Knowledge and development : a cross-section approach

This paper assesses the effects of knowledge on economic growth. By using an array of indicators, each of which represents an aspect of knowledge, as independent variables in cross-section regressions that span 92 countries for the period 1960 to 2000, they show that knowledge is a significant determinant of long-term economic growth. In particular, the authors find that the stock of human capital, the level of domestic innovation and technological adaptation, and the level of information and communications technologies (ICT) infrastructure all exert statistically significant positive effects on long-term economic growth. More specifically with regard to the growth effects of the human capital stock, they find that an increase of 20 percent in the average years of schooling of a population tends to increase the average annual economic growth by 0.15 percentage point. In terms of innovation, the authors find that a 20 percent increase in the annual number of USPTO patents granted is associated with an increase of 3.8 percentage points in annual economic growth. Lastly, when the ICT infrastructure, measured by the number of telephones per 1,000 persons, is increased by 20 percent, they find that annual economic growth tends to increase by 0.11 percentage point.Environmental Economics&Policies,Labor Policies,Public Health Promotion,Economic Theory&Research,Health Monitoring&Evaluation,Environmental Economics&Policies,Economic Growth,Health Monitoring&Evaluation,Achieving Shared Growth,Economic Theory&Research

IKK/NF-κB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

Nuclear factor κB (NF-κB) is involved in multiple skeletal muscle disorders, but how it functions in differentiation remains elusive given that both anti- and promyogenic activities have been described. In this study, we resolve this by showing that myogenesis is controlled by opposing NF-κB signaling pathways. We find that myogenesis is enhanced in MyoD-expressing fibroblasts deficient in classical pathway components RelA/p65, inhibitor of κB kinase β (IKKβ), or IKKγ. Similar increases occur in myoblasts lacking RelA/p65 or IKKβ, and muscles from RelA/p65 or IKKβ mutant mice also contain higher fiber numbers. Moreover, we show that during differentiation, classical NF-κB signaling decreases, whereas the induction of alternative members IKKα, RelB, and p52 occurs late in myogenesis. Myotube formation does not require alternative signaling, but it is important for myotube maintenance in response to metabolic stress. Furthermore, overexpression or knockdown of IKKα regulates mitochondrial content and function, suggesting that alternative signaling stimulates mitochondrial biogenesis. Together, these data reveal a unique IKK/NF-κB signaling switch that functions to both inhibit differentiation and promote myotube homeostasis

FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence

Adipose tissue pathways involved in weight loss of cancer cachexia

White adipose tissue (WAT) constitutes our most expandable tissue and largest endocrine organ secreting hundreds of polypeptides collectively termed adipokines. Changes in WAT mass induce alterations in adipocyte secretion and function, which are linked to disturbed whole-body metabolism. Although the mechanisms controlling this are not clear they are dependent on changes in gene expression, a complex process which is regulated at several levels. Results in recent years have highlighted the role of small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene expression via post-transcriptional mechanisms. The aim of this thesis was to characterize global gene expression levels and describe novel miRNAs and adipokines controlling the function of human WAT in conditions with pathological increases or decreases in WAT mass. Obesity and cancer cachexia were selected as two models since they are both clinically relevant and characterized by involuntary changes in WAT mass. In Study I, expressional analyses were performed in subcutaneous WAT from cancer patients with or without cachexia and obese versus non-obese subjects. In total, 425 transcripts were found to be regulated in cancer cachexia. Pathway analyses based on this set of genes revealed that processes involving extracellular matrix, actin cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid metabolism was upregulated comparing cachectic with weight-stable cancer subjects. Furthermore, by overlapping these results with microarray data from an obesity study, many transcripts were found to be reciprocally regulated comparing the two conditions. This suggests that WAT gene expression in cancer cachexia and obesity are regulated by similar, albeit opposing, mechanisms. In Study II, the focus was on the family of fibroblast growth factors (FGFs), members of which have recently been implicated in the development of obesity and insulin resistance. A retrospective analysis of global gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in WAT. However, only one, FGF1, was actively secreted from WAT and predominantly so from the adipocyte fraction. Moreover, FGF1 release was increased in obese compared to non-obese subjects, but was not normalized by weight loss. Although the clinical significance of these findings is not yet clear, it can be hypothesized that FGF1 may play a role in WAT growth, possibly by promoting fat cell proliferation and/or differentiation. In Study III, we identified adipose miRNAs regulated in obesity. Out of eleven miRNAs regulated by changes in body fat mass, ten controlled the production of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2) when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits were defined. In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was identified by combining transcriptome and secretome data. Detailed studies focusing on SEMA3C revealed that this factor was secreted from adipocytes and induced the expression of extracellular matrix and matricellular genes in preadipocytes. Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin resistance in WAT derived from subjects with a wide range in BMI. In summary, the results presented in this thesis have delineated transcriptional alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia. This has allowed the identification of novel adipokines and microRNAs with potential pathophysiological importance. These findings form the basis for further studies aiming at understanding the central role of WAT in disorders associated with metabolic complications

MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition

Abstract Background: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored. Methods: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue. Findings: We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways. Interpretation: These data identify a role for miR-196a in regulating human body fat distribution.: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1

Cardiovascular roles of estrogen receptors: insights gained from knockout models

The effects of estrogen are mediated through two functionally distinct receptors, estrogen receptor α (ER- α ), and estrogen receptor β (ER- β ), both of which are expressed in the cardiovascular system. The etiology of cardiovascular disease is believed to result in part from the loss of endogenous estrogen, indicating that estrogen and its receptors may play important roles in the prevention of cardiovascular disease in women