Custom Array Comparative Genomic Hybridization: the Importance of DNA Quality, an Expert Eye, and Variant Validation.

The presence of false positive and false negative results in the Array Comparative Genomic Hybridization (aCGH) design is poorly addressed in literature reports. We took advantage of a custom aCGH recently carried out to analyze its design performance, the use of several Agilent aberrations detection algorithms, and the presence of false results. Our study provides a confirmation that the high density design does not generate more noise than standard designs and, might reach a good resolution. We noticed a not negligible presence of false negative and false positive results in the imbalances call performed by the Agilent software. The Aberration Detection Method 2 (ADM-2) algorithm with a threshold of 6 performed quite well, and the array design proved to be reliable, provided that some additional filters are applied, such as considering only intervals with average absolute log2ratio above 0.3. We also propose an additional filter that takes into account the proportion of probes with log2ratio exceeding suggestive values for gain or loss. In addition, the quality of samples was confirmed to be a crucial parameter. Finally, this work raises the importance of evaluating the samples profiles by eye and the necessity of validating the imbalances detected

Conjugacy in Baumslag's group, generic case complexity, and division in power circuits

The conjugacy problem belongs to algorithmic group theory. It is the following question: given two words x, y over generators of a fixed group G, decide whether x and y are conjugated, i.e., whether there exists some z such that zxz^{-1} = y in G. The conjugacy problem is more difficult than the word problem, in general. We investigate the complexity of the conjugacy problem for two prominent groups: the Baumslag-Solitar group BS(1,2) and the Baumslag(-Gersten) group G(1,2). The conjugacy problem in BS(1,2) is TC^0-complete. To the best of our knowledge BS(1,2) is the first natural infinite non-commutative group where such a precise and low complexity is shown. The Baumslag group G(1,2) is an HNN-extension of BS(1,2). We show that the conjugacy problem is decidable (which has been known before); but our results go far beyond decidability. In particular, we are able to show that conjugacy in G(1,2) can be solved in polynomial time in a strongly generic setting. This means that essentially for all inputs conjugacy in G(1,2) can be decided efficiently. In contrast, we show that under a plausible assumption the average case complexity of the same problem is non-elementary. Moreover, we provide a lower bound for the conjugacy problem in G(1,2) by reducing the division problem in power circuits to the conjugacy problem in G(1,2). The complexity of the division problem in power circuits is an open and interesting problem in integer arithmetic.Comment: Section 5 added: We show that an HNN extension G = < H, b | bab^-1 = {\phi}(a), a \in A > has a non-amenable Schreier graph with respect to the base group H if and only if A \neq H \neq

Desogestrel down-regulates PHOX2B and its target genes in progesterone responsive neuroblastoma cells

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO2/H+ chemosensitivity. The recovery of CO2/H+ chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients

Symmetries, weak symmetries and related solutions of the Grad-Shafranov equation

We discuss a new family of solutions of the Grad--Shafranov (GS) equation that describe D-shaped toroidal plasma equilibria with sharp gradients at the plasma edge. These solutions have been derived by exploiting the continuous Lie symmetry properties of the GS equation and in particular a special type of "weak" symmetries. In addition, we review the continuous Lie symmetry properties of the GS equation and present a short but exhaustive survey of the possible choices for the arbitrary flux functions that yield GS equations admitting some continuous Lie symmetry. Particular solutions related to these symmetries are also discussed.Comment: 8 pages, 4 figure

Can MR Imaging Diagnose Adult-Onset Alexander Disease?

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Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome

Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps (\u201cframe 2\u201d and \u201cframe 3\u201d mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one \u201cframe 3\u201d mutation identified in a patient with isolated CCHS, and one \u201cframe 2\u201d mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCH