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)

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)

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)

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 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)

MutL family proteins contain an N‐terminal ATPase domain (NTD), an unstructured interdomain linker, and a C‐terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand‐specific DNA mismatch repair by cleaving the error‐containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two‐ or three‐metal ion cleavage mechanism. A motif required for this endonuclease activity is present (...) in the unstructured linker of Mlh1 and is conserved in all eukaryotic Mlh1 proteins, except those from metamonads, which also lack the almost absolutely conserved Mlh1 C‐terminal phenylalanine‐glutamate‐arginine‐cysteine (FERC) sequence. We hypothesize that the cysteine in the FERC sequence is autoinhibitory, as it sequesters the active site. We further hypothesize that the evolutionary co‐occurrence of the conserved linker motif with the FERC sequence indicates a functional interaction, possibly by linker motif‐mediated displacement of the inhibitory cysteine. This role is consistent with available data for interactions between the linker motif with DNA and the CTDs in the vicinity of the active site. (shrink)

Mars 1980. Une série d'entretiens publiés par le Nouvel Observateur fait scandale. Jean-Paul Sartre, un mois avant sa mort, y révoque des pans entiers de son oeuvre, dénigrant la notion d'angoisse et reléguant l'athéisme pour s'intéresser au messianisme juif et à la résurrection des corps. Face à lui, son dernier secrétaire, Benny Lévy. Accusé par Simone de Beauvoir de manipuler Sartre, Benny Lévy offre à l'écrivain une dernière occasion de revisiter son oeuvre.

Receptor oligomerization plays a key role in maintaining genome stability and restricting protein mutagenesis. When properly folded, protein monomers assemble as oligomeric receptors and interact with environmental ligands. In a gene-centered view, the ligand specificity expressed by these receptors is assumed to be causally predetermined by the cell genome. However, this mechanism does not fully explain how differentiated cells have come to express specific receptor repertoires and which combinatorial codes have been explored to activate their associated signaling pathways. It is (...) our contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible for receptor monomers to assemble along the membrane and to sustain meaningful relationships with environmental ligands. How could a cell lineage deal with these loss-of-function mutations during evolution and restrain gene redundancy accordingly? In this paper, we will be arguing that the easiest way for bacteria clones to accomplish this goal is by getting rid of cells expressing mutated receptor proteins. The mechanism sustaining this cell selection is also occurring in many somatic tissues and its function is currently believed to counteract in vivo protein mutagenesis. Our discussion will be mainly focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms. (shrink)

Somatic diversification of antigen receptor genes depends on the activity of enzymes whose homologs participate in a mutagenic DNA repair in unicellular species. Indeed, by engaging error-prone polymerases, gap filling molecules and altered mismatch repair pathways, lymphocytes utilize conserved components of genomic stress response systems, which can already be found in bacteria and archaea. These ancient systems of mutagenesis and repair act to increase phenotypic diversity of microbial cell populations and operate to enhance their ability to produce fit variants (...) during stress. Coopted by lymphocytes, the ancient mutagenic processing systems retained their diversification functions instilling the adaptive immune cells with enhanced evolvability and defensive capacity to resist infection and damage. As reviewed here, the ubiquity and conserved character of specialized variation-generating mechanisms from bacteria to lymphocytes highlight the importance of these mechanisms for evolution of life in general. (shrink)

Many proteins responsible for genome maintenance interact with one another via short sequence motifs. The best known of these are PIP motifs, which mediate interactions with the replication protein PCNA. Others include RIR motifs, which bind the translesion synthesis protein Rev1, and MIP motifs, which bind the mismatch repair protein Mlh1. Although these motifs have similar consensus sequences, they have traditionally been viewed as separate motifs, each with their own target protein. In this article, we review several recent studies (...) that challenge this view. Taken together, they imply that these different motifs are not distinct entities. Instead, there is a single, broader class of motifs, which we call “PIP‐like” motifs, which have overlapping specificities and are capable of binding multiple target proteins. Given this, we must reassess the role of these motifs in forming the network of interacting proteins responsible for genome maintenance. (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)

Mitotic recombination is a repair process which is known to repair double strand breaks and to fill double‐strand gaps by copying a homologous sequence. Meiotic recombination is a process of heteroduplex formation which sometimes generates crossovers. Evidence is presented that the later stages of meiotic recombination have some characteristics of mitotic repair recombination, leading to the conclusion that mismatch repair may be a recombinogenic repair process. The evidence suggests that the recombinational repair process generates hetero‐duplex bubbles which can move. (...) Some bubbles become crossovers. Others cease to exist, perhaps because topoisomerase activity breaks them down. (shrink)

We examine several cases of object movement from various languages, and demonstrate that the syntactic behavior of objects can be derived from certain conditions on LF representations. Conditions on LF relevant to the distribution of arguments are identified as relative scope fixing and type mismatch repair. These two conditions interact with the multiple semantic types that may be assigned to NPs (cf. Partee 1987) to induce movement of certain objects out of the VP, universally by LF and parametrically in (...) the overt syntax. Diesing's (1992b) Mapping Hypothesis combined with the multiple NP types predicts that quantificational NPs in object position will have to undergo movement by LF. This movement is forced by the principles of semantic composition as a mechanism of type mismatch resolution. The existential closure operation over VP is claimed to be genuinely unselective: any NP that introduces a free variable and does not receive an existential interpretation must move out of the scope of existential closure (and thus out of the VP) by LF. Pronouns are variables, limited in semantic type assignment, that by virtue of their definiteness cannot be bound by existential closure and must move out of its scope. In Egyptian Arabic, object pronouns escape from the VP via attachment to a verb that raises to adjoin to an Aspect inflectional head above the VP. The movement of object pronouns and definite/specific NPs in Scandinavian is also associated with verb movement. (shrink)

A major barrier to recombination between bacterial species lies in the mismatch repair system, a complex of proteins that has evolved to proof‐read freshly replicated DNA. It now appears that a second system, involving an inducible DNA recombination, repair and mutagenesis pathway, also regulates interspecies recombination, but in a positive way, being required for recombination between Escherichia coli and Salmonella typhimurium(1). Thus the rate at which newly emerging species of bacteria diverge can be seen as a balance between a (...) permissive state associated with inducible repair and recombination, and the proof‐reading of intermediates in the recombination pathway by the mismatch correction system. (shrink)

The review gives an introductory description of the successive development of data patterns based on comparisons between hearing-impaired and normal hearing participants’ speech understanding skills, later prompting the formulation of the Ease of Language Understanding model. The model builds on the interaction between an input buffer and three memory systems: working memory, semantic long-term memory, and episodic long-term memory. RAMBPHO input may either match or mismatch multimodal SLTM representations. Given a match, lexical access is accomplished rapidly and implicitly within (...) approximately 100–400 ms. Given a mismatch, the prediction is that WM is engaged explicitly to repair the meaning of the input – in interaction with SLTM and ELTM – taking seconds rather than milliseconds. The multimodal and multilevel nature of representations held in WM and LTM are at the center of the review, being integral parts of the prediction and postdiction components of language understanding. Finally, some hypotheses based on a selective use-disuse of memory systems mechanism are described in relation to mild cognitive impairment and dementia. Alternative speech perception and WM models are evaluated, and recent developments and generalisations, ELU model tests, and boundaries are discussed. (shrink)

In contrast to bilaterian animals, non‐bilaterian mitochondrial genomes contain atypical genes, often attributed to horizontal gene transfer (HGT) as an ad hoc explanation. Although prevalent in plants, HGT into animal mitochondrial genomes is rare, lacking suitable explanatory models for their occurrence. HGT of the mismatch DNA repair gene (mtMutS) from giant viruses to octocoral (soft corals and their kin) mitochondrial genomes provides a model for how barriers to HGT to animal mitochondria may be overcome. A review of the available (...) literature suggests that this HGT was mediated by an alveolate endosymbiont infected with a lysogenic phycodnavirus that enabled insertion of the homing endonuclease containing mtMutS into octocoral mitochondrial genomes. We posit that homing endonuclease domains and similar selfish elements play a crucial role in such inter‐domain gene transfers. Understanding the role of selfish genetic elements in HGT has the potential to aid development of tools for manipulating animal mitochondrial DNA. (shrink)

Mammalian cells frequently depend on homologous recombination (HR) to repair DNA damage accurately and to help rescue stalled or collapsed replication forks. The essence of HR is an exchange of nucleotides between identical or nearly identical sequences. Although HR fulfills important biological roles, recombination between inappropriate sequence partners can lead to translocations or other deleterious rearrangements and such events must be avoided. For example, the recombination machinery must follow stringent rules to preclude recombination between the many repetitive elements in a (...) mammalian genome that share significant but imperfect homology. This paper takes a conceptual approach in addressing the homology requirements for recombination in mammalian genomes as well as the general strategy used by cells to reject recombination between similar but imperfectly matched sequences. A mechanism of heteroduplex rejection that involves the unwinding of recombination intermediates that may form between mismatched sequences is discussed. BioEssays 30:1163–1171, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

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)

Moral Repair examines the ethics and moral psychology of responses to wrongdoing. Explaining the emotional bonds and normative expectations that keep human beings responsive to moral standards and responsible to each other, Margaret Urban Walker uses realistic examples of both personal betrayal and political violence to analyze how moral bonds are damaged by serious wrongs and what must be done to repair the damage. Focusing on victims of wrong, their right to validation, and their sense of justice, Walker presents a (...) unified and detailed philosophical account of hope, trust, resentment, forgiveness, and making amends - the emotions and practices that sustain moral relations. Moral Repair joins a multidisciplinary literature concerned with transitional and restorative justice, reparations, and restoring individual dignity and mutual trust in the wake of serious wrongs. (shrink)

Mismatch is a prominent concept in evolutionary medicine and a number of philosophers have published analyses of this concept. The word ‘mismatch’ has been used in a diversity of ways across a range of sciences, leading these authors to regard it as a vague concept in need of philosophical clarification. Here, in contrast, we concentrate on the use of mismatch in modelling and experimentation in evolutionary medicine. This reveals a rigorous theory of mismatch within which the (...) term ‘mismatch’ is indeed used in several ways, not because it is ill-defined but because different forms of mismatch are.distinguished within the theory. Contemporary evolutionary medicine has unified the idea of ‘evolutionary mismatch’, derived from the older idea of ‘adaptive lag’ in evolution, with ideas about mismatch in development and physiology derived from the Developmental Origins of Health and Disease (DOHaD) paradigm. A number of publications in evolutionary medicine have tried to make this theoretical framework explicit. We build on these to present the theory in as simple and general a form as possible. We introduce terminology, largely drawn from the existing literature, to distinguish the different forms of mismatch. This integrative theory of mismatch captures how organisms track environments across space and time on multiple scales in order to maintain an adaptive match to the environment, and how failures of adaptive tracking lead to disease. Mismatch is a productive organising concept within this theory which helps researchers articulate how physiology, development and evolution interact with one another and with environmental change to explain health outcomes. (shrink)

Yarkoni recommends that psychology researchers should take care to align their statistical models to the verbal theories they are studying and testing. This principle applies not just to qualitative theories in psychology but also to more quantitative sciences: there, too, mismatch between open-ended theories and specific statistical models have led to confusion.

Our behavior doesn't always match the beliefs attributed to us, and sometimes the mismatch raises questions about what our beliefs actually are. I compare two approaches to such cases, and argue in favor of the one which allows some belief-attributions to lack a determinate truth-value. That approach avoids an inappropriate assumption about cognitive activity: namely, that whenever we fail in performing one cognitive activity, there is a distinct cognitive activity at which we succeed. The indeterminacy-allowing approach also meshes well (...) with an attractive view of folk-psychology: that ascriptions can help shape the attitudes they report. (shrink)

This article explores the forms of moral repair that the wrongdoer has to perform in an attempt to make amends for her past wrongdoing, with a focus on the issues of interpersonal moral repair; that is, what a wrongdoer can do to merit her victim‘s forgiveness and achieve reconciliation with her community. The article argues against the very general demands of atonement that amount to an obligation to stop being someone who commits wrongs—to become a moral saint—and suggests a new (...) form of atonement that is more practical and useful in our everyday life. (shrink)

Healey et al. use experiments with chat dialogues to test the hypothesis that language co‐ordination is driven by ‘running repairs’. They replace signals of understanding such as “okay” with weaker, ‘spoof’ signals like “ummm”, and replace specific requests for clarification like “on the left?” with signals that suggest a higher degree of misunderstanding like “what?”. The latter manipulation causes participants to switch rapidly to more abstract forms of referring expression.

