C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration

Structure and function of a spectrin-like regulator of bacterial cytokinesis

© 2014 Macmillan Publishers Limited. All rights reserved. Bacterial cell division is facilitated by a molecular machine - the divisome - that assembles at mid-cell in dividing cells. The formation of the cytokinetic Z-ring by the tubulin homologue FtsZ is regulated by several factors, including the divisome component EzrA. Here we describe the structure of the 60-kDa cytoplasmic domain of EzrA, which comprises five linear repeats of an unusual triple helical bundle. The EzrA structure is bent into a semicircle, providing the protein with the potential to interact at both N- and C-termini with adjacent membrane-bound divisome components. We also identify at least two binding sites for FtsZ on EzrA and map regions of EzrA that are responsible for regulating FtsZ assembly. The individual repeats, and their linear organization, are homologous to the spectrin proteins that connect actin filaments to the membrane in eukaryotes, and we thus propose that EzrA is the founding member of the bacterial spectrin family

The Gtpase Rho Controls a P53-Dependent Survival Checkpoint during Thymopoiesis

During the early stages of thymopoiesis, cell survival is controlled by cytokines that regulate the expression of antiapoptotic proteins such as Bcl-2. At the pre-T cell stage, a critical checkpoint for β chain selection is monitored by the tumor suppressor p53: pre-T cells can survive and differentiate when p53 is removed genetically or when its proapoptotic function is inactivated physiologically as a consequence of signaling through the pre-T cell receptor complex. Previous work has shown that the guanine nucleotide binding protein Rho controls cell survival in T cell progenitors. Here we define the survival pathways controlled by Rho in pre-T cells and show that this GTPase is a pivotal regulator of the p53-mediated checkpoint operating at the time of β selection: loss of Rho function results in apoptosis in pre-T cells, but this cell death is prevented by loss of p53. The prevention of cell death by loss of p53 restored numbers of early T cell progenitors but did not fully restore thymic cellularity. Further analysis revealed that loss of Rho function caused survival defects in CD4/8 double-positive thymocytes that is independent of p53 but can be prevented by ectopic expression of Bcl-2. These studies highlight that the GTPase Rho is a crucial component of survival signaling pathways in at least two different thymocyte subpopulations: Rho controls the p53 survival checkpoint in pre-T cells and is also crucial for a p53 independent survival signaling pathway in CD4/8 double positives

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)–mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB–Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity

Microscale data to macroscale processes: A review of microcharacterization applied to mineral systems

Microanalysis can provide rapid, quantitative characterization of mineral systems that complements the field- and core-scale observations traditionally made in ore deposits. We review recent innovations in microanalytical procedures and their application to studies of ore deposits. Case studies are presented examining how microanalysis can provide constraints on macroscopic processes within mineral systems. Synchrotron X-ray fluorescence shows centimetre-scale chemical variations associated with proximity to mineralization in samples from Sunrise Dam Gold Mine, Western Australia. Pseudomorphs of igneous plagioclase and chemically driven recrystallization interpreted from electron backscatter diffraction suggest that the system was dominated by fluid-driven brecciation with very little shearing. Both the fluid chemistry and fluid pressure evolved during a protracted sequence of vein formation and alteration accompanying gold mineralization. A second case study of sulphide mineralogy at the Mt Keith nickel sulphide deposit, Western Australia demonstrates how X-ray computed tomography combined with trace element mapping can constrain the chemistry and dynamics of magmatic systems. Large-scale interaction between silicate and sulphide melts, shown by homogenous palladium enrichment in pentlandite, leads to a large proportion of globular ores with a high nickel content. Increasing use of microanalysis in ore deposit geology is resulting in the constant reassessment of established models for ore genesis though a combination of micro- and macroscale datasets.This research was undertaken on the X-ray fluorescence microscopy beamline at the Australian Synchrotron, Victoria, Australia and was funded by AngloGold Ashanti. LS acknowledges support from a CSIRO Mineral Resources Flagship Internship to support this work

Successful treatment of HIV-associated multicentric Castleman's disease and multiple organ failure with rituximab and supportive care: a case report

<p>Abstract</p> <p>Introduction</p> <p>Multicentric Castleman's Disease (MCD), a lymphoproliferative disorder associated with Human Herpes Virus-8 (HHV-8) infection, is increasing in incidence amongst HIV patients. This condition is associated with lymphadenopathy, polyclonal gammopathy, hepato-splenomegaly and systemic symptoms. A number of small studies have demonstrated the efficacy of the anti-CD20 monoclonal antibody, rituximab, in treating this condition.</p> <p>Case presentation</p> <p>We report the case of a 46 year old Zambian woman who presented with pyrexia, diarrhoea and vomiting, confusion, lymphadenopathy, and renal failure. She rapidly developed multiple organ failure following the initiation of treatment of MCD with rituximab. Following admission to intensive care (ICU), she received prompt multi-organ support. After 21 days on the ICU she returned to the haematology medical ward, and was discharged in remission from her disease after 149 days in hospital.</p> <p>Conclusion</p> <p>Rituximab, the efficacy of which has thus far been examined predominantly in patients <it>outside </it>the ICU, in conjunction with extensive organ support was effective treatment for MCD with associated multiple organ failure. There is, to our knowledge, only one other published report of its successful use in an ICU setting, where it was combined with cyclophosphamide, adriamycin and prednisolone. Reports such as ours support the notion that critically unwell patients with HIV and haematological disease <it>can </it>benefit from intensive care.</p

The Maia detector array and x-ray fluorescence imaging system: Locating rare precious metal phases in complex samples

X-ray fluorescence images acquired using the Maia large solid-angle detector array and integrated real-time processor on the X-ray Fluorescence Microscopy (XFM) beamline at the Australian Synchrotron capture fine detail in complex natural samples with images beyond 100M pixels. Quantitative methods permit real-time display of deconvoluted element images and for the acquisition of large area XFM images and 3D datasets for fluorescence tomography and chemical state (XANES) imaging. This paper outlines the Maia system and analytical methods and describes the use of the large detector array, with a wide range of X-ray take-off angles, to provide sensitivity to the depth of features, which is used to provide an imaging depth contrast and to determine the depth of rare precious metal particles in complex geological samples. © 2013 SPIE