Quantitative T1 mapping of the normal brain from early infancy to adulthood

Abstract Background Quantitative mapping of MRI relaxation times is expected to uncover pathological processes in the brain more subtly than standard MRI techniques with weighted contrasts. So far, however, most mapping techniques suffer from a long measuring time, low spatial resolution or even sensitivity to magnetic field inhomogeneity. Objective To obtain T1 relaxation times of the normal brain from early infancy to adulthood using a novel technique for fast and accurate T1 mapping at high spatial resolution. Materials and methods We performed whole-brain T1 mapping within less than 3 min in 100 patients between 2 months and 18 years of age with normal brain at a field strength of 3 T. We analyzed T1 relaxation times in several gray-matter nuclei and white matter. Subsequently, we derived regression equations for mean value and confidence interval. Results T1 relaxation times of the pediatric brain rapidly decrease in all regions within the first 3 years of age, followed by a significantly weaker decrease until adulthood. These characteristics are more pronounced in white matter than in deep gray matter. Conclusion Regardless of age, quantitative T1 mapping of the pediatric brain is feasible in clinical practice. Normal age- dependent values should contribute to improved discrimination of subtle intracerebral alterations

Brain deposition of gadobutrol in children—a cross-sectional and longitudinal MRI T1 mapping study

Objectives:Depositions of linear gadolinium-based MRI contrast agents are readily visible in T1-weighted MRIs of certain brain regions in both adults and children. Macrocyclic contrast agents such as gadobutrol have so far escaped detection by qualitative MRI in children. This study aimed to assess whether there is evidence for deposition of gadobutrol in children using quantitative T1 mapping.Methods:This retrospective study included patients, naive to other gadolinium-based contrast agents than gadobutrol, who had received gadobutrol as part of a clinically indicated MRI. For each patient, T1 relaxation times at 3 T were measured using single-shot T1 mapping at two time points. In each of six brain regions, age-adjusted T1 relaxation times were correlated with a number of previous gadobutrol administrations. To combine interindividual, cross-sectional effects with intraindividual, longitudinal effects, both linear mixed model and generalized additive mixed model were applied.Results:One hundred four examinations of 52 children (age median 11.4, IQR 6.3–15, 26 female) with a median of 7 doses of gadobutrol in the history of their neurological or neurooncological disease were included. After correction for age and indeterminate disease-related effects to T1 time, a negative correlation of T1 time with the number of gadobutrol doses administered was observed in both mixed models in the putamen (beta − 1.65, p = .03) and globus pallidus (beta − 1.98, p = .012)Conclusions:The results indicate that in children, gadobutrol is deposited in the globus pallidus and putamen

Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression.

Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA Pol(II) is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts

The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells

A panel of mutant embryonic stem (ES) cell lines lacking important chromatin modifiers was used to dissect the relationship between chromatin structure and replication timing, revealing the importance of several chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells

REST selectively represses a subset of RE1-containing neuronal genes in mouse embryonic stem cells.

REST is a transcriptional repressor that targets a group of neuronal genes in non-neuronal cells. In embryonic stem (ES) cells, REST has been implicated in controlling the expression of transcription factor genes that are crucial for lineage determination and for maintaining ES cell potential. Here, we asked whether REST directly regulates neural-specifying genes in mouse ES cells using siRNA-mediated REST knockdown and ES cells that lack functional REST protein as a result of gene targeting. Loss of REST did not affect the expression of any of ten transcription factor genes known to promote neural commitment and did not affect the expression of several microRNAs, including miR-21, a putative REST target in ES cells. REST-deficient ES cells retained the ability to self-renew and to undergo appropriate differentiation towards mesoderm, endoderm and ectoderm lineages upon LIF withdrawal. Genome-wide expression profiling showed that genes that were deregulated in the absence of REST were preferentially expressed in the brain and highly enriched for the presence of canonical REST binding sites (RE1). Chromatin immunoprecipitation studies confirmed these genes as direct targets of REST in ES cells. Collectively, these data show that REST selectively silences a cohort of neuronal genes in ES cells

Principles of meiotic chromosome assembly revealed in S. cerevisiae

During meiotic prophase, chromosomes organise into a series of chromatin loops emanating from a proteinaceous axis, but the mechanisms of assembly remain unclear. Here we use Saccharomyces cerevisiae to explore how this elaborate three-dimensional chromosome organisation is linked to genomic sequence. As cells enter meiosis, we observe that strong cohesin-dependent grid-like Hi-C interaction patterns emerge, reminiscent of mammalian interphase organisation, but with distinct regulation. Meiotic patterns agree with simulations of loop extrusion with growth limited by barriers, in which a heterogeneous population of expanding loops develop along the chromosome. Importantly, CTCF, the factor that imposes similar features in mammalian interphase, is absent in S. cerevisiae, suggesting alternative mechanisms of barrier formation. While grid-like interactions emerge independently of meiotic chromosome synapsis, synapsis itself generates additional compaction that matures differentially according to telomere proximity and chromosome size. Collectively, our results elucidate fundamental principles of chromosome assembly and demonstrate the essential role of cohesin within this evolutionarily conserved process

Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia

Mesenchymal cell populations contribute to microenvironments regulating stem cells and the growth of malignant cells. Osteolineage cells participate in the hematopoietic stem cell niche. Here, we report that deletion of the miRNA processing endonuclease Dicer1 selectively in mesenchymal osteoprogenitors induces markedly disordered hematopoiesis. Hematopoietic changes affected multiple lineages recapitulating key features of human myelodysplastic syndrome (MDS) including the development of acute myelogenous leukemia. These changes were microenvironment dependent and induced by specific cells in the osteolineage. Dicer1−/− osteoprogenitors expressed reduced levels of Sbds, the gene mutated in the human bone marrow failure and leukemia predisposition Shwachman-Bodian-Diamond Syndrome. Deletion of Sbds in osteoprogenitors largely phenocopied Dicer1 deletion. These data demonstrate that differentiation stage-specific perturbations in osteolineage cells can induce complex hematological disorders and indicate the central role individual cellular elements of ‘estroma’ can play in tissue homeostasis. They reveal that primary changes in the hematopoietic microenvironment can initiate secondary neoplastic disease

The PI3K p110δ regulates expression of CD38 on regulatory T cells.

The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop