Exocyclic DNA adducts are mutagenic lesions that can be formed by both exogenous and endogenous mutagens/carcinogens. These adducts are structurally analogs but can differ in certain features such as ring size, conjugation, planarity and substitution. Although the information on the biological role of the repair activities for these adducts is largely unknown, considerable progress has been made on their reaction mechanisms, substrate specificities and kinetic properties that are affected by adduct structures. At least four different mechanisms appear to have (...) evolved for the removal of specific exocyclic adducts. These include base excision repair, nucleotide excision repair, mismatch repair, and AP endonuclease‐mediated repair. This overview highlights the recent progress in such areas with emphasis on structure–activity relationships. It is also apparent that more information is needed for a better understanding of the biological and structural implications of exocyclic adducts and their repair. BioEssays 26:1195–1208, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Poly(ADP‐ribosyl)ation is a post‐translational modification occurring in the nucleus. The most abundant and best‐characterized enzyme catalyzing this reaction, poly(ADP‐ribose) polymerase 1 (PARP1), participates in fundamental nuclear events. The enzyme functions as molecular “nick sensor”. It binds with high affinity to DNA single‐strand breaks resulting in the initiation of its catalytic activity. Activated PARP1 promotes base excision repair. In addition, PARP1 modifies several transcription factors and thereby precludes their binding to DNA. We propose that a major function of (...) PARP1 includes the silencing of transcription preventing expression of damaged genes. Concomitant stimulation of DNA repair suggests that PARP1 acts as a switch between transcription and DNA repair. Another PARP‐type enzyme, tankyrase, is involved in the regulation of telomere elongation. Tankyrase modifies a telomere‐associated protein and thereby prevents it masking telomeric repeats providing access of telomerase for telomere elongation. Therefore, poly(ADP‐ribosyl)ation reactions may act as molecular switches in DNA metabolism. BioEssays 23:543–548, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In addition to double‐ and single‐strand DNA breaks and isolated base modifications, ionizing radiation induces clustered DNA damage, which contains two or more lesions closely spaced within about two helical turns on opposite DNA strands. Post‐irradiation repair of single‐base lesions is routinely performed by base excision repair and a DNA strand break is involved as an intermediate. Simultaneous processing of lesions on opposite DNA strands may generate double‐strand DNA breaks and enhance nonhomologous end joining, (...) which frequently results in the formation of deletions. Recent studies support the possibility that the mechanism of base excision repair contributes to genome stability by diminishing the formation of double‐strand DNA breaks during processing of clustered lesions. BioEssays 23:745–749, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

DNA glycosylases remove aberrant DNA nucleobases as the first enzymatic step of the base excision repair (BER) pathway. The alkyl‐DNA glycosylases AlkC and AlkD adopt a unique structure based on α‐helical HEAT repeats. Both enzymes identify and excise their substrates without a base‐flipping mechanism used by other glycosylases and nucleic acid processing proteins to access nucleobases that are otherwise stacked inside the double‐helix. Consequently, these glycosylases act on a variety of cationic nucleobase modifications, including bulky adducts, (...) not previously associated with BER. The related non‐enzymatic HEAT‐like repeat (HLR) proteins, AlkD2, and AlkF, have unique nucleic acid binding properties that expand the functions of this relatively new protein superfamily beyond DNA repair. Here, we review the phylogeny, biochemistry, and structures of the HLR proteins, which have helped broaden our understanding of the mechanisms by which DNA glycosylases locate and excise chemically modified DNA nucleobases. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted (...) multiple pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate (...) mRNA synthesis or shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed. (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)

Base pair mismatches in DNA arise from errors in DNA replication, recombination, and biochemical modification of bases. Mismatches are inherently transient. They are resolved passively by DNA replication, or actively by enzymatic removal and resynthesis of one of the bases. The first step in removal is recognition of strand discontinuity by one of the MutS proteins. Mismatches arising from errors in DNA replication are repaired in favor of the base on the template strand, but other mismatches trigger (...) class='Hi'>base excision or nucleotide excision repair (NER), or non‐repair pathways such as hypermutation, cell cycle arrest, or apoptosis. We argue that MutL homologues play a key role in determining biologic outcome by recruiting and/or activating effector proteins in response to lesion recognition by MutS. We suggest that the process is regulated by conformational changes in MutL caused by cycles of ATP binding and hydrolysis, and by physiologic changes which influence effector availability. (shrink)

Cells fine‐tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV‐induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair‐defective (...) diseases may involve repair‐transcription coupling: three candidate genes have been suggested.However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription.Repair of other damage departs further from the paradigm, even in some UV‐mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV‐induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted. (shrink)

The maintenance of genetic integrity is of vital importance to all living organisms. However, DNA – the carrier of genetic information – is continuously subject to damage induced by numerous agents from the environment and endogenous cellular metabolites. To prevent the deleterious consequences of DNA injury, an intricate network of repair systems has evolved. The biological impact of these repair mechanisms is illustrated by a number of genetic diseases that are characterized by a defect in one of the (...) repair machineries and in general predispose individuals to cancer. This article intends to review our current understanding of the complex nucleotide excision repair pathway, a universal repair system with a broad lesion specificity. Emphasis will be on the recent advances in the genetic analysis of this process in mammalian cells. (shrink)

We highlight a recent study exploring the hand‐off of UV damage to several key nucleotide excision repair (NER) proteins in the cascade: UV‐DDB, XPC and TFIIH. The delicate dance of DNA repair proteins is choreographed by the dynamic hand‐off of DNA damage from one recognition complex to another damage verification protein or set of proteins. These DNA transactions on chromatin are strictly chaperoned by post‐translational modifications (PTM). This new study examines the role that ubiquitylation and subsequent DDB2 (...) degradation has during this process. In total, this study suggests an intricate cellular timer mechanism that under normal conditions DDB2 helps recruit and ubiquitylate XPC, stabilizing XPC at damaged sites. If DDB2 persists at damaged sites too long, it is turned over by auto‐ubiquitylation and removed from DNA by the action of VCP/p97 for degradation in the 26S proteosome. (shrink)

One of the immediate eukaryotic cellular responses to DNA breakage is the covalent post‐translational modification of nuclear proteins with poly(ADP‐ribose) from NAD+ as precursor, mostly catalysed by poly(ADP‐ribose) polymerase‐1 (PARP‐1). Recently several other polypeptides have been shown to catalyse poly(ADP‐ribose) formation. Poly(ADP‐ribosyl)ation is involved in a variety of physiological and pathophysiological phenomena. Physiological functions include its participation in DNA‐base excision repair, DNA‐damage signalling, regulation of genomic stability, and regulation of transcription and proteasomal function, supporting the previously observed (...) correlation of cellular poly(ADP‐ribosyl)ation capacity with mammalian life. The pathophysiology effects are mediated through PARP‐1 overactivity, which can cause cell suicide by NAD+ depletion. It is apparent that the latter effect underlies the pathogenesis of a wide range of disease states including type‐1 diabetes, ischaemic infarcts in various organs, and septic or haemorrhagic shock. Therefore pharmacological modulation of poly(ADP‐ribosyl)ation may prove to be an exciting option for various highly prevalent, disabling and even lethal diseases. BioEssays 23:795–806, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

DNA metabolic events such as replication, repair and recombination require the concerted action of several enzymes and cofactors. Nature has provided a set of proteins that support DNA polymerases in performing processive, accurate and rapid DNA synthesis. Two of them, the proliferating cell nuclear antigen and its adapter protein replication factor C, cooperate to form a moving platform that was initially thought of only as an anchor point for DNA polymerases δ and ε. It now appears that proliferating cell (...) nuclear antigen is also a communication point between a variety of important cellular processes including cell cycle control, DNA replication, nucleotide excision repair, post‐replication mismatch repair, base excision repair and at least one apoptotic pathway. The dynamic movement of proliferating cell nuclear antigen on and off the DNA renders this protein an ideal communicator for a variety of proteins that are essential for DNA metabolic events in eukaryotic cells. (shrink)

