Androgen Receptor Copy Number Variation and Androgenetic Alopecia: A Case-Control Study

BACKGROUND: The functional polymorphism that explains the established association of the androgen receptor (AR) with androgenetic alopecia (AGA) remains unidentified, but Copy Number Variation (CNV) might be relevant. CNV involves changes in copy number of large segments of DNA, leading to the altered dosage of gene regulators or genes themselves. Two recent reports indicate regions of CNV in and around AR, and these have not been studied in relation to AGA. The aim of this preliminary case-control study was to determine if AR CNV is associated with AGA, with the hypothesis that CNV is the functional AR variant contributing to this condition. METHODOLOGY/PRINCIPAL FINDINGS: Multiplex Ligation-dependent Probe Amplification was used to screen for CNV in five AR exons and a conserved, non-coding region upstream of AR in 85 men carefully selected as cases and controls for maximal phenotypic contrast. There was no evidence of CNV in AR in any of the cases or controls, and thus no evidence of significant association between AGA and AR CNV. CONCLUSIONS/SIGNIFICANCE: The results suggest this form of genomic variation at the AR locus is unlikely to predispose to AGA

Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the <it>NF2 </it>gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient.</p> <p>Case presentation</p> <p>We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing <it>NF2</it>, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including <it>NF2 </it>and <it>MN1 </it>(meningioma 1).</p> <p>Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing <it>NF2 </it>were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed <it>MN1</it>, <it>PITPNB </it>and <it>TTC28</it>. <it>MN1</it>, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (<it>TEL</it>/<it>MN1</it>) in human myeloid leukemias. Interestingly, <it>Mn1</it>-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, <it>Mn1 </it>regulates maturation and function of calvarial osteoblasts and is an upstream regulator of <it>Tbx22</it>, a gene associated with murine and human cleft palate. This suggests that deletion of <it>MN1 </it>in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities.</p> <p>Conclusions</p> <p>Thus, our report describes a <it>NF2</it>-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of <it>MN1 </it>deletion with abnormal craniofacial development and/or cleft palate in humans.</p

Current variables, definitions and endpoints of the European Cardiovascular Magnetic Resonance Registry

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used in daily clinical practice. However, little is known about its clinical utility such as image quality, safety and impact on patient management. In addition, there is limited information about the potential of CMR to acquire prognostic information. METHODS: The European Cardiovascular Magnetic Resonance Registry (EuroCMR Registry) will consist of two parts: 1) Multicenter registry with consecutive enrolment of patients scanned in all participating European CMR centres using web based online case record forms. 2) Prospective clinical follow up of patients with suspected coronary artery disease (CAD) and hypertrophic cardiomyopathy (HCM) every 12 months after enrolment to assess prognostic data. CONCLUSION: The EuroCMR Registry offers an opportunity to provide information about the clinical utility of routine CMR in a large number of cases and a diverse population. Furthermore it has the potential to gather information about the prognostic value of CMR in specific patient populations

De-Novo Transcriptome Sequencing of a Normalized cDNA Pool from Influenza Infected Ferrets

The ferret is commonly used as a model for studies of infectious diseases. The genomic sequence of this animal model is not yet characterized, and only a limited number of fully annotated cDNAs are currently available in GenBank. The majority of genes involved in innate or adaptive immune response are still lacking, restricting molecular genetic analysis of host response in the ferret model. To enable de novo identification of transcriptionally active ferret genes in response to infection, we performed de-novo transcriptome sequencing of animals infected with H1N1 A/California/07/2009. We also included splenocytes induced with bacterial lipopolysaccharide to allow for identification of transcripts specifically induced by Gram-negative bacteria. We pooled and normalized the cDNA library in order to delimit the risk of sequencing only highly expressed genes. While normalization of the cDNA library removes the possibility of assessing expression changes between individual animals, it has been shown to increase identification of low abundant transcripts. In this study, we identified more than 19000 partial ferret transcripts, including more than 1000 gene orthologs known to be involved in the innate and the adaptive immune response

Ontogenetic De Novo Copy Number Variations (CNVs) as a Source of Genetic Individuality: Studies on Two Families with MZD Twins for Schizophrenia

Genetic individuality is the foundation of personalized medicine, yet its determinants are currently poorly understood. One issue is the difference between monozygotic twins that are assumed identical and have been extensively used in genetic studies for decades [1]. Here, we report genome-wide alterations in two nuclear families each with a pair of monozygotic twins discordant for schizophrenia evaluated by the Affymetrix 6.0 human SNP array. The data analysis includes characterization of copy number variations (CNVs) and single nucleotide polymorphism (SNPs). The results have identified genomic differences between twin pairs and a set of new provisional schizophrenia genes. Samples were found to have between 35 and 65 CNVs per individual. The majority of CNVs (∼80%) represented gains. In addition, ∼10% of the CNVs were de novo (not present in parents), of these, 30% arose during parental meiosis and 70% arose during developmental mitosis. We also observed SNPs in the twins that were absent from both parents. These constituted 0.12% of all SNPs seen in the twins. In 65% of cases these SNPs arose during meiosis compared to 35% during mitosis. The developmental mitotic origin of most CNVs that may lead to MZ twin discordance may also cause tissue differences within individuals during a single pregnancy and generate a high frequency of mosaics in the population. The results argue for enduring genome-wide changes during cellular transmission, often ignored in most genetic analyses

Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood

Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands

Neural mechanisms of interstimulus interval-dependent responses in the primary auditory cortex of awake cats

<p>Abstract</p> <p>Background</p> <p>Primary auditory cortex (AI) neurons show qualitatively distinct response features to successive acoustic signals depending on the inter-stimulus intervals (ISI). Such ISI-dependent AI responses are believed to underlie, at least partially, categorical perception of click trains (elemental vs. fused quality) and stop consonant-vowel syllables (eg.,/da/-/ta/continuum).</p> <p>Methods</p> <p>Single unit recordings were conducted on 116 AI neurons in awake cats. Rectangular clicks were presented either alone (single click paradigm) or in a train fashion with variable ISI (2–480 ms) (click-train paradigm). Response features of AI neurons were quantified as a function of ISI: one measure was related to the degree of stimulus locking (temporal modulation transfer function [tMTF]) and another measure was based on firing rate (rate modulation transfer function [rMTF]). An additional modeling study was performed to gain insight into neurophysiological bases of the observed responses.</p> <p>Results</p> <p>In the click-train paradigm, the majority of the AI neurons ("synchronization type"; <it>n </it>= 72) showed stimulus-locking responses at long ISIs. The shorter cutoff ISI for stimulus-locking responses was on average ~30 ms and was level tolerant in accordance with the perceptual boundary of click trains and of consonant-vowel syllables. The shape of tMTF of those neurons was either band-pass or low-pass. The single click paradigm revealed, at maximum, four response periods in the following order: 1st excitation, 1st suppression, 2nd excitation then 2nd suppression. The 1st excitation and 1st suppression was found exclusively in the synchronization type, implying that the temporal interplay between excitation and suppression underlies stimulus-locking responses. Among these neurons, those showing the 2nd suppression had band-pass tMTF whereas those with low-pass tMTF never showed the 2nd suppression, implying that tMTF shape is mediated through the 2nd suppression. The recovery time course of excitability suggested the involvement of short-term plasticity. The observed phenomena were well captured by a single cell model which incorporated AMPA, GABA_A, NMDA and GABA_Breceptors as well as short-term plasticity of thalamocortical synaptic connections.</p> <p>Conclusion</p> <p>Overall, it was suggested that ISI-dependent responses of the majority of AI neurons are configured through the temporal interplay of excitation and suppression (inhibition) along with short-term plasticity.</p

An examination of the factorial and convergent validity of four measures of conspiracist ideation, with recommendations for researchers

A number scales have been developed to measure conspiracist ideation, but little attention has been paid to the factorial validity of these scales. We reassessed the psychometric properties of four widely-used scales, namely the Belief in Conspiracy Theories Inventory (BCTI), the Conspiracy Mentality Questionnaire (CMQ), the Generic Conspiracist Beliefs Scale (GCBS), and the One-Item Conspiracy Measure (OICM). Eight-hundred-and-three U. S. adults completed all measures, along with measures of endorsement of 9/11 and anti- vaccination conspiracy theories. Through both exploratory and confirmatory factor analysis, we found that only the BCTI had acceptable factorial validity. We failed to confirm the factor structures of the CMQ and the GBCS, suggesting these measures had poor factorial valid- ity. Indices of convergent validity were acceptable for the BCTI, but weaker for the other measures. Based on these findings, we provide suggestions for the future refinement in the measurement of conspiracist ideation

Sequence comparison of prefrontal cortical brain transcriptome from a tame and an aggressive silver fox (Vulpes vulpes)

<p>Abstract</p> <p>Background</p> <p>Two strains of the silver fox (<it>Vulpes vulpes</it>), with markedly different behavioral phenotypes, have been developed by long-term selection for behavior. Foxes from the tame strain exhibit friendly behavior towards humans, paralleling the sociability of canine puppies, whereas foxes from the aggressive strain are defensive and exhibit aggression to humans. To understand the genetic differences underlying these behavioral phenotypes fox-specific genomic resources are needed.</p> <p>Results</p> <p>cDNA from mRNA from pre-frontal cortex of a tame and an aggressive fox was sequenced using the Roche 454 FLX Titanium platform (> 2.5 million reads & 0.9 Gbase of tame fox sequence; >3.3 million reads & 1.2 Gbase of aggressive fox sequence). Over 80% of the fox reads were assembled into contigs. Mapping fox reads against the fox transcriptome assembly and the dog genome identified over 30,000 high confidence fox-specific SNPs. Fox transcripts for approximately 14,000 genes were identified using SwissProt and the dog RefSeq databases. An at least 2-fold expression difference between the two samples (p < 0.05) was observed for 335 genes, fewer than 3% of the total number of genes identified in the fox transcriptome.</p> <p>Conclusions</p> <p>Transcriptome sequencing significantly expanded genomic resources available for the fox, a species without a sequenced genome. In a very cost efficient manner this yielded a large number of fox-specific SNP markers for genetic studies and provided significant insights into the gene expression profile of the fox pre-frontal cortex; expression differences between the two fox samples; and a catalogue of potentially important gene-specific sequence variants. This result demonstrates the utility of this approach for developing genomic resources in species with limited genomic information.</p