Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis

Five structurally and functionally different proteins, an enzyme superoxide dismutase 1 (SOD1), a TAR-DNA binding protein-43 (TDP-43), an RNA-binding protein FUS, a cofilin-binding protein C9orf72, and polypeptides generated as a result of its intronic hexanucleotide expansions, and to lesser degree actin-binding profilin-1 (PFN1), are considered to be the major drivers of amyotrophic lateral sclerosis. One of the features common to these proteins is the presence of significant levels of intrinsic disorder. The goal of this study is to consider these neurodegeneration-related proteins from the intrinsic disorder perspective. To this end, we employed a broad set of computational tools for intrinsic disorder analysis and conducted intensive literature search to gain information on the structural peculiarities of SOD1, TDP-43, FUS, C9orf72, and PFN1 and their intrinsic disorder predispositions, and the roles of intrinsic disorder in their normal and pathological functions.     

Crystal structure of the RNA component of bacterial ribonuclease P

Transfer RNA (tRNA) is produced as a precursor molecule that needs to be processed at its 3' and 5' ends. Ribonuclease P is the sole endonuclease responsible for processing the 5' end of tRNA by cleaving the precursor and leading to tRNA maturation. It was one of the first catalytic RNA molecules identified and consists of a single RNA component in all organisms and only one protein component in bacteria. It is a true multi-turnover ribozyme and one of only two ribozymes (the other being the ribosome) that are conserved in all kingdoms of life. Here we show the crystal structure at 3.85 A resolution of the RNA component of Thermotoga maritima ribonuclease P. The entire RNA catalytic component is revealed, as well as the arrangement of the two structural domains. The structure shows the general architecture of the RNA molecule, the inter- and intra-domain interactions, the location of the universally conserved regions, the regions involved in pre-tRNA recognition and the location of the active site. A model with bound tRNA is in agreement with all existing data and suggests the general basis for RNA-RNA recognition by this ribozyme.     

Second-Order Auditing Practices

This paper describes the process that was followed at the Colombian National Audit Office, during 3.5 years, to develop new auditing practices, called second-order auditing. The purpose of the second-order control is to detect possible faults in the internal control mechanisms of the audited entities. General and particular models for second-order audit are presented, along with a method to carry out this type of auditing. Finally, a particular application of second-order auditing carried out in a Colombian national institution is presented.     

Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia

Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.     

Forecasting with money demand functions: the UK case

Money demand functions have long been known to be frequently subject to structural change. Since their use for optimal monetary policy design is basically a forecasting exercise, it is crucial to analyse the effect of time instability on the quality of their forecasts. We discuss in this paper whether instability of demand for money functions precludes their use for policy experiments, analysing a 1963–84 sample for the UK which has been widely used in the literature. © 1998 John Wiley & Sons, Ltd.     

The first hominin of Europe

The earliest hominin occupation of Europe is one of the most debated topics in palaeoanthropology. However, the purportedly oldest of the Early Pleistocene sites in Eurasia lack precise age control and contain stone tools rather than human fossil remains. Here we report the discovery of a human mandible associated with an assemblage of Mode 1 lithic tools and faunal remains bearing traces of hominin processing, in stratigraphic level TE9 at the site of the Sima del Elefante, Atapuerca, Spain. Level TE9 has been dated to the Early Pleistocene (approximately 1.2-1.1 Myr), based on a combination of palaeomagnetism, cosmogenic nuclides and biostratigraphy. The Sima del Elefante site thus emerges as the oldest, most accurately dated record of human occupation in Europe, to our knowledge. The study of the human mandible suggests that the first settlement of Western Europe could be related to an early demographic expansion out of Africa. The new evidence, with previous findings in other Atapuerca sites (level TD6 from Gran Dolina), also suggests that a speciation event occurred in this extreme area of the Eurasian continent during the Early Pleistocene, initiating the hominin lineage represented by the TE9 and TD6 hominins.     

