Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.Peer reviewe

Effects of early feeding on growth velocity and overweight/obesity in a cohort of HIV unexposed South African infants and children

BACKGROUND: South Africa has the highest prevalence of overweight/obesity in Sub-Saharan Africa. Assessing the effect of modifiable factors such as early infant feeding on growth velocity and overweight/obesity is therefore important. This paper aimed to assess the effect of infant feeding in the transitional period (12 weeks) on 12–24 week growth velocity amongst HIV unexposed children using WHO growth velocity standards and on the age and sex adjusted body mass index (BMI) Z-score distribution at 2 years. METHODS: Data were from 3 sites in South Africa participating in the PROMISE-EBF trial. We calculated growth velocity Z-scores using the WHO growth standards and assessed feeding practices using 24-hour and 7-day recall data. We used quantile regression to study the associations between 12 week infant feeding and 12–24 week weight velocity (WVZ) with BMI-for-age Z-score at 2 years. We included the internal sample quantiles (70th and 90th centiles) that approximated the reference cut-offs of +2 (corresponding to overweight) and +3 (corresponding to obesity) of the 2 year BMI-for-age Z-scores. RESULTS: At the 2-year visit, 641 children were analysed (median age 22 months, IQR: 17–26 months). Thirty percent were overweight while 8.7% were obese. Children not breastfed at 12 weeks had higher 12–24 week mean WVZ and were more overweight and obese at 2 years. In the quantile regression, children not breastfed at 12 weeks had a 0.37 (95% CI 0.07, 0.66) increment in BMI-for-age Z-score at the 50th sample quantile compared to breast-fed children. This difference in BMI-for-age Z-score increased to 0.46 (95% CI 0.18, 0.74) at the 70th quantile and 0.68 (95% CI 0.41, 0.94) at the 90th quantile . The 12–24 week WVZ had a uniform independent effect across the same quantiles. CONCLUSIONS: This study demonstrates that the first 6 months of life is a critical period in the development of childhood overweight and obesity. Interventions targeted at modifiable factors such as early infant feeding practices may reduce the risks of rapid weight gain and subsequent childhood overweight/obesity.Scopu

Sulfated Polysaccharide, Curdlan Sulfate, Efficiently Prevents Entry/Fusion and Restricts Antibody-Dependent Enhancement of Dengue Virus Infection In Vitro: A Possible Candidate for Clinical Application

10.1371/journal.pntd.0002188PLoS Neglected Tropical Diseases74

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE

„Ex vivo” replication of the pathogenic prion protein

Das Prion Protein (PrP) ist ein ubiquitär vorkommendes Protein. Prion steht dabei für "proteinaceous infections particle" und ist laut der "protein-only hypothesis" das infektiöse Agens der Transmissiblen Spongiformen Enzephalopathien (TSE). Die TSE-Erkrankungen werden durch eine Konformationsänderung einer apathogenen zellulären Isoform (PrPC) in eine pathogene Isoform (PrPSc) verursacht. Diese Konformationsänderung kann entweder spontan oder induziert durch exogenes PrPSc erfolgen. Dabei kommt es zur Anlagerung von PrPSc an PrPC. Diese Erkrankung wirkt sich vor allem im Gehirn der betroffenen Organismen aus. Dabei kommt es zur Ausbildung eines durchlöcherten schwammartigen Gewebes mit amyloiden Proteinablagerungen, den Plaques. Diese sind allerdings erst nach einer histologischen "post mortem" Analyse zu beobachten. So können TSE-Erkrankungen beim Menschen gegenüber anderen neurodegenerativen Erkrankungen abgegrenzt werden. Diese Erkrankung tritt ebenfalls bei anderen Organismen wie z.B. Rind, Schaf und Affe auf. Die Funktion des PrP ist bis heute noch nicht vollkommen geklärt. Es wird jedoch vermutet dass es bei der Immunabwehr und den Alterungsprozessen eine Rolle spielt. Zur Untersuchung der PrP Funktion wurden in dieser Arbeit 3T3, N2a und PrP knock-out (PrP0/0)Zellen mit einem durch Tetracyclin regulierbaren Schalter versehen. Dadurch konnte das anschließend stabil transfizierte Prion Protein reguliert exprimiert werden. Die Expression konnte durch den Western Blot (Wb) und eine fluorescence activated cell sorting (FACS) Analyse gezeigt werden, sowie die Anreicherung des PrP durch die Circulardichroismus (CD) - Spektroskopie. Das so reguliert exprimierte PrPC wurde mit PrPSc infiziert. Die anschließende Konformationsänderung des PrPC wurde durch den Proteinase K (PK) Verdau im Wb gezeigt. Mit Hilfe der FACS Analyse konnte außerdem die Zunahme des PrP Gehaltes dargestellt werden. Die in dieser Arbeit hergestellten Zelllinien können als neues Tool für die Identifizierung der Interaktionspartner des PrP, möglicher Diagnostik und therapeutischer Ansätze verwendet werden

On some fractional order Hardy inequalities

Weighted inequalities for fractional derivatives (= fractional order Hardy-type inequalities) have recently been proved in [4] and [1]. In this paper, new inequalities of this type are proved and applied. In particular, the general mixed norm case and a general twodimensional weight are considered. Moreover, an Orlicz norm version and a multidimensional fractional order Hardy inequality are proved. The connections to related results are pointed out.Godkänd; 1997; 20070111 (evan

On some fractional order hardy inequalities

<p/> <p>Weighted inequalities for fractional derivatives ( <inline-formula><graphic file="1029-242X-1997-787248-i1.gif"/></inline-formula> fractional order Hardy-type inequalities) have recently been proved in [4] and [1]. In this paper, new inequalities of this type are proved and applied. In particular, the general mixed norm case and a general twodimensional weight are considered. Moreover, an Orlicz norm version and a multidimensional fractional order Hardy inequality are proved. The connections to related results are pointed out.</p

Duality theorem over the cone of monotone functions and sequences in higher dimensions

Let f be a non-negative function defined on ℝ+n which is monotone in each variable separately. If 1 &lt; p &lt; ∞, g ≥ 0 and v a product weight function, then equivalent expressions for sup ∫ℝ(+)(n) fg/(ℝ+nfpv)1/p are given, where the supremum is taken over all such functions f. Variants of such duality results involving sequences are also given. Applications involving weight characterizations for which operators defined on such functions (sequences) are bounded in weighted Lebesgue (sequence) spaces are also pointed out.Validerad; 2002; 20061025 (evan)</p