MYH9-related disease: Five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations

MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.Fil: de Rocco, Daniela. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; ItaliaFil: Zieger, Barbara. University of Freiburg; AlemaniaFil: Platokouki, Helen. “Aghia Sophia” Children; GreciaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pastore, Annalisa. National Institute for Medical Research; Reino UnidoFil: Bottega, Roberta. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; ItaliaFil: Noris, Patrizia. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; ItaliaFil: Barozzi, Serena. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; ItaliaFil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Pergantou, Helen. “Aghia Sophia” Children; GreciaFil: Balduini, Carlo L.. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; ItaliaFil: Savoia, Anna. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. Universita Degli Studi Di Trieste; ItaliaFil: Pecci, Alessandro. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; Itali

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Catalytic Hydrogenation of meso-Octamethylporphyrinogen (Calix[4]pyrrole)

Hydrogenation of meso-octamethylporphyrinogen (calix[4]pyrrole) with a number of heterogeneous catalysts under different experimental conditions has been investigated. GC-MS analyses of the reaction mixtures showed the formation of one to four products in low to moderate yields: three of them were diastereoisomers of the product derived from half-hydrogenation of the substrate, and displayed alternating pyrrolidine and pyrrole rings, while the fourth was the all-cis saturated product. An acidic medium was necessary to achieve hydrogenation. However, the use of too strongly acidic solvents or additives was detrimental to the stability of the substrate and/or the catalyst

Pyrrole Macrocyclic Ligands for Cu-Catalyzed Asymmetric Henry Reactions

none4siNew chiral perazamacrocycles containing four pyrrole rings have been synthesized by the [2+2] condensation of (R,R)-diaminocyclohexane and 5,5'-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes). These macrocycles, differing for the alkyl/aryl meso-substituents, were used as ligands in the copper-catalyzed Henry reactions of aromatic and aliphatic aldehydes with nitroalkanes. In the optimized experimental conditions, the reactions of nitromethane with catalytic amounts of copper diacetate and the methyl-substituted macrocyclic ligand (1:2 ratio) in ethanol at room temperature, high enantiomeric excesses (up to 95% e.e.) were achieved. The positive influence of the pyrrole-containing macrocyclic structure on the efficiency/enantioselectivity of the catalytic system was demonstrated by comparison with the Henry reactions performed using analogous macrocyclic ligands (trianglamines) derived from (R,R)-diaminocyclohexane and aromatic aldehydes and open-chain ligands derived from (R,R)-diaminocyclohexane or 2-pyrrolecarbaldehyde.mixedA.Gualandi; L. Cerisoli; H. Stoeckli-Evans; D. SavoiaA.Gualandi; L. Cerisoli; H. Stoeckli-Evans; D. Savoi