Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0.00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

A normal β-globin allele as a modifier gene ameliorating the severity of α-thalassemia in mice

Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the α- or the β-chain of hemoglobin. The expressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of α-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the α-thalassemia mutation resides [129sv/ev/129sv/ev (severe) or 129sv/ev/C57BL/6 (mild)]. Linkage mapping indicates that the modifying gene is very tightly linked to the β-globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype correlates with the size of β-chain-containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The β-major globin chains encoded by the two strains differ by three amino acids, one of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should be available for interchain disulfide bridging and consequent aggregation between excess β-chains. This normal polymorphic variation between murine β-globin chains could account for the modifying action of the unlinked β-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between α- and β-chains but on the chemical nature of the normal β-chain, which is in excess. This work also indicates that modifying genes can be normal variants that—absent an apparent physiologic rationale—may be difficult to identify on the basis of structure alone.

An authoring tool for decision support systems in context questions of ecological knowledge

Decision support systems (DSS) support business or organizational decision-making activities, which require the access to information that is internally stored in databases or data warehouses, and externally in the Web accessed by Information Retrieval (IR) or Question Answering (QA) systems. Graphical interfaces to query these sources of information ease to constrain dynamically query formulation based on user selections, but they present a lack of flexibility in query formulation, since the expressivity power is reduced to the user interface design. Natural language interfaces (NLI) are expected as the optimal solution. However, especially for non-expert users, a real natural communication is the most difficult to realize effectively. In this paper, we propose an NLI that improves the interaction between the user and the DSS by means of referencing previous questions or their answers (i.e. anaphora such as the pronoun reference in “What traits are affected by them?”), or by eliding parts of the question (i.e. ellipsis such as “And to glume colour?” after the question “Tell me the QTLs related to awn colour in wheat”). Moreover, in order to overcome one of the main problems of NLIs about the difficulty to adapt an NLI to a new domain, our proposal is based on ontologies that are obtained semi-automatically from a framework that allows the integration of internal and external, structured and unstructured information. Therefore, our proposal can interface with databases, data warehouses, QA and IR systems. Because of the high NL ambiguity of the resolution process, our proposal is presented as an authoring tool that helps the user to query efficiently in natural language. Finally, our proposal is tested on a DSS case scenario about Biotechnology and Agriculture, whose knowledge base is the CEREALAB database as internal structured data, and the Web (e.g. PubMed) as external unstructured information.

How buildings visualise client and architect: The problem that today’s user is typically not the client

An article presented at the last ICAT- conference stated at the end that buildings at all times tend to picture the people who had them erected. This paper aims to show the correctness of that statement. To this end, it will examine a number of typical residential buildings dating from the beginning of the seventeenth century up to today, investigate who had the buildings erected, and relate that to the performance of the buildings. This relation analysis will mainly use the scale but also the degree of diversity in function and appearance as factors. Furthermore, using economic data and data on the buildings to identify patterns, it will investigate how size of the property and relative size of the capital interest behind the building has developed. Since the authors live in Copenhagen and Copenhagen is very typical in its historical development, buildings and environments in and around the centre of Copenhagen are used as examples.

Mandibular Torus : A Synthesis of New and Previously Reported Data and a Discusssion of its Cause

Usinig original data on 1,5000 mandibles, but mainly previously published data, I present a overview of the distribution characteristics of mandibular torus and a hypothesis concerning its cause. Pedigree studies have established that genetic factors influence torus development. Extrinsic factors are strongly implicated by other evidence: prevalence among Arctic peoples, effect of dietary change, age regression, preponderance in males and on the right side, effect of cranial deformation, concurrence with palatine torus and maxillary alveolar exostoses, and clinical evidence. I propose that the primary factor is masticatory stress. According to a mechanism suggested by orthodontic research, the horizontal component of bite force tips the lower canine, premolars and first molar so that their root apices exert pressure on the periodontal membrane, causing formation of new bone on the lingual cortical plate of the alveolar process. Thus formed, the hyperostosis is vulnerable to trauma and its periosteal covering becomes bruised causing additional deposition of bone. Genes influence torus indirectly through their effect on occlusion. A patern of increased expressivity with incidence suggests that a quasicontinuous model may provide a better fit to pedigree data than single locus models previously tested.

Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.

Polynomial function intervals for floating-point software verification

The focus of our work is the verification of tight functional properties of numerical programs, such as showing that a floating-point implementation of Riemann integration computes a close approximation of the exact integral. Programmers and engineers writing such programs will benefit from verification tools that support an expressive specification language and that are highly automated. Our work provides a new method for verification of numerical software, supporting a substantially more expressive language for specifications than other publicly available automated tools. The additional expressivity in the specification language is provided by two constructs. First, the specification can feature inclusions between interval arithmetic expressions. Second, the integral operator from classical analysis can be used in the specifications, where the integration bounds can be arbitrary expressions over real variables. To support our claim of expressivity, we outline the verification of four example programs, including the integration example mentioned earlier. A key component of our method is an algorithm for proving numerical theorems. This algorithm is based on automatic polynomial approximation of non-linear real and real-interval functions defined by expressions. The PolyPaver tool is our implementation of the algorithm and its source code is publicly available. In this paper we report on experiments using PolyPaver that indicate that the additional expressivity does not come at a performance cost when comparing with other publicly available state-of-the-art provers. We also include a scalability study that explores the limits of PolyPaver in proving tight functional specifications of progressively larger randomly generated programs. © 2014 Springer International Publishing Switzerland.

What Google Maps can do for Biomedical Data Dissemination: Examples and a Design Study

Background: Biologists often need to assess whether unfamiliar datasets warrant the time investment required for more detailed exploration. Basing such assessments on brief descriptions provided by data publishers is unwieldy for large datasets that contain insights dependent on specific scientific questions. Alternatively, using complex software systems for a preliminary analysis may be deemed as too time consuming in itself, especially for unfamiliar data types and formats. This may lead to wasted analysis time and discarding of potentially useful data. Results: We present an exploration of design opportunities that the Google Maps interface offers to biomedical data visualization. In particular, we focus on synergies between visualization techniques and Google Maps that facilitate the development of biological visualizations which have both low-overhead and sufficient expressivity to support the exploration of data at multiple scales. The methods we explore rely on displaying pre-rendered visualizations of biological data in browsers, with sparse yet powerful interactions, by using the Google Maps API. We structure our discussion around five visualizations: a gene co-regulation visualization, a heatmap viewer, a genome browser, a protein interaction network, and a planar visualization of white matter in the brain. Feedback from collaborative work with domain experts suggests that our Google Maps visualizations offer multiple, scale-dependent perspectives and can be particularly helpful for unfamiliar datasets due to their accessibility. We also find that users, particularly those less experienced with computer use, are attracted by the familiarity of the Google Maps API. Our five implementations introduce design elements that can benefit visualization developers. Conclusions: We describe a low-overhead approach that lets biologists access readily analyzed views of unfamiliar scientific datasets. We rely on pre-computed visualizations prepared by data experts, accompanied by sparse and intuitive interactions, and distributed via the familiar Google Maps framework. Our contributions are an evaluation demonstrating the validity and opportunities of this approach, a set of design guidelines benefiting those wanting to create such visualizations, and five concrete example visualizations.

Characterization of a Novel Mouse Phenotype with Marked Hydrocephalus

In multigenic diseases, disorders where mutations in multiple genes affect the expressivity of the disease, genetic interactions play a major role in prevalence and phenotypic severity. While studying the genetic interactions between Pax3 and EdnrB in the melanocyte lineage, a new phenotype was noted in 80% of Pax3 mutants that we believe to be a novel murine model for hydrocephalus. Hydrocephalus, an accumulation of cerebrospinal fluid in the cranial cavity due to obstruction of flow in and out of the cavity, is one of the most common birth defects surpassing Down syndrome. Characteristic to hydrocephalus is a "domed" head appearance, expansion of the ventricles of the brain, and loss of neurons with hyperproliferation of glial cell types all three of which were seen in the mutant mice. The phenotype also consisted of craniofacial deformities coupled with skeletal defects including, but not limited to kyphosis, lordosis, and an apparent shortening of the some limbs. For the cellular analysis of the hydrocephalus phenotype, brains were removed and stained with two antibodies: Glial Fibrillary Acidic Protein (GFAP) and Neurofilament (NF), which are astrocyte- and neuron- specific respectively. A higher number of cells expressing GF AP and a lower number of cells expressing NF were seen in the mutant brain, when compared to control. For skeletal deformity analysis, affected mice skeletons were stained with Alizarin Red and Alcian Blue showing no apparent difference in ossification. Future genetic analysis of these mutant mice has the potential to identify novel gene modifiers involved in the promotion of this particular phenotype.

Os usos do território e a economia solidária no Rio Grande do Norte

The solidary economy as the organization of production, alternative to the capitalist economy provides new forms of organization and social behavior, that, in the sight of geography, it is shown by the different territory uses. The territory assume new meanings that, influenced by the Solidary Economy movement, tries to reach for new ways of acting that differ from social order already stablished. However, the different uses show themselves in a more complex and contradictory way, given that, in solidary undertakings, different corporative agents start to act, the State being a last resource on this process. Given this reality, our goal on the present paper is to analyze the different uses of the territory from the rural economic solidary undertakings and the relationship it establishes to the different agents involved on the socio-territorial dynamics on Rio Grande do Norte. Starting from a study that contemplates the territorial organization forms and contents of the analyzed phenomena, the methodology utilized for this research is based on a bibliographic review, with authors from the geography and areas related to the Solidary Economy, besides the use of secondary data, acquired from official offices such as SIES and IBGE, from the documented research, SENAES and field interviews conducted with local solidary undertakings. The results obtained in the study reveal the complexity of the agricultural use of the territory by Solidary Economy on the RN, while a resource of intensified use, from the state actions and important economical agents, and regulating the use while shelter, that marginalize solidary workers, making them subdued to the hegemonic logic. Therefore, we can infer that the solidary economy, despite its image of new form of organization between agricultural workers, given the expressivity of the rural solidary undertakings presented on RN, it hasn’t shown a full social development as an instrument of reproduction and emancipation of the associates. Nevertheless, the undertakings articulated in nets excel, even when considering its punctual and residual form. The given contradictions show that it is necessary to fortify the building of the solidary economy as being horizontal and popular based for it to have strength to surpass the regulative actions of the capitalist state and ownership created by the Capital.

Other Than a Citizen: Vernacular Poetics in Postwar America

Few symbols of 1950s-1960s America remain as central to our contemporary conception of Cold War culture as the iconic ranch-style suburban home. While the house took center stage in the Nixon/Khrushchev kitchen debates as a symbol of modern efficiency and capitalist values, its popularity depended largely upon its obvious appropriation of vernacular architecture from the 19th century, those California haciendas and Texas dogtrots that dotted the American west. Contractors like William Levitt modernized the historical common houses, hermetically sealing their porous construction, all while using the ranch-style roots of the dwelling to galvanize a myth of an indigenous American culture. At a moment of intense occupational bureaucracy, political uncertainty and atomized social life, the rancher gave a self-identifying white consumer base reason to believe they could master their own plot in the expansive frontier. Only one example of America’s mid-century love affair with commodified vernacular forms, the ranch-style home represents a broad effort on the part of corporate and governmental interest groups to transform the vernacular into a style that expresses a distinctly homogenous vision of American culture. “Other than a Citizen” begins with an anatomy of that transformation, and then turns to the work of four poets who sought to reclaim the vernacular from that process of standardization and use it to countermand the containment-era strategies of Cold War America.

In four chapters, I trace references to common speech and verbal expressivity in the poetry and poetic theory of Charles Olson, Robert Duncan, LeRoi Jones/Amiri Baraka and Gwendolyn Brooks, against the historical backdrop of the Free-Speech Movement and the rise of mass-culture. When poets frame nonliterary speech within the literary page, they encounter the inability of writing to capture the vital ephemerality of verbal expression. Rather than treat this limitation as an impediment, the writers in my study use the poem to dramatize the fugitivity of speech, emphasizing it as a disruptive counterpoint to the technologies of capture. Where critics such as Houston Baker interpret the vernacular strictly in terms of resistance, I take a cue from the poets and argue that the vernacular, rooted etymologically at the intersection of domestic security and enslaved margin, represents a gestalt form, capable at once of establishing centralized power and sparking minor protest. My argument also expands upon Michael North’s exploration of the influence of minstrelsy and regionalism on the development of modernist literary technique in The Dialect of Modernism. As he focuses on writers from the early 20th century, I account for the next generation, whose America was not a culturally inferior collection of immigrants but an imperial power, replete with economic, political and artistic dominance. Instead of settling for an essentially American idiom, the poets in my study saw in the vernacular not phonetic misspellings, slang terminology and fragmented syntax, but the potential to provoke and thereby frame a more ethical mode of social life, straining against the regimentation of citizenship.

My attention to the vernacular argues for an alignment among writers who have been segregated by the assumption that race and aesthetics are mutually exclusive categories. In reading these writers alongside one another, “Other than a Citizen” shows how the avant-garde concepts of projective poetics and composition by field develop out of an interest in black expressivity. Conversely, I trace black radicalism and its emphasis on sociality back to the communalism practiced at the experimental arts college in Black Mountain, North Carolina, where Olson and Duncan taught. In pressing for this connection, my work reveals the racial politics embedded within the speech-based aesthetics of the postwar era, while foregrounding the aesthetic dimension of militant protest.

Not unlike today, the popular rhetoric of the Cold War insists that to be a citizen involves defending one’s status as a rightful member of an exclusionary nation. To be other than a citizen, as the poets in my study make clear, begins with eschewing the false certainty that accompanies categorical nominalization. In promoting a model of mutually dependent participation, these poets lay the groundwork for an alternative model of civic belonging, where volition and reciprocity replace compliance and self-sufficiency. In reading their lines, we become all the more aware of the cracks that run the length of our load-bearing walls.

Behavior Genetics and Post Genomics

The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. DNA, once held to be the unchanging template of heredity, now appears subject to a good deal of environmental change; considered to be identical in all cells and tissues of the body, there is growing evidence that somatic mosaicism is the normal human condition; and treated as the sole biological agent of heritability, we now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, these phenomena appear to be particularly prevalent in the human brain, and likely are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period, and in enabling phenotypic plasticity in offspring in particular. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of “minimal shared maternal effects,” in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology

Mandibular Torus : A Synthesis of New and Previously Reported Data and a Discusssion of its Cause

Using original data on 1,5000 mandibles, but mainly previously published data, I present a overview of the distribution characteristics of mandibular torus and a hypothesis concerning its cause. Pedigree studies have established that genetic factors influence torus development. Extrinsic factors are strongly implicated by other evidence: prevalence among Arctic peoples, effect of dietary change, age regression, preponderance in males and on the right side, effect of cranial deformation, concurrence with palatine torus and maxillary alveolar exostoses, and clinical evidence. I propose that the primary factor is masticatory stress. According to a mechanism suggested by orthodontic research, the horizontal component of bite force tips the lower canine, premolars and first molar so that their root apices exert pressure on the periodontal membrane, causing formation of new bone on the lingual cortical plate of the alveolar process. Thus formed, the hyperostosis is vulnerable to trauma and its periosteal covering becomes bruised causing additional deposition of bone. Genes influence torus indirectly through their effect on occlusion. A patern of increased expressivity with incidence suggests that a quasicontinuous model may provide a better fit to pedigree data than single locus models previously tested.

‘The Emergence of the Operatic’

The chapter discusses the notion of the ‘operatic’ with particular reference to movement. Through observation of singers in rehearsal and through interviews with singers over two years, the research posits that ‘operatic’ movement may be identified and explored as a discrete quality of movement in performance and recognised as an, albeit underappreciated, aspect of the artistry of the opera singer. The paper explores the effects of the demands of singing on the dramatic expressivity of the body and the strategies employed by singers to navigate, the sometimes conflicting demands of the composer and the director. ‘Operatic’ movement is regarded as that which is not generated through character or narrative (positioned as a normative approach to acting) but through the negotiation of the physical constrictions and artificiality of breath associated with operatic singing, combined with sensitivity towards opera’s non-normative performance conventions. This position is aided by an interrogation of opera through the lens of gender theory. The chapter makes two propositions, that the ‘operatic’, which does not form part of the formal pedagogy of singers, is an emergent property, especially evident at the intersection of the various creative disciplines that contribute to opera, such as when the orchestra is introduced to the rehearsal process, and that ‘operaticness’ is acquired and passed on through a process of kinaesthetic empathy.

Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11

Purpose Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.