Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.     

Role for DNA methylation in the control of cell type specific maspin expression

The major histocompatibility complex (MHC) is a source of unique individual odors that influence individual recognition, mating preferences, nesting behavior and selective block of pregnancy in animals. Such phenomena have been difficult to study in humans, because the human leukocyte antigen (HLA, human MHC) loci are the most polymorphic loci in the human genome, with the potential to generate millions of unique combinations of genotypes. In addition, high variability in background odors, encoded by the rest of the genome and influenced by cultural practices, contribute to a low signal-to-noise ratio that could mask HLA-based olfactory cues. Here we show that women can detect differences of one HLA allele among male odor donors with different MHC genotypes. Notably, the mechanism for a woman's ability to discriminate and choose odors is based on HLA alleles inherited from her father but not her mother. The parents' HLA alleles that she does not inherit show no relationship with odor choice, despite exposure to these HLA-encoded odors throughout her life. Our data indicate that paternally inherited HLA-associated odors influence odor preference and may serve as social cues.     

Therapeutic approaches to protein-misfolding diseases

Several sporadic and genetic diseases are caused by protein misfolding. These include cystic fibrosis and other devastating diseases of childhood as well as Alzheimer's, Parkinson's and other debilitating maladies of the elderly. A unified view of the molecular and cellular pathogenesis of these conditions has led to the search for chemical chaperones that can slow, arrest or revert disease progression. Molecules are now emerging that link our biophysical insights with our therapeutic aspirations.     

New evidence on deinonychosaurian dinosaurs from the Late Cretaceous of Patagonia

Most of what is known about the evolution of deinonychosaurs (that is, the group of theropods most closely related to birds) is based on discoveries from North America and Asia. Except for Unenlagia comahuensis and some fragmentary remains from northern Africa, no other evidence was available on deinonychosaurian diversity in Gondwana. Here we report a new, Late Cretaceous member of the clade, Neuquenraptor argentinus gen. et sp. nov., representing uncontroversial evidence of a deinonychosaurian theropod in the Southern Hemisphere. The new discovery demonstrates that Cretaceous theropod faunas from the southern continents shared greater similarity with those of the northern landmasses than previously thought. Available evidence suggests that deinonychosaurians were probably distributed worldwide at least by the beginning of the Cretaceous period. The phylogenetic position of the new deinonychosaur, as well as other Patagonian coelurosaurian theropods, is compatible with a vicariance model of diversification for some groups of Gondwanan and Laurasian dinosaurs.     

Influence of mean climate change on climate variability from a 155-year tropical Pacific coral record

Today, the El Ni?o/Southern Oscillation (ENSO) system is the primary driver of interannual variability in global climate, but its long-term behaviour is poorly understood. Instrumental observations reveal a shift in 1976 towards warmer and wetter conditions in the tropical Pacific, with widespread climatic and ecological consequences. This shift, unique over the past century, has prompted debate over the influence of increasing atmospheric concentrations of greenhouse gases on ENSO variability. Here we present a 155-year ENSO reconstruction from a central tropical Pacific coral that provides new evidence for long-term changes in the regional mean climate and its variability. A gradual transition in the early twentieth century and the abrupt change in 1976, both towards warmer and wetter conditions, co-occur with changes in variability. In the mid-late nineteenth century, cooler and drier background conditions coincided with prominent decadal variability; in the early twentieth century, shorter-period (approximately 2.9 years) variability intensified. After 1920, variability weakens and becomes focused at interannual timescales; with the shift in 1976, variability with a period of about 4 years becomes prominent. Our results suggest that variability in the tropical Pacific is linked to the region's mean climate, and that changes in both have occurred during periods of natural as well as anthropogenic climate forcing.     

Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis

Autosomal dominant distal renal tubular acidosis (ddRTA) is caused by mutations in SLC4A1, which encodes the polytopic chloride-bicarbonate exchanger AE1 that is normally expressed at the basolateral surface of alpha-intercalated cells in the distal nephron. Here we report that, in contrast with many disorders in which mutant membrane proteins are retained intracellularly and degraded, ddRTA can result from aberrant targeting of AE1 to the apical surface.     

Detoxification of vinyl chloride to ethene coupled to growth of an anaerobic bacterium

Tetrachloroethene (PCE) and trichloroethene (TCE) are ideal solvents for numerous applications, and their widespread use makes them prominent groundwater pollutants. Even more troubling, natural biotic and abiotic processes acting on these solvents lead to the accumulation of toxic intermediates (such as dichloroethenes) and carcinogenic intermediates (such as vinyl chloride). Vinyl chloride was found in at least 496 of the 1,430 National Priorities List sites identified by the US Environmental Protection Agency, and its precursors PCE and TCE are present in at least 771 and 852 of these sites, respectively. Here we describe an unusual, strictly anaerobic bacterium that destroys dichloroethenes and vinyl chloride as part of its energy metabolism, generating environmentally benign products (biomass, ethene and inorganic chloride). This organism might be useful for cleaning contaminated subsurface environments and restoring drinking-water reservoirs.     

A new type of mutation causes a splicing defect in ATM

Disease-causing splicing mutations described in the literature primarily produce changes in splice sites and, to a lesser extent, variations in exon-regulatory sequences such as the enhancer elements. The gene ATM is mutated in individuals with ataxia-telangiectasia; we have identified the aberrant inclusion of a cryptic exon of 65 bp in one affected individual with a deletion of four nucleotides (GTAA) in intron 20. The deletion is located 12 bp downstream and 53 bp upstream from the 5' and 3' ends of the cryptic exon, respectively. Through analysis of the splicing defect using a hybrid minigene system, we identified a new intron-splicing processing element (ISPE) complementary to U1 snRNA, the RNA component of the U1 small nuclear ribonucleoprotein (snRNP). This element mediates accurate intron processing and interacts specifically with U1 snRNP particles. The 4-nt deletion completely abolished this interaction, causing activation of the cryptic exon. On the basis of this analysis, we describe a new type of U1 snRNP binding site in an intron that is essential for accurate intron removal. Deletion of this sequence is directly involved in the splicing processing defect.     

Magnetic trapping of neutrons

Accurate measurement of the lifetime of the neutron (which is unstable to beta decay) is important for understanding the weak nuclear force and the creation of matter during the Big Bang. Previous measurements of the neutron lifetime have mainly been limited by certain systematic errors; however, these could in principle be avoided by performing measurements on neutrons stored in a magnetic trap. Neutral-particle and charged-particle traps are widely used for studying both composite and elementary particles, because they allow long interaction times and isolation of particles from perturbing environments. Here we report the magnetic trapping of neutrons. The trapping region is filled with superfluid 4He, which is used to load neutrons into the trap and as a scintillator to detect their decay. Neutrons in the trap have a lifetime of 750(+330)(-200) seconds, mainly limited by their beta decay rather than trap losses. Our experiment verifies theoretical predictions regarding the loading process and magnetic trapping of neutrons. Further refinement of this method should lead to improved precision in the neutron lifetime measurement.