DNA joining enzymes play an essential role in the maintenance of genomic integrity and stability. Three mammalian genes encoding DNA ligases, LIG1, LIG3 and LIG4, have been identified. Since DNA ligase II appears to be derived from DNA ligase III by a proteolytic mechanism, the three LIG genes can account for the four biochemically distinct DNA ligase activities, DNA ligases I, II, III and IV, that have been purified from mammalian cell extracts. It is probable that the specific cellular roles (...) of these enzymes are determined by the proteins with which they interact. The specific involvement of DNA ligase I in DNA replication is mediated by the non‐catalytic amino‐terminal domain of this enzyme. Furthermore, DNA ligase I participates in DNA base excision repair as a component of a multiprotein complex. Two forms of DNA ligase III are produced by an alternative splicing mechanism. The ubiqitously expressed DNA ligase III‐α forms a complex with the DNA single‐strand break repair protein XRCC1. In contrast, DNA ligase III‐β, which does not interact with XRCC1, is only expressed in male meiotic germ cells, suggesting a role for this isoform in meiotic recombination. At present, there is very little information about the cellular functions of DNA ligase IV. (shrink)

Flap EndoNuclease‐1 (FEN‐1) is a multifunctional and structure‐specific nuclease involved in nucleic acid processing pathways. It plays a critical role in maintaining human genome stability through RNA primer removal, long‐patch base excision repair and resolution of dinucleotide and trinucleotide repeat secondary structures. In addition to its flap endonuclease (FEN) and nick exonuclease (EXO) activities, a new gap endonuclease (GEN) activity has been characterized. This activity may be important in apoptotic DNA fragmentation and in resolving stalled DNA replication (...) forks. The multiple functions of FEN‐1 are regulated via several means, including formation of complexes with different protein partners, nuclear localization in response to cell cycle or DNA damage and post‐translational modifications. Its functional deficiency is predicted to cause genetic diseases, including Huntington's disease, myotonic dystrophy and cancers. This review summarizes the knowledge gained through efforts in the past decade to define its structural elements for specific activities and possible pathological consequences of altered functions of this multirole player. BioEssays 27:717–729, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Studies on transposable elements of the Ac family have led to different models for excision gap repair in either plants or Drosophila. Excision products generated by the plant transposable elements Ac and Tam3 imply a more or less straightforward ligation of broken ends; excision products of the Drosophila P element indicate the involvement of ‘double‐strand break’ (DSB) repair. Recent findings that excision products of Ac and Tam3 can also contain traces of the element ends (...) indicate, however, that DSB repair might be an alternative repair mechanism in plants. A functional DSB repair mechanism in plants can also be deduced from the observed rapid increases of Ac copy number during plant development and from the involvement of Ac in the generation of internal Ac deletions. On the other hand, alternative repair mechanisms may also be functional in Drosophila, because some of the ‘footprints’ generated upon P excision can be explained by a mechanism that has been postulated for excision gap repair in plants. It is concluded that plants and Drosophila can use similar repair mechanisms, but that the predominance of a certain repair mechanism is determined by the host. (shrink)

The aim of the present study was to examine whether offspring at high and low familial risk for depression differ in the immediate and more lasting behavioural and physiological effects of hedonica...

During the process of E. coli nucleotide excision repair, DNA damage recognition and processing are achieved by the action of the uvrA, uvrB, and uvrC gene products. The availability of highly purified proteins has lead to a detailed molecular description of E. coli nucleotide excision repair that serves as a model for similar processes in eukaryotes. An interesting aspect of this repair system is the protein complex's ability to work on a vast array of DNA (...) lesions that differ widely in their chemical composition and molecular architecture. Here we propose a model for damage recognition in which the UvrB protein serves as the component that confers enhanced specificity to a preincision complex. We hypothesize that one major determinant for the formation of a stable preincision complex appears to be the disruption of base stacking interactions by DNA lesions. (shrink)

With the rapid development of sports science, human motion recognition technology, as a new biometric recognition technology, has many advantages, such as noncontact target, long recognition distance, secret recognition process, and so on. Traditional human motion recognition technology is affected by environmental factors such as motion background, which is prone to rough edges of the recognized objects and loss of motion tracking information, thus further reducing the recognition accuracy. In this paper, the traditional snake model will be improved and optimized (...) to improve the defect of human motion model contour extraction, so as to realize the accurate repair of image contour; in terms of algorithm running time, this paper innovatively improves the construction process of the snake model, further improves the running time of model evaluation, and solves the concave contour problem of corresponding moving objects in the snake model. In order to solve the problem of accurate convergence, this paper improves the snake model of the average moving algorithm and sets the corresponding weight coefficient to distinguish the corresponding moving target background, so as to achieve the convergence of the differential concave contour. In order to verify the superiority of the improved optimized snake model, experiments are carried out in the corresponding database. The experimental results show that the contour of the moving object extracted by the improved snake model algorithm is complete and the segmentation effect is obvious. At the same time, the running speed of the whole algorithm has been significantly improved. (shrink)

Pragmatic language competence plays a central role in how aviation flight crews perform crew resource management ; this competence significantly affects aviation safety. This paper contributes to existing literature on interventionist applications of conversation analysis by defining and evaluating a novel collaborative transcription and repair based learning method for aviation CRM learning. CTRBL was evaluated using a quantitative quasi-­experimental repeated-measure design with 42 novice, university pilots. Results support that CTRBL is an effective, low-resource CRM learning method that will benefit (...) from exploratory applications and further study in pragmatics, aviation, and other sociotechnical domains. The views in this article were the result of independent research of the authors. Views herein do not necessarily represent the views of the National Transportation Safety Board or the United States. (shrink)

This study examined the effect of verbal and written apologies on trust repair based on competence and integrity after a trust violation. Through three experiments, the empirical results showed that the written apology was more effective than verbal ones a restoring trust for integrity-based trust violations. However, the verbal apology was more effective against competency-based trust violations than a written one. Moreover, the results also showed that perceived trustworthiness played a mediating role between trust violation and trust repair, (...) while positive emotions played a moderating role. Finally, this study provided a general discussion, implications, and suggestions for future research. (shrink)

1. Introduction A series of laboratory tests mandated by the Ephorate of Antiquities of Cyclades were undertaken in 2017 to determine the characteristics and properties of four samples of earth‑based material from the joints of ancient walls at the archaeological site of Delos. Based on the experimental results, three variations of an earth‑based mortar were tested in order to select the most compatible one in terms of characteristics and properties, for the stabilization of said structures....

Some people in global health are systematically subjected to epistemic wrongs, harms and injustices. And sometimes, with these epistemic wrongs, come more fundamental harms to their sense of self or dignity. -/- Each person has a moral right not to be treated as inferior. This moral right has found different forms of protection under dignity-based mechanisms. But these mechanisms do not extend, at least not explicitly, to epistemic wrongs, harms and injustices. -/- This article tries to pave the way for (...) a dignity-based approach to epistemic repair in global health, specifically through the lens of human rights. (shrink)

This paper describes a generative theory of bugs. It claims that all bugs of a procedural skill can be derived by a highly constrained form of problem solving acting on incomplete procedures. These procedures are characterized by formal deletion operations that model incomplete learning and forgetting. The problem solver and the deletion operator have been constrained to make it impossible to derive “star‐bugs”—algorithms that are so absurd that expert diagnosticians agree that the alogorithm will never be observed as a bug. (...) Hence, the theory not only generates the observed bugs, it fails to generate star‐bugs.The theory has been tested on an extensive data base of bugs for multidigit subtraction that was collected with the aid of the diagnostic systems buggy and debuggy. In addition to predicting bug occurrence, by adoption of additional hypotheses, the theory also makes predictions about the frequency and stability of bugs, as well as the occurrence of certain latencies in processing time during testing. Arguments are given that the theory can be applied to domains other than subtraction and that it can be extended to provide a theory of procedural learning that accounts for bug acquisition. Lastly, particular care has been taken to make the theory principled so that it can not be tailored to fit any possible data. (shrink)

The tumor suppressor protein p53 is intimately involved in the cellular response to DNA damage, controlling cell cycle arrest, apoptosis and the transcriptional induction of DNA damage inducible genes. A transcriptional target of p53, Gadd45, was recently found to bind to PCNA, a component of DNA replication/repair complexes, thereby implicating Gadd45 in DNA metabolism(1). Using biochemical assays, a role for Gadd45 in excision repair in vitro has been demonstrated(1). Antisense experiments have also indicated an in vivo role (...) for the GADD45 gene in UV‐irradiation survival. These discoveries establish a link between p53 and DNA repair through Gadd45. (shrink)

DNA topoisomerases are enzymes that can modify, and may regulate, the topological state of DNA through concerted breaking and rejoining of the DNA strands. They have been believed to be directly involved in DNA excision repair, and perhaps to be required for the control of repair as well. The vicissitudes of this hypothesis provide a noteworthy example of the dangers of interpreting cellular phenomena without genetic information and vice versa.

Ontology engineering is a hard and error-prone task, in which small changes may lead to errors, or even produce an inconsistent ontology. As ontologies grow in size, the need for automated methods for repairing inconsistencies while preserving as much of the original knowledge as possible increases. Most previous approaches to this task are based on removing a few axioms from the ontology to regain consistency. We propose a new method based on weakening these axioms to make them less restrictive, employing (...) the use of refinement operators. We introduce the theoretical framework for weakening DL ontologies, propose algorithms to repair ontologies based on the framework, and provide an analysis of the computational complexity. Through an empirical analysis made over real-life ontologies, we show that our approach preserves significantly more of the original knowledge of the ontology than removing axioms. (shrink)

The major mechanism of repair of damage to DNA involves a conceptually simple process of enzymatic excision and resynthesis of small regions of DNA. In man and other mammals, this process is regulated by several gene loci; up to 15 mutually complementary genes or gene products may be involved. Repair deficiency results in an array of clinical symptoms in skin, central nervous system, and hematopoietic and immune systems, the major example being xeroderma pigmentosum (XP), a disease with (...) a high incidence of cancer. Cloning repair genes by straightforward methods has proved difficult, but we have begun the effort by demonstrating that correction of a human repair deficiency can be achieved by transferring very small fragments of DNA from normal hamsters into XP cells. One of the complementation groups of XP cells (group C) appears to express a change in gene regulation such that these cells repair only a small clustered region of the DNA with high efficiency. (shrink)

The formation of DNA photoproducts by ultraviolet (UV) light is responsible for induction of mutations and development of skin cancer. To understand UV mutagenesis, it is important to know the mechanisms of formation and repair of these lesions. Cyclobutane pyrimidine dimers and (6–4)photoproducts are the two major classes of UV‐induced DNA lesions. Their distribution along DNA sequences in vivo is strongly influenced by nucleosomes and other DNA binding proteins. Repair of UV photoproducts is dependent on the transcriptional status (...) of the sequences to be repaired and on the chromatin environment. Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells. With the aid of in vitro systems, the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate. Future work will focus on the development of in vitro assays for transcription‐coupled repair and repair in chromatin. (shrink)

Peer interaction constitutes a focal site for understanding learning orientations and autonomous learning behaviors. Based on 10 h of video-recorded data collected from small-size conversation-for-learning classes, this study, through the lens of Conversation Analysis, analyzes instances in which L2 learners spontaneously exploit learning opportunities from the on-task public talk and make them relevant for private learning in sequential private peer interaction. The analysis of extended negation-for-meaning practices in peer interaction displays how L2 learners orient to public repair for their (...) learning opportunities in an immediate manner and in so doing, how different participation framework is being utilized to maximize their learning outcomes. As these extended repair practices are entirely managed by learners themselves, they yield both efficient and inefficient learning outcomes. Findings reveal that learners frequently resort to their peers to recycle the focal trouble words for learning opportunities, shifting their participating role from the on looking audience to active learners. By reporting the rather under-researched post-repair negotiation-for-meaning sequence in peer interactions, the study highlights the relevance between on-task classroom activities and private learning, contributing to understanding private learning behaviors in the language classroom and learning as a co-constructed activity locally situated in peer interaction. (shrink)

The progression of research and scholarly inquiry does not occur in isolation and is wholly dependent on accurate reporting of methods and results, and successful replication of prior work. Without mechanisms to correct the literature, much time and money is wasted on research based on a crumbling foundation. These guidelines serve to outline the respective responsibilities of researchers, institutions, agencies, and publishers or editors in maintaining the integrity of the research record. Delineating these complementary roles and proposing solutions for common (...) barriers provide a foundation for best practices. (shrink)

The recent finding of a role for the recA gene in DNA replication restart does not negate previous data showing the existence of recA‐dependent recombinational DNA repair, which occurs when there are two DNA duplexes present, as in the case for recA‐dependent excision repair, for postreplication repair (i.e., the repair of DNA daughter‐strand gaps), and for the repair of DNA double‐strand breaks. Recombinational DNA repair is critical for the survival of damaged cells. BioEssays (...) 26:1322–1326, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

A vital process in maintaining a low genetic error rate is the removal of mismatched bases in DNA. The importance of this process in E. coli is demonstrated by the 100–1000 fold increase in mutation frequency observed in cells deficient in this repair system(1). Mismatches can arise as a consequence of recombination, errors in replication and as a result of spontaneous chemical deamination, the latter process resulting in an estimated twelve T:G mismatches per genome per day in mammalian cells(2). (...) Recent studies, discussed here, provide evidence for the existence of specific mismatch repair systems in mammalian and human cells. (shrink)

Ontologies represent principled, formalised descriptions of agents’ conceptualisations of a domain. For a community of agents, these descriptions may differ among agents. We propose an aggregative view of the integration of ontologies based on Judgement Aggregation (JA). Agents may vote on statements of the ontologies, and we aim at constructing a collective, integrated ontology, that reflects the individual conceptualisations as much as possible. As several results in JA show, many attractive and widely used aggregation procedures are prone to return inconsistent (...) collective ontologies. We propose to solve the possible inconsistencies in the collective ontology by applying suitable weakenings of axioms that cause inconsistencies. (shrink)

In this review, we discuss a novel on‐site remodeling function that is mediated by the H2A‐ubiquitin binding protein ZRF1. ZRF1 facilitates the remodeling of multiprotein complexes at chromatin and lies at the heart of signaling processes that occur at DNA damage sites and during transcriptional activation. In nucleotide excision repair ZRF1 remodels E3 ubiquitin ligase complexes at the damage site. During embryonic stem cell differentiation, it contributes to retinoic acid‐mediated gene activation by altering the subunit composition of the (...) Mediator complex. We postulate that ZRF1 operates in conjunction with cellular remodeling machines and suggest that on‐site remodeling might be a hallmark of many chromatin‐associated signaling pathways. We discuss yet unexplored functions of ZRF1‐mediated remodeling in replication and double strand break repair. In conclusion, we postulate that on‐site remodeling of multiprotein complexes is essential for the timing of chromatin signaling processes. (shrink)

Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, have (...) been proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors. (shrink)

Concerns over the carbon footprint resulting from the manufacturing, usage and disposal of hardware have been growing. The right-to-repair legislation was introduced to promote sustainable utilisation of hardware by encouraging stakeholders to prolong the lifetime of products, such as electronic devices. As there is little empirical evidence from a consumer perspective on exercising the right to repair, this study aims firstly to examine the factors that underpin consumers’ intention to repair their hardware and secondly to investigate the (...) perceived outcomes of repair practices. Based on 510 responses, the results showed that intention to repair is dependent on three groups of factors, namely the facilitators of pro-environmental behaviour, repair-related factors and beliefs about legislation. If consumers have a stronger intention to repair, they have a stronger feeling of emotional self-assurance, satisfaction with the repair decision and the technology manufacturer, an intention to engage with the manufacturer and a positive perception of a repaired device’s performance. The findings contribute to the literature on sustainable behaviour and the right to repair, offering insight for policymakers and manufacturers about the strategies facilitating the wider adoption of repair practices. (shrink)

Transcription is a fundamental cellular process and the first step in gene regulation. Although RNA polymerase (RNAP) is highly processive, in growing cells the progression of transcription can be hindered by obstacles on the DNA template, such as damaged DNA. The authors recent findings highlight a trade‐off between transcription fidelity and DNA break repair. While a lot of work has focused on the interaction between transcription and nucleotide excision repair, less is known about how transcription influences the (...) repair of DNA breaks. The authors suggest that when the cell experiences stress from DNA breaks, the control of RNAP processivity affects the balance between preserving transcription integrity and DNA repair. Here, how the conflict between transcription and DNA double‐strand break (DSB) repair threatens the integrity of both RNA and DNA are discussed. In reviewing this field, the authors speculate on cellular paradigms where this equilibrium is well sustained, and instances where the maintenance of transcription fidelity is favored over genome stability. (shrink)

DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6‐methylguanine and 6‐thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a (...) consequence of this defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers. (shrink)