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)

Moral repair is an important way for firms to heal moral relationships with stakeholders following a transgression. The concept is rooted in recognition theory, which is often used to develop normative perspectives and prescriptions, but the same theory has also propelled a view of moral repair as premised on negotiation between offender and victim(s), which involves the complex social construction of the transgression and the appropriate amends. The tension between normative principles and socioconstructivist implementation begs the question how offending firms (...) should approach moral repair. Addressing this question, we develop a two-level conceptualization of moral repair, distinguishing between procedural and substantive levels of practice, which accommodate normativity and socioconstructivism, respectively. In so doing, we enrich the literature by 1) promoting conceptual clarity, 2) refining understanding of the moral repair process, and 3) suggesting the use of a unified, configurational approach to studying (nonlinear) relations between amends and moral outcomes. (shrink)

In this mini-review, we summarized the results of 12 visual mismatch negativity studies that attempted to use this component as a tool for investigating differences between non-clinical samples of participants as well as the possibility of automatic discrimination in the case of specific categories of visual stimuli. These studies investigated the effects of gender, the effects of long-term differences between the groups of participants, and the effects of short-term states, as well as the vMMN effect elicited by artworks as (...) a special stimulus category. (shrink)

A fundamental assumption of theories of decision-making is that we detect mismatches between intention and outcome, adjust our behavior in the face of error, and adapt to changing circumstances. Is this always the case? We investigated the relation between intention, choice, and introspection. Participants made choices between presented face pairs on the basis of attractiveness, while we covertly manipulated the relationship between choice and outcome that they experienced. Participants failed to notice conspicuous mismatches between their intended choice and the outcome (...) they were presented with, while nevertheless offering introspectively derived reasons for why they chose the way they did. We call this effect choice blindness. (shrink)

Masculine/feminine pairs of human-denoting nouns in Greek fall into three distinct classes under predicative ellipsis: those that license ellipsis of their counterpart regardless of gender, those that only license ellipsis of a same-gendered noun, and those in which the masculine noun of the pair licenses ellipsis of the feminine version, but not vice versa. The three classes are uniform in disallowing any gender mismatched ellipses in argument uses, however. This differential behavior of gender in nominal ellipsis can be captured by (...) positing that human-denoting nouns in Greek, while syntactically and morphological uniform in showing a masculine/feminine contrast, do not all encode this contrast in their semantics. Under a semantic identity theory of ellipsis, the attested variation in nominal ellipses in Greek is posited to derive from the fact that nominal ellipsis has two possible sources: a nominal constituent can be elided (true ellipsis), or a null nominal proform can be used (model-theoretic anaphora). (shrink)

Albert and De Ruiter provide an introduction to the Conversation Analytic approach to ‘repair’: the ways in which people detect and deal with troubles in speaking, hearing and understanding in conversation. They explain the basic turn‐taking structures involved, provide examples, explain recent developments in the field and highlight some important points of contact and contrast with work in the Cognitive Sciences.

Most of us have had the experience of resisting our currently strongest desire, for example, resisting the desire to eat another cookie when eating another cookie is what we most want to do. The puzzle of synchronic self‐control, however, says that this is impossible: an agent cannot ever resist her currently strongest desire. The paper argues that one prominent solution to this puzzle – the solution offered by Al Mele – faces a serious ‘mismatch problem’, which ultimately undermines its (...) plausibility. It is furthermore argued that this problem can be avoided if we adopt a ‘divided mind’ solution instead. (shrink)

The topic of moral repair in the aftermath of breaches of trust and harmdoing has grown in importance within the past few years. In this paper, we present the results of a qualitative study that offers insight into a series of key issues related to offender efforts to repair interpersonal harm in the workplace: What factors motivate offenders to make amends with those they have harmed? In what ways do offenders attempt to make amends? What outcomes emerge from attempts to (...) make amends? Drawing from the findings, we build an inductive model intended to guide future business ethics and management inquiry and research in this area. (shrink)

I present the mismatch problem for Act Consequentialism, and I critically evaluate some popular solutions before offering my own solution to a specific version of the problem. The mismatch problem arises for Act Consequentialism when a group could have done better, but no individual in the group had an alternative with a better outcome. In such cases, the theory delivers mismatched verdicts: it condemns what the group does, but it cannot condemn any of the individual acts. In the (...) first chapter of the dissertation, I explain exactly how this problem works. In the next four chapters, I identify a variety of cases that give rise to the mismatch problem, and I explain why the most popular strategies for modifying Act Consequentialism do not get around it. In the final chapter, I introduce a novel taxonomy of problem cases, and I introduce a 'cautious' version of Act Consequentialism that doesn't encounter the mismatch problem for a certain class of case. (shrink)

The present article is a continuation of the debate two sets of authors have been engaging in regarding one type of maturity mismatching: borrowing short and lending long. All four authors had agreed that this practice can set up the Austrian Business Cycle; the present author denies that BSLL would be a legitimate commercial interaction in the free society; Bagus and Howden continue to maintain that it would be licit. Our main criticism of Bagus and Howden is a reductio ad (...) absurdum: that this opens them up to the charge of embracing the doctrine of market failure; this is something highly problematic for the two of them, since all four contributors to this debate are well-known supporters of laissez faire capitalism. (shrink)

In order to understand involuntary autobiographical memories and déjà vu experiences, we argue that it is important to take an evolutionary medicine perspective. Here, we propose that these memory anomalies can be understood as the outcomes of an inevitable design trade-off between type I and type II errors in memory processing.

This paper advances a fresh theorization of historicity. The word and concept of historicity has become so widespread and popular that they have ceased to have definite meaning and are used to stand for unsupported notions of the values inherent in human experience. This paper attempts to repair the concept by re-defining it as the temporal aspect of the interdependence of life; having history is to have a life intertwined with the lives of all others and with the universe. After (...) separating out the looser uses, surveying some of the literature, and defining what needs to be done, the paper examines shortcomings in the very different and widely influential conceptions of historicity of Koselleck and Heidegger. It then advances a new conception and fits it into the theoretical and moral capabilities of the philosophy of history as a core of philosophical anthropology. (shrink)

The repair of chromosomal double‐strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the RecA/Rad51‐mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template to repair the lesion. Here, in reviewing research about DSB repair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination mechanisms.

(1996). Repairing the moral deficits of capitalism: The role of the nonprofit sector. The European Legacy: Vol. 1, Fourth International Conference of the International Society for the study of European Ideas, pp. 595-600.

"Repairing the Tower of Babel" addresses three major themes. The thesis begins with the question of how James Fergusson felt he could describe both Samuel Taylor Coleridge and Auguste Comte as influential in the development of his own theory of beauty in art. Following from this initial question, the thesis examines in detail the attempts at the reconciliation of Romanticism and Positivism at the beginning of the nineteenth century, especially in the works of William Whewell, Auguste Comte, and Samuel (...) Taylor Coleridge. In light of these attempts, the work looks at the influence of the developing sciences of geology, chemistry, and biology and the various methodologies associated with these organic sciences that were to overturn the Newtonian methods of science which had been followed throughout the eighteenth century. Finally, the thesis provides an overview of the development of aesthetic theory from John Locke to Immanual Kant in an attempt to outline the development of the fundamental dichotomies in aesthetics and theory of mind that the nineteenth century felt it must resolve. (shrink)

Frege’s writings contain arguments for the thesis (i) that a thought expressed by a sentence S is a structured object whose composition pictures the composition of S, and for the thesis (ii) that a thought is an unstructured object. I will argue that Frege’s reasons for both (i) and (ii) are strong. Frege’s explanation of the difference in sense between logically equivalent sentences rests on assumption (i), while Frege’s claim that the same thought can be decomposed differently makes (ii) plausible. (...) Thoughts are supposed to do work that requires that they be structured and work that requires that they be unstructured. But this cannot be! While the standard response to this problem is to reject either (i) or (ii), I propose a charitable repair in the spirit of Frege’s theory that accepts both. The key idea can be found in Frege’s Basic Laws of Arithmetic(BL, GGA). Frege argues that the thought expressed by a sentence is determined by the truth-conditions that can be derived from the semantic axioms for the sentence constituents. The fact that the same axiomatic truth-condition can be derived in different ways from different semantic axioms suggests a Fregean solution of the dilemma: A thought is a type that is instantiated by all sequences of senses (decomposed thoughts) that have the same axiomatic truth-conditions. This allows for multiple decomposability of the same thought (for different decomposed thoughts can have the same axiomatic truth-conditions) and for a notion of containment (the decomposed thought contains those senses whose semantic axioms are needed in the derivation of the truth-conditions). My proposal combines the virtues of (i) and (ii) without inheriting their vices. (shrink)

Automatic detection of information changes in the visual environment is crucial for individual survival. Researchers use the oddball paradigm to study the brain’s response to frequently presented stimuli and occasionally presented stimuli. The component that can be observed in the difference wave is called visual mismatch negativity, which is obtained by subtracting event-related potentials evoked by the deviant from ERPs evoked by the standard. There are three hypotheses to explain the vMMN. The sensory fatigue hypothesis considers that weakened neural (...) activity caused by repetition results in decreased ERPs of the standard. The memory trace hypothesis proposes that vMMN results from increased responses to the deviant. The predictive coding hypothesis attributes the difference to enhanced responses for deviants and suppression for standards. However, when distinguishing between these effects, previous researchers did not consider the effect of low-level features on the vMMN. In this experiment, we used face sequences composed of different emotions and presented an oddball sequence, a reverse oddball sequence, and an equiprobable sequence to participants. The deviant of the oddball sequence was subtracted from the standard of the oddball sequence, the reverse oddball sequence, and the same type of stimulus of the equiprobable sequence to get oddball-vMMN, reverse oddball-vMMN, and equiprobable-vMMN, respectively. The results showed no significant difference between vMMN2 and vMMN3 in 100–350 ms following stimulus onset, while the vMMN effect was significant, indicating that the probability of the standard did not affect vMMN, which supported the memory trace hypothesis. Additionally, the fearful-related vMMN were more negative than the neutral-related vMMN within the range of 100–150 ms, suggesting a negative bias. We analyzed the source location of different vMMNs. There was no significant difference in brain regions between different vMMNs. Time-frequency analysis showed that the deviant had stronger theta-band oscillatory than the standard. However, there was no difference between vMORs2 and vMORs3, indicating that vMORs reflect an enhanced response to the deviant in terms of neural oscillation, supporting the memory trace hypothesis. (shrink)

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions (...) that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

In this peer commentary on Maura Priest's "Transgender Children and the Right to Transition: Medical Ethics When Parents Mean Well but Cause Harm", I argue against the "mismatch" model of trans identity. On this model, which is prevalent in institutional and medical contexts, to be trans is to have one's gender identity "mismatch" with one's sexed body.

When interlocutors repeatedly describe referents to each other, they rapidly converge on referring expressions which become increasingly systematized and abstract as the interaction progresses. Previous experimental research suggests that interactive repair mechanisms in dialogue underpin convergence. However, this research has so far only focused on the role of other-initiated repair and has not examined whether self-initiated repair might also play a role. To investigate this question, we report the results from a computer-mediated maze task experiment. In this task, participants communicate (...) with each other via an experimental chat tool, which selectively transforms participants’ private turn-revisions into public self-repairs that are made visible to the other participant. For example, if a participant, A, types “On the top square,” and then before sending, A revises the turn to “On the top row,” the server automatically detects the revision and transforms the private turn-revisions into a public self-repair, for example, “On the top square umm I meant row.” Participants who received these transformed turns used more abstract and systematized referring expressions, but performed worse at the task. We argue that this is due to the artificial self-repairs causing participants to put more effort into diagnosing and resolving the referential coordination problems they face in the task, yielding better grounded spatial semantics and consequently increased use of abstract referring expressions. (shrink)

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)