Replacement of huntingtin exon 1 by trans-splicing

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a “gain-of-function” mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders.     

Record of mid-Archaean subduction from metamorphism in the Barberton terrain, South Africa

Although plate tectonics is the central geological process of the modern Earth, its form and existence during the Archaean era (4.0-2.5 Gyr ago) are disputed. The existence of subduction during this time is particularly controversial because characteristic subduction-related mineral assemblages, typically documenting apparent geothermal gradients of 15 degrees C km(-1) or less, have not yet been recorded from in situ Archaean rocks (the lowest recorded apparent geothermal gradients are greater than 25 degrees C km(-1)). Despite this absence from the rock record, low Archaean geothermal gradients are suggested by eclogitic nodules in kimberlites and circumstantial evidence for subduction processes, including possible accretion-related structures, has been reported in Archaean terrains. The lack of spatially and temporally well-constrained high-pressure, low-temperature metamorphism continues, however, to cast doubt on the relevance of subduction-driven tectonics during the first 1.5 Gyr of the Earth's history. Here we report garnet-albite-bearing mineral assemblages that record pressures of 1.2-1.5 GPa at temperatures of 600-650 degrees C from supracrustal amphibolites from the mid-Archaean Barberton granitoid-greenstone terrain. These conditions point to apparent geothermal gradients of 12-15 degrees C-similar to those found in recent subduction zones-that coincided with the main phase of terrane accretion in the structurally overlying Barberton greenstone belt. These high-pressure, low-temperature conditions represent metamorphic evidence for cold and strong lithosphere, as well as subduction-driven tectonic processes, during the evolution of the early Earth.     

Antarctic climate cooling and terrestrial ecosystem response.

The average air temperature at the Earth's surface has increased by 0.06 degrees C per decade during the 20th century, and by 0.19 degrees C per decade from 1979 to 1998. Climate models generally predict amplified warming in polar regions, as observed in Antarctica's peninsula region over the second half of the 20th century. Although previous reports suggest slight recent continental warming, our spatial analysis of Antarctic meteorological data demonstrates a net cooling on the Antarctic continent between 1966 and 2000, particularly during summer and autumn. The McMurdo Dry Valleys have cooled by 0.7 degrees C per decade between 1986 and 2000, with similar pronounced seasonal trends. Summer cooling is particularly important to Antarctic terrestrial ecosystems that are poised at the interface of ice and water. Here we present data from the dry valleys representing evidence of rapid terrestrial ecosystem response to climate cooling in Antarctica, including decreased primary productivity of lakes (6-9% per year) and declining numbers of soil invertebrates (more than 10% per year). Continental Antarctic cooling, especially the seasonality of cooling, poses challenges to models of climate and ecosystem change.     

A globally coherent fingerprint of climate change impacts across natural systems

Causal attribution of recent biological trends to climate change is complicated because non-climatic influences dominate local, short-term biological changes. Any underlying signal from climate change is likely to be revealed by analyses that seek systematic trends across diverse species and geographic regions; however, debates within the Intergovernmental Panel on Climate Change (IPCC) reveal several definitions of a 'systematic trend'. Here, we explore these differences, apply diverse analyses to more than 1,700 species, and show that recent biological trends match climate change predictions. Global meta-analyses documented significant range shifts averaging 6.1 km per decade towards the poles (or metres per decade upward), and significant mean advancement of spring events by 2.3 days per decade. We define a diagnostic fingerprint of temporal and spatial 'sign-switching' responses uniquely predicted by twentieth century climate trends. Among appropriate long-term/large-scale/multi-species data sets, this diagnostic fingerprint was found for 279 species. This suite of analyses generates 'very high confidence' (as laid down by the IPCC) that climate change is already affecting living systems.     

Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni

Schistosoma mansoni is the primary causative agent of schistosomiasis, which affects 200 million individuals in 74 countries. We generated 163,000 expressed-sequence tags (ESTs) from normalized cDNA libraries from six selected developmental stages of the parasite, resulting in 31,000 assembled sequences and 92% sampling of an estimated 14,000 gene complement. By analyzing automated Gene Ontology assignments, we provide a detailed view of important S. mansoni biological systems, including characterization of metazoa-specific and eukarya-conserved genes. Phylogenetic analysis suggests an early divergence from other metazoa. The data set provides insights into the molecular mechanisms of tissue organization, development, signaling, sexual dimorphism, host interactions and immune evasion and identifies novel proteins to be investigated as vaccine candidates and potential drug targets.     

Pleistocene Homo sapiens from Middle Awash,Ethiopia

The origin of anatomically modern Homo sapiens and the fate of Neanderthals have been fundamental questions in human evolutionary studies for over a century. A key barrier to the resolution of these questions has been the lack of substantial and accurately dated African hominid fossils from between 100,000 and 300,000 years ago. Here we describe fossilized hominid crania from Herto, Middle Awash, Ethiopia, that fill this gap and provide crucial evidence on the location, timing and contextual circumstances of the emergence of Homo sapiens. Radioisotopically dated to between 160,000 and 154,000 years ago, these new fossils predate classic Neanderthals and lack their derived features. The Herto hominids are morphologically and chronologically intermediate between archaic African fossils and later anatomically modern Late Pleistocene humans. They therefore represent the probable immediate ancestors of anatomically modern humans. Their anatomy and antiquity constitute strong evidence of modern-human emergence in Africa.