Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas

Background Genetic testing is recommended when the probability of a disease-associated germline mutation exceeds 10%. Germline mutations are found in approximately 25% of individuals with phaeochromcytoma (PCC) or paraganglioma (PGL); however, genetic heterogeneity for PCC/PGL means many genes may require sequencing. A phenotype-directed iterative approach may limit costs but may also delay diagnosis, and will not detect mutations in genes not previously associated with PCC/PGL. Objective To assess whether whole exome sequencing (WES) was efficient and sensitive for mutation detection in PCC/PGL. Methods Whole exome sequencing was performed on blinded samples from eleven individuals with PCC/PGL and known mutations. Illumina TruSeq™ (Illumina Inc, San Diego, CA, USA) was used for exome capture of seven samples, and NimbleGen SeqCap EZ v3.0 (Roche NimbleGen Inc, Basel, Switzerland) for five samples (one sample was repeated). Massive parallel sequencing was performed on multiplexed samples. Sequencing data were called using Genome Analysis Toolkit and annotated using annovar. Data were assessed for coding variants in RET, NF1, VHL, SDHD, SDHB, SDHC, SDHA, SDHAF2, KIF1B, TMEM127, EGLN1 and MAX. Target capture of five exome capture platforms was compared. Results Six of seven mutations were detected using Illumina TruSeq™ exome capture. All five mutations were detected using NimbleGen SeqCap EZ v3.0 platform, including the mutation missed using Illumina TruSeq™ capture. Target capture for exons in known PCC/PGL genes differs substantially between platforms. Exome sequencing was inexpensive (<$A800 per sample for reagents) and rapid (results <5 weeks from sample reception). Conclusion Whole exome sequencing is sensitive, rapid and efficient for detection of PCC/PGL germline mutations. However, capture platform selection is critical to maximize sensitivity.

Pheo-type: A diagnostic gene-expression assay for the classification of pheochromocytoma and paraganglioma

Context: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. Objective: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. Design: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. Results: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1–3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. Conclusions: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

The sequence and structure of snake gourd (Trichosanthes anguina) seed lectin, a three-chain nontoxic homologue of type II RIPs

The sequence and structure of snake gourd seed lectin (SGSL), a nontoxic homologue of type II ribosome-inactivating proteins (RIPs), have been determined by mass spectrometry and X-ray crystallography, respectively. As in type II RIPs, the molecule consists of a lectin chain made up of two beta-trefoil domains. The catalytic chain, which is connected through a disulfide bridge to the lectin chain in type II RIPs, is cleaved into two in SGSL. However, the integrity of the three-dimensional structure of the catalytic component of the molecule is preserved. This is the first time that a three-chain RIP or RIP homologue has been observed. A thorough examination of the sequence and structure of the protein and of its interactions with the bound methyl-alpha-galactose indicate that the nontoxicity of SGSL results from a combination of changes in the catalytic and the carbohydrate-binding sites. Detailed analyses of the sequences of type II RIPs of known structure and their homologues with unknown structure provide valuable insights into the evolution of this class of proteins. They also indicate some variability in carbohydrate-binding sites, which appears to contribute to the different levels of toxicity exhibited by lectins from various sources.

El problema del innatismo en Antonio Rosmini : (parte II)

Resumen: Esta parte del artículo repasa las principales teorías modernas sobre el innatismo, analizando sus puntos fuertes y débiles a partir de la teoría rosminiana de la presencia innata de la idea de ser. Se subraya la simplicidad de esta teoría, lo que le confiere un elevado carácter explicativo, en contraste con los dificultades que suscitan las filosofías de Descartes, Locke, Leibniz, Malebranche y Kant.

Dios entre las mónadas : la centralidad del tema de Dios en algunas tesis metafísicas de G. W. Leibniz

Resumen: En el presente trabajo buscaremos introducir ciertas tesis distintivas del pensamiento de Leibniz en lo que respecta a su metafísica subrayando el papel de Dios en cada una de ellas. Fundamentalmente, las tesis a tratar son la teoría de las mónadas y dos teorías que se siguen de ella: la de la armonía preestablecida y la del mejor de los mundos posibles. Además, buscaremos mostrar que las pruebas de la existencia de Dios (o al menos dos de ellas: el denominado “argumento cosmológico” y el denominado “ontológico”), poseen subyacentemente una fundamentación metafísica. En este sentido, no nos centraremos en las pruebas mismas sino en su fundamentación.

El laberinto del continuo

Resumen: La expresión “Laberinto del continuo” se debe a Leibniz. Sin embargo, Leibniz carecía de los instrumentos conceptuales necesarios para tratar el tema adecuadamente. La teoría de conjuntos de Cantor hizo posible resolver el problema del continuo de modo satisfactorio desde el punto de vista conjuntista. Se debe atribuir a R. Dedekind una resolución más cabal del problema. No obstante, el autor sostiene que la concepción de éste último tampoco pone de manifiesto todos los aspectos involucrados en el continuo.

A relação entre o principio de razão suficiente e o principio da contradição em Leibniz

De acordo com Leibniz, nossos raciocínios estão fundados em dois grandes princípios, o Princípio de Razão Suficiente e o Princípio de Contradição. Apesar da reconhecida relevância de tais princípios para sua filosofia, muitas são as interpretações sobre o real papel que eles desempenham dentro dela e sobre a relação deles entre si. Nosso estudo pauta-se não só pela interpretação de Leibniz como pela visão de alguns de seus comentadores, especialmente três deles: Russell, Couturat e Deleuze. Iremos pesquisar, entre outras coisas, se tais princípios são independentes um do outro; se são aplicáveis a todo tipo de verdade; se o Princípio de Perfeição é uma particularização do Princípio de Razão Suficiente ou se é irredutível a ele; e se as verdades da razão são regidas pelo Princípio de Contradição e as verdades de fato são regidas pelo Princípio de Razão Suficiente. A articulação entre tais princípios remete a um terceiro ponto: a concepção da verdade como inclusão do conceito do predicado no sujeito, tema este que iremos analisar com base nos diferentes pontos de vista acerca das proposições essenciais e existenciais. Em relação a esta última, investigaremos se representam ou não uma exceção ao caráter analítico de todas as proposições verdadeiras.

Heróis a contrapelo: lampejos do gênio na escrita dos jovens Goethe e Schiller

O estilo de época Sturm und Drang, o primeiro movimento literário genuinamente alemão, surgido na segunda metade do século XVIII, possibilitou a emancipação literária da Alemanha e introduziu naquele país o conceito de gênio original. A partir da descoberta da obra do gênio inglês Shakespeare (possibilitada pelas traduções de Christoph Martin Wieland), os alemães se depararam com o modelo de revolução literária que necessitavam para instituir as bases da originalidade literária alemã. Pautando-se na estrutura dramática shakespeariana, Johann Wolfgang von Goethe e Friedrich Schiller elaboraram seus dramas de estreia, obras foco da presente pesquisa: Götz von Berlichingen e Os bandoleiros, respectivamente. O presente estudo propõe-se, por conseguinte, a analisar as obras supracitadas à luz da temática do gênio original. Mas, primeiramente, são observados os fatores (como a ascenção do romance inglês) e escritores (como Gothold Ephraim Lessing, Johann Jakob Bodmer, Johann Jakob Breitinger, Friedrich Gottlieb Klopstock, Johann Joachim Winckelmann, Wieland e Johann Gottfried von Herder) que colaboraram para a instituição da era genial na Alemanha

Mündliche Literatur und nationale Identitätskonstruktion bei José de Alencar und Mário de Andrade

O presente trabalho tem por objetivo analisar a construção da identidade nos discursos literários de José de Alencar e Mário de Andrade em que o recurso à literatura oral aparece como elemento central. O foco da análise são os textos críticos e teóricos desses autores, tomando-se especialmente em consideração questões da teoria de Johann Gottfried Herder sobre a poesia popular enquanto poesia natural, que deveria servir de matéria prima para a literatura erudita

Application of electron beams in thermal processing of semiconductor materials and devices

Rapid and effective thermal processing methods using electron beams are described in this paper. Heating times ranging from a fraction of a second to several seconds and temperatures up to 1400°C are attainable. Applications such as the annealing of ion implanted material, both without significant dopant diffusion and with highly controlled diffusion of impurities, are described. The technique has been used successfully to activate source/drain regions for fine geometry NMOS transistors. It is shown that electron beams can produce localised heating of semiconductor substrates and a resolution of approximately 1 μm has been achieved. Electron beam heating has been applied to improving the crystalline quality of silicon-on sapphire used in CMOS device fabrication. Silicon layers with defect levels approaching bulk material have been obtained. Finally, the combination of isothermal and selective annealing is shown to have application in recrystallisation of polysilicon films on an insulating layer. The approach provides the opportunity of producing a silicon-on-insulator substrate with improved crystalline quality compared to silicon-on-sapphire at a potentially lower cost. It is suggested that rapid heating methods are expected to provide a real alternative to conventional furnace processing of semiconductor devices in the development of fabrication technology. © 1984 Benn electronics Publications Ltd, Luton.

沉水植物分布格局对湖泊水环境N、P因子影响

利用实地调查数据模拟保安湖沉水植物分布及水环境生态因子场。应用GIS空间分析功能 ,分别空间选取四种优势沉水植物 (金鱼藻CeratophyllumdemersumL .,穗状狐尾藻MyriophyllumspicatumL .,微齿眼子菜PotamogetonmaackianusA .Benn .,及苦草VallisneriaspiralisL .)的分布水域及无沉水植物分布水域的局部生态因子场。根据得到的局部因子场特征 ,比较分析不同水生植物分布格局对水环境中N、P因子的影响。结果显示四种沉水植物的分

保安湖沉水植物分布的GIS模拟

以 GPS为辅助 ,在保安湖主体湖和桥墩湖进行沉水植物调查。将野外调查数据构建 GIS数据库 ,基于 GIS软件平台 ,运用 Kringing插值法对保安湖沉水植物分布进行模拟。模拟结果清楚地显示出调查时保安湖沉水植物及 4优势种 (金鱼藻 Ceratophyllum demersum L.、穗状狐尾藻 Myriophyllum spicatum L .、微齿眼子菜 Potamogeton maackianus A.Benn.及苦草 Vallisneria spiralis L.)分别在湖中的分布情况。统

Effect of plant architecture on the structure of epiphytic macro invertebrate communities in a Chinese lake

We examined the effect of different plant architecture types on epiphytic macroinvertebrates of a shallow macrophyte-dominated lake in China. Macroinvertebrates were sampled from four dominant submersed macrophytes in the lake - two dissected plants (Myriophyllum spicatum L. and Ceratophyllum demersum L.) and two undissected plants (Potamogeton maackianus A. Benn. and Vallisneria spiralis L.). Macro invertebrate richness showed significant differences among four submersed macrophyte habitats, and higher density per g of dry plant were associated with dissected plants than undissected plants. The average abundance in dissected plants was as three-six times as in undissected plants. The biodiversity of epiphytic macroinvertebrates was higher in dissected plants than undissected plants. Our results suggest that dissected plants provide different habitat for macroinvertebrates than dissected plant, and this concurs with the hypothesis that the former could support more epiphytic macroinvertebrates than the latter.

Battling Reality

In the four years that the MIT Mobile Robot Project has benn in existence, we have built ten robots that focus research in various areas concerned with building intelligent systems. Towards this end, we have embarked on trying to build useful autonomous creatures that live and work in the real world. Many of the preconceived notions entertained before we started building our robots turned out to be misguided. Some issues we thought would be hard have worked successfully from day one and subsystems we imagined to be trivial have become tremendous time sinks. Oddly enough, one of our biggest failures has led to some of our favorite successes. This paper describes the changing paths our research has taken due to the lessons learned from the practical realities of building robots.

The Deve­lop­ment of Leibniz’s Con­si­de­ra­tions in John Yench’s Pro­ject

The purpose of the article is to present John Yench’s a priori language as a continuation of Leibniz’s idea. Before I proceed to show the project of the Inter-Disciplinary International Reference Language, I would like to discuss the development of Gottfried Wilhelm Leibniz’s view on artificial languages. I will try to show the evolution of Leibniz’s universal language: from its ideal conception to a tool which formalizes the whole of human knowledge. Also, I will show Leibniz’s influence on further ideas of artificial language. I will compare his projects with Yench’s language – Idirl. An analysis of Idirl’s main assumptions will be useful to show the degree of continuation of Leibniz’s ideas in the a priori language of John Yench.