Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.     

Connexins and pannexins in the skeleton: gap junctions,hemichannels and more

Regulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and function of bone cells relies on the presence of connexins. Connexin43 regulates the expression of genes required for osteoblast and osteoclast differentiation directly or by changing the levels of osteocytic genes, and connexin45 may oppose connexin43 actions in osteoblastic cells. Connexin37 is required for osteoclast differentiation and its deletion results in increased bone mass. Less is known on the role of connexins in cartilage, ligaments and tendons. Connexin43, connexin45, connexin32, connexin46 and connexin29 are expressed in chondrocytes, while connexin43 and connexin32 are expressed in ligaments and tendons. Similarly, although the expression of pannexin1, pannexin2 and pannexin3 has been demonstrated in bone and cartilage cells, their function in these tissues is not fully understood.     

2010 BP Oil Spill and the Systemic Construct of the Gulf Coast Shrimp Supply Chain

On April 20, 2010, the blast on the rig Deepwater Horizon, and the ensuing disaster known as the BP oil spill, has disrupted the Gulf Coast Shrimp supply chain. Six elements of the systemic supply and demand side of that supply chain are identified and discussed. On the supply side are shrimpers, processors, wholesalers, retailers, and restaurants. On the demand side is the consumer. Qualitative investigative methods shed light upon the systemic practice within the gulf coast shrimp industry in the United States.     

Semi-annual oscillations in Saturn's low-latitude stratospheric temperatures

Observations of oscillations of temperature and wind in planetary atmospheres provide a means of generalizing models for atmospheric dynamics in a diverse set of planets in the Solar System and elsewhere. An equatorial oscillation similar to one in the Earth's atmosphere has been discovered in Jupiter. Here we report the existence of similar oscillations in Saturn's atmosphere, from an analysis of over two decades of spatially resolved observations of its 7.8-microm methane and 12.2-microm ethane stratospheric emissions, where we compare zonal-mean stratospheric brightness temperatures at planetographic latitudes of 3.6 degrees and 15.5 degrees in both the northern and the southern hemispheres. These results support the interpretation of vertical and meridional variability of temperatures in Saturn's stratosphere as a manifestation of a wave phenomenon similar to that on the Earth and in Jupiter. The period of this oscillation is 14.8 +/- 1.2 terrestrial years, roughly half of Saturn's year, suggesting the influence of seasonal forcing, as is the case with the Earth's semi-annual oscillation.     

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit(mid)CD3(+)Lin(-) compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3(+)Lin(-) LSCs and CD3(+) leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.     

Suan Shu Shu A Book on Numbers and Computations

In December and January of 1983–1984, archaeologists excavating the tomb of an ancient Chinese provincial bureaucrat at a Western Han Dynasty site near Zhangjiashan, in Jiangling county, Hubei Province, discovered a number of books on bamboo strips, including inter alia works on legal statutes, military practice, and medicine. Among these was a previously unknown mathematical work on some 200 bamboo strips, the Suan shu shu, or Book of Numbers and Computations. Based upon other works found in the tomb, especially a copy of the Er nian lü ling (Laws and Decrees of the Second Year (of the reign of empress Lü, i.e. Lü Hou)), archaeologists have dated the tomb to ca. 186 BCE (Lü Hou’s regency lasted from 188 to 180 BCE). The Suan shu shu, as the earliest yet discovered work devoted specifically to mathematics from ancient China, has stirred considerable interest among Chinese historians of science. The translation and commentary offered here draw extensively on the works cited in Sect. 3 below. Several appendixes devoted to specific issues related to translating the Suan shu shu, including its title and the problem of determining English equivalents for various commodities that arise in the text, may be found in Appendix II. An erratum to this article can be found at     

Cellular internalization of proinsulin C-peptide

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at 4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action. Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006     

Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer

Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.     

Recombination and linkage disequilibrium in Arabidopsis thaliana

Linkage disequilibrium (LD) is a major aspect of the organization of genetic variation in natural populations. Here we describe the genome-wide pattern of LD in a sample of 19 Arabidopsis thaliana accessions using 341,602 non-singleton SNPs. LD decays within 10 kb on average, considerably faster than previously estimated. Tag SNP selection algorithms and 'hide-the-SNP' simulations suggest that genome-wide association mapping will require only 40%-50% of the observed SNPs, a reduction similar to estimates in a sample of African Americans. An Affymetrix genotyping array containing 250,000 SNPs has been designed based on these results; we demonstrate that it should have more than adequate coverage for genome-wide association mapping. The extent of LD is highly variable, and we find clear evidence of recombination hotspots, which seem to occur preferentially in intergenic regions. LD also reflects the action of selection, and it is more extensive between nonsynonymous polymorphisms than between synonymous polymorphisms.