The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-L?ken syndrome) and ocular motor apraxia (Cogan syndrome). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion. Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.     

Earliest date for milk use in the Near East and southeastern Europe linked to cattle herding

The domestication of cattle, sheep and goats had already taken place in the Near East by the eighth millennium bc. Although there would have been considerable economic and nutritional gains from using these animals for their milk and other products from living animals-that is, traction and wool-the first clear evidence for these appears much later, from the late fifth and fourth millennia bc. Hence, the timing and region in which milking was first practised remain unknown. Organic residues preserved in archaeological pottery have provided direct evidence for the use of milk in the fourth millennium in Britain, and in the sixth millennium in eastern Europe, based on the delta(13)C values of the major fatty acids of milk fat. Here we apply this approach to more than 2,200 pottery vessels from sites in the Near East and southeastern Europe dating from the fifth to the seventh millennia bc. We show that milk was in use by the seventh millennium; this is the earliest direct evidence to date. Milking was particularly important in northwestern Anatolia, pointing to regional differences linked with conditions more favourable to cattle compared to other regions, where sheep and goats were relatively common and milk use less important. The latter is supported by correlations between the fat type and animal bone evidence.     

Projected increase in continental runoff due to plant responses to increasing carbon dioxide

In addition to influencing climatic conditions directly through radiative forcing, increasing carbon dioxide concentration influences the climate system through its effects on plant physiology. Plant stomata generally open less widely under increased carbon dioxide concentration, which reduces transpiration and thus leaves more water at the land surface. This driver of change in the climate system, which we term 'physiological forcing', has been detected in observational records of increasing average continental runoff over the twentieth century. Here we use an ensemble of experiments with a global climate model that includes a vegetation component to assess the contribution of physiological forcing to future changes in continental runoff, in the context of uncertainties in future precipitation. We find that the physiological effect of doubled carbon dioxide concentrations on plant transpiration increases simulated global mean runoff by 6 per cent relative to pre-industrial levels; an increase that is comparable to that simulated in response to radiatively forced climate change (11 +/- 6 per cent). Assessments of the effect of increasing carbon dioxide concentrations on the hydrological cycle that only consider radiative forcing will therefore tend to underestimate future increases in runoff and overestimate decreases. This suggests that freshwater resources may be less limited than previously assumed under scenarios of future global warming, although there is still an increased risk of drought. Moreover, our results highlight that the practice of assessing the climate-forcing potential of all greenhouse gases in terms of their radiative forcing potential relative to carbon dioxide does not accurately reflect the relative effects of different greenhouse gases on freshwater resources.     

The grapevine genome sequence suggests ancestral hexaploidization in major angiosperm phyla

The analysis of the first plant genomes provided unexpected evidence for genome duplication events in species that had previously been considered as true diploids on the basis of their genetics. These polyploidization events may have had important consequences in plant evolution, in particular for species radiation and adaptation and for the modulation of functional capacities. Here we report a high-quality draft of the genome sequence of grapevine (Vitis vinifera) obtained from a highly homozygous genotype. The draft sequence of the grapevine genome is the fourth one produced so far for flowering plants, the second for a woody species and the first for a fruit crop (cultivated for both fruit and beverage). Grapevine was selected because of its important place in the cultural heritage of humanity beginning during the Neolithic period. Several large expansions of gene families with roles in aromatic features are observed. The grapevine genome has not undergone recent genome duplication, thus enabling the discovery of ancestral traits and features of the genetic organization of flowering plants. This analysis reveals the contribution of three ancestral genomes to the grapevine haploid content. This ancestral arrangement is common to many dicotyledonous plants but is absent from the genome of rice, which is a monocotyledon. Furthermore, we explain the chronology of previously described whole-genome duplication events in the evolution of flowering plants.     

Changing time scale for short-term forecasting in financial markets

A forecasting model based on high-frequency market makers quotes of financial instruments is presented. The statistical behaviour of these time series leads to discussion of the appropriate time scale for forecasting. We introduce variable time scales in a general way and define the new concept of intrinsic time. The latter reflects better the actual trading activity. Changing time scale means forecasting in two steps, first an intrinsic time forecast against physical time, then a price forecast against intrinsic time. The forecasting model consists, for both steps, of a linear combination of non-linear price-based indicators. The indicator weights are continuously re-optimized through a modified linear regression on a moving sample of past prices. The out-of-sample performance of this algorithm is reported on a set of important FX rates and interest rates over many years. It is remarkably consistent. Results for short horizons as well as techniques to measure this performance are discussed.     

Data Model and Classification by Trees: The Minimum Variance Reduction (MVR) Method

O (n ⁴), where n is the number of objects. We describe the application of the MVR method to two data models: the weighted least-squares (WLS) model (V is diagonal), where the MVR method can be reduced to an O(n ³) time complexity; a model arising from the study of biological sequences, which involves a complex non-diagonal V matrix that is estimated from the dissimilarity matrix Δ. For both models, we provide simulation results that show a significant error reduction in the reconstruction of T, relative to classical agglomerative algorithms.