Apolipoprotein B containing lipoproteins contribute to host innate immune pulmonary defense against Staphylococcus aureus

Circulating lipoproteins are increasingly recognized as innate immune effector molecules. Severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. Importantly, pneumonia caused by Staphylococcus aureus is a major cause of morbidity and mortality in both hospital- and community-acquired pneumonia cases. Here we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing dependent pathogenesis. Specifically, apoB levels in the lung early post-infection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact post-trauma pneumonia susceptibility to both Gram positive and Gram negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung

Automated Computational Processing of 3-D MR Images of Mouse Brain for Phenotyping of Living Animals

Magnetic resonance (MR) imaging provides a method to obtain anatomical information from the brain in vivo that is not typically available by optical imaging because of this organ's opacity. MR is nondestructive and obtains deep tissue contrast with 100-µm^3 voxel resolution or better. Manganese-enhanced MRI (MEMRI) may be used to observe axonal transport and localized neural activity in the living rodent and avian brain. Such enhancement enables researchers to investigate differences in functional circuitry or neuronal activity in images of brains of different animals. Moreover, once MR images of a number of animals are aligned into a single matrix, statistical analysis can be done comparing MR intensities between different multi-animal cohorts comprising individuals from different mouse strains or different transgenic animals, or at different time points after an experimental manipulation. Although preprocessing steps for such comparisons (including skull stripping and alignment) are automated for human imaging, no such automated processing has previously been readily available for mouse or other widely used experimental animals, and most investigators use in-house custom processing. This protocol describes a stepwise method to perform such preprocessing for mouse

Curvature contraction of convex hypersurfaces by nonsmooth speeds

We consider contraction of convex hypersurfaces by convex speeds, homogeneous of degree one in the principal curvatures, that are not necessarily smooth. We show how to approximate such a speed by a sequence of smooth speeds for which behaviour is well known. By obtaining speed and curvature pinching estimates for the flows by the approximating speeds, independent of the smoothing parameter, we may pass to the limit to deduce that the flow by the nonsmooth speed converges to a point in finite time that, under a suitable rescaling, is round in the C^2 sense, with the convergence being exponential

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population

RNA-binding protein CPEB1 remodels host and viral RNA landscapes.

Host and virus interactions occurring at the post-transcriptional level are critical for infection but remain poorly understood. Here, we performed comprehensive transcriptome-wide analyses revealing that human cytomegalovirus (HCMV) infection results in widespread alternative splicing (AS), shortening of 3' untranslated regions (3' UTRs) and lengthening of poly(A)-tails in host gene transcripts. We found that the host RNA-binding protein CPEB1 was highly induced after infection, and ectopic expression of CPEB1 in noninfected cells recapitulated infection-related post-transcriptional changes. CPEB1 was also required for poly(A)-tail lengthening of viral RNAs important for productive infection. Strikingly, depletion of CPEB1 reversed infection-related cytopathology and post-transcriptional changes, and decreased productive HCMV titers. Host RNA processing was also altered in herpes simplex virus-2 (HSV-2)-infected cells, thereby indicating that this phenomenon might be a common occurrence during herpesvirus infections. We anticipate that our work may serve as a starting point for therapeutic targeting of host RNA-binding proteins in herpesvirus infections

Approaches for Studying Fish Production: Do River and Lake Researchers Have Different Perspectives? – Extended Abstract

Biased perspectives of fisheries researchers may hinder scientific progress and effective management if limiting factors controlling productivity go unrecognized. We investigated whether river and lake researchers used different approaches when studying salmonid production and whether any differences were ecologically supported. We assessed 564 peer‐reviewed papers published between 1966 and 2012 that studied salmonid production or surrogate variables (e.g., abundance, growth, biomass, population) and classified them into five major predictor variable categories: physical habitat, fertility (i.e., nutrients, bottom‐up), biotic, temperature, and pollution. The review demonstrated that river researchers primarily analyzed physical habitat (65% of studies) and lake researchers primarily analyzed fertility (45%) and biotic (51%) variables. Nevertheless, understudied variables were often statistically significant predictors of production for lake and river systems and, combined with other evidence, suggests that unjustified a priori assumptions may dictate the choice of independent variables studied. Broader consideration of potential limiting factors on fish production, greater research effort on understudied genera, and increased publication in broadly scoped journals would likely promote integration between lentic and lotic perspectives and improve fisheries management

Designating eukaryotic orthology via processed transcription units

Orthology is a widely used concept in comparative and evolutionary genomics. In addition to prokaryotic orthology, delineating eukaryotic orthology has provided insight into the evolution of higher organisms. Indeed, many eukaryotic ortholog databases have been established for this purpose. However, unlike prokaryotes, alternative splicing (AS) has hampered eukaryotic orthology assignments. Therefore, existing databases likely contain ambiguous eukaryotic ortholog relationships and possibly misclassify alternatively spliced protein isoforms as in-paralogs, which are duplicated genes that arise following speciation. Here, we propose a new approach for designating eukaryotic orthology using processed transcription units, and we present an orthology database prototype using the human and mouse genomes. Currently existing programs cover less than 69% of the human reference sequences when assigning human/mouse orthologs. In contrast, our method encompasses up to 80% of the human reference sequences. Moreover, the ortholog database presented herein is more than 92% consistent with the existing databases. In addition to managing AS, this approach is capable of identifying orthologs of embedded genes and fusion genes using syntenic evidence. In summary, this new approach is sensitive, specific and can generate a more comprehensive and accurate compilation of eukaryotic orthologs