The lifespan and function of murine intraepithelial lymphocytes

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3-D Reconstruction of Macroscopic Optical Brain Slice Images

We present a method for reconstruction of macroscopic optical images of post-mortem brain slices to form a 3-D volume. This forms a key part of a series of procedures to allow post mortem findings to be accurately registered with MR images, and more generally provides a method for 3-D mapping of the distribution of pathological changes throughout the brain. In this preliminary work, four brains from a study of Creutzfeldt-Jakob disease were examined. After brain fixation, the pathologist cut coronal slices several mm thick through the brain. The anterior and posterior faces of each slice were photographed. We show that the 2-D co-registration of each such pair of images was most effectively obtained if the slice was placed in a jig before photographing. Fiducials on the jig were detected automatically and point-based rigid registration computed. For co-registration between slices, i.e., across a single cut, an intensity-based method for 2-D non-rigid registration is used which provided satisfactory results. By propagating the 2-D registrations through the volume and using the known slice thickness, the 3-D volume was reconstructed

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS