Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders

BACKGROUND:Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. METHODS:Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. RESULTS:Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. CONCLUSIONS:These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.Siddharth Srivastava, Tejasvi Niranjan, Melanie M. May, Patrick Tarpey, William Allen ... Jozef Gecz ... et al

Threshold effect of foreign direct investment on environmental degradation

The aim of this paper is to investigate the threshold effect of foreign direct investment (FDI) on environmental degradation. In empirical analysis, FDI and environmental degradation are jointly determined under the given threshold variable and other exogenous variables. Using carbon dioxide (CO2) emissions per capita as a proxy for environmental degradation, the results show that increasing FDI worsens CO2 emissions after a threshold level of corruption has been reached. Our results demonstrate that increasing FDI will increase CO2 emissions when the degree of corruptibility is relatively high. The study suggests that further FDI and improved environmental quality are competing rather than compatible objectives in high-corruption countries and are compatible rather than competing objectives in low-corruption countries. Higher trade liberalization in low-corruption countries could contribute to negative environmental consequences because of the increased output or economic activity which results from increased trade. The robustness estimation confirms the evidence that pollution and economic development increase together up to a certain income level, after which the trend reverses.info:eu-repo/semantics/publishedVersio

How to avoid the problems of target-setting

Purpose: Advocates and critics of target-setting in the workplace seem unable to reach beyond their own well-entrenched battle lines. While the advocates of goal-directed behaviour point to what they see as demonstrable advantages, the critics of target-setting highlight equally demonstrable disadvantages. Indeed, the academic literature on this topic is currently mired in controversy, with neither side seemingly capable of envisaging a better way forward. This paper seeks to break the current deadlock and move thinking forward in this important aspect of performance measurement and management by outlining a new, more fruitful approach, based on both theory and practical experience. Design/methodology/approach: The topic was approached in three phases: assembling and reading key academic and other literature on the subject of target-setting and goal-directed behaviour, with a view to understanding, in depth, the arguments advanced by the advocates and critics of target-setting; comparing these published arguments with one's own experiential findings, in order to bring the essence of disagreement into much sharper focus; and then bringing to bear the academic and practical experience to identify the essential elements of a new, more fruitful approach offering all the benefits of goal-directed behaviour with none of the typical disadvantages of target-setting. Findings: The research led to three key findings: the advocates of goal-directed behaviour and critics of target-setting each make valid points, as seen from their own current perspectives; the likelihood of these two communities, left to themselves, ever reaching a new synthesis, seems vanishingly small (with leading thinkers in the goal-directed behaviour community already acknowledging this); and, between the three authors, it was discovered that their unusual combination of academic study and practical experience enabled them to see things differently. Hence, they would like to share their new thinking more widely. Research limitations/implications: The authors fully accept that their paper is informed by extensive practical experience and, as yet, there have been no opportunities to test their findings, conclusions and recommendations through rigorous academic research. However, they hope that the paper will move thinking forward in this arena, thereby informing future academic research. Practical implications: The authors hope that the practical implications of the paper will be significant, as it outlines a novel way for organisations to capture the benefits of goal-directed behaviour with none of the disadvantages typically associated with target-setting. Social implications: Given that increased efficiency and effectiveness in the management of organisations would be good for society, the authors think the paper has interesting social implications. Originality/value: Leading thinkers in the field of goal-directed behaviour, such as Locke and Latham, and leading critics of target-setting, such as Ordóñez et al. continue to argue with one another - much like, at the turn of the nineteenth century, proponents of the "wave theory of light" and proponents of the "particle theory of light" were similarly at loggerheads. Just as this furious scientific debate was ultimately resolved by Taylor's experiment, showing that light could behave both as a particle and wave at the same time, the authors believe that the paper demonstrates that goal-directed behaviour and target-setting can successfully co-exist. © Emerald Group Publishing Limited

Are your goals hitting the right target?

Setting targets is normal in most organisations. Alan Meekings, Steve Briault and Andy Neely think such a practice can cause more harm than good. They offer a better way. © 2010 London Business School

Comment j’explore une bronchopneumopathie chronique obstructive ?

International audienceLa bronchopneumopathie chronique obstructive (BPCO) est une maladie fréquente que l’on peut prévenir et traiter, qui est caractérisée par des symptômes respiratoires persistants et un trouble ventilatoire obstructif dû à des lésions des voies aériennes (bronchite chronique et/ou du tissu alvéolaire (emphysème), en général en relation avec une exposition significative à des particules ou à des gaz toxiques, selon la définition mise à jour par les recommandations internationales [...