The RNA-Binding Protein Musashi1 Affects Medulloblastoma Growth via a Network of Cancer- Related Genes and Is an Indicator of Poor Prognosis

Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target

Realising consilience: How better communication between archaeologists, historians and natural scientists can transform the study of past climate change in the Mediterranean

This paper reviews the methodological and practical issues relevant to the ways in which natural scientists, historians and archaeologists may collaborate in the study of past climatic changes in the Mediterranean basin. We begin by discussing the methodologies of these three disciplines in the context of the consilience debate, that is, attempts to unify different research methodologies that address similar problems. We demonstrate that there are a number of similarities in the fundamental methodology between history, archaeology, and the natural sciences that deal with the past (“palaeoenvironmental sciences”), due to their common interest in studying societal and environmental phenomena that no longer exist. The three research traditions, for instance, employ specific narrative structures as a means of communicating research results. We thus present and compare the narratives characteristic of each discipline; in order to engage in fruitful interdisciplinary exchange, we must first understand how each deals with the societal impacts of climatic change. In the second part of the paper, we focus our discussion on the four major practical issues that hinder communication between the three disciplines. These include terminological misunderstandings, problems relevant to project design, divergences in publication cultures, and differing views on the impact of research. Among other recommendations, we suggest that scholars from the three disciplines should aim to create a joint publication culture, which should also appeal to a wider public, both inside and outside of academia.This paper emerged as a result of a workshop at Costa Navarino and the Navarino Environmental Observatory (NEO), Greece in April 2014, which addressed Mediterranean Holocene climate and human societies. The workshop was co-sponsored by IGBP/PAGES, NEO, the MISTRALS/PaleoMex program, the Labex OT-Med, the Bolin Centre for Climate Research at Stockholm University, and the Institute of Oceanography at the Hellenic Centre for Marine Research. We also acknowledge funding from the National Science Centre, Poland, within the scheme of the Centre's postdoctoral fellowships (DEC-2012/04/S/HS3/00226 (A.I)); the Swedish Research Council (grant numbers 421-2014-1181 (E.W.) and 621-2012-4344 (K.H.)); CSIC-Ramón y Cajal post-doctoral program RYC-2013-14073 and Clare Hall College, Cambridge, Shackleton Fellowship (B.M.); the EU/FP7 Project ‘Sea for Society’ (Science and Society - 2011-1, 289066)

Arizona\u27s Vulnerable Populations

Arizona’s vulnerable populations are struggling on a daily basis but usually do so in silence, undetected by traditional radar and rankings, often unaware themselves of their high risk for being pushed or pulled into a full crisis. Ineligible for financial assistance under strict eligibility guidelines, they don’t qualify as poor because vulnerable populations are not yet in full crisis. To be clear, this report is not about the “poor,” at least not in the limited sense of the word. It is about our underemployed wage earners, our single-parent households, our deployed or returning military members, our under-educated and unskilled workforce, our debt-ridden neighbors, our uninsured friends, our family members with no savings for an emergency, much less retirement

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

Conceptual Exchanges for Understanding Free-Living and Host-Associated Microbiomes.

Whether a microbe is free-living or associated with a host from across the tree of life, its existence depends on a limited number of elements and electron donors and acceptors. Yet divergent approaches have been used by investigators from different fields. The "environment first" research tradition emphasizes thermodynamics and biogeochemical principles, including the quantification of redox environments and elemental stoichiometry to identify transformations and thus an underlying microbe. The increasingly common "microbe first" research approach benefits from culturing and/or DNA sequencing methods to first identify a microbe and encoded metabolic functions. Here, the microbe itself serves as an indicator for environmental conditions and transformations. We illustrate the application of both approaches to the study of microbiomes and emphasize how both can reveal the selection of microbial metabolisms across diverse environments, anticipate alterations to microbiomes in host health, and understand the implications of a changing climate for microbial function

Cerebral Vasculature Is the Major Target of Oxidative Protein Alterations in Bacterial Meningitis

We have previously shown that antioxidants such as a-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or alpha-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations