In this commentary, I consider variability as an ordinary and irremediable feature related to the indexicality not only of transcripts but first of all of transcribing. In this sense, it is not just a characteristic of transcripts as texts, which can be assessed in a kind of philological comparison comparing formal features of autonomous and fixed textual objects, but a characteristic of transcribing as a situated practice. Practices are irremediably indexical, reflexively tied to the context of their production and to (...) the practical purposes of their accomplishment. Thus, a transcript is an evolving flexible object; it changes as the transcriber engages in listening and looking again at the tape, endlessly checking, revising, reformatting it. Transcribing relies in a fundamental way not only on the possibility of fixing the relevant details in a complex multilayered representation but also on the possibility of manipulating them, playing them again and again, at different paces, positions, fragments, while transcribing their finely tuned coordination, their synchronization, the fine articulation between different projections and sequential implicativenesses. These manipulations are one of the ways in which transcribing is accomplished as a situated practice. (shrink)

Rather than abstracting Augustine’s exploration of time from the whole of the Confessions, as philosophers have been tempted to do, I take up his exploration in terms of what I call a ‘companioning relation’ between philosophy and theology. There is a porosity between religion/theology and philosophy in Augustine that need not be taken as a philosophical or theological deficiency. This reflection speaks of Augustine’s intentions and intuitions in terms of the theme: Wording Time. How might one word this wording, and (...) how might Augustine’s approach to time be thus illuminated? I approach the question in different stages, dealing first with theological, ontological, and psychological considerations. Then I follow the breadth of Augustine’s concerns to a sense of sacred heterogeneities that yet are deeply intimate, and to a sense of time that is in communication with what is above time. In keeping with the musical motif that runs through this reflection, I offer some thoughts on agapē as not only an agapē sonans but an agapē personans. I will sometimes be transcribing Augustine’s themes, sometimes offering variations on them, and sometimes composing improvisations in tune with Augustinian themes. (shrink)

The entextualization and recontextualization of speech via transcription is a fundamental methodology of discourse analysis. However, particularly for researchers concerned with sociopolitical issues in discourse, transcription is not a straightforward tool but a highly problematic yet necessary form of linguistic representation. Recent commentators have critiqued the inconsistency of researcher transcripts; by contrast, this article seeks to understand rather than remedy such variability, conceptualizing diversity in transcripts as a kind of linguistic variation. Examining four different types of variation in (...) transcription practice — global format choices based on an analytic focus on content versus form, variation in the details of transcription format in reproducing one's own or others' transcripts, orthographic variation in a single transcript, and variation in translation — the article argues that although reflection about the transcription process cannot overcome the difficulties inherent in this methodology, it can allow scholars to be more attentive to their own transcription choices and their limitations and to make these explicit in their writing. (shrink)

This response picks up on the four key points developed in `Variation in Transcription'. The focus is on how transcription practices are implicated in extended histories of data processing by arguing for a wider take on the `dyad' of researcher and represented voice. The article addresses the relevance of historically specific contexts of `hearing' and interpretative-analytical appropriation, the practical exigencies of publication and how these have shifted over time, the contemporary challenges posed by transcription-in-translation, as well as the affordances (...) and constraints of past and current technologies. (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)

Nous présentons une étude originale en cours visant la compréhension des relations entre variations sociolinguistiques et réseau social. Sa démarche empirique repose sur le recueil de données sociales et langagières massives et longitudinales au sein d’une école maternelle. Environ 200 individus (enfants et adultes) sont équipés une semaine par mois pendant 3 ans de capteurs qui enregistrent en continu à la fois leurs interactions verbales et leurs contacts sociaux. Dans cet article, à visée principalement méthodologique, nous exposons les dispositifs mis (...) en place pour le recueil et les procédures mises en œuvre pour la transcription et l’annotation de données orales massives. Enfin, nous présentons les potentialités offertes par ce type de recueil pour affiner, automatiser et systématiser l’analyse variationniste des relations entre réseau social et variations sociolinguistiques. (shrink)

One of the central issue of developmental biology concerns the molecular mechanisms whereby a multipotent cell gives rise to distinct differentiated progeny. Differences between specialised cell types reflect variations in their patterns of gene expression. The regulation of transcription initiation is an important control point for gene expression and it is, therefore, not surprising that transcription factors play a pivotal role in mammalian development and differentiation.Haemopoiesis offers a uniquely tractable system for the study of lineage commitment and differentiation. The importance (...) of transcription factor in the normal regulation of haemopoiesis is underlined by the frequency with which transcription factors are targeted by leukaemogenic mutations. Studies of the function and regulation of haemopoietic transcription factors, especially those expressed in lineage‐restricted patterns, should greatly increase our understanding of the molecular control of haemopoiesis. In this review we have focused on insights provided by recent studies of the GATA and SCL proteins. (shrink)

The DNA in a eukaryotic nucleus is packaged into a nucleosome array, punctuated by variations in the regular pattern. The local chromatin structure of inducible genes appears to fall into two categories: preset and remodeling. Preset genes are those in which the binding sites for trans‐acting factors are accessible (;i.e. in a non‐nucleosomal, DNase I hypersensitive configuration) prior to activation. In response to the activation signal, positive factors bind to cis‐acting regulatory elements and trigger transcription with no major alterations in (...) the chromatin structure of the promoter region. In contrast, remodeling genes are those in which some of the required cis‐acting regulatory elements are packaged into nucleosomes. The nucleosomes must be perturbed in response to an activation signal in order for the trans‐acting factors to gain access to cis‐acting elements; a chromatin remodeling process which forms DNase I hypersensitive sites must occur. In both cases, precise positioning of nucleosomes along the promoter region of a gene appears to be critical for appropriate regulation of expression. (shrink)

Deletions, duplications, insertions, inversions, and translocations, collectively called structural variations (SVs), affect more base pairs of the genome than any other sequence variant. The recent technological advancements in genome sequencing have enabled the discovery of tens of thousands of SVs per human genome. These SVs primarily affect non‐coding DNA sequences, but the difficulties in interpreting their impact limit our understanding of human disease etiology. The functional annotation of non‐coding DNA sequences and methodologies to characterize their three‐dimensional (3D) organization in the (...) nucleus have greatly expanded our understanding of the basic mechanisms underlying gene regulation, thereby improving the interpretation of SVs for their pathogenic impact. Here, we discuss the various mechanisms by which SVs can result in altered gene regulation and how these mechanisms can result in rare genetic disorders. Beyond changing gene expression, SVs can produce novel gene‐intergenic fusion transcripts at the SV breakpoints. (shrink)

In many species of reptiles, sex is determined at fertilization by zygotic sex chromosome composition. In other species, including all crocodilians, most turtles and some lizards, sex is determined by temperature during the earlier stages of gonadal differentiation. The effects of exogenous estrogens, antiestrogens and aromatase inhibitors at different temperatures have unambiguously demonstrated the involvement of estrogens in sexual differentiation of the gonads. Aromatase is the enzyme that converts androgens to estrogens. Gonadal aromatase activity is well correlated with gonadal structure. (...) It increases exponentially in differentiating ovaries, whereas it remains low in differentiating testes. Moreover, there is a high correlation between the thermosensitive periods for both ovary differentiation and increase in aromatase activity. We suggest that a thermosensitive factor intervenes, directly or indirectly, in the transcriptional regulation of the aromatase gene in reptiles with temperature‐dependent sex determination. (shrink)

This commentary addresses the complexities of representation in sociolinguistic transcripts, considering the meaning potentials of different representational choices at the level of both ideology and identity. It considers the kinds of authenticity and evidence that are indexed by simplified versus more detailed transcripts, suggesting that a simplified transcript may give more direct access to elements of the original speaker's voice. Second, it discusses the role of transcripts as scholarly texts, and questions their use as sociolinguistic records suitable for reinterpretation by (...) scholars who do not have access to the original recordings. Third, it emphasizes that the use of non-standard orthographies is an unreliable source of data on sociolinguistic variation, because few authors use non-standard forms in consistent and principled ways. Fourth, it proposes that translations may take different forms depending on whether they are efforts to be `faithful' to `authentic' speech in the target versus the source language. Finally, it reflects on the act of transcription as part of professional practice and identity among linguists. (shrink)

mRNA synthesis in all organisms is performed by RNA polymerases, which work as nanomachines on DNA templates. The rate at which their product is made is an important parameter in gene expression. Transcription rate encompasses two related, yet different, concepts: the nascent transcription rate, which measures the in situ mRNA production by RNA polymerase, and the rate of synthesis of mature mRNA, which measures the contribution of transcription to the mRNA concentration. Both parameters are useful for molecular biologists, but they (...) are not interchangeable and they are expressed in different units. It is important to distinguish when and where each one should be used. We propose that for functional genomics the use of nascent transcription rates should be restricted to the evaluation of the transcriptional process itself, whereas mature mRNA synthesis rates should be employed to address the transcriptional input to mRNA concentration balance leading to variation of gene expression. (shrink)

This article introduces the 2012 Montréal FRAN-HOMA corpus, collected in the Francophone neighborhood of Hochelaga-Maisonneuve, and how it relates to the heritage corpora of Montréal French collected since the 1970s. We discuss the methodological choices made regarding the composition of this corpus including the historical and demo-linguistic information that led to the selection of the Hochelaga-Maisonneuve neighborhood for fieldwork. A presentation of the socially stratified sample and criteria for participant selection is followed by a discussion on data collection and the (...) sociolinguistic interview. After a brief review of the transcription protocol and the advantages of audio-aligned transcription, we provide two illustrations of the revival of research on linguistic variation made possible by this new corpus. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the (...) biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

Since the idea of a canon seems so closely bound up with the idea of history, there should be something to be learned from the persistent efforts that have been going on for nearly two hundred years to extend the musical repertory back in time. What is involved here is nothing less than a continuous effort to endow music with a history. From the workings of this process in the nineteenth century, we learn that where the ideology is right the (...) past can indeed yield up a canon of works and even a canon of performance. Bach, to take the most weighty example, would appear to have entered the canon—Hoffman’s canon—before entering the repertory. The history of the nineteenth-century Bach revival begins as a triumph of ideology over practice. Only after J. N. Forkel, in his famous biography, canonized Bach as the archetypal German master was The Well-tempered Clavier published for the first time—and if any one work of music deserved to be called canonic, it would have to be The Well-tempered Clavier.14 Gradually other Bach works, works which fitted better into nineteenth-century concert life, did enter various nineteenth-century repertories; Mendelssohn’s revival of the St. Matthew Passion is a famous landmark, and various piano transcriptions and orchestral arrangements, not to speak of Gounod’s “Ave Maria,” followed in due course. Bach was made to sound like a premature Romantic. There was as yet no call for historical “authenticity.” But I do not think it was Bach that Hood was thinking of when he complained of musical traditions of the past whose “real identities are gone.” The skeleton may not have been bodied out with authentic flesh and blood, but it was made into a handsome waxwork which was quite real enough for the nineteenth century. 14. This point is made by Crocker, “Is There Really a ‘Written Tradition’?” Joseph Kerman, professor of music at the University of California, Berkeley, is the author of Opera as Drama, The Beethoven Quartets, The Masses and Motets of William Byrd, and The New Grove Beethoven. He is also coeditor of Beethoven Studies and Nineteenth-Century Music and is presently working on a concise study of modern musical scholarship. “How We Got into Analysis, and How to Get Out,” his previous contribution to Critical Inquiry, appeared in the Winter 1980 issue. (shrink)

Cellular identity and its response to external or internal signalling variations are encoded in a cell's genome as regulatory information. The genomic regions that specify this type of information are highly variable and degenerated in their sequence determinants, as it is becoming increasingly evident through the application of genome‐scale methods to study gene expression. Here, we speculate that the same scenario applies to the regulatory regions controlling where DNA replication starts in the metazoan genome. We propose that replication origins cannot (...) be defined as unique genomic features, but rather that DNA synthesis initiates opportunistically from accessible DNA sites, making cells highly robust and adaptable to environmental or developmental changes. (shrink)

Resumen: La variación lingüística es un fenómeno presente en casi todos los idiomas. Su interés para los estudios traductológicos es incuestionable. En el presente trabajo pretendemos investigar cómo se resuelven los problemas que plantea la variación lingüística para la traducción literaria chino-español. Con tal objetivo, hemos elegido la obra La casa de té y sus dos versiones de español como corpus de análisis. Partiendo de la hipótesis de que en la traducción de los elementos de la variación lingüística de esta (...) obra se recurre a la estandarización como solución traductora preferente, hemos analizado el corpus para obtener datos tanto cualitativos como cuantitativos. Los resultados nos permiten confirmar la hipótesis general, así como identificar las características específicas y problemas que presenta la traducción de la variación lingüística del chino al español. Abstract: Linguistic variation is a phenomenon present in almost all languages. Its importance for translation studies is unquestionable. In this paper, we intend to investigate how the problems posed by linguistic variation are solved for Chinese-Spanish literary translation. To this end, we have chosen the work Teahouse and its two Spanish versions as the corpus of analysis. Based on the hypothesis that in the translation of the elements of linguistic variation in this work, standardization is used as the preferred translation solution, we analyzed the corpus to obtain both qualitative and quantitative data. The results allow us to confirm the general hypothesis, as well as to identify the specific characteristics and problems presented by the translation of linguistic variation from Chinese into Spanish. (shrink)

Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, the Wnt-dependent (...) induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression. (shrink)

The target article raises the question of whether transcription-based evidence is sufficient to support assumptions relating to patterns of mandibular activity in young children. Studies on the perception of both adult and infant speech indicate that the argument needs to be reexamined on the basis of acoustic and articulatory data.

Wnt proteins are involved in a large number of events during development and disease. The crucial element in the transduction of the signal elicited by Wnt is the state and activity of β-catenin. There are two pools of β-catenin, one associated with cadherins at the cell surface and a soluble one in the cytolasm, whose state and concentration are critical for Wnt signalling. In the absence of Wnt, the cytoplasmic pool is low due to targetted degradation of β-catenin. Upon Wnt (...) signalling, β-catenin is stabilized. As a consequence, it can access the nucleus where it interacts with members of the Tcf family of transcription factors to modulate the expression of defined targets. Recent reports indicate that, in addition to Tcfs, β-catenin can interact with other nuclear proteins raising the possibility that Wnt signalling has a wider modulatory effect on transcription than is mediated by its interactions with Tcfs. BioEssays 23:311–318, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Humans’ indigenous microbes strongly influence organ functions in an age‐ and diet‐dependent manner, adding an important dimension to aging biology that remains poorly understood. Although age‐related differences in the gut microbiota composition correlate with age‐related loss of organ function and diseases, including inflammation and frailty, variation exists among the elderly, especially centenarians and people living in areas of extreme longevity. Studies using short‐lived as well as nonsenescent model organisms provide surprising functional insights into factors affecting aging and implicate attenuating (...) effects of microbes as well as a crucial role for certain transcription factors like forkhead box O. The unexpected beneficial effects of microbes on aged animals imply an even more complex interplay between the gut microbiome and the host. The microbiome constitutes the major interface between humans and the environment, is influenced by biosocial stressors and behaviors, and mediates effects on health and aging processes, while being moderated by sex and developmental stages. (shrink)

Le but de cet article est double. Il s’agit d’abord d’introduire un nouveau corpus de français oral numérisé, accessible sans restriction sur le web. CFPP2000 (Corpus du français parlé parisien des années 2000), qui comporte actuellement 500 000 mots alignés à l’oral au tour de parole, est constitué par un ensemble d’interviews conversationnelles sur les quartiers de Paris d’une à deux heures qui ont été réalisées en dyades ou le plus souvent en triades. L’article envisage l’influence pour la constitution du (...) corpus du but que nous nous étions fixé au départ, faciliter l’étude de la variation à l’oral pour le français parisien « commun ». Il aborde le choix des informateurs qui découle de cet objectif, les conduites d’entretien qui ont été adoptées. Il envisage ce qu’apporte la transcription d’entretiens relativement longs qui permet d’atténuer l’opposition entre analyse quantitative et analyse qualitative, ainsi que les précautions à prendre dans l’interprétation des résultats. Dans un deuxième temps, l’article présente les métadonnées, les concordanciers et les outils statistiques qui viennent enrichir le corpus et mentionne quelques travaux qu’il a permis de mener, tantôt en syntaxe de l’oral, tantôt autour de problèmes de variation morphologique. (shrink)

Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease‐related DNA methylation variations within disease‐associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that closely define the (...) expression of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease‐associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co‐residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases.Editor's suggested further reading in BioEssays DNA methylation reprogramming in cancer: Does it act by re‐configuring the binding landscape of Polycomb repressive complexes? Abstract. (shrink)

Variation in transcription is due in large part to variability in transcribers' theoretical and methodological commitments and goals. This reply addresses issues raised in the commentaries on the article `Variation in Transcription' concerning problems of representing different discourse genres in transcripts, the question of how research relationships shape the transcription process, the intellectual and institutional contexts in which transcription occurs and circulates, and the injunction to consider the practices as opposed to the products of transcription.

La base de données orales de français de Suisse romande (OFROM) contient des transcriptions d’enregistrements auxquels ont participé des locuteurs nés et vivant en Suisse. Elle a été créée par des linguistes soucieux de documenter les usages oraux du français en Suisse romande, et de combler ainsi le retard dans la description des usages oraux de la langue parlée dans cette partie de la francophonie, notamment sur le plan du lexique, de la syntaxe et de la phonologie. La base de (...) données OFROM a été mise en ligne en décembre 2012 ; elle est encore jeune et d’ampleur modeste (65 heures de parole pour près de 410 000 mots transcrits, au moment où nous écrivons), mais il est prévu de l’enrichir et de la diversifier régulièrement au cours des années à venir. La première partie de cet article présente les principes fondamentaux qui ont guidé la constitution de la base (choix des locuteurs, des supports et conventions de transcription, annotations, etc.). La seconde partie contient les résultats obtenus à l’issue d’études en cours ou de sondages prospectifs, portant sur la variation lexicale et la variation syntaxique. Ils permettront d’illustrer quelques-unes des potentialités qu’offrent la base et son moteur de recherche. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

La comparaison de deux corpus d’enquêtes sociolinguistiques réalisés à quarante ans d’intervalle permet de mettre en perspective certains aspects centraux de la constitution des données et d’interroger, par delà une description des différents choix méthodologiques et théoriques opérés, la place des données dans la linguistique de corpus.

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)

In this review we highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start and poly-adenylation events in high-throughput transcriptomic data. The fate of eukaryotic transcripts is closely linked to their untranslated regions, which are determined by the position at which transcription starts and ends at a genomic locus. Although the extent of alternative transcription starts and alternative poly-adenylation sites has been revealed by sequencing (...) methods focused on the ends of transcripts, the application of these methods is not yet widely adopted by the community. We suggest that computational methods applied to standard high-throughput technologies are a useful, albeit less accurate, alternative to the expertise-demanding 5′ and 3′ sequencing and they are the only option for analysing legacy transcriptomic data. We review these methods here, focusing on technical challenges and arguing for the need to include better normalization of the data and more appropriate statistical models of the expected variation in the signal. We highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start site and alternative poly-adenylation events from standard high-throughput transcriptomic data. We discuss the challenges faced by these methods and argue for the use of better statistical models for dealing with biases in the data and variation in the signal. (shrink)

Le but de cet article est double. Il s’agit d’abord d’introduire un nouveau corpus de français oral numérisé, accessible sans restriction sur le web. CFPP2000 (Corpus du français parlé parisien des années 2000), qui comporte actuellement 500 000 mots alignés à l’oral au tour de parole, est constitué par un ensemble d’interviews conversationnelles sur les quartiers de Paris d’une à deux heures qui ont été réalisées en dyades ou le plus souvent en triades. L’article envisage l’influence pour la constitution du (...) corpus du but que nous nous étions fixé au départ, faciliter l’étude de la variation à l’oral pour le français parisien « commun ». Il aborde le choix des informateurs qui découle de cet objectif, les conduites d’entretien qui ont été adoptées. Il envisage ce qu’apporte la transcription d’entretiens relativement longs qui permet d’atténuer l’opposition entre analyse quantitative et analyse qualitative, ainsi que les précautions à prendre dans l’interprétation des résultats. Dans un deuxième temps, l’article présente les métadonnées, les concordanciers et les outils statistiques qui viennent enrichir le corpus et mentionne quelques travaux qu’il a permis de mener, tantôt en syntaxe de l’oral, tantôt autour de problèmes de variation morphologique. (shrink)

Cet article présente le Corpus FRAN, premier corpus panfrancophone en ligne sur les variétés de français nord-américaines, élaboré dans le cadre du projet international Le français à la mesure d’un continent (dir. F. Martineau). Il présente d’abord les grandes questions théoriques qui sous-tendent le projet et l’élaboration du Corpus FRAN, puis discute de l’architecture du Corpus FRAN ainsi que de l’interface élaborée pour son interrogation et du protocole de transcription. La configuration du Corpus FRAN, couvrant plusieurs siècles et plusieurs communautés, (...) permet des recherches croisées qui sont susceptibles de mettre en évidence les convergences et divergences entre ces communautés et d’examiner le parcours particulier des locuteurs et scripteurs. Nous illustrons les perspectives qu’ouvre le Corpus FRAN sur la variation et le changement linguistiques par l’étude de deux traits typiques du français nord-américain : la variante m’as (et les variantes associées je vas et je vais) et les variantes de la conséquence ça fait que et so (et les variantes associées alors et donc). (shrink)

Background There is considerable variation in the functionality of bioethical services in different institutions and countries for children in hospital, despite new challenges due to increasing technology supports for children with serious illness and medical complexity. We aimed to understand how bioethics services address bioethical concerns that are increasingly encountered in paediatric intensive care. Methods A qualitative descriptive design was used to describe clinician’s perspectives on the functionality of clinical bioethics services for paediatric intensive care units. Clinicians who were (...) members of formal or informal clinical bioethics groups, or who were closely involved with the process of working through ethically challenging decisions, were interviewed. Interviews took place online. Resulting transcripts were analysed using thematic analysis. Results From 33 interviews, we identified four themes that described the functionality of bioethics services when a child requires technology to sustain life: striving for consensus; the importance of guidelines; a structure that facilitates a time-sensitive and relevant response; and strong leadership and teamwork. Conclusions Clinical bioethics services have the potential to expand their role due to the challenges brought by advancing medical technology and the increasing options it brings for treatment. Further work is needed to identify where and how bioethics services can evolve and adapt to fully address the needs of the decision-makers in PICU. (shrink)

Enormous phylogenetic variation exists in the number and sizes of introns in protein‐coding genes. Although some consideration has been given to the underlying role of the population‐genetic environment in defining such patterns, the influence of the intracellular environment remains virtually unexplored. Drawing from observations on interactions between co‐transcriptional processes involved in splicing and mRNA 3′‐end formation, a mechanistic model is proposed for splice‐site recognition that challenges the commonly accepted intron‐ and exon‐definition models. Under the suggested model, splicing factors (...) that outcompete 3′‐end processing factors for access to intronic binding sites concurrently favor the recruitment of 3′‐end processing factors at the pre‐mRNA tail. This hypothesis sheds new light on observations such as the intron‐mediated enhancement of gene expression and the negative correlation between intron length and levels of gene expression. (shrink)

Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short‐range cell–cell signalling molecules, hormones and structural proteins. It has been implicated in a number of key biological processes including cell proliferation, migration, adhesion and signalling both in normal development and in oncogenesis. The mechanisms by which Pax6 regulates its downstream (...) targets likely involve the use of different splice variants and interactions with multiple proteins, allowing it to generate different effects in different cells. Extrapolation to developmental transcription factors in general suggests that variation in the nature of individual factors is likely to contribute to the emergence of differences between tissues. BioEssays 24:1041–1051, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Our aim in this article is to attempt to discuss propagating organization of process, a poorly articulated union of matter, energy, work, constraints and that vexed concept, “information”, which unite in far from equilibrium living physical systems. Our hope is to stimulate discussions by philosophers of biology and biologists to further clarify the concepts we discuss here. We place our discussion in the broad context of a “general biology”, properties that might well be found in life anywhere in the cosmos, (...) freed from the specific examples of terrestrial life after 3.8 billion years of evolution. By placing the discussion in this wider, if still hypothetical, context, we also try to place in context some of the extant discussion of information as intimately related to DNA, RNA and protein transcription and translation processes. While characteristic of current terrestrial life, there are no compelling grounds to suppose the same mechanisms would be involved in any life form able to evolve by heritable variation and natural selection. In turn, this allows us to discuss at least briefly, the focus of much of the philosophy of biology on population genetics, which, of course, assumes DNA, RNA, proteins, and other features of terrestrial life. Presumably, evolution by natural selection—and perhaps self-organization—could occur on many worlds via different causal mechanisms. Here we seek a non-reductionist explanation for the synthesis, accumulation, and propagation of information, work, and constraint, which we hope will provide some insight into both the biotic and abiotic universe, in terms of both molecular self reproduction and the basic work energy cycle where work is the constrained release of energy into a few degrees of freedom. The typical requirement for work itself is to construct those very constraints on the release of energy that then constitute further work. Information creation, we argue, arises in two ways: first information as natural selection assembling the very constraints on the release of energy that then constitutes work and the propagation of organization. Second, information in a more extended sense is “semiotic”, that is about the world or internal state of the organism and requires appropriate response. The idea is to combine ideas from biology, physics, and computer science, to formulate explanatory hypotheses on how information can be captured and rendered in the expected physical manifestation, which can then participate in the propagation of the organization of process in the expected biological work cycles to create the diversity in our observable biosphere. Our conclusions, to date, of this enquiry suggest a foundation which views information as the construction of constraints, which, in their physical manifestation, partially underlie the processes of evolution to dynamically determine the fitness of organisms within the context of a biotic universe. (shrink)

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein-coding RNA (ncRNA) transcription in the higher eukaryotes (...) and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of the structure of genetic regulatory systems in animals and plants may be incorrect. ncRNA dominates the genomic output of the higher organisms and has been shown to control chromosome architecture, mRNA turnover and the developmental timing of protein expression, and may also regulate transcription and alternative splicing. This paper re-examines the available evidence and suggests a new framework for considering and understanding the genomic programming of biological complexity, autopoletic development and phenotypic variation. BioEssays 25:930-939,2003. (C) 2003 Wiley Periodicals, Inc. (shrink)

Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in (...) fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles. (shrink)

Recent advances in biomarkers may soon make it possible to identify persons at high risk for late-onset Alzheimer’s disease at a presymptomatic stage. Popular demand for testing is increasing despite the lack of cure and effective prevention options and despite uncertainties regarding the predictive value of biomarker tests. This underscores the relevance of the ethical, cultural and social implications of predictive testing and the need to advance the bioethical debate beyond considerations of clinical consequences. Our qualitative study included three groups (...) of affected persons: People with mild neurocognitive disorder, their relatives and family caregivers of people with dementia. We explored their moral motivations regarding predictive, biomarker-based testing and preclinical diagnostics. We interviewed affected individuals in Germany and Israel. Transcripts of 12 focus groups and 12 semistructured interviews were content analysed with a focus on the moral motivations of affected persons in their justification of why they accept or reject predictive testing and early diagnosis. We grouped the underlying aspects of moral motivation into four ethical categories: beneficence as a form of personal utility focusing on well-being, the ties of responsibility linking families and their individual members, the importance of self-determination by later life planning and notions of a good life. In general, cultural parallels among these motives were very obvious. Cultural variation occurred mainly in openness to suicide, scepticism about test validity and emphasis on personal autonomy. The study underscores the importance of counselling for life-planning issues and of informing test candidates about problems with test validity and about the ambiguity of test results. All data relevant to the study are included in the article or uploaded as supplementary information. (shrink)

During development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld–Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both epithelial (...) and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes. BioEssays 26:374–386, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

A widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the (...) evolution of local mutation rates and identify the main limiting factors. Both targeted hyper‐ and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin‐associated proteins could overcome the drift limit and lead to non‐random hypomutation along the genome in most organisms.Editor's suggested further reading in BioEssays Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine Abstract. (shrink)

Minimal genetic pre-formationism is defended, in that primacy is ascribed to DNA in the structuring of molecules through molecular codes. This together with the importance of such codes for stability and variation in living systems makes DNA categorically different from other causal factors. It is argued that post-transcriptional and post-translational processing in protein synthesis does not rob DNA of this structuring role. Notions of structuring causal powers that may vary in degree, of arbitrary molecular codes that are more (...) or less realized, of partial templating and of genetic information as a subspecies of mechanistic information are brought in to support this and to rival causal and semantic notions of information. It is concluded that the primacy of genes in their structuring of molecules goes together with parity between genes and non-genetic causal factors in regulation of living systems. This is seen to hold independently of the radical reconceptualization of organism cum environment that has been suggested in developmental systems theory. (shrink)

These comments focus on issues of genre in transcription formats. Bucholtz's paper takes conversation to be the a priori organizational genre of everyday talk, following a long line of interactional and conversational studies. Narrative, however, could as well be seen as an a priori genre for the organization of interaction, and many instances of talk would reflect polygeneric blending. This form of blending should be reflected in transcription practices, so that we can do justice to variation in talk by (...) means of variation in transcription procedures. (shrink)

One of the most interesting challenges facing paleobiologists is explaining the Cambrian explosion, the dramatic appearance of most metazoan animal phyla in the Early Cambrian, and the subsequent stability of these body plans over the ensuing 530 million years. We propose that because phenotypic variation decreases through geologic time, because microRNAs (miRNAs) increase genic precision, by turning an imprecise number of mRNA transcripts into a more precise number of protein molecules, and because miRNAs are continuously being added to metazoan (...) genomes through geologic time, miRNAs might be instrumental in the canalization of development. Further, miRNAs ultimately allow for natural selection to elaborate morphological complexity, because by reducing gene expression variability, miRNAs increase heritability, allowing selection to change characters more effectively. Hence, miRNAs might play an important role in shaping metazoan macroevolution, and might be part of the solution to the Cambrian conundrum. (shrink)

Low mean fundamental frequency (F 0) in men’s voices has been found to positively influence perceptions of dominance by men and attractiveness by women using standardized speech. Using natural speech obtained during an ecologically valid social interaction, we examined relationships between multiple vocal parameters and dominance and attractiveness judgments. Male voices from an unscripted dating game were judged by men for physical and social dominance and by women in fertile and non-fertile menstrual cycle phases for desirability in short-term and long-term (...) relationships. Five vocal parameters were analyzed: mean F 0 (an acoustic correlate of vocal fold size), F 0 variation, intensity (loudness), utterance duration, and formant dispersion (D f , an acoustic correlate of vocal tract length). Parallel but separate ratings of speech transcripts served as controls for content. Multiple regression analyses were used to examine the independent contributions of each of the predictors. Physical dominance was predicted by low F 0 variation and physically dominant word content. Social dominance was predicted only by socially dominant word content. Ratings of attractiveness by women were predicted by low mean F 0, low D f , high intensity, and attractive word content across cycle phase and mating context. Low D f was perceived as attractive by fertile-phase women only. We hypothesize that competitors and potential mates may attend more strongly to different components of men’s voices because of the different types of information these vocal parameters provide. (shrink)

Genetic variability is considered a key to the evolvability of species. The conversion of an adenosine (A) to inosine (I) in primary RNA transcripts can result in an amino acid change in the encoded protein, a change in secondary structure of the RNA, creation or destruction of a splice consensus site, or otherwise alter RNA fate. Substantial transcriptome and proteome variability is generated by A‐to‐I RNA editing through site‐selective post‐transcriptional recoding of single nucleotides. We posit that this epigenetic source (...) of phenotypic variation is an unrecognized mechanism of adaptive evolution. The genetic variation introduced through editing occurs at low evolutionary cost since predominant production of the wild‐type protein is retained. This property even allows exploration of sequence space that is inaccessible through mutation, leading to increased phenotypic plasticity and provides an evolutionary advantage for acclimatization as well as long‐term adaptation. Furthermore, continuous probing for novel RNA editing sites throughout the transcriptome is an intrinsic property of the editing machinery and represents the molecular basis for increased adaptability. We propose that higher organisms have therefore evolved to systems with increasing RNA editing activity and, as a result, to more complex systems. (shrink)