GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists

<p>Abstract</p> <p>Background</p> <p>Since the inception of the GO annotation project, a variety of tools have been developed that support exploring and searching the GO database. In particular, a variety of tools that perform GO enrichment analysis are currently available. Most of these tools require as input a target set of genes and a background set and seek enrichment in the target set compared to the background set. A few tools also exist that support analyzing ranked lists. The latter typically rely on simulations or on union-bound correction for assigning statistical significance to the results.</p> <p>Results</p> <p><it>GOrilla </it>is a web-based application that identifies enriched GO terms in ranked lists of genes, without requiring the user to provide explicit target and background sets. This is particularly useful in many typical cases where genomic data may be naturally represented as a ranked list of genes (e.g. by level of expression or of differential expression). <it>GOrilla </it>employs a flexible threshold statistical approach to discover GO terms that are significantly enriched at the <it>top </it>of a ranked gene list. Building on a complete theoretical characterization of the underlying distribution, called mHG, <it>GOrilla </it>computes an exact p-value for the observed enrichment, taking threshold multiple testing into account without the need for simulations. This enables rigorous statistical analysis of thousand of genes and thousands of GO terms in order of seconds. The output of the enrichment analysis is visualized as a hierarchical structure, providing a clear view of the relations between enriched GO terms.</p> <p>Conclusion</p> <p><it>GOrilla </it>is an efficient GO analysis tool with unique features that make a useful addition to the existing repertoire of GO enrichment tools. <it>GOrilla</it>'s unique features and advantages over other threshold free enrichment tools include rigorous statistics, fast running time and an effective graphical representation. <it>GOrilla </it>is publicly available at: <url>http://cbl-gorilla.cs.technion.ac.il</url></p

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed

Tropical forcing of increased Southern Ocean climate variability revealed by a 140-year subantarctic temperate reconstruction

Occupying 14% of the world’s surface, the Southern Ocean plays a fundamental role in global climate, ocean circulation, carbon cycling and Antarctic ice-sheet stability. Unfortunately, high interannual variability and a dearth of instrumental observations before the 1950s limits our understanding of how marine-atmosphere-ice domains interact on multi-decadal timescales and the impact of anthropogenic forcing. Here we integrate climate-sensitive tree growth with ocean and atmospheric observations on southwest Pacific subantarctic islands that lie at the boundary of polar and subtropical climates (52–54˚S). Our annually-resolved temperature reconstruction captures regional change since the 1870s and demonstrates a significant increase in variability from the mid-twentieth century, a phenomenon predating the observational record. Climate reanalysis and modelling shows a parallel change in tropical Pacific sea surface temperatures that generate an atmospheric Rossby wave train which propagates across a large part of the Southern Hemisphere during the austral spring and summer

Multi-decadal variations in Southern Hemisphere atmospheric ¹⁴C: Evidence against a Southern Ocean sink at the end of the Little Ice Age CO₂ anomaly.

Northern Hemisphere-wide cooling during the Little Ice Age (LIA; CE 1650-1775) is associated with a ~5 ppmv decrease in atmospheric carbon dioxide. Changes in terrestrial and ocean carbon reservoirs have been postulated as possible drivers of this relatively large shift in atmospheric CO₂, potentially providing insights into the mechanisms and sensitivity of the global carbon cycle. Here we report decadally-resolved radiocarbon (¹⁴C) levels in a network of tree rings series spanning CE 1700-1950 located along the northern boundary of, and within, the Southern Ocean. We observe regional dilutions in atmospheric radiocarbon (relative to the Northern Hemisphere) associated with upwelling of ¹⁴CO₂–depleted abyssal waters. We find the inter-hemispheric ¹⁴C offset approaches zero during increasing global atmospheric CO₂ at the end of the LIA, with reduced ventilation in the Southern Ocean and a Northern Hemisphere source of old carbon (most probably originating from deep Arctic peat layers). The coincidence of the atmospheric CO₂ increase and reduction in the inter-hemispheric ¹⁴C offset imply a common climate control. Possible mechanisms of synchronous change in the high latitudes of both hemispheres are discussed

An Analytically Solvable Model for Rapid Evolution of Modular Structure

Biological systems often display modularity, in the sense that they can be decomposed into nearly independent subsystems. Recent studies have suggested that modular structure can spontaneously emerge if goals (environments) change over time, such that each new goal shares the same set of sub-problems with previous goals. Such modularly varying goals can also dramatically speed up evolution, relative to evolution under a constant goal. These studies were based on simulations of model systems, such as logic circuits and RNA structure, which are generally not easy to treat analytically. We present, here, a simple model for evolution under modularly varying goals that can be solved analytically. This model helps to understand some of the fundamental mechanisms that lead to rapid emergence of modular structure under modularly varying goals. In particular, the model suggests a mechanism for the dramatic speedup in evolution observed under such temporally varying goals

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US)

Hyperthermia Induces the ER Stress Pathway

The ER chaperone GRP78/BiP is a homolog of the Hsp70 family of heat shock proteins, yet GRP78/BiP is not induced by heat shock but instead by ER stress. However, previous studies had not considered more physiologically relevant temperature elevation associated with febrile hyperthermia. In this report we examine the response of GRP78/BiP and other components of the ER stress pathway in cells exposed to 40°C.AD293 cells were exposed to 43°C heat shock to confirm inhibition of the ER stress response genes. Five mammalian cell types, including AD293 cells, were then exposed to 40°C hyperthermia for various time periods and induction of the ER stress pathway was assessed.The inhibition of the ER stress pathway by heat shock (43°C) was confirmed. In contrast cells subjected to more mild temperature elevation (40°C) showed either a partial or full ER stress pathway induction as determined by downstream targets of the three arms of the ER stress pathway as well as a heat shock response. Cells deficient for Perk or Gcn2 exhibit great sensitivity to ER stress induction by hyperthermia.The ER stress pathway is induced partially or fully as a consequence of hyperthermia in parallel with induction of Hsp70. These findings suggest that the ER and cytoplasm of cells contain parallel pathways to coordinately regulate adaptation to febrile hyperthermia associated with disease or infection

Higher fungal diversity is correlated with lower CO2 emissions from dead wood in a natural forest

Wood decomposition releases almost as much CO2 to the atmosphere as does fossil-fuel combustion, so the factors regulating wood decomposition can affect global carbon cycling. We used metabarcoding to estimate the fungal species diversities of naturally colonized decomposing wood in subtropical China and, for the first time, compared them to concurrent measures of CO2 emissions. Wood hosting more diverse fungal communities emitted less CO2, with Shannon diversity explaining 26 to 44% of emissions variation. Community analysis supports a ‘pure diversity’ effect of fungi on decomposition rates and thus suggests that interference competition is an underlying mechanism. Our findings extend the results of published experiments using low-diversity, laboratory-inoculated wood to a high-diversity, natural system. We hypothesize that high levels of saprotrophic fungal biodiversity could be providing globally important ecosystem services by maintaining dead-wood habitats and by slowing the atmospheric contribution of CO2 from the world’s stock of decomposing wood. However, large-scale surveys and controlled experimental tests in natural settings will be needed to test this hypothesis