Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population

The number of CAG repeats in the mitochondrial DNA-polymerase gamma (POLG1) gene has been associated with Parkinson disease (PD) in some populations. We sequenced the CAG tract of POLG1 in 191 Norwegian patients with PD and an equal number of controls and found an association between non-10 or 11 CAG repeats and PD in our population. While our results were significant, this trend was not maintained following correction for multiple testing. We also performed a meta-analysis of all published studies including our own that shows PD is associated with the number of CAG repeats in POLG1. The meta-analysis reveals that the rare allelic variation encompassed by non-10 CAG repeats associates significantly with PD (p = 0.0017). Whether this reflects a direct influence of POLG on the pathogenesis of PD or linkage disequilibrium between POLG1 alleles and nearby, disease-influencing genetic variants remains unknown.     

Mydj2 as a potent partner of hsc70 in mammalian cells.

Dj2 is a member of the DnaJ family of proteins, which regulate the chaperoning function of the hsp70s. We isolated a monkey cDNA dj2 clone corresponding to the large mRNA species encoded by the gene. This mRNA differs from the small mRNA produced by the same gene in that it contains a long 3' untranslated region. Both messages were found to be equally stable and to produce the same protein, which is susceptible to farnesylation. Studies in mouse tissues and various cell lines revealed that these messages and their products are differentially expressed. Surprisingly, we found that only the nonfarnesylated form of dj2 is capable of translocating to the cell nucleus, especially after heat shock. Finally, based on protein interaction studies, our results indicate that dj2 is a specific partner for hsc70 and not for hsp70.     

RNA-Mediated Feedback Control of Transcriptional Condensates

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Comparative study between synthetic and phospholipids of natural origin: effect of phospholipid selection on the behavior of a topical liposomal dosage form incorporating terbinafine

Selection of excipients used is a critical step in the design of a pharmaceutical dosage form as it affects its behavior upon application, as during storage. The purpose of the present study is to evaluate and compare the behavior of six liposomal formulations intended for topical application composed of two widely used phospholipids 1,2-diacyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine with and without incorporation of cholesterol. Liposomal hydrogels made of hydroxyethylcellulose 3% and incorporating the anti-fungal agent terbinafine hydrochloride (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalene-methanamine (-hydrochloride) were prepared, their viscosity was measured and in vitro drug release was studied. Moreover, physical stability and drug retention during storage at two different temperatures (2–8?°C and RT) were examined over time. The results showed differences in the behavior between the two phospholipids while incorporation of cholesterol at the studied concentrations was found to be of minor importance. Drug release was found to be favorable from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomal hydrogels and drug retention was found to be higher at lower storage temperature for all batches. Original physicochemical properties of all batches were found to be retained at least for a week.     

Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro

Adiponectin protects the liver from steatosis caused by obesity or alcohol and therefore the influence of adiponectin on human hepatocytes was analyzed. GeneChip experiments indicated that recombinant adiponectin downregulates aldehyde oxidase 1 (AOX1) expression and this was confirmed by real-time RT-PCR and immunoblot. AOX1 is a xenobiotic metabolizing protein and produces reactive oxygen species (ROS), that promote cell damage and fibrogenesis. Adiponectin and fenofibric acid activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and both suppress AOX1 protein and this is blocked by the PPAR-alpha antagonist RU486. Obesity is associated with low adiponectin, reduced hepatic PPAR-alpha activity and fatty liver, and AOX1 was found induced in the liver of rats on a high-fat diet when compared to controls. Free fatty acids and leptin, that are elevated in obesity, failed to upregulate AOX1 in vitro. The current data indicate that adiponectin reduces AOX1 by activating PPAR-alpha whereas fatty liver disease is associated with elevated hepatic AOX1. High AOX1 may be associated with higher ROS well described to induce fibrogenesis in liver tissue but may also influence drug metabolism and activity.     

Toward a Wolbachia Multilocus Sequence Typing System: Discrimination of Wolbachia Strains Present in Drosophila Species

Among the diverse maternally inherited symbionts in arthropods, Wolbachia are the most common and infect over 20% of all species. In a departure from traditional genotyping or phylogenetic methods relying on single Wolbachia genes, the present study represents an initial Multilocus Sequence Typing (MLST) analysis to discriminate closely related Wolbachia pipientis strains, and additional data on sequence diversity in Wolbachia. We report a new phylogenetic characterization of four genes (aspC, atpD, sucB, and pdhB), and provide an expanded analysis of markers described in previous studies (16S rDNA, ftsZ, groEL, dnaA, and gltA). MLST analysis of the bacterial strains present in 16 different Drosophila–Wolbachia associations detected four distinct clonal complexes that also corresponded to maximum-likelihood identified phylogenetic clades. Among the 16 associations analyzed, six could not be assigned to MLST clonal complexes and were also shown to be in conflict with relationships predicted by maximum-likelihood phylogenetic inferences. The results demonstrate the discriminatory power of MLST for identifying strains and clonal lineages of Wolbachia and provide a robust foundation for studying the ecology and evolution of this widespread endosymbiont.     

Navajo neurohepatopathy is caused by a mutation in the MPV17 gene

Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.     

Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy

Hereditary myopathy with lactic acidosis, or myopathy with exercise intolerance, Swedish type (OMIM #255125) is caused by mutations in the iron–sulfur cluster scaffold (ISCU) gene. The g.7044G > C ISCU mutation induces a splicing error in the pre-mRNA that strengthens a weak intronic splice site leading to inclusion of a new exon and subsequent loss of mRNA and protein. While ISCU is widely expressed, homozygosity for this particular intronic mutation gives rise to a pure myopathy. In order to investigate tissue specificity and disease mechanism, we studied muscle, myoblasts, fibroblasts and blood cells from the first non-Swedish case of this disease. Consistent with the recognised role of ISCU, we found abnormal activities of respiratory chain complexes containing iron–sulfur clusters in patient muscle. We confirmed that, in the presence of the g.7044G > C mutation, splicing produces both abnormally and normally spliced mRNA in all tissues. The ratio of these products varies dramatically between tissues, being most abnormal in mature skeletal muscle that also has the lowest relative starting levels of ISCU mRNA compared with other tissues. Myoblasts and fibroblasts have more of the normally spliced variant as well as higher starting levels of ISCU mRNA. Up-regulation of mtDNA copy number was found in skeletal muscle and myoblasts, but not fibroblasts, and is thought to represent a compensatory response. Tissue specificity in this disorder appears therefore to be dependent on the mRNA starting level, the amount of remaining normally spliced RNA, and the degree to which compensatory mechanisms can respond.     

They are here to stay: the biology and ecology of lionfish (Pterois miles) in the Mediterranean Sea

The lionfish, Pterois miles, is one of the most recent Lessepsian immigrants into the Mediterranean Sea, and it poses a serious threat to marine ecosystems in the region. This study assesses the basic biology and ecology of lionfish in the Mediterranean, examining morphometrics, reproduction and diet as well as population structure and distribution. The population density of lionfish has increased dramatically in Cyprus since the first sighting in late 2012; by 2018 aggregations of up to 70 lionfish were found on rocky grounds with complex reefs and artificial reefs in depths of 0–50 m. Lionfish in Cyprus become mature within a year, and adults are capable of spawning year-round, with peak spawning in summer when the sea-surface temperature reaches 28.4°C. The Cypriot lionfish grow faster and bigger than in their native range, and females are more common than males. Lionfish are generalist predators in these waters, as also found in their native range, consuming a range of teleost and crustacean prey, some of which are of high economic value (e.g., Spicara smaris and Sparisoma cretense) or have an important role in local trophic webs (e.g., Chromis chromis). Overall, the reproductive patterns, the presence of juveniles and adults throughout the year, the rapid growth rates and the generalist diet indicate that lionfish are thriving and are now already well established in the region and could potentially become the serious nuisance that they are in their temperate and tropical western Atlantic–invasive range.     

Marburg virus VP40 antagonizes interferon signaling in a species-specific manner

Marburgviruses are zoonotic pathogens that cause lethal hemorrhagic fever in humans and nonhuman primates. However, they do not cause lethal disease in immunocompetent mice unless they are adapted to this species. The adaptation process can therefore provide insight into the specific virus-host interactions that determine virulence. In primate cells, the Lake Victoria marburgvirus Musoke strain (MARV) VP40 matrix protein antagonizes alpha/beta interferon (IFN-α/β) and IFN-γ signaling by inhibiting the activation of the cellular tyrosine kinase Jak1. Here, VP40 from the Ravn strain (RAVV VP40)-from a distinct Marburg virus clade-is demonstrated to also inhibit IFN signaling in human cells. However, neither MARV nor RAVV VP40 effectively inhibited IFN-signaling in mouse cells, as assessed by assays of the antiviral effects of IFN-α/β and the IFN-α/β-induced phosphorylation of Jak1, STAT1, and STAT2. In contrast, the VP40 from a mouse-adapted RAVV (maRAVV) did inhibit IFN signaling. Effective Jak1 inhibition correlated with the species from which the cells were derived and did not depend upon whether Jak1 was of human or mouse origin. Of the seven amino acid changes that accumulated in VP40 during mouse adaptation, two (V57A and T165A) are sufficient to allow efficient IFN signaling antagonism by RAVV VP40 in mouse cells. The same two changes also confer efficient IFN antagonist function upon MARV VP40 in mouse cells. The mouse-adaptive changes did not affect the budding of RAVV VP40 in mouse cells, suggesting that this second major function of VP40 did not undergo adaptation. These data identify an apparent determinant of RAVV host range and virulence and define specific genetic determinants of this function.