bluuebunny/crossref_metadata_2025 huggingface dataset:
Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in
Drosophila
Authors: Jiang Kai , Liu Yajuan , Fan Junkai , Epperly Garretson , Gao Tianyan , Jiang Jin , Jia Jianhang
Published: October 2014

Significance

Hedgehog (Hh) signaling by Smoothened (Smo) is mediated by phosphorylation and cell surface/cilium accumulation, but how the localization of Smo is controlled remains poorly understood. We show that the atypical PKC (aPKC)–partition defective 6 (Par6) complex promotes Hh signaling by phosphorylating Smo and regulating Smo basolateral accumulation in addition to phosphorylating the transcription factor cubitus interruptus (Ci). Our results demonstrate direct involvement of aPKC in Hh signaling beyond its role in cell polarity and suggest that basolateral accumulation of Smo is critical for its activity. Abnormal activation of Smo results in several types of cancers, and Smo can easily acquire drug resistance through mutations. A better understanding of the mechanisms of Smo regulation is critical to developing more effective therapeutic treatments for cancers caused by Smo dysregulation.
The general mode of translation inhibition by macrolide antibiotics
Authors: Kannan Krishna , Kanabar Pinal , Schryer David , Florin Tanja , Oh Eugene , Bahroos Neil , Tenson Tanel , Weissman Jonathan S. , Mankin Alexander S.
Published: October 2014

Significance

Macrolide antibiotics inhibit translation by binding in the ribosomal nascent peptide exit tunnel. It was believed that macrolides interfere with protein synthesis by obstructing the egress of nascent proteins. In contrast to this view, the results of ribosome profiling analysis suggest that the main mode of macrolide action is context-specific inhibition of peptide bond formation. The ribosome with a macrolide molecule bound in the tunnel is impaired in catalysis of peptide bond formation between specific combinations of the peptidyl donors and aminoacyl acceptors, leading to interruption of translation when such problematic substrates are encountered. These findings underscore the existence of a link between the ribosomal tunnel and the peptidyl transferase center and pave the way for development of superior antibiotics.
Mathematical model of sarcoidosis
Authors: Hao Wenrui , Crouser Elliott D. , Friedman Avner
Published: October 2014

Significance

Sarcoidosis is a disease involving abnormal collection of granulomas that develop in the lung and other organs. The origin of the disease is unknown, clinical data are very limited, and there is no current effective treatment. This paper develops a mathematical model with simulations that are validated by the available clinical data. The model is then used to explore potential treatments of the disease, to suggest therapeutic targets that may reduce the disease activity, and thus to predict treatment responses in preclinical settings.
Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death
Authors: Rao Feng , Xu Jing , Khan A. Basit , Gadalla Moataz M. , Cha Jiyoung Y. , Xu Risheng , Tyagi Richa , Dang Yongjun , Chakraborty Anutosh , Snyder Solomon H.
Published: October 2014

Significance

Attachment of the small protein ubiquitin to other proteins, a process called “ubiquitylation,” triggers protein degradation. The Cullin and signalosome protein families cooperatively mediate this process, but how they are regulated has been obscure. We show that an inositol polyphosphate with seven phosphates, hence designated IP7, is critical. Under basal conditions, the enzyme that generates IP7 is bound to the Cullin/signalosome complex, which is thereby maintained in an inactive state. Stressful stimuli, such as UV radiation, stimulate the enzyme to form IP7, which dissociates the complex, leading to activation of the Cullins with attendant ubiquitylation and degradation of target proteins. This process may play a key role in how cells respond to environmental stressors.
Lethal coalitionary aggression and long-term alliance formation among Yanomamö men
Authors: Macfarlan Shane J. , Walker Robert S. , Flinn Mark V. , Chagnon Napoleon A.
Published: October 2014

Significance

Humans, like chimpanzees, engage in coalitionary violence: Members of both species coordinate lethal activity against conspecifics. The origin and adaptive functions of this behavior are poorly understood, and data from tribal populations are rare. We examine the composition of lethal coalitions from the Yanomamö, a tribal society in Amazonia. In contrast to chimpanzees, Yanomamö coalitions are composed of individuals from different lineages and natal communities. Many coalition partners are ideal marriage exchange partners. Men who kill together more often are more likely to live together in the same village later in life and to engage in marriage exchange. Our results highlight connections between coalitionary aggression and alliance formation and illuminate differences in social structure distinguishing humans from other primates.
Quantitative proteomics reveals the dynamics of protein changes during
Drosophila
oocyte maturation and the oocyte-to-embryo transition
Authors: Kronja Iva , Whitfield Zachary J. , Yuan Bingbing , Dzeyk Kristina , Kirkpatrick Joanna , Krijgsveld Jeroen , Orr-Weaver Terry L.
Published: October 2014

Significance

Oogenesis aberrations are an important cause of birth defects. During oocyte development, meiotic divisions are coordinated with intense transcription and translation, which produce maternally encoded RNAs and proteins that drive early embryonic development. Oocyte maturation and egg activation result in eggs competent for fertilization and embryogenesis, respectively, and these events occur in the absence of transcription or RNA degradation. Therefore, it is likely that changes in protein levels or activity govern these developmental transitions. By providing the first proteome-wide overview, to our knowledge, of the proteins whose levels change during oocyte maturation and combining these data with our previous description of proteome remodeling at egg activation, we describe critical events and factors driving the development of immature oocyte into an embryogenesis-competent egg.
Distal transport of dissolved hydrothermal iron in the deep South Pacific Ocean
Authors: Fitzsimmons Jessica N. , Boyle Edward A. , Jenkins William J.
Published: October 2014

Significance

Low concentrations of the micronutrient iron in seawater are known to limit primary production and nitrogen fixation in large regions of the global ocean. Thus, it is important to constrain the sources and sinks controlling the marine dissolved iron distribution and consequent micronutrient supply to surface plankton. Although the major dissolved iron sources have been historically thought to be atmospheric dust inputs and fluxes from the continental margin, we show here the first data to our knowledge demonstrating that dissolved iron from hydrothermal vents can be transported thousands of kilometers from the venting site, which to date has only been suggested and modeled. Thus, hydrothermal vents must be considered when determining the marine dissolved iron inventory, especially in the abyssal ocean.
Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice
Authors: Yolken Robert H. , Jones-Brando Lorraine , Dunigan David D. , Kannan Geetha , Dickerson Faith , Severance Emily , Sabunciyan Sarven , Talbot C. Conover , Prandovszky Emese , Gurnon James R. , Agarkova Irina V. , Leister Flora , Gressitt Kristin L. , Chen Ou , Deuber Bryan , Ma Fangrui , Pletnikov Mikhail V. , Van Etten James L.
Published: October 2014

Significance

Human mucosal surfaces contain a wide range of microorganisms. The biological effects of these organisms are largely unknown. Large-scale metagenomic sequencing is emerging as a method to identify novel microbes. Unexpectedly, we identified DNA sequences homologous to virus ATCV-1, an algal virus not previously known to infect humans, in oropharyngeal samples obtained from healthy adults. The presence of ATCV-1 was associated with a modest but measurable decrease in cognitive functioning. A relationship between ATCV-1 and cognitive functioning was confirmed in a mouse model, which also indicated that exposure to ATCV-1 resulted in changes in gene expression within the brain. Our study indicates that viruses in the environment not thought to infect humans can have biological effects.
Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress
Authors: Kinoshita Yayoi , Hunter Richard G. , Gray Jason D. , Mesias Roxana , McEwen Bruce S. , Benson Deanna L. , Kohtz D. Stave
Published: October 2014

Significance

Associated with depression and cognitive impairment, chronic stress causes reversible dendritic shrinkage particularly evident in the hippocampal CA3 region in several animal models. In further elucidating the molecular events leading to dendritic shrinkage, this study reveals two unexpected mechanisms reduction in translated transcripts of a nuclear pore complex protein, nucleoporin p62 (NUP62), and tyrosine phosphorylation of NUP62, that appear to act cumulatively in chronic stress to reduce NUP62 content in CA3 neurons. Subcellular redistribution of activated proline-rich tyrosine kinase 2 in chronically stressed pyramidal neurons suggests a mechanism for stress-induced tyrosine phosphorylation of NUP62. Furthermore, evidence from cultured hippocampal neurons shows that diminishing the content of NUP62, which functions in nucleocytoplasmic transport and chromatin organization, results in simplification and shortening of dendritic arbors.
Antisense
COOLAIR
mediates the coordinated switching of chromatin states at
FLC
during vernalization
Authors: Csorba Tibor , Questa Julia I. , Sun Qianwen , Dean Caroline
Published: October 2014

Significance

Long noncoding RNAs (lncRNAs) play important roles in chromatin regulation in higher eukaryotes. Studies analysing how lncRNAs influence Polycomb silencing suggested they specifically bind and recruit Polycomb Repressive Complex 2 (PRC2) to defined targets. However, the promiscuous binding of PRC2 to RNA has raised questions as to the mechanism by which lncRNA contributes to Polycomb silencing. We investigate the function of a set of cold-induced antisense transcripts in the Polycomb-dependent epigenetic silencing of a floral repressor gene in
Arabidopsis
. Through analysis of a transgene, in which antisense transcripts are no longer cold-induced, we show that these antisense transcripts are required for coordinated switching of opposing chromatin states. This mechanism links transcriptional shutdown by cold to long-term epigenetic silencing.
The story of “Danish Happiness”
Authors: Levisen Carsten
Published: October 2014

According to a new global narrative, the Danes are the happiest people in the world. This paper takes a critical look at the international media discourse of “happiness”, tracing its roots and underlying assumptions. Equipped with the Natural Semantic Metalanguage approach to linguistic and cultural analysis, a new in-depth semantic analysis of the story of “Danish happiness” is developed. It turns out that the allegedly happiest people on earth do not (usually) talk and think about life in terms of ”happiness”, but rather through a different set of cultural concepts and scripts, all guided by the Danish cultural keyword lykke. The semantics of lykke is explicated along with two related concepts livsglæde, roughly, ‘life joy’ and livslyst ‘life pleasure’, and based on semantic and ethnopragmatic analysis, a set of lykke-related cultural scripts is provided. With new evidence from Danish, it is argued that global Anglo-International “happiness discourse” misrepresents local meanings and values, and that the one-sided focus on “happiness across nations” in the social sciences is in dire need of cross-linguistic confrontation. The paper calls for a post-happiness turn in the study of words and values across languages, and for a new critical awareness of linguistic and conceptual biases in Anglo-international discourse.
Rape is rape (except when it’s not)
Authors: Attenborough Frederick
Published: October 2014

This article contributes to a body of research in which media reports of violence against women are analysed for the ways they gloss precisely what it is that constitutes ‘violence against women’ in the event under report. To catch this glossingin flight, as it were, mediated reports of violence are conceptualised as recontextualisations; that is, reports that may differ in rhetorically consequential ways from those provided by victims of, or witnesses to, that violence. A mediated stylistic analysis of press reportage of the charges of rape made against Julian Assange, the founder ofWikiLeaks, in 2010, subsequently shows that and how Assange’s allegedly violent actions were recontextualised such that their status asviolentwas readably downgraded, mitigated or even deleted. The article ends by calling for more attention to be paid to the various techniques of recontextualisation via which reports of violence against women are presented in the media.
Gender ideology and social identity processes in online language aggression against women
Authors: Bou-Franch Patricia , Garcés Blitvich Pilar
Published: October 2014

This paper examines language aggression against women in public online deliberation regarding crimes of violence against women. To do so, we draw upon a corpus of 460 unsolicited digital comments sent in response to four public service advertisements against women abuse posted on YouTube. Our analysis reveals that three patriarchal strategies of abuse — namely, minimize the abuse, deny its existence, and blame women — are enacted in the online discourse under scrutiny and shows how, at the micro-level of interaction, these strategies relate to social identity and gender ideology through complex processes of positive in-group description and negative out-group presentation. We also argue that despite the few comments thatexplicitlysupport abuse, this situation changes atimplicit,indirectlevels of discourse.
Public/Private language aggression against women
Authors: Anderson Kristin L. , Cermele Jill
Published: October 2014

Verbal aggression against women often serves to naturalize a binary construction of gender. The form and content of verbal aggression against women may be shifting in the 21st century context, in which overtly sexist language in public settings is viewed as unacceptable. However, we argue that in fact, sexist language continues, albeit at times in less overt ways and particularly so when the discourse is public, or likely to be made public. This study examines the specific content of language aggression against women with two sources of data: 1) the population of tweets containing the handle @femfreq posted during 17 days in the fall of 2013, and 2) the population of 130 civil protection order petitions filed in the first 8 months of 2010 in a small city in the Pacific Northwest. We consider how the content of gendered language aggression in Tweets — a form of verbal discourse that is authored by people who do not personally know the object of their aggression — is similar to and different from the language aggression perpetrated by the intimate partners of women seeking legal protection from abuse from the courts — a form of verbal discourse enacted in intimate contexts.
The development of coherence and cohesion in monolingual and sequential bilingual children’s narratives
Authors: Kupersmitt Judy , Yifat Rachel , Blum-Kulka Shoshana
Published: October 2014

Studies of monolingual narrative production have revealed interacting paths in the development of coherence and cohesion across languages but less is known about bilingual narratives, where a gap may exist between socio-cognitive and linguistic abilities. The present longitudinal study explores the relations between measures of coherence and cohesion in the picture-based oral narratives elicited from 23 sequential bilinguals at two times — 2nd and 4th years of exposure to Hebrew as L2 (ages 6 and 8, respectively), compared to those produced by age-matched Hebrew speaking monolinguals. Measures of coherence included reference to story components, and to four types of causal relations: psychological, motivational, enabling and physical. These analyses served as a basis to explore cohesion in terms of (1) inter-clausal connectivity, and (2) the linguistic encoding of the causal chain, which in this context demanded reference to a complex motion event. We found that reference to narrative components and causal relations improved with age in both L1 and L2, but were largely delayed among bilinguals at age 6, particularly regarding the most complex scenes. While coherence measures reached to a parallel level among the 8 year-old children, measures of cohesion showed a different path of development in L1 and L2. Thus, the constraints imposed by language use in organizing the discourse resulted in a poorer connectivity between the clauses, and in less accurate lexico-grammatical encoding of the events in the bilingual narratives. The study underscores the mutual attraction between local and global principles of narrative construction, which may become dissociated in a bilingual situation, and pinpoints to vulnerable domains of L2 discourse-embedded acquisition.
“Happily ever after”
Authors: Purnell David , Bowman Jim
Published: October 2014

The domination of a happy narrative frame has gradually broadened to include different kinds of endings, but a positive resolution is still often expected. Do narratives need an optimistic ending? Do hopeful endings begin to loose their credibility? Should we buy into the Hollywood scripts presenting an ending that solves or completes the plot by the end of its telling? Endings point to a potential future, and culturally we have been conditioned to write this future optimistically. Not everything ends well, however. Sometimes, things just end. Narrative conclusions can be optimistic and have catharsis, but not end with a “happily ever after” (Purnell, 2013).
The internal dimension of tasks
Authors: Manchón Rosa M.
Published: October 2014

This chapter considers how an “internal dimension of tasks” can both shed new light on the relationship between task interpretation, task performance, and learning outcomes, and advance the research agenda on task learning with worthwhile new empirical questions. Building on an expanded notion of the construct of task and the premise that language learning through task is closely linked to the problem-solving activity learners engage in while they are composing, the chapter explores the nature of learner agency in this problem-solving activity and hence the close connection between learners’ own perceptions of task demands, goals, and expected outcomes, and their processing activity during task execution. The chapter claims that TBLT-based understandings of the interplay between task factors and learner factors can benefit from incorporating insights derived from the cognitively-oriented L2 writing theoretical and empirical literature. This should facilitate the quest for answers to theoretically and pedagogically relevant empirical questions on task learning in general.
Theorizing language development at the intersection of ‘task’ and L2 writing
Authors: Byrnes Heidi
Published: October 2014

The chapter argues that advantageous synergies between task and L2 writing can come about through a bidirectional link between them that recovers existing shared interests and discovers new commonalities. It suggests that a multiple literacies orientation that focuses on textual meaning-making might help create the needed platform for addressing fundamental concerns in both areas regarding L2 learning, L2 development over long instructional periods, and pressing educational issues in a global world, particularly with regard to attaining advanced ability levels. On the one hand, this involves an expansion of the notion of task, made possible through a meaning-oriented theory of language; on the other hand, the introduction of ‘task’ offers an advantageous focus for both writing research and practice. Taking a historical perspective and focusing on the central construct of complexity, the chapter first probes the presence in TBLT and writing theorizing and research of a textual meaning orientation. Thereafter it addresses issues in the language studies field that a synergistic link between these two areas that embraces a textual and meaning focus might usefully address in the interest of language teaching and learning. It concludes with brief comments on how such an approach repositions assessment and how it relates to the call for the development of symbolic competence in the era of multilingualism and globalization.
Linking task and writing for language development
Authors: Byrnes Heidi
Published: October 2014

This chapter explores the link between task and writing by taking an education-oriented view, in order to contribute to answering the question of how L2 writing development to advanced ability levels might best be fostered through genre-oriented TBLT instruction. A companion to the theoretical treatment of task and writing offered in Chapter 4, the chapter interprets language development as an increase in textual meaning-making through genre-based writing tasks. Within that approach it reshapes ‘complexity’ in terms of choices in textual meaning-making and proposes textually oriented parameters for operationalizing complexification. In addition, it suggests the construct of grammatical metaphor (GM) as theorized in systemic functional linguistics (SFL) as especially well-suited for delineating, fostering, and assessing critical aspects of language development. Reflecting this approach, the chapter presents evidence from a longitudinal study about how L2 writing development unfolded in a genre-based approach to task within a curricular context. The focal area of analysis and interpretation are formal aspects of GM, realized through nominalization, and their implications for a developing textual meaning-making ability. Aligning itself with recent scholarship that has called for the careful specification of educational contexts if research findings are to be relevant for language teaching and learning, the chapter concludes with reflections that affirm the potential for genre-based writing tasks to provide a suitably differentiated awareness of the nature of instructed language development within a well-specified curricular framework.
Task, task performance, and writing development
Authors: Byrnes Heidi , Manchón Rosa M.
Published: October 2014

This closing chapter aims to assess the contribution of the book to TBLT theory and research and to put forward directions for advancing TBLT constructs and research agendas. We consider the volume’s overall contribution to the TBLT field to lie in linking the psycholinguistic with the textual, meaning-making nature of writing and in presenting theoretical and methodological refinements along with empirical advances that reflect that orientation. We have organized the details of that contribution as well as the suggestions for future research directions along four closely inter-related foci, namely: (a) a learner-internal perspective that explores the volume’s findings regarding the learner dimension of tasks and the learner’s agency in task execution; (b) a learning orientation that summarizes the studies’ findings and suggests new research paths that elaborate the proposed new theoretical positions, particularly in terms of their ability to specify the nature of learning and development through task-based writing; (c) a textual meaning-making orientation that expands the empirical research agenda for tasks as meaning-making environments and considers implications for assessing task performance from a psycholinguistic and a textual perspective; and (d) a curricular orientation that would illuminate what instructed learners might be able to accomplish when they have the benefit of a principled task- and text-oriented instructional framework.
Mechanisms of the tRNA wobble cytidine modification essential for AUA codon decoding in prokaryotes
Authors: Numata Tomoyuki
Published: October 2014

Bacteria and archaea have 2-lysylcytidine (L or lysidine) and 2-agmatinylcytidine (agm2C or agmatidine), respectively, at the first (wobble) position of the anticodon of the AUA codon-specific tRNAIle. These lysine- or agmatine-conjugated cytidine derivatives are crucial for the precise decoding of the genetic code. L is synthesized by tRNAIle-lysidine synthetase (TilS), which uses l-lysine and ATP as substrates. Agm2C formation is catalyzed by tRNAIle-agm2C synthetase (TiaS), which uses agmatine and ATP for the reaction. Despite the fact that TilS and TiaS synthesize structurally similar cytidine derivatives, these enzymes belong to non-related protein families. Therefore, these enzymes modify the wobble cytidine by distinct catalytic mechanisms, in which TilS activates the C2 carbon of the wobble cytidine by adenylation, while TiaS activates it by phosphorylation. In contrast, TilS and TiaS share similar tRNA recognition mechanisms, in which the enzymes recognize the tRNA acceptor stem to discriminate tRNAIle and tRNAMet.
The “Acts” of Paul: micro-processes and new institution creation
Authors: Almond Bradley A.
Published: October 2014

How do new institutions get created? And what role do micro-processes play in this creative process? To date, there have been minimal efforts to fully describe and model the process by which the discrete and various micro-level activities of institutional actors contribute to the creation of new institutions. Drawing from recent scholarship ininstitutional work, in this paper, I employ a grounded theory approach to the life and works of Paul of Tarsus as recorded in biblical texts to develop a process model of the creation of a new institution which emphasizes micro-level processes, particularlysensemaking. The model centers on two simultaneous and iterative processes by which Paul crafts a message for his various audiences and reinforces these teachings with behavioral, relational, and doctrinal structures. The emergence of an institution is conceived as the long-term accretion of many discrete institutional acts.
Staphylococcus aureus infection induces protein A–mediated immune evasion in humans
Authors: Pauli Noel T. , Kim Hwan Keun , Falugi Fabiana , Huang Min , Dulac John , Henry Dunand Carole , Zheng Nai-Ying , Kaur Kaval , Andrews Sarah F. , Huang Yunping , DeDent Andrea , Frank Karen M. , Charnot-Katsikas Angella , Schneewind Olaf , Wilson Patrick C.
Published: October 2014

Staphylococcus aureus bacterial infection commonly results in chronic or recurrent disease, suggesting that humoral memory responses are hampered. Understanding how S. aureus subverts the immune response is critical for the rescue of host natural humoral immunity and vaccine development. S. aureus expresses the virulence factor Protein A (SpA) on all clinical isolates, and SpA has been shown in mice to expand and ablate variable heavy 3 (VH3) idiotype B cells. The effects of SpA during natural infection, however, have not been addressed. Acutely activated B cells, or plasmablasts (PBs), were analyzed to dissect the ongoing immune response to infection through the production of monoclonal antibodies (mAbs). The B cells that were activated by infection had a highly limited response. When screened against multiple S. aureus antigens, only high-affinity binding to SpA was observed. Consistently, PBs underwent affinity maturation, but their B cell receptors demonstrated significant bias toward the VH3 idiotype. These data suggest that the superantigenic activity of SpA leads to immunodominance, limiting host responses to other S. aureus virulence factors that would be necessary for protection and memory formation.
Vascular Stiffening in Pulmonary Hypertension: Cause or Consequence? (2013 Grover Conference Series)
Authors: Tan Wei , Madhavan Krishna , Hunter Kendall S. , Park Daewon , Stenmark Kurt R.
Published: October 2014

Recent studies have indicated that systemic arterial stiffening is a precursor to hypertension and that hypertension, in turn, can perpetuate arterial stiffening. Pulmonary artery (PA) stiffening is also well documented to occur in pulmonary hypertension (PH), and there is evidence that pulmonary vascular stiffness (PVS) may be a better predictor of outcome than pulmonary vascular resistance (PVR). We have hypothesized that the decreased flow‐damping function of elastic PAs in PH likely initiates and/or perpetuates dysfunction of pulmonary microvasculature. Recent studies have shown that large‐vessel stiffening increases flow pulsatility in the distal pulmonary vasculature, leading to endothelial dysfunction within a proinflammatory, vasoconstricting, and profibrogenic environment. The intricate role of stiffening‐stimulated high pulsatile flow in endothelial cell dysfunction includes stepwise molecular events underlying PA hypertrophy, inflammation, endothelial‐mesenchymal transition, and fibrosis. In addition to contributing to microenvironmental alterations of the distal vasculature, disordered proximal‐distal PA coupling likely also plays a role in increasing ventricular afterload, ultimately causing right ventricle (RV) dysfunction and death. Current therapeutic treatments do not provide a realistic approach to destiffening arteries and, thus, to potentially abrogating the effects of high pulsatile flow on the distal pulmonary vasculature or the increased work imposed by stiffening on the RV. Scrutinizing the effect of PA stiffening on high pulsatile flow–induced cellular and molecular changes, and vice versa, might lead to important new therapeutic options that abrogate PA remodeling and PH development. With a clear understanding that PA stiffening may contribute to the progression of PH to an irreversible state by contributing to chronic microvascular damage in lungs, future studies should be aimed first at defining the underlying mechanisms leading to PA stiffening and then at improved treatment approaches based on these findings.
‘As in heart, so in mouth’: Translating the Scandal of Wolfish Desire from Fables to Peire Vidal
Authors: Kay Sarah
Published: October 2014

