Forecast Combination and Bayesian Model Averaging: A Prior Sensitivity Analysis

In this study we evaluate the forecast performance of model‐averaged forecasts based on the predictive likelihood carrying out a prior sensitivity analysis regarding Zellner's g prior. The main results are fourfold. First, the predictive likelihood does always better than the traditionally employed ‘marginal’ likelihood in settings where the true model is not part of the model space. Secondly, forecast accuracy as measured by the root mean square error (RMSE) is maximized for the median probability model. On the other hand, model averaging excels in predicting direction of changes. Lastly, g should be set according to Laud and Ibrahim (1995: Predictive model selection. Journal of the Royal Statistical Society B 57 : 247–262) with a hold‐out sample size of 25% to minimize the RMSE (median model) and 75% to optimize direction of change forecasts (model averaging). We finally apply the aforementioned recommendations to forecast the monthly industrial production output of six countries, beating for almost all countries the AR(1) benchmark model. Copyright © 2011 John Wiley & Sons, Ltd.     

Nesprin interchain associations control nuclear size

Nesprins-1/-2/-3/-4 are nuclear envelope proteins, which connect nuclei to the cytoskeleton. The largest nesprin-1/-2 isoforms (termed giant) tether F-actin through their N-terminal actin binding domain (ABD). Nesprin-3, however, lacks an ABD and associates instead to plectin, which binds intermediate filaments. Nesprins are integrated into the outer nuclear membrane via their C-terminal KASH-domain. Here, we show that nesprin-1/-2 ABDs physically and functionally interact with nesprin-3. Thus, both ends of nesprin-1/-2 giant are integrated at the nuclear surface: via the C-terminal KASH-domain and the N-terminal ABD-nesprin-3 association. Interestingly, nesprin-2 ABD or KASH-domain overexpression leads to increased nuclear areas. Conversely, nesprin-2 mini (contains the ABD and KASH-domain but lacks the massive nesprin-2 giant rod segment) expression yields smaller nuclei. Nuclear shrinkage is further enhanced upon nesprin-3 co-expression or microfilament depolymerization. Our findings suggest that multivariate intermolecular nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size.     

An eicosanoid-centric view of atherothrombotic risk factors

Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors.     

Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.     

Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.     

Dominant missense mutations in ABCC9 cause Cantú syndrome

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.     

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration

Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.     

Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules

Plasticity is a well-known property of macrophages that is controlled by different changes in environmental signals. Macrophage polarization is regarded as a spectrum of activation phenotypes adjusted from one activation extreme, the classic (M1), to the other, the alternative (M2) activation. Here we show, in vitro and in vivo, that both M1 and M2 macrophage phenotypes are tightly coupled to specific patterns of gene expression. Novel M2-associated markers were characterized and identified as genes controlling the extracellular metabolism of ATP to generate pyrophosphates (PPi). Stimulation of M1 macrophages with PPi dampens both NLR and TLR signaling and thus mediates cytokine production. In this context extracellular PPi enhanced the resolution phase of a murine peritonitis model via a decrease in pro-inflammatory cytokine production. Therefore, our study reveals an additional level of plasticity modulating the resolution of inflammation.     

Comparative ecology of Sarcobatus baileyi and Sarcobatus vermiculatus in estern California

Greasewood ( Sarcobatus ) is a succulent-leaved, halophytic shrub of North American origin. The genus comprises 2 species: Sarcobatus baileyi and Sarcobatus vermiculatus. Sarcobatus vermiculatus is common throughout much of western North America, but S. baileyi is much more limited in distribution and was previously thought to be endemic to Nevada. Here we document and describe a S. baileyi population in eastern California, comparing its morphology and ecology to an adjacent S. vermiculatus population. Morphologically, S. baileyi is smaller in stature but produces larger seeds; however, fewer S. baileyi seeds germinated and survived a 20-day laboratory incubation compared to seeds of S. vermiculatus. Sarcobatus baileyi has higher leaf Na concentrations and operates at much lower plant water potentials than S. vermiculatus under field conditions; however, no significant differences were observed between the 2 species in long-term water-use efficiency as measured by leaf δ13C. Leaf Na concentrations were very low in both species. Overall, these species differ greatly in a number of traits that are consistent with the upland, nonphreatophytic character of S. baileyi, which is in stark contrast to the phreatophytic character of S. vermiculatus. Both species, however, are very salt tolerant and have low leaf N concentrations, indicating the low nutrient availability and the potentially high salinity of their extreme habitats. Further investigation of comparable desert ridge environments should be conducted to determine the extent of S. baileyi in eastern California, and common garden comparisons of the 2 species should be conducted to compare their ecophysiological traits. El ";greasewood” ( Sarcobatus ) es un arbusto halofítico de origen norteamericano con hojas suculentas. El género consta de dos especies: Sarcobatus baileyi y Sarcobatus vermiculatus. Aunque S. vermiculatus es común en gran parte del oeste de Norteamerica, S. baileyi tiene una distribución mucho más limitada. Se pensaba anteriormente que S. baileyi era endémico a Nevada, pero aquí documentamos y describimos una población en el este de California, comparando su morfología y ecología con las de una población adyacente de S. vermiculatus. Morfológicamente, S. baileyi es más pequeña de altura, pero produce semillas más grandes. Sin embargo, menos semillas de S. baileyi germinaron y sobrevivieron a una incubación en laboratorio de 20 días, comparado con S. vermiculatus. Sarcobatus baileyi opera con potenciales de agua mucho más bajos que los de S. vermiculatus en condiciones de campo y tiene mayores concentraciones de Na en sus hojas. No obstante, no se observaron diferencias significativas en la eficiencia del uso de agua a largo plazo, medida en términos de δ13C entre las 2 especies. Las concentraciones de N en las hojas fueron muy bajas en ambas especies. En general, estas especies difieren mucho en varios rasgos que son consistentes con el carácter no freatofítico de S. baileyi de tierras altas, el cual contrasta claramente con el carácter freatofítico de S. vermiculatus. Ambas especies, sin embargo, son bastante tolerantes a la sal y tienen concentraciones bajas de N en hojas, lo cual indica la baja disponibilidad de nutrientes y la potencial alta salinidad en sus hábitats extremos. Investigaciones adicionales en ambientes comparables de bordes desérticos deberán llevarse a cabo para determinar la extensión S. baileyi en el este de California, además de comparaciones de las dos especies en jardín para comparar sus rasgos ecofisiológicos.     

CEP152 is a genome maintenance protein disrupted in Seckel syndrome

Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.