ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.     

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.     

Haploinsufficiency of NSD1 causes Sotos syndrome

We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.     

An unconventional myosin in Drosophila reverses the default handedness in visceral organs

The internal organs of animals often have left-right asymmetry. Although the formation of the anterior-posterior and dorsal-ventral axes in Drosophila is well understood, left-right asymmetry has not been extensively studied. Here we find that the handedness of the embryonic gut and the adult gut and testes is reversed (not randomized) in viable and fertile homozygous Myo31DF mutants. Myo31DF encodes an unconventional myosin, Drosophila MyoIA (also referred to as MyoID in mammals; refs 3, 4), and is the first actin-based motor protein to be implicated in left-right patterning. We find that Myo31DF is required in the hindgut epithelium for normal embryonic handedness. Disruption of actin filaments in the hindgut epithelium randomizes the handedness of the embryonic gut, suggesting that Myo31DF function requires the actin cytoskeleton. Consistent with this, we find that Myo31DF colocalizes with the cytoskeleton. Overexpression of Myo61F, another myosin I (ref. 4), reverses the handedness of the embryonic gut, and its knockdown also causes a left-right patterning defect. These two unconventional myosin I proteins may have antagonistic functions in left-right patterning. We suggest that the actin cytoskeleton and myosin I proteins may be crucial for generating left-right asymmetry in invertebrates.     

Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome

By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.     

Quantum interference during high-order harmonic generation from aligned molecules

High-order harmonic generation (HHG) from atoms and molecules offers potential application as a coherent ultrashort radiation source in the extreme ultraviolet and soft X-ray regions. In the three-step model of HHG, an electron tunnels out from the atom and may recombine with the parent ion (emitting a high-energy photon) after undergoing laser-driven motion in the continuum. Aligned molecules can be used to study quantum phenomena in HHG associated with molecular symmetries; in particular, simultaneous observations of both ion yields and harmonic signals under the same conditions serve to disentangle the contributions from the ionization and recombination processes. Here we report evidence for quantum interference of electron de Broglie waves in the recombination process of HHG from aligned CO2 molecules. The interference takes place within a single molecule and within one optical cycle. Characteristic modulation patterns of the harmonic signals measured as a function of the pump-probe delay are explained with simple formulae determined by the valence orbital of the molecules. We propose that simultaneous observations of both ion yields and harmonic signals can serve as a new route to probe the instantaneous structure of molecular systems.     

Ultrastructural localization of glucose 6-phosphatase activity in the cells of the epididymis of the mouse

Summary Glucose 6-phosphatase activity is localized in the endoplasmic reticulum and nuclear envelope of all cell types composing mouse epididymis. It is higher in the principal cell than in other cell types in the terminal and caudal half of the middle segment.     

Biological effects of radioactive <Superscript>9</Superscript>C-ion beams on cells

~~Biological effects of radioactive ~9C-ion beams on cells@A.Kitagawa$National Institute of Radiological Sciences,Chiba 263-8555, Japan @T, Kanai$National Institute of Radiological Sciences,Chiba 263-8555, Japan @M. Kanazawa$National Institute of Radiological Sciences,Chiba 263-8555, Japan @Y .Furusawa$National Institute of Radiological Sciences,Chiba 263-8555, Japan @E. Urakabe$National Institute of Radiological Sciences,Chiba 263-8555, Japan1.Castro,J.R.,Results …