PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.This work was supported by the Center Prevention and Research Institute of Texas (CPRIT) (RP160451 and R120501) and the NIH (DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, and P30 CA016672). The Welch Foundation (G-0040), MD Anderson’s MoonShot Program, the Baylor Research Advocates for Student Scientists, and the BCM MSTP program also provided support. K.T. is supported by a Khalifa Physician Scientist Award, the Physician Scientist Program at MD Anderson, and a Leukemia SPORE Career Enhancement Award. G.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015), the Kay Kendall Leukaemia Fund, Bloodwise, and core funding from the Sanger Institute (WT098051). We also thank the Samuel Waxman Cancer Research Foundation

Glutathione and Adaptive Immune Responses against Mycobacterium tuberculosis Infection in Healthy and HIV Infected Individuals

Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in diverse cellular functions. Individuals who are infected with Human immuno deficiency virus (HIV) are known to be susceptible to Mycobacterium tuberculosis (M. tb) infection. We report that by enhancing GSH levels, T-cells are able to inhibit the growth of M. tb inside macrophages. In addition, those GSH-replenished T cell cultures produced increased levels of Interleukin-2 (IL-2), Interleukin-12 (IL-12), and Interferon-gamma (IFN-γ), cytokines, which are known to be crucial for the control of intracellular pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and enhanced growth of M. tb inside human macrophages

Discovery of Sclerotinia sclerotiorum Hypovirulence-Associated Virus-1 in Urban River Sediments of Heathcote and Styx Rivers in Christchurch City, New Zealand

In samples of benthic and bank river sediments of two urban rivers in Christchurch city (New Zealand), we identified and recovered isolates of Sclerotinia sclerotiorum hypovirulence-associated virus-1 (SsHADV-1), a fungus-infecting circular single-stranded DNA virus. This is the first report of SsHADV-1 outside of China and in environmental samples

The global distribution of Banana bunchy top virus reveals little evidence for frequent recent, human-mediated long distance dispersal events

Banana bunchy top virus (BBTV; family Nanoviridae, genus Babuvirus) is a multi-component single-stranded DNA virus, which infects banana plants in many regions of the world, often resulting in large-scale crop losses. We analyzed 171 banana leaf samples from fourteen countries and recovered, cloned, and sequenced 855 complete BBTV components including ninety-four full genomes. Importantly, full genomes were determined from eight countries, where previously no full genomes were available (Samoa, Burundi, Republic of Congo, Democratic Republic of Congo, Egypt, Indonesia, the Philippines, and the USA [HI]). Accounting for recombination and genome component reassortment, we examined the geographic structuring of global BBTV populations to reveal that BBTV likely originated in Southeast Asia, that the current global hotspots of BBTV diversity are Southeast Asia/Far East and India, and that BBTV populations circulating elsewhere in the world have all potentially originated from infrequent introductions. Most importantly, we find that rather than the current global BBTV distribution being due to increases in human-mediated movements of bananas over the past few decades, it is more consistent with a pattern of infrequent introductions of the virus to different parts of the world over the past 1,000 years

Molecular characterisation of dicot-infecting mastreviruses from Australia

Monocotyledonous and dicotyledonous plant infecting mastreviruses threaten various agricultural systems throughout Africa, Eurasia and Australasia. In Australia three distinct mastrevirus species are known to infect dicotyledonous hosts such as chickpea, bean and tobacco. Amongst 34 new "dicot-infecting" mastrevirus full genome sequences obtained from these hosts we discovered one new species, four new strains, and various variants of previously described mastrevirus species. Besides providing additional support for the hypothesis that evolutionary processes operating during dicot-infecting mastrevirus evolution (such as patterns of pervasive homologous and non-homologous recombination, and strong purifying selection acting on all genes) have mostly mirrored those found in their monocot-infecting counterparts, we find that the Australian dicot-infecting viruses display patterns of phylogeographic clustering reminiscent of those displayed by monocot infecting mastrevirus species such as Panicum streak virus and Maize streak virus. (C) 2012 Elsevier B.V. All rights reserved

Non-invasive surveys of mammalian viruses using environmental DNA

(1) Environmental DNA (eDNA) and invertebrate-derived DNA (iDNA) have been used to survey biodiversity non-invasively to mitigate difficulties of obtaining wildlife samples, particularly in remote areas or for rare species. Recently, eDNA/iDNA have been applied to monitor known wildlife pathogens, however, most wildlife pathogens are unknown and often evolutionarily divergent. (2) To detect and identify known and novel mammalian viruses from eDNA/iDNA sources, we used a curated set of RNA oligonucleotides as viral baits in a hybridization capture system coupled with high throughput sequencing. (3) We detected multiple known and novel mammalian RNA and DNA viruses from multiple viral families from both waterhole eDNA and leech derived iDNA. Congruence was found between detected hosts and viruses identified in leeches and waterholes. (4) Our results demonstrate that eDNA/iDNA samples represent an effective non-invasive resource for studying wildlife viral diversity and for detecting novel potentially zoonotic viruses prior to their emergence