Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis

Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six miR-124 alleles in human induced pluripotent stem cells. Upon neuronal induction, miR-124-deleted cells underwent neurogenesis and became functional neurons, albeit with altered morphology and neurotransmitter specification. Using RNA-induced-silencing-complex precipitation, we identified 98 high-confidence miR-124 targets, of which some directly led to decreased viability. By performing advanced transcription-factor-network analysis, we identified indirect miR-124 effects on apoptosis, neuronal subtype differentiation, and the regulation of previously uncharacterized zinc finger transcription factors. Our data emphasize the need for combined experimental- and system-level analyses to comprehensively disentangle and reveal miRNA functions, including their involvement in the neurogenesis of diverse neuronal cell types found in the human brain

Universality in Bacterial Colonies

The emergent spatial patterns generated by growing bacterial colonies have been the focus of intense study in physics during the last twenty years. Both experimental and theoretical investigations have made possible a clear qualitative picture of the different structures that such colonies can exhibit, depending on the medium on which they are growing. However, there are relatively few quantitative descriptions of these patterns. In this paper, we use a mechanistically detailed simulation framework to measure the scaling exponents associated with the advancing fronts of bacterial colonies on hard agar substrata, aiming to discern the universality class to which the system belongs. We show that the universal behavior exhibited by the colonies can be much richer than previously reported, and we propose the possibility of up to four different sub-phases within the medium-to-high nutrient concentration regime. We hypothesize that the quenched disorder that characterizes one of these sub-phases is an emergent property of the growth and division of bacteria competing for limited space and nutrients.Comment: 12 pages, 5 figure

Approaching the Gamow Window with Stored Ions : Direct Measurement of Xe 124 (p,γ) in the ESR Storage Ring

© 2019 American Physical Society. All rights reserved.We report the first measurement of low-energy proton-capture cross sections of Xe124 in a heavy-ion storage ring. Xe12454+ ions of five different beam energies between 5.5 and 8 AMeV were stored to collide with a windowless hydrogen target. The Cs125 reaction products were directly detected. The interaction energies are located on the high energy tail of the Gamow window for hot, explosive scenarios such as supernovae and x-ray binaries. The results serve as an important test of predicted astrophysical reaction rates in this mass range. Good agreement in the prediction of the astrophysically important proton width at low energy is found, with only a 30% difference between measurement and theory. Larger deviations are found above the neutron emission threshold, where also neutron and γ widths significantly impact the cross sections. The newly established experimental method is a very powerful tool to investigate nuclear reactions on rare ion beams at low center-of-mass energies.Peer reviewedFinal Published versio

Exploring the relationship between media coverage and participation in entrepreneurship : initial global evidence and research implications

Using a set of variables measured in the Global Entrepreneurship Monitor (GEM) study, our empirical investigation explored the influence of mass media through national culture on national entrepreneurial participation rates in 37 countries over 4 years (2000 to 2003). We found that stories about successful entrepreneurs, conveyed in mass media, were not significantly associated with the rate of nascent (opportunity searching) or the rate of actual (business activities commenced up to 3 months old) start-up activity, but that there was a significant positive association between the volume of entrepreneurship media stories and a nation&rsquo;s volume of people running a young business (that is in GEM terminology, a business aged greater than 3 but less than 42 months old). More particularly, such stories had strong positive association with opportunity oriented operators of young businesses. Together, these findings are compatible with what in the mass communications theory literature may be called the &lsquo;reinforcement model&rsquo;. This argues that mass media are only capable of reinforcing their audience&rsquo;s existing values and choice propensities but are not capable of shaping or changing those values and choices. In the area covered by this paper, policy-makers are committing public resources to media campaigns of doubtful utility in the absence of an evidence base. A main implication drawn from this study is the need for further and more sophisticated investigation into the relationship between media coverage of entrepreneurship, national culture and the rates and nature of people&rsquo;s participation in the various stages of the entrepreneurial process.<br /

Determination of luminosity for in-ring reactions:A new approach for the low-energy domain

Luminosity is a measure of the colliding frequency between beam and target and it is a crucial parameter for the measurement of absolute values, such as reaction cross sections. In this paper, we make use of experimental data from the ESR storage ring to demonstrate that the luminosity can be precisely determined by modelling the measured Rutherford scattering distribution. The obtained results are in good agreement with an independent measurement based on the x-ray normalization method. Our new method provides an alternative way to precisely measure the luminosity in low-energy stored-beam configurations. This can be of great value in particular in dedicated low-energy storage rings where established methods are difficult or impossible to apply.Comment: 8 pages, 5 figure

Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility

Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE) and type θ (GABRQ) genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining a set of 3 single nucleotide polymorphisms (SNPs) in the coding region (exons 3, 5 and 9) of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05). Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility

On the Effects of Authority on Peer Motivation:Learning from Wikipedia

__Research Summary:__ We investigate the conditions under which authority can be deployed without reducing subordinate motivation. We show that lateral authority, the legitimacy to resolve task-specific problems, is welcomed by members of an organization in the resolution of coordination conflicts, the more so (a) the fiercer the conflict to be resolved, (b) the higher the competence-based status of the authority, (c) the lower the tenure of, and (d) the more focused the organizational members are. Analyzing the discussion behavior of members of Wikipedia between 2002 and 2014, we corroborate our allegations empirically by analyzing 642,916 article–discussion pages. Our findings, obtained for a modern collective production community, provide learning opportunities for how traditional organizations may want to govern activities of their idiosyncratically motivated staff. __Managerial Summary:__ When managers use their (legitimate) power to take decisions on behalf of their staff, they risk setting back employees and making them detach from the firm. This danger is particularly salient whenever highly motivated teams of staff autonomously work on corporate problems and are used to governing themselves. Examples range from skunkwork initiatives within traditional firms to entire team-based organizations, such as Valve or Zappos. When and how managers can add value by resolving conflicts within and across these teams once their self-organization fails is what we study in this article. Inspired by data from Wikipedia, we suggest that managers should not intervene prematurely, benefit from visible competence, and are respected most for their actions by specialized peers who recently joined the organization

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Challenges in microbial ecology: building predictive understanding of community function and dynamics.

The importance of microbial communities (MCs) cannot be overstated. MCs underpin the biogeochemical cycles of the earth's soil, oceans and the atmosphere, and perform ecosystem functions that impact plants, animals and humans. Yet our ability to predict and manage the function of these highly complex, dynamically changing communities is limited. Building predictive models that link MC composition to function is a key emerging challenge in microbial ecology. Here, we argue that addressing this challenge requires close coordination of experimental data collection and method development with mathematical model building. We discuss specific examples where model-experiment integration has already resulted in important insights into MC function and structure. We also highlight key research questions that still demand better integration of experiments and models. We argue that such integration is needed to achieve significant progress in our understanding of MC dynamics and function, and we make specific practical suggestions as to how this could be achieved

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer