No evidence for parental imprinting of mouse 22q11 gene orthologues

Non-mendelian factors may influence CNS phenotypes in patients with 22q11 deletion syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome), and similar mechanisms may operate in mice carrying a deletion of one or more 22q11 gene orthologues. Accordingly, we examined the influence of parent of origin on expression of 25 murine 22q11 orthologues in the developing and mature CNS using SNP-based analysis in interspecific crosses, as well as quantification of mRNA in a murine model of 22q11DS. We found no evidence for absolute genomic imprinting or silencing. All 25 genes are biallelically expressed in the developing and adult brain. Furthermore, if more subtle forms of allelic biasing are present, they are very small in magnitude, and most likely beyond the resolution of currently available quantitative approaches. Given the high degree of similarity of human 22q11 and the orthologous region of mmChr16, genomic imprinting most likely cannot explain apparent parent-of-origin effects in 22q11DS

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Rational Design of Topographical Helix Mimics as Potent Inhibitors of Protein–Protein Interactions

Protein–protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed “hotspot residues”, have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein–protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein–protein interactions

The N-glycome regulates the endothelial-to-hematopoietic transition

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate

Pediatric cardiovascular interventional devices: effect on CMR images at 1.5 and 3 Tesla

BACKGROUND: To predict the type and extent of CMR artifacts caused by commonly used pediatric trans-catheter devices at 1.5 T and 3 T as an aid to clinical planning and patient screening. METHODS: Eleven commonly used interventional, catheter-based devices including stents, septal occluders, vascular plugs and embolization coils made from either stainless steel or nitinol were evaluated ex-vivo at both 1.5T and 3T. Pulse sequences and protocols commonly used for cardiovascular magnetic resonance (CMR) were evaluated, including 3D high-resolution MR angiography (MRA), time-resolved MRA, 2D balanced-SSFP cine and 2D phase-contrast gradient echo imaging (GRE). We defined the signal void amplification factor (F) as the ratio of signal void dimension to true device dimension. F1 and F2 were measured in the long axis and short axes respectively of the device. We defined F3 as the maximum extent of the off-resonance dark band artifact on SSFP measured in the B(0)direction. The effects of field strength, sequence type, orientation, flip angle and phase encode direction were tested. Clinical CMR images in 3 patients with various indwelling devices were reviewed for correlation with the in-vitro findings. RESULTS: F1 and F2 were higher (p<0.05) at 3T than at 1.5T for all sequences except 3D-MRA. Stainless steel devices produced greater off-resonance artifact on SSFP compared to nitinol devices (p<0.05). Artifacts were most severe with the stainless steel Flipper detachable embolization coil (Cook Medical, Bloomington, IN), with F1 and F2 10 times greater than with stainless steel stents. The orientation of stents changed the size of off-resonance artifacts by up to two fold. Sequence type did influence the size of signal void or off-resonance artifact (p<0.05). Varying the flip angle and phase encode direction did not affect image artifact. CONCLUSION: Stainless steel embolization coils render large zones of anatomy uninterpretable, consistent with predictions based on ex-vivo testing. Most other commonly used devices produce only mild artifact ex-vivo and are compatible with diagnostic quality in-vivo studies. Knowledge of ex-vivo device behavior can help predict the technical success or failure of CMR scans and may preempt the performance of costly, futile studies