This paper analyses the right to repair (R2R) movement through the lens of radical democracy, elucidating the opportunities and limitations for advancing a democratic repair ethics against a backdrop of power imbalances and vested interests. We commence our analysis by exploring broader political-economic trends, demonstrating that Original Equipment Manufacturers (OEMs) are increasingly shifting towards asset-based repair strategies. In this landscape, hegemony is preserved not solely through deterrence tactics like planned obsolescence but also by conceding repairability while monopolizing (...) repair and maintenance services. We further argue that the R2R serves as an ‘empty signifier’, whose content is shaped by four counter-hegemonic frames used by the R2R movement: consumer advocacy, environmental sustainability, communitarian values, and creative tinkering. These frames, when viewed through Laclau and Mouffe’s theory of radical democracy, reveal different potentials for sustaining dissent and confronting OEMs' hegemony in the field of repair. Analysed in this way, an emerging business ethics of repair can be understood as driven by _the politics of repair beyond repair._ This notion foregrounds the centrality of non-violent conflict and antagonism for bringing radical democratic principles to repair debates, looking beyond narrow instrumentalist conversations, where repairability is treated as an apolitical arena solely defined by concerns for eco-efficiency and resource productivity. (shrink)

The management of children born with trisomy 18 is controversial, and both providers and parents often have differing opinions. Many parents choose to terminate the pregnancy while others go forward, making decisions based on their beliefs, understanding, and physician recommendations. Physicians are similarly divided regarding treatment of these children, as some feel that aggressive treatments are futile while others defer to the parents' wishes.Interrupted aortic arch with ventricular septal defect in children with trisomy 18 presents an ethical dilemma that highlights (...) the kinds of controversies in medical decision making facing physicians on a daily basis. Repair of interrupted aortic arch with ventricular septal defect poses a high risk to newborns with or without trisomy 18. Therefore, the option for surgery should be treated as with any routine informed consent process. Parents should be counseled about the risks, benefits, alternatives, and the likelihood of success both short and long term and be should offered a choice between surgery and palliative care. (shrink)

Targeted gene alteration (TGA) is a strategy for correcting single base mutations in the DNA of human cells that cause inherited disorders. TGA aims to reverse a phenotype by repairing the mutant base within the chromosome itself, avoiding the introduction of exogenous genes. The process of how to accurately repair a genetic mutation is elucidated through the use of single‐stranded DNA oligonucleotides (ODNs) that can enter the cell and migrate to the nucleus. These specifically designed ODNs hybridize (...) to the target sequence and act as a beacon for nucleotide exchange. The key to this reaction is the frequency with which the base is corrected; this will determine whether the approach becomes clinically relevant or not. Over the course of the last five years, workers have been uncovering the role played by the cells in regulating the gene repair process. In this essay, we discuss how the impact of the cell on TGA has evolved through the years and illustrate ways that inherent cellular pathways could be used to enhance TGA activity. We also describe the cost to cell metabolism and survival when certain processes are altered to achieve a higher frequency of repair. (shrink)

UV‐radiation‐induced lesions in DNA result in the formation of: (1) excision gaps (i.e. a lesion is excised, leaving a gap), (2) daughter‐strand gaps (i.e. a lesion can be skipped during replication, leaving a gap), and (3) double‐strand breaks (i.e. the DNA strand opposite a gap can be cut). In Escherichia coli, the recA gene product is involved in repairs of all three types of lesions – repair of daughter‐strand gaps (2) and double‐strand breaks (3) constitutes post‐replication repair. (...) The evidence suggests, furthermore, that recA‐dependent repair of excision gaps (1) produced in DNA replicated prior to UV irradiation (pre‐replication repair) appears to occur by similar mechanisms. (shrink)

This conceptual paper explores the theoretical possibilities of posthumanism and presents ecologies of repair as a heuristic device to explore the association modes of different entities, which, when confronted with the effects of human-induced destructive events, seek to repair the damage and transform the conditions of coexistence of various life forms. The central idea is that severe socio-environmental crisis caused by an intensification of industrial activity are conducive to observing new sociomaterial configurations and affective dispositions that, through the (...) reorganization of practices of resistance, remediation, and mutual care, are oriented to generating reparative and/or transformative processes from damaged ecologies and communities. Crises constitute true ontological experimentation processes where the presence of other-than-human natures, and of artifacts or devices that participate in reparative actions, become visible. A post-human approach to nature allows us to use languages and methodologies that do not restrict the emergence of assemblages under the assumption of theira prioriontological separation, but rather examine their reparative potential based on the efficacy of situated relationships. Methodologically, transdisciplinarity is relevant, with ethnography and other engaged methods applied over units of observation and experience called socio-geo-ecologies. The relevant attributes of these socio-geo-ecologies, beyond the individual, community, or institutional aspects, are the specific geological characteristics that make possible an entanglement of interdependent relationships between human and non-human agents. The conceptual analysis is illustrated with empirical examples stemming from socio-geo-ecologies researched in Southern Chile. (shrink)

The newest innovation in assisted reproduction is oocyte cryopreservation, more commonly known as egg freezing, which has been developed as a method of fertility preservation. Studies emerging from around the world show that highly educated professional women are turning to egg freezing in their late thirties to early forties, because they are still searching for a male partner with whom to have children. For these women, egg freezing may be a new “hope technology” for future romance; but it may also (...) be a “technology of despair,” as women navigate the ends of a failing relationship. Based on the largest ethnographic study to date, undertaken with 150 women who froze their eggs for nonmedical reasons in the United States and Israel, we examine egg freezing at the end of romance. Relationship dissolution—involving divorce, separation, broken engagements, and relationship breakups from men who are unfaithful, controlling, rejecting, uncommitted, or unready for fatherhood—is one of the major pathways to egg freezing. When such relationship dissolution ruptures a woman’s reproductive life course, egg freezing may become a “technology of repair,” allowing women to find new strengths and opportunities as well as new visions for the future. (shrink)

The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP‐ribose) (PAR) chains at damage sites through a previously uncharacterized coiled‐coil domain, a novel binding mode for PAR interactions. While KDM5A is a well‐known transcriptional regulator, its function in DNA repair is only now emerging. Here we review the molecular mechanisms that regulate this PARP1‐macroH2A1.2‐KDM5A axis in DNA damage and consider the potential involvement of this pathway (...) in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA‐based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies. (shrink)

ABSTRACT:Re-establishing trust presents a complex challenge for a firm after it commits corporate misconduct. We introduce a new construct, moral salience, which we define as the extent to which the firm’s behavior is morally noticeable to the stakeholder. Moral salience is a function of both the moral intensity of the firm’s behavior and the relational intensity of the firm-stakeholder psychological contract. We apply this moral salience construct to firm misconduct to develop a model of trust repair that is based (...) on goodwill, and moderated by the firm’s stakeholder culture. (shrink)

How to mobilize a traumatic national history on behalf of a less fractured polity? How to gain closure over a past that bifurcates the nation and establishes (at least) two national histories — history as told by the victims and by the perpetrators, now to be replaced by a history, as Mark Sanders (2003: 79) describes it, not of `bare facts but, at a crucial level, a history judged, and thus shaped, according to norms of universal human rights'. How to (...) engineer through politics the creation of new national selves, no longer pathologically attached to old and circumscribed forms of identification? These are now the critical questions confronting many elites: the overcoming of traumatic memory through various publicly mandated `technologies of the self'. To heal the nation requires the curing of the self. The politics of social repair understands itself largely through a psychologically inflected vocabulary of regret, apology, and forgiveness — the language of reconciliation. `Social cure', or reconciliation is understood as a process of social healing. In the face of traumatic ruptures in the body politic, in short, governments have sought to repair past wrongs and to heal an emotionally infirmed community. Such politics imply that societies have the capacity to repair themselves, to overcome traumatic pasts, just as an individual possesses the potential to overcome his or her own psychic trauma and fragmentation. But what evidence is there to support the claim that trauma — even for the individual — can be overcome, that history can be overridden, that forgiveness is possible? Psychoanalysis offers the most fully developed systematic body of work embracing a concept of the healing of the self. The article's aim, based upon an empirically derived (case-based) psychoanalysis, is to move toward a more robust theory of self-transformation and political reconciliation in post-traumatic communities. Thus, the article considers contemporary psychoanalytic evidence and asks of it the following questions: How is traumatic experience in the past recovered, and disabled, in the present? Is it necessary through memory to `return to the scene of the crime', in order to move beyond it? What features in the present-day therapeutic setting and in the therapeutic relationship promote healing? The objective is a grounded theory of reconciliation that includes discussion for whole societies of the role of historical recovery in social repair, the relation of the present to the past in self-constitution, and the requisite structure of the present-day reparative community to promote self-transformations. (shrink)