Stuffed Rare Earth Pyrochlore Solid Solutions

Synthesis and crystal structures are described for the compounds Ln2(Ti2-xLnx)O7-x/2, where Ln = Tb, Dy, Ho, Er, Tm, Yb, Lu, and x ranges from 0 to 0.67. Rietveld refinements on X-ray powder diffraction data indicate that in Tb and Dy titanate pyrochlores, extra Ln3+ cations mix mainly on the Ti4+ site with little disorder on the original Ln3+ site. For the smaller rare earths (Ho-Lu), stuffing additional lanthanide ions results in a pyrochlore to defect fluorite transition, where the Ln3+ and Ti4+ ions become completely randomized at the maximum (x=0.67). In all of these Ln-Ti-O pyrochlores, the addition of magnetic Ln3+ in place of nonmagnetic Ti4+ adds edge sharing tetrahedral spin interactions to a normally corner sharing tetrahedral network of spins. The increase in spin connectivity in this family of solid solutions represents a new avenue for investigating geometrical magnetic frustration in the rare earth titanate pyrochlores.Comment: 25 pages, 7 figures, submitted to J. Solid State Che

Cloning and characterization of a novel gene, striamin, that interacts with the tumor suppressor protein p53

Expression analysis of a novel cDNA isolated from immortal murine fibroblasts revealed a single transcript of 3.0 kilobase pairs that was highly expressed in mouse and human striated muscle and in mouse heart. The gene has therefore been named striamin. Its expression was confined to skeletal muscle types with a fast glycolytic (2B) contractile phenotype. It was also detected in C2C12 mouse myoblasts and was down-regulated during in vitro myogenesis. The cDNA has a single open reading frame encoding a predicted 16.8-kDa protein of 149 amino acids with no homology to known proteins. Microinjection and transfection of green fluorescence protein-tagged striamin demonstrated that it localizes to the nucleus. Coimmunoprecipitations revealed that it can interact with p53 (a positive marker for myoblast differentiation) in vivo and in vitro. Furthermore, it repressed p53 activity in p53-mediated reporter assays. Fluorescence in situ hybridization with a mouse P1 genomic clone localized the gene to chromosome 12C3, which is syntenic to human chromosome 14q21-22

Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours

A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay

The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control

Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex

The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; and causes varying phenotypic severity of osteogenesis imperfecta type V

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5’ untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5’ UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family

Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p < 0.01). Among patients undergoing HCT who develop respiratory failure and require advanced therapeutic support, neutrophil recovery at time of IMV and/or presence of a respiratory pathogen should not be used as determining factors when counseling families about survival