The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.     

Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica

Tunicate embryos and larvae have small cell numbers and simple anatomical features in comparison with other chordates, including vertebrates. Although they branch near the base of chordate phylogenetic trees, their degree of divergence from the common chordate ancestor remains difficult to evaluate. Here we show that the tunicate Oikopleura dioica has a complement of nine Hox genes in which all central genes are lacking but a full vertebrate-like set of posterior genes is present. In contrast to all bilaterians studied so far, Hox genes are not clustered in the Oikopleura genome. Their expression occurs mostly in the tail, with some tissue preference, and a strong partition of expression domains in the nerve cord, in the notochord and in the muscle. In each tissue of the tail, the anteroposterior order of Hox gene expression evokes spatial collinearity, with several alterations. We propose a relationship between the Hox cluster breakdown, the separation of Hox expression domains, and a transition to a determinative mode of development.     

Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14?years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.     

Increased terrestrial methane cycling at the Palaeocene-Eocene thermal maximum

The Palaeocene-Eocene thermal maximum (PETM), a period of intense, global warming about 55 million years ago, has been attributed to a rapid rise in greenhouse gas levels, with dissociation of methane hydrates being the most commonly invoked explanation. It has been suggested previously that high-latitude methane emissions from terrestrial environments could have enhanced the warming effect, but direct evidence for an increased methane flux from wetlands is lacking. The Cobham Lignite, a recently characterized expanded lacustrine/mire deposit in England, spans the onset of the PETM and therefore provides an opportunity to examine the biogeochemical response of wetland-type ecosystems at that time. Here we report the occurrence of hopanoids, biomarkers derived from bacteria, in the mire sediments from Cobham. We measure a decrease in the carbon isotope values of the hopanoids at the onset of the PETM interval, which suggests an increase in the methanotroph population. We propose that this reflects an increase in methane production potentially driven by changes to a warmer and wetter climate. Our data suggest that the release of methane from the terrestrial biosphere increased and possibly acted as a positive feedback mechanism to global warming.     

Digenic inheritance of severe insulin resistance in a human pedigree

Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.     

旋转压缩机 三维计算流体动力学和固体流体相互作用

旋转压缩机是完全旋转位移的机器，它比较紧凑，有较少的运动元件，能够在较大的速度和压力差范围内有效地运行，因此，当前相当大部分的工业压缩机是这种类型的。     

Regulation of DNA methylation of Rasgrf1.

In mammals, DNA is methylated at cytosines within CpG dinucleotides. Properly regulated methylation is crucial for normal development. Inappropriate methylation may contribute to tumorigenesis by silencing tumor-suppressor genes or by activating growth-stimulating genes. Although many genes have been identified that acquire methylation and whose expression is methylation-sensitive, little is known about how DNA methylation is controlled. We have identified a DNA sequence that regulates establishment of DNA methylation in the male germ line at Rasgrf1. In mice, the imprinted Rasgrf1 locus is methylated on the paternal allele within a differentially methylated domain (DMD) 30 kbp 5' of the promoter. Expression is exclusively from the paternal allele in neonatal brain. Methylation is regulated by a repeated sequence, consisting of a 41-mer repeated 40 times, found immediately 3' of the DMD. This sequence is present in organisms in which Rasgrf1 is imprinted. In addition, DMD methylation is required for imprinted Rasgrf1 expression. Together the DMD and repeat element constitute a binary switch that regulates imprinting at the locus.     

Sylvaticin: A new cytotoxic and insecticidal acetogenin fromRollinia sylvatica (Annonaceae)

Summary Sylvaticin (I), a new tetrahydroxy annonaceous acetogenin with nonadjacent tetrahydrofuran rings, has been isolated from the dried fruits ofRollinia sylvatica St. Hil. (Annonaceae). This compound is extremely cytotoxic to human tumor cells and shows promising insect control properties.     

Nonseparable processes and causal explanation

If physical reality is nonseparable, as quantum mechanics suggests, then it may contain processes of a quite novel kind. Such nonseparable processes could connect spacelike separated events without violating relativity theory or any defensible locality condition. Appeal to nonseparable processes could ground theoretical explanations of such otherwise puzzling phenomena as the two-slit experiment, and EPR-type correlations. We find such phenomena puzzling because they threaten cherished conceptions of how causes operate to produce their effects. But nonseparable processes offer us an alternative deal of natural order, conformity to which makes such phenomena seem quite normal and not at all unexpected. Attempts to answer the further question, as to whether an appeal to a nonseparable process provides a genuine causal explanation, have something to teach us about our concept of causation, but do not threaten to undermine the value of the explanation itself.     

Bovine papillomavirus E5 oncoprotein binds to the 16K component of vacuolar H(+)-ATPases.

The major transforming protein of bovine papillomavirus type 1, E5, is mainly associated with endomembranes, specifically binding to a cellular protein of relative molecular mass 16,000 (16K). At the same time as transformation, E5 causes the phosphorylation of tyrosine residues in epidermal and platelet-derived growth factor receptors. We show here that the 16K protein associated with E5 is the 16K component of vacuolar ATPases. This protein is known to be an integral membrane protein in endosomes, bovine chromaffin granules, synaptic vesicles, fungal and plant vacuoles and clathrin-coated vesicles, as well as a component of gap-junction-like membrane complexes. Because proton pumps are critical for the function of cellular compartments that process growth-factor receptors, the interaction of E5 with the 16K protein could explain the pleiomorphic features of cells transformed by E5.