Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a “transcriptional switch,” repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known (...) to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. Wnt targets are regulated by a “switch” where TLE co-repressors are displaced from TCFs by β-catenin, leading to activation of transcription. Recent reports challenge this view and suggest that additional processes, including exchange of specific TCF proteins and Wnt-dependent ubiquitination of TLEs, play important roles in the Wnt transcriptional switch. (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)

Recent evidence indicates that transcriptional bursts are intrinsically amplified by messenger RNA cytoplasmic processing to generate large stochastic fluctuations in protein levels. These fluctuations can be exploited by cells to enable probabilistic bet‐hedging decisions. But large fluctuations in gene expression can also destabilize cell‐fate commitment. Thus, it is unclear if cells temporally switch from high to low noise, and what mechanisms enable this switch. Here, the discovery of a post‐transcriptional mechanism that attenuates noise in HIV is (...) reviewed. Early in its life cycle, HIV amplifies transcriptional fluctuations to probabilistically select alternate fates, whereas at late times, HIV utilizes a post‐transcriptional feedback mechanism to commit to a specific fate. Reanalyzing various reported post‐transcriptional negative feedback architectures reveals that they attenuate noise more efficiently than classic transcriptional autorepression, leading to the derivation of an assay to detect post‐transcriptional motifs. It is hypothesized that coupling transcriptional and post‐transcriptional autoregulation enables efficient temporal noise control to benefit developmental bet‐hedging decisions. (shrink)

Genomic imprinting is an epigenetic mechanism resulting in the preferential expression of the maternal or paternal alleles of a specific subset of genes in the mammalian genome. A key but relatively unexplored question is how imprints are established in the germline. New observations(1) on two classical imprinting disorders, the Prader‐Willi (PWS) and Angleman (AS) syndromes, offer the first genetic insight into this process. Molecular analysis of imprinting mutations that interfere with the appropriate establishment of the maternal and paternal epigenotypes has (...) led to the identification of imprinted transcripts that could be involved in switching imprints in the germlines. (shrink)

Pleiotropically acting eukaryotic corepressors such as retinoblastoma and SIN3 have been found to physically interact with many widely expressed “housekeeping” genes. Evidence suggests that their roles at these loci are not to provide binary on/off switches, as is observed at many highly cell‐type specific genes, but rather to serve as governors, directly modulating expression within certain bounds, while not shutting down gene expression. This sort of regulation is challenging to study, as the differential expression levels can be small. We hypothesize (...) that depending on context, corepressors mediate “soft repression,” attenuating expression in a less dramatic but physiologically appropriate manner. Emerging data indicate that such regulation is a pervasive characteristic of most eukaryotic systems, and may reflect the mechanistic differences between repressor action at promoter and enhancer locations. Soft repression may represent an essential component of the cybernetic systems underlying metabolic adaptations, enabling modest but critical adjustments on a continual basis. (shrink)

Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been (...) presumed that GLI proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre‐patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time. These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre‐patterning, digit regulation, and HH‐driven disease. (shrink)

Clp ATPase chaperone proteins are found in procaryotes and eucaryotes. Recently, ClpC of Bacillus subtilis was found to be part of a regulatory switch(1). ClpC, in combination with the MecA and ComS proteins, regulates the activity of a transcription factor, ComK, which is necessary for the development of genetic competence (the ability to bind and take up exogenous DNA). The complex of ClpC:MecA:ComK renders ComK inactive. Interaction between ComS and the ternary complex releases active ComK. This regulatory switch (...) controls ComK activity in response to cell density signals that affect production of ComS. Regulated interaction between Clp ATPases and target proteins might prove to be widespread. (shrink)

The precise orchestration of two opposing protein complexes – one in the cytoplasm (β‐catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co‐factor β‐catenin, and subsequent activation of the Wnt/β‐catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β‐catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study (...) in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini‐review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β‐catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. (shrink)

ObjectiveTo compare techniques for computing clustering and switching scores in terms of agreement, correlation, and empirical value as predictors of incident cognitive impairment.MethodsWe transcribed animal and letter F fluency recordings on 640 cases of ICI and matched controls from a national epidemiological study, amending each transcription with word timings. We then calculated clustering and switching scores, as well as scores indexing speed of responses, using techniques described in the literature. We evaluated agreement among the techniques with Cohen’s κ and calculated (...) correlations among the scores. After fitting a base model with raw scores, repetitions, and intrusions, we fit a series of Bayesian logistic regression models adding either clustering and switching scores or speed scores, comparing the models in terms of several metrics. We partitioned the ICI cases into acute and progressive cases and repeated the regression analysis for each group.ResultsFor animal fluency, we found that models with speed scores derived using the slope difference algorithm achieved the best values of the Watanabe–Akaike Information Criterion, but with good net reclassification improvement only for the progressive group. For letter fluency, different models excelled for prediction of acute and progressive cases. For acute cases, NRI was best for speed scores derived from a network model, while for progressive cases, the best model used clustering and switching scores derived from the same network model. Combining variables from the best animal and letter F models led to marginal improvements in model fit and NRI only for the all-cases and acute-cases analyses.ConclusionSpeed scores improve a base model for predicting progressive cognitive impairment from animal fluency. Letter fluency scores may provide complementary information. (shrink)

"And I Quote": Direct and Indirect Point-of-View Switches in Clusivity-Oriented Discourse The aim of this paper is to approach the notion of speech/thought representation from a pragma-cognitive perspective. The use of direct and indirect representation in political discourse allows the speaker to construe the speech situation from a perspective other than her/his own. The speaker normally occupies the focal position in relation to other discourse entities in a particular speech situation, and thus presents discourse events from her/his point of view, (...) however, on some occasions she/he allows other "voices." It is the distinction between the Speaker and the Sayer that provides means of capturing the phenomenon in question: the Speaker construes the actual/present speech situation presenting events from her/his own perspective, while in the represented speech situation the Speaker represents the words of the Sayer, i.e. the original speaker of the represented speech situation. Assuming the existence of the Sayer's consciousness separate from the Speaker's consciousness, it is clear that the Sayer's perspective is independent of the Speaker's perspective. The Speaker may employ a series of shifts occurring in spatio-temporal and axiological dimensions of the actual speech situation leading either to a full switch or to an apparent switch to the Sayer's perspective. In both cases, the distance between the Speaker and a particular discourse entity may be reduced or increased to indicate its inclusionary or exclusionary status, as well as to include the entity in or exclude it from the "us" group. The data analysed and samples used for illustrative purposes have been selected from a corpus of 35 speeches delivered by Barack Obama between 10th February 2007, i.e. the announcement of his candidacy for the presidency of the USA, and 4th November 2008, i.e. the day of the election. The transcripts of the speeches have been downloaded from the official Obama's website "Organizing for America". (shrink)

Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF‐mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof‐of‐principle support for the physiological relevance of uORF‐mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) gene resulted in deregulated C/EBPβ protein isoform expression, associated (...) with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5′ RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression. (shrink)

Nonsense‐mediated RNA decay (NMD) represents an established quality control checkpoint for gene expression that protects cells from consequences of gene mutations and errors during RNA biogenesis that lead to premature termination during translation. Characterization of NMD‐sensitive transcriptomes has revealed, however, that NMD targets not only aberrant transcripts but also a broad array of mRNA isoforms expressed from many endogenous genes. NMD is thus emerging as a master regulator that drives both fine and coarse adjustments in steady‐state RNA levels in the (...) cell. Importantly, while NMD activity is subject to autoregulation as a means to maintain homeostasis, modulation of the pathway by external cues provides a means to reprogram gene expression and drive important biological processes. Finally, the unanticipated observation that transcripts predicted to lack protein‐coding capacity are also sensitive to this translation‐dependent surveillance mechanism implicates NMD in regulating RNA function in new and diverse ways. (shrink)

Transcription and replication of genes in mammalian cells always requires a promoter or replication origin, respectively, but the ability of enhancers to stimulate these regulatory elements and the interactions that mediate this stimulation are developmentally acquired. The primary function of enhancers is to prevent repression, which appears to result from particular components of chromatin structure. Factors responsible for this repression are present in the maternal nucleus of oocytes and its descendant, the maternal pronucleus of mouse 1‐cell embryos and in mouse (...) 2‐cell embryos, but are absent in the paternal pronucleus. Thus, enhancers are not needed to achieve efficient transcription and replication in paternal pronuclei. However, enhancers, even in the presence of their specific activation protein, are inactive prior to formation of a 2‐cell embryo, suggesting that a coactivator essential for enhancer function is not available until zygotic gene expression begins. Furthermore, enhancer stimulation of transcription appears to be mediated through a promoter transcription factor, but this interaction can change as cells undergo differentiation, switching from a TATA‐box independent to a TATA‐box dependent mode. (shrink)

The discovery and ongoing investigation of microRNAs suggest important conceptual and methodological lessons for philosophers and historians of biology. This paper provides an account of miRNA research and the shift from viewing these tiny regulatory entities as minor curiosities to seeing them as major players in the post-transcriptional regulation of genes. Conceptually, the study of miRNAs is part of a broader change in understandings of genetic regulation, in which simple switch-like mechanisms were reinterpreted as aspects of complex cellular (...) and genome-wide processes. Among them are the activities of small RNAs, previously regarded as non-functional. Methodologically, the miRNA story suggests new ways of characterizing biological research that should prove helpful to philosophers of science who seek to develop more pluralistic, pragmatic models of scientific inquiry. miRNA research displays iterative movements between multiple modes of investigation that include not only the proposal and testing of hypotheses but also exploratory, technology-oriented and question-driven modes of research. As an exemplary story of scientific discovery and development, the miRNA case illustrates transitions from genetics to genomics and systems biology, and it shows how diverse configurations of research practice are related to major scientific advances. (shrink)

Whenever the state of a biological system is not determined solely by present conditions but depends on its past history, we can say that the system has memory. Bacteria and bacteriophage use a variety of memory mechanisms, some of which seem to convey adaptive value. A genetic type of heritable memory is the programmed inversion of specific DNA sequences, which causes switching between alternative patterns of gene expression. Heritable memory can also be based on epigenetic circuits, in which a system (...) with two possible steady states is locked in one or the other state by a positive feedback loop. Epigenetic states have been observed in a variety of cellular processes, and are maintained by diverse mechanisms. Some of these involve alternative DNA methylation patterns that are stably transmitted to daughter molecules and can affect DNA–protein interactions (e.g., gene transcription). Other mechanisms exploit autocatalytic loops whereby proteins establish the proper conditions for their continued synthesis. Template polymers other than nucleic acids (e.g., components of the cell wall) may also propagate epigenetic states. Non‐heritable memory is exemplified by parasitic organisms that bear a signature of their previous host, such as host‐controlled modification of phage DNA or porin hitchhiking in predatory bacteria. The heterogeneous nature of the examples known may be indicative of widespread occurrence of memory mechanisms in bacteria and phage. However, the actual extent, variety and potential selective value of prokaryotic memory devices remain open questions, still to be addressed experimentally. BioEssays 24:512–518, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing (...) replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

Higher plants must undergo a major developmental switch, the transition to flowering, if they are to successfully complete their life cycle. In many plants, the crucial decision of when to begin to produce flowers is primarily controlled by environmental signals. The process of floral induction involves the integration of the activities of two types of genes: those that control flowering time as a response to the environment as well as an endogenous clock, and those that determine the floral identity (...) of the cells. The first direct link between these two classes of genes has now been demonstrated(1). Forced expression of CONSTANS, a flowering‐time gene, promotes flowering through the transcriptional activation of LEAFY, a flower‐meristem‐identity gene. (shrink)

After viral entry into the cell, the nuclear envelope poses a major cellular barrier that needs to be overcome upon adaptation of highly pathogenic avian influenza viruses (HPAIV) to the new host. To ensure efficient viral transcription and replication in the nucleus of the host cell, the viral polymerase complex of avian influenza viruses needs to switch from recognition of avian to mammalian components of the nuclear import machinery. Recent evidence suggests that influenza viruses have evolved different mechanisms to (...) utilize importin‐α isoforms as components of this machinery, bridging pre‐ and post‐nuclear import on both sides of the nuclear envelope. (shrink)

Despite ever‐increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage‐specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co‐factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information (...) is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a ‘transcriptional hub’ containing a high concentration of TFs and co‐factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α‐globin gene cluster during erythropoiesis, as a model. (shrink)

At least seven orphan members of the nuclear receptor superfamily are transcriptionally regulated by the steroid hormone ecdysone and expressed during the onset of Drosophila metamorphosis. A recent paper provides functions for two of these receptors, E75B and DHR3, through trans‐regulation and heterodimerization(1). DHR3 appears to function as a switch that defines the transition from a late larva to a prepupa, and E75B functions as a timer that modulates this transition. This study provides a biological function for orphan receptor (...) interactions during development. (shrink)

Significant strides have been made in recent years towards understanding the molecular basis of cell cycle progression in the model bacterium Caulobacter crescentus. At the heart of cell cycle regulation is a multicomponent transcriptional feedback loop, governing the production of successive regulatory waves or pulses of at least three master regulatory proteins. These oscillating master regulators direct the execution of phase‐specific events and, importantly, through intrinsic genetic switches not only determine the length of a given phase, but also provide (...) the driving force that catapults the cell into the next stage of the cell cycle. The genetic switches act as fail safe mechanisms that prevent the cell cycle from relapsing and thus govern the ordered production and the periodicity of these regulatory waves. Here, we detail how the master regulators CtrA, GcrA and DnaA coordinate cell cycle progression and polar development in Caulobacter. BioEssays 28: 355–361, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Mammalian synthetic biology holds the promise of providing novel therapeutic strategies, and the first success stories are beginning to be reported. Here we focus on the latest generation of mammalian transgene control devices, highlight state‐of‐the‐art synthetic gene network design, and cover prototype therapeutic circuits. These will have an impact on future gene‐ and cell‐based therapies and help bring drug discovery into a new era. The inventory of biological parts that are essential for life on this planet is becoming increasingly complete. (...) The postgenomic era has provided encyclopedic information on gene‐function correlations and systems biology is now delivering comprehensive details on the dynamics of biochemical reaction networks in living organisms. The time has come to reassemble these catalogued items and design new biological devices and systems with novel and useful functionality in a rational and systematic manner. This is the premise of synthetic biology, a constructive systems biology discipline likely to become the life science revolution of the 21st century. (shrink)

Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male‐specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male‐specific genes during development, postnatally (...) and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. (shrink)

The contributions to this volume are concerned with questions of form, function, and genesis of canonical switch-reference systems.

This essay is about a special kind of transformative choice that plays a key role in debates about permissivism, the view that some bodies of evidence permit more than one rational response. A prominent objection to this view contends that its defender cannot vindicate our aversion to arbitrarily switching between belief states in the absence of any new evidence. A prominent response to that objection tries to provide the desired vindication by appealing to the idea that arbitrary switching would involve (...) a special kind of transformative choice: the choice to change one’s epistemic standards, i.e., one’s commitments regarding the relative importance of achieving true belief and avoiding false belief. My first aims here are to argue that this response is unsuccessful and propose an alternative. My secondary aim is to consider how this discussion might bear on more general debates about transformative choice. (shrink)

Based on content externalism, the question of whether self-knowledge is authoritative or not has launched a real controversy in the philosophy of mind. Boghossian proposed slow switching argument in defense of incompatibility of the two views. This argument has been criticized by some philosophers through different approaches. Vahid is one of them. He claimed that Boghossian's argument appeals to some controversial assumptions without which it cannot achieve its conclusion. In this article, I criticize Vahid's response to slow switching argument and (...) show that self-knowledge in Vahid's response differs in having authority and therefore in function from that of Boghossian. (shrink)

Theories of embodied cognition hold that the conceptual system uses perceptual simulations for the purposes of representation. A strong prediction is that perceptual phenomena should emerge in conceptual processing, and, in support, previous research has shown that switching modalities from one trial to the next incurs a processing cost during conceptual tasks. However, to date, such research has been limited by its reliance on the retrieval of familiar concepts. We therefore examined concept creation by asking participants to interpret modality-specific compound (...) phrases (i.e., conceptual combinations). Results show that modality switching costs emerge during the creation of new conceptual entities: People are slower to simulate a novel concept (e.g., auditory jingling onion) when their attention has already been engaged by a different modality in simulating a familiar concept (e.g., visual shiny penny). Furthermore, these costs cannot be accounted for by linguistic factors alone. Rather, our findings support the embodied view that concept creation, as well as retrieval, requires situated perceptual simulation. (shrink)

John Searle and Susanna Siegel have argued that cases of aspect‐switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. I respond that cases of aspect‐switching can be explained without holding that visual experience represents rich properties. I also argue that even if Searle and Siegel are right, and aspect‐switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural‐kind properties, such as being a (...) tomato. (shrink)

John Searle and Susanna Siegel have argued that cases of aspect‐switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. I respond that cases of aspect‐switching can be explained without holding that visual experience represents rich properties. I also argue that even if Searle and Siegel are right, and aspect‐switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural‐kind properties, such as being a (...) tomato. (shrink)

This article deals with an argument reported by Razi (d. 1210) that attempted to undermine the immaterialist position about human nature. After some introductory remarks and explanation of the conceptual background, the article analyses the structure of the argument, with special attention to the idea of soul-switching.’ Some comparisons are made between the argument reported by Razi and a number of arguments from modern and contemporary eras of philosophy. One section is devoted to the critique of the argument and its (...) conceptual basis. This article shows that the argument reported by Razi is a methodological antecedent of a family of contemporary epistemological arguments against substance dualism. It is also shown that discussion of the argument could be useful to highlight a weakness in some, but not all, versions of immaterialism about human nature. (shrink)

Based on a crowdsourced truth value judgment experiment, we provide empirical evidence challenging two classical views in semantics, and we develop a novel account of counterfactuals that combines ideas from inquisitive semantics and causal reasoning. First, we show that two truth-conditionally equivalent clauses can make different semantic contributions when embedded in a counterfactual antecedent. Assuming compositionality, this means that the meaning of these clauses is not fully determined by their truth conditions. This finding has a clear explanation in inquisitive semantics: (...) truth-conditionally equivalent clauses may be associated with different propositional alternatives, each of which counts as a separate counterfactual assumption. Second, we show that our results contradict the common idea that the interpretation of a counterfactual involves minimizing change with respect to the actual state of affairs. We propose to replace the idea of minimal change by a distinction between foreground and background for a given counterfactual assumption: the background is held fixed in the counterfactual situation, while the foreground can be varied without any minimality constraint. (shrink)

Half a century into the digital era, the profound impact of information technology on intellectual and cultural life is universally acknowledged but still poorly understood. The sheer complexity of the technology coupled with the rapid pace of change makes it increasingly difficult to establish common ground and to promote thoughtful discussion. Responding to this challenge, _Switching Codes _brings together leading American and European scholars, scientists, and artists—including Charles Bernstein, Ian Foster, Bruno Latour, Alan Liu, and Richard Powers—to consider how the (...) precipitous growth of digital information and its associated technologies are transforming the ways we think and act. Employing a wide range of forms, including essay, dialogue, short fiction, and game design, this book aims to model and foster discussion between IT specialists, who typically have scant training in the humanities or traditional arts, and scholars and artists, who often understand little about the technologies that are so radically transforming their fields. _Switching Codes_ will be an indispensable volume for anyone seeking to understand the impact of digital technology on contemporary culture, including scientists, educators, policymakers, and artists, alike. (shrink)

Formal methods developed for modeling levels of selection problems have recently been applied to the investigation of major evolutionary transitions. We discuss two new tools of this kind. First, the ‘near-variant test’ can be used to compare the causal adequacy of predictively equivalent representations. Second, ‘state-variable gestalt-switching’ can be used to gain a useful dual perspective on evolutionary processes that involve both higher and lower level populations.

This article deals with an argument reported by Razi (d. 1210) that attempted to undermine the immaterialist position about human nature. After some introductory remarks and explanation of the conceptual background, the article analyses the structure of the argument, with special attention to the idea of soul-switching.’ Some comparisons are made between the argument reported by Razi and a number of arguments from modern and contemporary eras of philosophy. One section is devoted to the critique of the argument and its (...) conceptual basis. This article shows that the argument reported by Razi is a methodological antecedent of a family of contemporary epistemological arguments against substance dualism. It is also shown that discussion of the argument could be useful to highlight a weakness in some, but not all, versions of immaterialism about human nature. (shrink)

Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome‐wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non‐functional’, TFBS inputs to their target genes may be generally cumulative, with varying (...) degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome‐wide association studies for complex traits. (shrink)

Amele (Papuan, New Guinea) is a tense-mood-based language (in the typology of Bittner 2014) with an elaborate system of clause chaining, including switch reference (SR) and serial verb constructions (SVC). This draft analyzes two interlinear Amele texts (from Roberts 2007) in Update with Centering of Bittner (2014). The basic idea is that an SR-chain is a topic-comment sequence about a 'topical development' — i.e. a topic time framing a chain of causally linked events. In contrast, an SVC is a (...) chain of verbs that jointly introduce a single eventuality into discourse. (shrink)

The contentious question of bilingual processing cost may be recast as a fresh question of code-switching (CS) strategies—quantitative preferences and structural adjustments for switching at particular junctures of two languages. CS strategies are established by considering prosodic and syntactic variables, capitalizing here on bidirectional multi-word CS, spontaneously produced by members of a bilingual community in northern New Mexico who regularly use both languages (Torres Cacoullos and Travis, 2018). CS strategies become apparent by extending the equivalence constraint, which states that bilinguals (...) avoid CS at points of word placement conflict (Poplack, 1980), to examine points of inconsistent equivalence between the languages. Such sites of variable equivalence are junctures where the word strings of the two languages are equivalent only sometimes due to language-internal variable structures. A case in point for the English-Spanish language pair is the boundary between main and complement clauses, where a conjunction occurs always in Spanish but variably in English. The prosodic distancing strategy is to separate the juncture of the two languages. Here the complement clause appears in a different prosodic unit from the main clause, disproportionately as compared both with monolingual benchmarks and with bilinguals' own unilingual English and Spanish. Prosodic distancing serves to mitigate variable equivalence. The syntactic selection strategy is to opt for the variant that is more quantitatively available and more discourse neutral. Here the preference is for the Spanish complementizer que—regardless of main or complement clause language— which is the more frequent option in bilinguals' combined experience in both their languages, whereas English complementizer that is subject to a number of conditioning factors. Syntactic selection serves to restore equivalence at sites of variable equivalence. Discovery of community CS strategies may spur reconsideration of processing cost as a matter of relative difficulty, which will depend on bilinguals' prosodic and syntactic choices at particular CS sites. (shrink)

The attempt to model the structure of consciousness in split-brain subjects is ongoing. This paper concerns the recently proposed ?switch model? of split-brain consciousness, according to which a split-brain subject possesses only a single stream of consciousness, unified at and across time, that shifts from one hemisphere to the other from moment to moment. The paper argues that while the central explanatory element of the switch model may account for some aspects of split-brain consciousness, the best general picture (...) of split-brain consciousness is still offered by some version of the ?conscious duality model.? (shrink)

Realists about group agency, according to whom corporate agents may have mental states and perform actions over and above those of their individual members, think that individual agents may switch between participating in individual and corporate agency. My aim is, however, to argue that the inescapability of individual agency spells out a difficulty for this kind of switching – and, therefore, for realism about corporate agency. To do so, I develop Korsgaard's notion of plight inescapability. On my take, it (...) suggests that individual agents are continuously faced with fully exercising their own individual agency (absent external limits at the time of its exercise). But then individual agents may not switch to acting as members of corporate agents, in the sense of taking on irreducible mental states that differ from their own. As it nevertheless is possible to participate fully in the action of a corporate entity, this incompatibility between individual and corporate mental states suggests a challenge for group agent realism. (shrink)

Seed development in this paper has been classified into the three landmark stages of cell division, organ initiation and maturation, based on morphological changes, and the available literature. The entire process proceeds at the behest of an interplay of various specific and general transcription factors (TFs). Monocots and dicots utilize overlapping, as well as distinct, TF networks during the process of seed development. The known TFs in rice and Arabidopsis have been chronologically categorized into the three stages. The main regulators (...) of seed development contain B3 or HAP3 domains. These interact with bZIP and AP2 TFs. Other TFs that play an indispensable role during the process contain homeobox‐, NAC‐, MYB‐, or ARF‐domains. This paper is a comprehensive analysis of the TFs essential for seed development and their interactions. An understanding of this interplay will not only help unravel an integrated developmental process, but will also pave the way for biotechnological applications. (shrink)

Code switching is defined as the use of two or more languages or varieties of language in conversation. It is a general phenomenon in Pakistani society. This research was conducted through a qualitative descriptive method; it produces descriptive data in the form of code switched sentences from editorial of Urdu newspaper. In this research paper I discussed code switching in editorial of an Urdu newspaper. Daily Khabrain Newspaper was selected for this purpose. One week newspapers were collected for research from (...) 1st January, 2020 to 7th January, 2020 to analyze code switching in editorial. In this research paper I discussed code switching in editorial of an Urdu newspaper. Aims and Objectives are; in this research paper I discussed code switching in editorial of an Urdu newspaper. Research Question was what type of code switching is in editorial in Daily Khabrain Newspaper? Daily Khabrain Newspaper from first January 2020 to 7th January 2020 was collected for the analysis of language or code switching and its type in editorial. Through the analysis of data of newspaper it can be concluded that the type of code switching was intra sentential, word code switching and total integrated Urdu. (shrink)

Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene (...) expression in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. (shrink)

Ontologies are today being applied in almost every field to support the alignment and retrieval of data of distributed provenance. Here we focus on new ontological work on dance and on related cultural phenomena belonging to what UNESCO calls the “intangible heritage.” Currently data and information about dance, including video data, are stored in an uncontrolled variety of ad hoc ways. This serves not only to prevent retrieval, comparison and analysis of the data, but may also impinge on our ability (...) to preserve the data that already exists. Here we explore recent technological developments that are designed to counteract such problems by allowing information to be retrieved across disciplinary, cultural, linguistic and technological boundaries. Software applications such as the ones envisaged here will enable speedier recovery of data and facilitate its analysis in ways that will assist both archiving of and research on dance. (shrink)