Software and methods for oligonucleotide and cDNA array data analysis.

Two HTML-based programs were developed to analyze and filter gene-expression data: 'Bullfrog' for Affymetrix oligonucleotide arrays and 'Spot' for custom cDNA arrays. The programs provide intuitive data-filtering tools through an easy-to-use interface. A background subtraction and normalization program for cDNA arrays was also built that provides an informative summary report with data-quality assessments. These programs are freeware to aid in the analysis of gene-expression results and facilitate the search for genes responsible for interesting biological processes and phenotypes

Spin-wave spectrum of copper metaborate in the commensurate phase 10K<T<21K

We have investigated the spin-wave spectrum of copper metaborate, CuB$_2$O$_4$, by means of inelastic neutron scattering in the commensurate magnetic phase. We have found two branches of spin-wave excitations associated with the two magnetic sublattices Cu(A) and Cu(B), respectively. In the temperature regime $10K \le T \le 21K$, where only the Cu(A) magnetic moments are ordered, the interaction between the two sublattices is found to be negligible. With this approximation we have determined the `easy plane' exchange parameters of the Cu(A) subsystem within standard spin-wave theory.Comment: 4 figure

Dislocation loops in overheated free-standing smectic films

Static and dynamic phenomena in overheated free-standing smectic-A films are studied using a generalization of de Gennes' theory for a confined presmectic liquid. A static application is to determine the profile of the film meniscus and the meniscus contact angle, the results being compared with those of a recent study employing de Gennes' original theory. The dynamical generalization of the theory is based on on a time-dependent Ginzburg-Landau approach. This is used to compare two modes for layer-thinning transitions in overheated films, namely "uniform thinning" vs. nucleation of dislocation loops. Properties such as the line tension and velocity of a moving dislocation line are evaluated self-consistently by the theory.Comment: 16 pages, 8 figure

Copy Number Variation in Familial Parkinson Disease

Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values<0.001). PARK2 CNVs tended to be larger, and all instances that were molecularly tested were validated. In contrast, the CNVs in both novel loci were smaller and failed to replicate using real-time PCR, MLPA, and gel electrophoresis. The DOCK5 variation is more akin to a VNTR than a typical CNV and the association is likely caused by artifact due to DNA source. DNA for all the cases was derived from whole blood, while the DNA for all controls was derived from lymphoblast cell lines. The USP32 locus contains many SNPs with low minor allele frequency leading to a loss of heterozygosity that may have been spuriously interpreted by the CNV calling algorithms as support for a deletion. Thus, only the CNVs within the PARK2 locus could be molecularly validated and associated with PD susceptibility

HLA homozygosity does not adversely affect measles vaccine-induced cytokine responses

AbstractThe association between HLA homozygosity and measles-specific Th1 (IFN-γ, IL-2 and IL-12p40) and Th2 (IL-4 and IL-10) cytokine responses were assessed in a group of 339 healthy schoolchildren 12–18 years of age previously immunized with two doses of live-attenuated measles virus vaccine. No associations were observed between class I HLA homozygosity and measles-specific cytokine levels. Children who were homozygous at the class II DRB1, DQA1, DPA1 and DPB1 loci had higher median IFN-γ secretion levels compared with children who were heterozygous for DRB1 (77.7 vs. 39.5 pg/ml, p=0.05), DQA1 (60.9 vs. 36.6 pg/ml, p=0.03), DPA1 (46.1 vs. 27.1 pg/ml, p=0.01) and DPB1 (61.5 vs. 36.0 pg/ml, p=0.01) loci, respectively. Homozygosity at increasing numbers of HLA loci ( >=4) was associated with increased IFN-γ secretion levels (test for trend p-value=0.01). Our results suggest that HLA homozygosity showed no disadvantage for measles-specific cytokine responses and instead was associated with increased IFN-γ levels

Letaler Stromunfall in der Badewanne durch ein zum Laden angeschlossenes Smartphone

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:p&gt;Stromtodesfälle in der Badewanne sind üblicherweise Folge suizidaler Handlungen oder ereignen sich unfallbedingt. Berichtet wird über einen letalen Stromunfall, bei dem über ein defektes, nicht den hiesigen Normen entsprechendes Ladegerät eines Smartphones, das während eines Vollbades in der Hand gehalten wurde, die volle Netzwechselspannung auf den Körper einer jungen Frau verschleppt wurde, der dadurch Teil eines geschlossenen Stromkreises wurde. Elektrogeräte von minderwertiger Qualität stellen ein nicht abschätzbares Gefährdungspotenzial für die Benutzer dar.&lt;/jats:p&gt

Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes

We mapped ∼85,000 rare nonsynonymous exonic single nucleotide polymorphisms ( SNPs ) to 17 psychophysiological endophenotypes in 4,905 individuals, including antisaccade eye movements, resting EEG , P 300 amplitude, electrodermal activity, affect‐modulated startle eye blink. Nonsynonymous SNPs are predicted to directly change or disrupt proteins encoded by genes and are expected to have significant biological consequences. Most such variants are rare, and new technologies can efficiently assay them on a large scale. We assayed 247,870 mostly rare SNPs on an Illumina exome array. Approximately 85,000 of the SNPs were polymorphic, rare ( MAF  < .05), and nonsynonymous. Single variant association tests identified a SNP in the PARD 3 gene associated with theta resting EEG power. The sequence kernel association test, a gene‐based test, identified a gene PNPLA 7 associated with pleasant difference startle, the difference in startle magnitude between pleasant and neutral images. No other single nonsynonymous variant, or gene‐based group of variants, was strongly associated with any endophenotype.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109617/1/psyp12349.pd

Genomewide association study for onset age in Parkinson disease

<p>Abstract</p> <p>Background</p> <p>Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age.</p> <p>Methods</p> <p>Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy.</p> <p>Results</p> <p>Meta-analysis across the three studies detected consistent association (p < 1 × 10^-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10^-7) lies between the genes <it>QSER1 </it>and <it>PRRG4</it>. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10^-6) which lies in an intron of the <it>AAK1 </it>gene. This gene is closely related to <it>GAK</it>, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases.</p> <p>Conclusion</p> <p>Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.</p

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120