA care as a new target for skin care research and anti-aging formulas. (shrink)

Promyelocytic leukaemia nuclear bodies (PML NBs) are generally present in all mammalian cells, and their integrity correlates with normal differentiation of promyelocytes. Mice that lack PML NBs have impaired immune function, exhibit chromosome instability and are sensitive to carcinogens. Although their direct role in nuclear activity is unclear, PML NBs are implicated in the regulation of transcription, apoptosis, tumour suppression and the anti‐viral response. An emerging view is that they represent sites where multi‐subunit complexes form and where post‐translational modification of (...) regulatory factors, such as p53, occurs in response to cellular stress. Following DNA damage, several repair factors transit through PML NBs in a temporally regulated manner implicating these bodies in DNA repair. We propose that PML NBs are dynamic sensors of cellular stress, which rapidly disassemble following DNA damage into large supramolecular complexes, dispersing associated repair factors to sites of damage. The dramatically increased total surface area available would enhance interactions between PML‐associated factors regulating DNA repair and apoptosis. BioEssays 26:963–977, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open (...) debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The functions of the Bloom syndrome helicase and its orthologs are well characterized in mitotic DNA damage repair, but their roles within the context of meiotic recombination are less clear. In meiotic recombination, multiple repair pathways are used to repair meiotic DSBs, and current studies suggest that BLM may regulate the use of these pathways. Based on literature from Saccharomyces cerevisiae, Arabidopsis thaliana, Mus musculus, Drosophila melanogaster, and Caenorhabditis elegans, we present a unified model for a critical meiotic role of (...) BLM and its orthologs. In this model, BLM and its orthologs utilize helicase activity to regulate the use of various pathways in meiotic recombination by continuously disassembling recombination intermediates. This unwinding activity provides the meiotic program with a steady pool of early recombination substrates, increasing the probability for a DSB to be processed by the appropriate pathway. As a result of BLM activity, crossovers are properly placed throughout the genome, promoting proper chromosomal disjunction at the end of meiosis. This unified model can be used to further refine the complex role of BLM and its orthologs in meiotic recombination. In meiotic recombination, Blm utilizes its helicase activity to disassemble early recombination intermediates, thereby retaining a pool of recombination sites from which some can be selected to enter the Class I crossover pathway while simultaneously promoting SDSA and preventing the use of the Class II pathway. (shrink)

Summary John Stuart Mill's classic tale of disillusionment from a ‘narrow creed’, an overt as much as a covert theme of his Autobiography (London, 1873), has for many years served as a guide to the search for the causes and sources of his ‘enlargement-of-the-utilitarian-creed’ project. As a result, in analyses of Mill's mature views, Samuel Taylor Coleridge—and friends—commonly take centre stage in terms of influence, whereas John's father—James Mill—is reduced either to a supernumerary or a villain in the last act (...) of John's intellectual development. However, students of Mill's works should not take at face value the story presented in Autobiography. Mill's own emphasis on the role of his ‘new influences’ has led scholars to disregard the role of his ‘old influences’ in his attempt to create a broader theory of living—one which takes into account both the intellectual and the emotional capacities of individuals. A close look at key aspects of John Stuart Mill's ‘enlargement project’ suggests that James Mill may have played a more positive role than is usually acknowledged. A way into the intellectual affinity of the two Mills is the person they both kept returning to for guidance and inspiration throughout their lives: Plato. (shrink)

John Stuart Mill considered his A System of Logic , first published in 1843, the methodological foundation and intellectual groundwork of his later works in ethical, social, and political theory. Yet no book has attempted in the past to engage with the most important aspects of Mill's Logic . This volume brings together leading scholars to elucidate the key themes of this influential work, looking at such topics as his philosophy of language and mathematics, his view on logic, induction and (...) deduction, free will, argumentation, ethology and psychology, as well as his account of normativity, kinds of pleasure, philosophical and political method and the "Art of Life.". (shrink)

The rise and fall of the historian of British India -- A classical education -- History, philosophy, and history -- Induction and deduction -- Rational persuasion -- Good government.

This book explores various connections of John Stuart Mill's thought to ancient Greek philosophy primarily in relation to his conception of happiness. It argues that a better understanding of Mill's background in ancient Greek thought and his reading(s) of Plato's dialogues leads to innovative interpretations of his moral and political thought.

