Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells

Frontotemporal dementia (FTD) describes a group of clinically heterogeneous conditions that frequently affect people under the age of 65 (1). There are multiple genetic causes of FTD, including coding or splice-site mutations in MAPT, GRN mutations that lead to haploinsufficiency of progranulin protein, and a hexanucleotide GGGGCC repeat expansion in C9ORF72. Pathologically, FTD is characterised by abnormal protein accumulations in neurons and glia. These aggregates can be composed of the microtubule-associated protein tau (observed in FTD with MAPT mutations), the DNA/RNA-binding protein TDP-43 (seen in FTD with mutations in GRN or C9ORF72 repeat expansions) or dipeptide proteins generated by repeat associated non-ATG translation of the C9ORF72 repeat expansion. There are currently no disease-modifying therapies for FTD and the availability of in vitro models that recapitulate pathologies in a disease-relevant cell type would accelerate the development of novel therapeutics. It is now possible to generate patient-specific stem cells through the reprogramming of somatic cells from a patient with a genotype/phenotype of interest into induced pluripotent stem cells (iPSCs). iPSCs can subsequently be differentiated into a plethora of cell types including neurons, astrocytes and microglia. Using this approach has allowed researchers to generate in vitro models of genetic FTD in human cell types that are largely inaccessible during life. In this review we explore the recent progress in the use of iPSCs to model FTD, and consider the merits, limitations and future prospects of this approach

Limb Size Discrepancy in a 29 yo Male

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A massive, distant proto-cluster at z=2.47 caught in a phase of rapid formation?

Numerical simulations of cosmological structure formation show that the Universe's most massive clusters, and the galaxies living in those clusters, assemble rapidly at early times (2.5 < z < 4). While more than twenty proto-clusters have been observed at z > 2 based on associations of 5-40 galaxies around rare sources, the observational evidence for rapid cluster formation is weak. Here we report observations of an asymmetric, filamentary structure at z = 2.47 containing seven starbursting, submillimeter-luminous galaxies and five additional AGN within a comoving volume of 15000 Mpc$^{3}$. As the expected lifetime of both the luminous AGN and starburst phase of a galaxy is ~100 Myr, we conclude that these sources were likely triggered in rapid succession by environmental factors, or, alternatively, the duration of these cosmologically rare phenomena is much longer than prior direct measurements suggest. The stellar mass already built up in the structure is $\sim10^{12}M_{\odot}$ and we estimate that the cluster mass will exceed that of the Coma supercluster at $z \sim 0$. The filamentary structure is in line with hierarchical growth simulations which predict that the peak of cluster activity occurs rapidly at z > 2.Comment: 7 pages, 3 figures, 2 tables, accepted in ApJL (small revisions from previous version

Dynamics of silver elution from functionalised antimicrobial nanofiltration membranes

In an effort to mitigate biofouling on thin film composite membranes such as nanofiltration and reverse osmosis, a myriad of different surface modification strategies has been published. The use of silver nanoparticles (Ag-NPs) has emerged as being particularly promising. Nevertheless, the stability of these surface modifications is still poorly understood, particularly under permeate flux conditions. Leaching or elution of Ag-NPs from the membrane surface can not only affect the antimicrobial characteristics of the membrane, but could also potentially present an environmental liability when applied in industrial-scale systems. This study sought to investigate the dynamics of silver elution and the bactericidal effect of an Ag-NP functionalised NF270 membrane. Inductively coupled plasma-atomic emission spectroscopy was used to show that the bulk of leached silver occurred at the start of experimental runs, and was found to be independent of salt or permeate conditions used. Cumulative amounts of leached silver did, however, stabilise following the initial release, and were shown to have maintained the biocidal characteristics of the modified membrane, as observed by a higher fraction of structurally damaged Pseudomonas fluorescens cells. These results highlight the need to comprehensively assess the time-dependent nature of bactericidal membranes

Electrical characterization of the soft breakdown failure mode in MgO layers

The soft breakdown (SBD) failure mode in 20 nm thick MgO dielectric layers grown on Si substrates was investigated. We show that during a constant voltage stress, charge trapping and progressive breakdown coexist, and that the degradation dynamics is captured by a power-law time dependence. We also show that the SBD current-voltage (I-V) characteristics follow the power-law model I = aVb typical of this conduction mechanism but in a wider voltage window than the one reported in the past for SiO2. The relationship between the magnitude of the current and the normalized differential conductance was analyzed

Novel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Ayme-Gripp syndrome)

Published online: 08 May 2017Background: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son. Method: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother. Result: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases. Conclusion: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.Shari Javadiyan, Jamie E. Craig, Shiwani Sharma, Karen M. Lower, Theresa Casey, Eric Haan, Emmanuelle Souzeau and Kathryn P. Burdo