Structure of a bacterial ribonuclease P holoenzyme in complex with tRNA

Ribonuclease (RNase) P is the universal ribozyme responsible for 5'-end tRNA processing. We report the crystal structure of the Thermotoga maritima RNase P holoenzyme in complex with tRNA(Phe). The 154?kDa complex consists of a large catalytic RNA (P RNA), a small protein cofactor and a mature tRNA. The structure shows that RNA-RNA recognition occurs through shape complementarity, specific intermolecular contacts and base-pairing interactions. Soaks with a pre-tRNA 5' leader sequence with and without metal help to identify the 5' substrate path and potential catalytic metal ions. The protein binds on top of a universally conserved structural module in P RNA and interacts with the leader, but not with the mature tRNA. The active site is composed of phosphate backbone moieties, a universally conserved uridine nucleobase, and at least two catalytically important metal ions. The active site structure and conserved RNase P-tRNA contacts suggest a universal mechanism of catalysis by RNase P.     

A Proposal for Robust Curve Clustering

Functional data sets appear in many areas of science. Although each data point may be seen as a large finite-dimensional vector it is preferable to think of them as functions, and many classical multivariate techniques have been generalized for this kind of data. A widely used technique for dealing with functional data is to choose a finite-dimensional basis and find the best projection of each curve onto this basis. Therefore, given a functional basis, an approach for doing curve clustering relies on applying the k-means methodology to the fitted basis coefficients corresponding to all the curves in the data set. Unfortunately, a serious drawback follows from the lack of robustness of k-means. Trimmed k-means clustering (Cuesta-Albertos, Gordaliza, and Matran 1997) provides a robust alternative to the use of k-means and, consequently, it may be successfully used in this functional framework. The proposed approach will be exemplified by considering cubic B-splines bases, but other bases can be applied analogously depending on the application at hand.     

Craniometric evidence for Palaeoamerican survival in Baja California

A current issue on the settlement of the Americas refers to the lack of morphological affinities between early Holocene human remains (Palaeoamericans) and modern Amerindian groups, as well as the degree of contribution of the former to the gene pool of the latter. A different origin for Palaeoamericans and Amerindians is invoked to explain such a phenomenon. Under this hypothesis, the origin of Palaeoamericans must be traced back to a common ancestor for Palaeoamericans and Australians, which departed from somewhere in southern Asia and arrived in the Australian continent and the Americas around 40,000 and 12,000 years before present, respectively. Most modern Amerindians are believed to be part of a second, morphologically differentiated migration. Here we present evidence of a modern Amerindian group from the Baja California Peninsula in Mexico, showing clearer affinities with Palaeoamerican remains than with modern Amerindians. Climatic changes during the Middle Holocene probably generated the conditions for isolation from the continent, restricting the gene flow of the original group with northern populations, which resulted in the temporal continuity of the Palaeoamerican morphological pattern to the present.     

Preservation of organic matter in sediments promoted by iron

The biogeochemical cycles of iron and organic carbon are strongly interlinked. In oceanic waters, organic ligands have been shown to control the concentration of dissolved iron. In soils, solid iron phases shelter and preserve organic carbon, but the role of iron in the preservation of organic matter in sediments has not been clearly established. Here we use an iron reduction method previously applied to soils to determine the amount of organic carbon associated with reactive iron phases in sediments of various mineralogies collected from a wide range of depositional environments. Our findings suggest that 21.5?±?8.6 per cent of the organic carbon in sediments is directly bound to reactive iron phases. We further estimate that a global mass of (19-45)?×?10(15)?grams of organic carbon is preserved in surface marine sediments as a result of its association with iron. We propose that these associations between organic carbon and iron, which are formed primarily through co-precipitation and/or direct chelation, promote the preservation of organic carbon in sediments. Because reactive iron phases are metastable over geological timescales, we suggest that they serve as an efficient 'rusty sink' for organic carbon, acting as a key factor in the long-term storage of organic carbon and thus contributing to the global cycles of carbon, oxygen and sulphur.