It seems that eudaimonistic reconstructions of John Stuart Mill's conception of happiness have fallen prey to what they thought Mill should have done with regard to the role of pleasure in his notion of happiness. Insisting that utility and eudaimonia make conflicting claims, something which mirrors Mill's ‘conflicting loyalties’, they downgrade pleasure to just one of the ingredients of happiness. However, a closer look at Mill's intellectual development suggests otherwise. By focusing on Mill's radical background, this paper argues that pleasure (...) retains a central role in his conception of happiness – even from a eudaimonistic point of view. (shrink)

Contemporary sociosemiotics is a way to transcend borderlines between trends inside semiotics, and also other disciplines. Whereas semiotics has been considered as an interdisciplinary field of research par excellence, sociosemiotics can point directions at transdisciplinary research. The present article will try toconjoin the structural and the processual views on culture and society, binding them together with the notion of signification. The signification of space willillustrate the dynamic between both cultures and metacultures, and cultural mainstreams and subcultures. This paper pays attention (...) to the practice of sociocultural semiotisation of space and territorialisation by diverse examples and different sociocultural levels that imply semiotic cooperation between several members of groups that can be characterised as socii. We analyse territorialisation by graffiti, by furnishing spatial environment through artistic manners, by shaping the semiotic essence of cities through naming, renaming and translating street names, by pinning and structuring territories with monuments, by landmarking and mapping cultural space through individualisation of cities. We will see how principles of semiotisation of space are valid on different levels (individual and social, formal and informal, democratic and hegemonic, cultural and subcultural) and how these principles form a transdisciplinary object of study as ‘semiotisation of space’, and how space can be regarded as a genuinely transdisciplinary research object. Individual, culture, and society are connected in such an object both as constituents and as a background of study. (shrink)

The article views the development of the Tartu–Moscow semiotic school from the analysis of texts to the study of spatial entities (semiosphere being most well known of them). It comes to light that ‘culture’ and ‘space’ have been such notions in Tartu–Moscow School to which, for instance, the ‘semiosphere’ does not add much. There are studied possibilities to join Uexküll’s and Lotman’s basic concepts (as certain grounds of Estonian semiotics) with Tartu–Moscow School’s treatment of culture and space through the notion (...) of ‘semiotic subject’. Such an approach allows to see transdisciplinarity, which has come to issue only during the last decade, already in the first conceptions of Tartu–Moscow School where transdisciplinarity revealed itself in the symbiotic use of ‘culture’ and ‘space’. (shrink)

British Journal for the History of Philosophy, Volume 20, Issue 1, Page 204-207, January 2012.

This chapter argues that two distinct, yet connected, contexts – Mill's “mental crisis” and his task as a “Logician” – led to the formation of two arguments on the value of art. On one hand, Mill argued that aesthetic cultivation was important as an end in itself. Excellence was to be pursued disinterestedly as part of a beautiful life. On the other, Mill argued aesthetic cultivation was important as a means to the utilitarian end – strengthening the social sympathies made (...) social happiness attainable. The first argument highlights what Mill thought was missing from the theory of his utilitarian predecessors, while the second brought Mill closer to this tradition, rather than moving him further away from it. (shrink)

James Mill'sHistory of British India(1817) made a rather strange claim: first-hand experience of India was not vital in writing a history – potentially, it led to false ideas about its subject-matter: eyewitnesses are susceptible to bias. The historian was thus to perform his task as a judge: sifting through various testimonies to obtain a ‘more perfect’ conception of the whole than those who witnessed its various parts. Although strange, Mill's claim does not bewilder his readers: after all, Mill was a (...) ‘militant’ exponent of theorizing utilitarianism. I argue that such a reading of Mill's method is injudiciously restrictive. Not only did Mill draw on well-known methodological concerns in contemporary historiographical practice, not necessarily linked with Jeremy Bentham or the Scottish theoretical historiography, but he also seemed to adopt the vocabulary of forensic rhetoric, making his claim that his was a ‘judging’ history more literal than it has been supposed. (shrink)

Contemporary sociosemiotics is a way to transcend borderlines between trends inside semiotics, and also other disciplines. Whereas semiotics has been considered as an interdisciplinary field of research par excellence, sociosemiotics can point directions at transdisciplinary research. The present article will try to conjoin the structural and the processual views on culture and society, binding them together with the notion of signification. The signification of space will illustrate the dynamic between both cultures and metacultures, and cultural mainstreams and subcultures. This paper (...) pays attention to the practice of sociocultural semiotisation of space and territorialisation by diverse examples and different sociocultural levels that imply semiotic cooperation between several members of groups that can be characterised as socii. We analyse territorialisation by graffiti, by furnishing spatial environment through artistic manners, by shaping the semiotic essence of cities through naming, renaming and translating street names, by pinning and structuring territories with monuments, by landmarking and mapping cultural space through individualisation of cities. We will see how principles of semiotisation of space are valid on different levels and how these principles form a transdisciplinary object of study as ‘semiotisation of space’, and how space can be regarded as a genuinely transdisciplinary research object. Individual, culture, and society are connected in such an object both as constituents and as a background of study. (shrink)