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We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1 E17K , a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor ( VLDLR ). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.

In many parts of the developing world and economies in transition, small-scale traditional brick kilns are a notorious source of urban air pollution. Many are both energy inefficient and burn highly polluting fuels that emit significant levels of black carbon (BC), organic carbon (OC) and other atmospheric pollutants into local communities, resulting in severe health and environmental impacts. However, only a very limited number of studies are available on the emission characteristics of brick kilns; thus, there is a need to characterize their gaseous and particulate matter (PM) emission factors to better assess their overall contribution to emissions inventories and to quantify their ecological, human health, and climate impacts. In this study, the fuel-, energy-, and brick-based emissions factors and time-based emission ratios of BC, OC, inorganic PM components, CO, SO2, CH4, NOx, and selected volatile organic compounds (VOCs) from three artisanal brick kilns with different designs in Mexico were quantified using the tracer ratio sampling technique. Simultaneous measurements of PM components, CO, and CO2 were also obtained using a sampling probe technique. Additional measurements included the internal temperature of the brick kilns, mechanical resistance of bricks produced, and characteristics of fuels employed. Average fuel-based BC emission factors ranged from 0.15 to 0.58 g (kg fuel)−1, whereas BC∕OC mass ratios ranged from 0.9 to 5.2, depending on the kiln type. The results show that both techniques capture similar temporal profiles of the brick kiln emissions and produce comparable emission factors. A more integrated inter-comparison of the brick kilns' performances was obtained by simultaneously assessing emissions factors, energy efficiency, fuel consumption, and the quality of the bricks produced.

Richard Lifton and colleagues report the identification of three susceptibility loci for intracranial aneurysm. Two of the loci are new, with SNPs on chromosome 8q likely acting through SOX17 , which is required for the formation and maintenance of endothelial cells. Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment 1 . The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm 2 , 3 , 4 , 5 . Associated SNPs on 8q likely act via SOX17 , which is required for formation and maintenance of endothelial cells 6 , 7 , 8 , suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role 9 . These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Dual-chamber pacing (atrial and ventricular) has been compared with single-chamber pacing (atrial or ventricular) in patients with bradycardia in 5 multicenter, parallel, randomized trials, in 1 meta-analysis of randomized trials, and in 1 systematic review that also included 30 randomized crossover comparisons and 4 economic analyses [3–9]. The net result is that the indications for programming the dual- chamber modes are weaker and the choice regarding the pacing mode should be individualized, taking into consideration the increased complication risk and costs of dual- chamber devices. Because ICD patients usually do not require bradycardia support, with the exception of patients who require cardiac resynchronization, programming choices should avoid pacing and in particular avoid single ventricular pacing, if possible [15,16]. 3 Programming of Rate Modulation The benefit of rate response programming has been evaluated in patients with bradycardia in 5 multicenter, randomized trials and in 1 systematic review that also included 7 single-center studies [17–22]. In 2 small studies on patients with chronotropic incompetence comparing DDD and DDDR pacing, the latter had improved quality of life and exercise capacity; however, a larger, multicenter randomized trial (Advanced Elements of Pacing Randomized Controlled Trial [ADEPT]) failed to show a difference in patients with a modest blunted heart rate response to exercise [17–19].

This study investigates researcher variability in computational reproduction, an activity for which it is least expected. Eighty-five independent teams attempted numerical replication of results from an original study of policy preferences and immigration. Reproduction teams were randomly grouped into a 'transparent group' receiving original study and code or 'opaque group' receiving only a method and results description and no code. The transparent group mostly verified original results (95.7% same sign and p-value cutoff), while the opaque group had less success (89.3%). Second-decimal place exact numerical reproductions were less common (76.9 and 48.1%). Qualitative investigation of the workflows revealed many causes of error, including mistakes and procedural variations. When curating mistakes, we still find that only the transparent group was reliably successful. Our findings imply a need for transparency, but also more. Institutional checks and less subjective difficulty for researchers 'doing reproduction' would help, implying a need for better training. We also urge increased awareness of complexity in the research process and in 'push button' replications.

[This corrects the article DOI: 10.1016/j.joa.2015.12.001.].

In July and August 2003 a field campaign was conducted to explore the diurnal circulation of the Bolivian Altiplano. Vertical soundings by remote-controlled aircraft yielded profiles of temperature, pressure, and humidity at six passes and in a valley. Pilot balloon observations provided wind profiles. Two permanent stations collected additional data. Typically, inflow toward the Altiplano commences a few hours after sunrise at about the time when the stable nocturnal layer near the ground is transformed by the solar heating into an almost neutrally stratified convective boundary layer. The depth of the inflow layer is comparable to but normally less than that of this boundary layer. There are indications of return flow aloft. The inflow continues at least until sunset. Moisture is imported at the passes leading to the Yungas in the east. Strong upvalley flows were found in the valley of the Rio de La Paz, which connects the wide canyon of La Paz with the tropical lowlands to the east. Inflow was absent at one of the passes despite favorable synoptic conditions. Cases of synoptically forced flows are presented as well where the diurnal signal is difficult to separate. A simple flow scheme is presented that fits the observations reasonably well.