A classifying procedure for signalling turning points

A Hidden Markov Model (HMM) is used to classify an out‐of‐sample observation vector into either of two regimes. This leads to a procedure for making probability forecasts for changes of regimes in a time series, i.e. for turning points. Instead of estimating past turning points using maximum likelihood, the model is estimated with respect to known past regimes. This makes it possible to perform feature extraction and estimation for different forecasting horizons. The inference aspect is emphasized by including a penalty for a wrong decision in the cost function. The method, here called a ‘Markov Bayesian Classifier (MBC)’, is tested by forecasting turning points in the Swedish and US economies, using leading data. Clear and early turning point signals are obtained, contrasting favourably with earlier HMM studies. Some theoretical arguments for this are given. Copyright © 2004 John Wiley & Sons, Ltd.     

Linking climate change to lemming cycles

The population cycles of rodents at northern latitudes have puzzled people for centuries, and their impact is manifest throughout the alpine ecosystem. Climate change is known to be able to drive animal population dynamics between stable and cyclic phases, and has been suggested to cause the recent changes in cyclic dynamics of rodents and their predators. But although predator-rodent interactions are commonly argued to be the cause of the Fennoscandian rodent cycles, the role of the environment in the modulation of such dynamics is often poorly understood in natural systems. Hence, quantitative links between climate-driven processes and rodent dynamics have so far been lacking. Here we show that winter weather and snow conditions, together with density dependence in the net population growth rate, account for the observed population dynamics of the rodent community dominated by lemmings (Lemmus lemmus) in an alpine Norwegian core habitat between 1970 and 1997, and predict the observed absence of rodent peak years after 1994. These local rodent dynamics are coherent with alpine bird dynamics both locally and over all of southern Norway, consistent with the influence of large-scale fluctuations in winter conditions. The relationship between commonly available meteorological data and snow conditions indicates that changes in temperature and humidity, and thus conditions in the subnivean space, seem to markedly affect the dynamics of alpine rodents and their linked groups. The pattern of less regular rodent peaks, and corresponding changes in the overall dynamics of the alpine ecosystem, thus seems likely to prevail over a growing area under projected climate change.     

Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype

Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 'cooperation response genes' were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.     

Mega-impact formation of the Mars hemispheric dichotomy

The Mars hemispheric dichotomy is expressed as a dramatic difference in elevation, crustal thickness and crater density between the southern highlands and northern lowlands (which cover approximately 42% of the surface). Despite the prominence of the dichotomy, its origin has remained enigmatic and models for its formation largely untested. Endogenic degree-1 convection models with north-south asymmetry are incomplete in that they are restricted to simulating only mantle dynamics and they neglect crustal evolution, whereas exogenic multiple impact events are statistically unlikely to concentrate in one hemisphere. A single mega-impact of the requisite size has not previously been modelled. However, it has been hypothesized that such an event could obliterate the evidence of its occurrence by completely covering the surface with melt or catastrophically disrupting the planet. Here we present a set of single-impact initial conditions by which a large impactor can produce features consistent with the observed dichotomy's crustal structure and persistence. Using three-dimensional hydrodynamic simulations, large variations are predicted in post-impact states depending on impact energy, velocity and, importantly, impact angle, with trends more pronounced or unseen in commonly studied smaller impacts. For impact energies of approximately (3-6) x 10(29) J, at low impact velocities (6-10 km s(-1)) and oblique impact angles (30-60 degrees ), the resulting crustal removal boundary is similar in size and ellipticity to the observed characteristics of the lowlands basin. Under these conditions, the melt distribution is largely contained within the area of impact and thus does not erase the evidence of the impact's occurrence. The antiquity of the dichotomy is consistent with the contemporaneous presence of impactors of diameter 1,600-2,700 km in Mars-crossing orbits, and the impact angle is consistent with the expected distribution.     

Which Wisdom Can Change the World?

The thoughts that Michel Puech formulates on wisdom, technology and the art of living are timely at a moment when social, ecological and economic problems are pressing upon our societies and the speed of technological development seems to overwhelm our ability to integrate and adapt new technologies in our lives and societies. However, he restricts his concept of wisdom too much to a personal endeavor and overestimates the relevance of non-confrontation. I argue that his project can only be of value when it is embedded in a broader societal and political strategy for change.     

Inflammatory bowel disease: is it a primary immunodeficiency?

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn’s disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott–Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.     

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?3 to P = 1.2 × 10?13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.     

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10???) and 9q31.2 (P = 2.2 × 10?33), we identified 30 new menarche loci (all P < 5 × 10??) and found suggestive evidence for a further 10 loci (P < 1.9 × 10??). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.