The motif of the ‘wolf at school’, in which a wolf is made to learn elementary Latin, typically the alphabet, occurs in medieval tales, church sculptures, and manuscript illuminations. Whatever the wolf's instructors try to teach him, he can only say ‘lamb’. The story's usual moral is ‘quod in corde, hoc in ore’ [as in heart, so in mouth]. I probe the meaning of this moral through the medieval Latin fables of Romulus and Odo of Cheriton, the well-known vernacular fable of Marie de France, and a hitherto unknown version attributed to the troubadour Peire Vidal, which in turn leads me to assess clerical and vernacular teaching of the alphabet. In Latin, the wolf's speech is invariably censured, even if readers may sneakingly have sided with him; but the vernacular texts accord him more sympathy, self-deprecatingly in Berenguer d'Anoia, equivocally in Marie, and flamboyantly in Peire Vidal, who elsewhere adopts a wolf as his emblem. The wolf's cry of ‘lamb’ gives voice, albeit impossibly, to the ‘insistence of the letter in the unconscious’ (Lacan): a beast that can thus openly speak his desire challenges human readers to reconsider the relationship of language to appetite and to question the human monopoly of language.
Integrated Neuroscience and Neurology
Authors: Marcus Elliott M. , Jacobson Stanley , Sabin Thomas D.
Published: October 2014

This online resource addresses the basic questions of clinical neurology, which include where the disease process is located, and the nature of the disease process. It reviews the makeup of the cells within the central nervous system and the development of the regions within the central nervous system, followed by a detailed anatomical overview of the nervous system, starting at the spinal cord, proceeding to the brain stem, diencephalon and cerebrum. It focuses not only on localized diseases caused by infectious diseases, trauma, tumors, and vascular lesions within the central nervous system, but also these diseases within the systems of the brain and spinal cord. Over 250 real cases with associated MRI or CTs and any pathological findings from these patients illustrate numerous disorders and fully explain the nature of the pathology. Also included are six problem solving sessions in which the student must identify the ongoing disease process, what caused it, and how best to treat it. Throughout the discussion the authors also correlate the neurological findings to the underlying anatomy of the region.
Epidemiology
Authors: Kay Chris , Fisher Emily , Hayden Michael R.
Published: October 2014

The prevalence and persistence of Huntington’s disease (HD) is crucially informed by the causative mutation. Diagnostic and predictive testing has enabled a new era of epidemiologic study of HD, whereby only those who carry an expanded CAG repeat are included in such measures. In Western populations, estimated prevalence of the disease is higher following the introduction of genetic testing, and prevalence may also be increasing in absolute terms. There are worldwide differences in the prevalence of HD by ethnicity and population, which may be accounted for in part by genetic diversity of the CAG repeat and the surrounding haplotype. HD is endemic to all populations, but is most common in populations of European ancestry in which specific disease haplotypes are found. New mutations maintain HD in a population, and genetic differences by population may contribute to differences in the de novo mutation rate.
Genetic Counseling and Testing
Authors: MacLeod Rhona , Tibben Aad
Published: October 2014

This chapter considers the challenges for clinicians involved in genetic counseling for Huntington’s disease, referring to the literature and best-practice guidelines. The issues involved in genetic testing and counseling around reproductive options are discussed. Ways of tailoring predictive test counseling to take better account of individuals’ experiences and knowledge are explored, and more complex predictive test counseling scenarios, such as requests from minors and individuals at 25% risk, are also covered. The process of assisting families near the time of diagnosis is explored, including ways of helping individuals in apparent denial of symptoms and facilitating communication among family members. Finally, this chapter reflects on lessons learned from our collective experiences and considers areas in which more work is needed.
Altered Neuronal Circuitry
Authors: Levine Michael S. , Wang Elizabeth A. , Chen Jane Y. , Cepeda Carlos , André Véronique M.
Published: October 2014

In mouse models of Huntington’s disease (HD), synaptic alterations in the cerebral cortex and striatum are present before overt behavioral symptoms and cell death. Similarly, in HD patients, it is now widely accepted that early deficits can occur in the absence of neural atrophy or overt motor symptoms. In addition, hyperkinetic movements seen in early stages are followed by hypokinesis in the late stages, indicating that different processes may be affected. In mouse models, such behavioral alterations parallel complex biphasic changes in glutamate-mediated excitatory, γ‎-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission and dopamine modulation in medium spiny neurons of the striatum as well as in cortical pyramidal neurons. The progressive electrophysiologic changes in synaptic communication that occur with disease stage in the cortical and basal ganglia circuits of HD mouse models strongly indicate that therapeutic interventions and strategies in human HD must be targeted to different mechanisms in each stage and to specific subclasses of neurons.
Structural Biology
Authors: Wetzel Ronald , Mishra Rakesh
Published: October 2014

The 3,144–amino acid huntingtin protein (HTT) folds in water into a structure consisting of compact, organized domains interspersed with intrinsically disordered protein (IDP) elements. The IDPs function as sites of post-translational modifications and proteolysis as well as in targeting, binding, and aggregation. Although the dominant structural motif of HTT is the α‎-helix–rich HEAT repeat, the expanded polyglutamine (polyQ) toxicity responsible for Huntington’s disease is most likely played out within intrinsically disordered HTT exon 1–like fragments consisting of the 16– to 17–amino acid N-terminal HTTNT segment, the polyQ segment, and a proline-rich segment. The physical behavior of HTT exon 1 fragments is dominated by interactive, polyQ repeat length–dependent structural transitions responsible for membrane and protein–protein interactions and the formation of tetramers, higher oligomers, amyloid fibrils, and inclusions. Understanding the basis of this solution behavior may be the key to disease mechanisms and molecular therapeutic strategies.
Comprehensive Care
Authors: Nance Martha A.
Published: October 2014

The care-defining characteristics of Huntington’s disease (HD) are that it is (1) neuropsychiatric, (2) autosomal dominant, (3) usually adult onset, (4) degenerative over years, and (5) fatal. Comprehensive care of HD requires an awareness of these features of the disease and careful attention to the timing and nature of the diagnosis and to the management of the motor, cognitive, psychiatric/behavioral, and nutritional/bioenergetic disorders. Genetic counseling and testing, social services, and psychological support for affected individuals and their families are all necessary components of a comprehensive approach to care. Comprehensive care ideally includes a team of health professionals who can collectively manage all of these areas and an awareness of the longitudinal course of the disease so that care is provided proactively, anticipating the next problem or disease milestone, rather than reacting to problems as they arise.
Preclinical Experimental Therapeutics
Authors: Bates Gillian P. , Landles Christian
Published: October 2014

This chapter begins by reviewing the mammalian models of Huntington’s disease (HD) that have been developed using mice, rats, and a number of large animals, including sheep, pigs, and nonhuman primates. Analysis of these models, together with genetically engineered mice created through specific manipulations of the mouse genome, has provided considerable insights into the molecular pathogenesis of HD. The number of potential therapeutic targets that have been proposed for HD is considerable, and their preclinical evaluation in HD mouse models is being used to select targets that should be pursued in drug development programs. Hence, mouse models have been used extensively to validate therapeutic targets and in the preclinical testing of therapeutic strategies. The limitations of these studies are discussed, and best-practice approaches are highlighted. The chapter concludes with a summary of the gene therapy approaches that are being developed, including strategies to lower the levels of huntingtin.
Experimental Therapeutics
Authors: Borowsky Beth , Sampaio Cristina
Published: October 2014

Bringing safe and effective treatments to patients with Huntington’s disease (HD) will require evaluation in properly designed and conducted clinical trials. Such clinical trials will require appropriate tools and practices, including therapeutics, patient registries, biomarkers, endpoints, trial design, and analysis tools. This chapter provides insight into the advances being made in each of these areas and highlights the challenges remaining. Lessons learned from prior HD trials as well as from trials in other neurodegenerative diseases affect our view of future HD clinical development. With much interest from both pharmaceutical companies and academic researchers, this final chapter of the book actually opens a new chapter in the history of HD drug development.
Primitive endoderm differentiation: from specification to epithelium formation
Authors: Hermitte Stéphanie , Chazaud Claire
Published: October 2014

In amniotes, primitive endoderm (PrE) plays important roles not only for nutrient support but also as an inductive tissue required for embryo patterning. PrE is an epithelial monolayer that is visible shortly before embryo implantation and is one of the first three cell lineages produced by the embryo. We review here the molecular mechanisms that have been uncovered during the past 10 years on PrE and epiblast cell lineage specification within the inner cell mass of the blastocyst and on their subsequent steps of differentiation.
Activin/Nodal signalling before implantation: setting the stage for embryo patterning
Authors: Papanayotou Costis , Collignon Jérôme
Published: October 2014

Activins and Nodal are members of the transforming growth factor beta (TGF-β) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-β-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression.
Mapping the route from naive pluripotency to lineage specification
Authors: Kalkan Tüzer , Smith Austin
Published: October 2014

In the mouse blastocyst, epiblast cells are newly formed shortly before implantation. They possess a unique developmental plasticity, termed naive pluripotency. For development to proceed, this naive state must be subsumed by multi-lineage differentiation within 72 h following implantation.In vitrodifferentiation of naive embryonic stem cells (ESCs) cultured in controlled conditions provides a tractable system to dissect and understand the process of exit from naive pluripotency and entry into lineage specification. Exploitation of this system in recent large-scale RNAi and mutagenesis screens has uncovered multiple new factors and modules that drive or facilitate progression out of the naive state. Notably, these studies show that the transcription factor network that governs the naive state is rapidly dismantled prior to upregulation of lineage specification markers, creating an intermediate state that we term formative pluripotency. Here, we summarize these findings and propose a road map for state transitions in ESC differentiation that reflects the orderly dynamics of epiblast progression in the embryo.
The birth of embryonic pluripotency
Authors: Boroviak Thorsten , Nichols Jennifer
Published: October 2014

Formation of a eutherian mammal requires concurrent establishment of embryonic and extraembryonic lineages. The functions of the trophectoderm and primitive endoderm are to enable implantation in the maternal uterus, axis specification and delivery of nutrients. The pluripotent epiblast represents the founding cell population of the embryo proper, which is protected from ectopic and premature differentiation until it is required to respond to inductive cues to form the fetus. While positional information plays a major role in specifying the trophoblast lineage, segregation of primitive endoderm from epiblast depends upon gradual acquisition of transcriptional identity, directed but not initiated by fibroblast growth factor (FGF) signalling. Following early cleavage divisions and formation of the blastocyst, cells of the inner cell mass lose totipotency. Developing epiblast cells transiently attain the state of naive pluripotency and competence to self-renewin vitroas embryonic stem cells andin vivoby means of diapause. This property is lost after implantation as the epiblast epithelializes and becomes primed in preparation for gastrulation and subsequent organogenesis.
Primoridal germ cell specification: a context-dependent cellular differentiation event
Authors: Günesdogan Ufuk , Magnúsdóttir Erna , Surani M. Azim
Published: October 2014

During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling. While the majority of epiblast cells undergo differentiation towards somatic cell lineages, PGCs initiate a unique cellular programme driven by the cooperation of the transcription factors BLIMP1, PRDM14 and AP2γ. These factors synergistically suppress the ongoing somatic differentiation and drive the re-expression of pluripotency and germ cell-specific genes accompanied by global epigenetic changes. However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling. One emerging concept is that transcriptional enhancers might play a central role in the establishment of developmental competence and the execution of cell fate determination. Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.
Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian embryogenesis
Authors: Matsuo Isao , Kimura-Yoshida Chiharu
Published: October 2014

During mouse embryogenesis, diffusible growth factors, i.e. fibroblast growth factors, Wnt, bone morphogenetic protein and Hedgehog family members, emanating from localized areas can travel through the extracellular space and reach their target cells to specify the cell fate and form tissue architectures in coordination. However, the mechanisms by which these growth factors travel great distances to their target cells and control the signalling activity as morphogens remain an enigma. Recent studies in mice and other model animals have revealed that heparan sulfate proteoglycans (HSPGs) located on the cell surface (e.g. syndecans and glypicans) and in the extracellular matrix (ECM; e.g. perlecan and agrin) play crucial roles in the extracellular distribution of growth factors. Principally, the function of HSPGs depends primarily on the fine features and localization of their heparan sulfate glycosaminoglycan chains. Cell-surface-tethered HSPGs retain growth factors as co-receptors and/or endocytosis mediators, and enzymatic release of HSPGs from the cell membrane allows HSPGs to transport or move multiple growth factors. By contrast, ECM-associated HSPGs function as a reservoir or barrier in a context-dependent manner. This review is focused on our current understanding of the extracellular distribution of multiple growth factors controlled by HSPGs in mammalian development.
Gutsy moves in mice: cellular and molecular dynamics of endoderm morphogenesis
Authors: Viotti Manuel , Foley Ann C. , Hadjantonakis Anna-Katerina
Published: October 2014

Despite the importance of the gut and its accessory organs, our understanding of early endoderm development is still incomplete. Traditionally, endoderm has been difficult to study because of its small size and relative fragility. However, recent advances in live cell imaging technologies have dramatically expanded our understanding of this tissue, adding a new appreciation for the complex molecular and morphogenetic processes that mediate gut formation. Several spatially and molecularly distinct subpopulations have been shown to exist within the endoderm before the onset of gastrulation. Here, we review findings that have uncovered complex cell movements within the endodermal layer, before and during gastrulation, leading to the conclusion that cells from primitive endoderm contribute descendants directly to gut.