Encoding of conditioned fear in central amygdala inhibitory circuits

The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.     

A frame-theoretic analysis of two rival conceptions of heat

Under what circumstances, if any, are we warranted to assert that a theory is true or at least has some truth content? Scientific realists answer that such assertions are warranted only for those theories or theory-parts that enjoy explanatory and predictive success. A number of challenges to this answer have emerged, chief among them those arising from scientific theory change. For example, if, as scientific realists suggest, successive theories are to increasingly get closer to the truth, any theory changes must not undermine (i) the accumulation of explanatory and predictive success and (ii) the theoretical content responsible for that success. In this paper we employ frame theory to test to what extent certain theoretical claims made by the outdated caloric theory of heat and that, prima facie at least, were used to produce some of that theory’s success have survived into the theory that superseded it, i.e. the kinetic theory of heat. Our findings lend credence to structural realism, the view that scientific theories at best reveal only structural features of the unobservable world.     

A Quantile Regression Approach to Equity Premium Prediction

We propose a quantile regression approach to equity premium forecasting. Robust point forecasts are generated from a set of quantile forecasts using both fixed and time‐varying weighting schemes, thereby exploiting the entire distributional information associated with each predictor. Further gains are achieved by incorporating the forecast combination methodology into our quantile regression setting. Our approach using a time‐varying weighting scheme delivers statistically and economically significant out‐of‐sample forecasts relative to both the historical average benchmark and the combined predictive mean regression modeling approach. Copyright © 2014 John Wiley & Sons, Ltd.     

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.     

Tumor cell migration in complex microenvironments

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.     

Forecasting football results and the efficiency of fixed‐odds betting

An ordered probit regression model estimated using 10 years' data is used to forecast English league football match results. As well as past match results data, the significance of the match for end‐of‐season league outcomes, the involvement of the teams in cup competition and the geographical distance between the two teams' home towns all contribute to the forecasting model's performance. The model is used to test the weak‐form efficiency of prices in the fixed‐odds betting market. A strategy of selecting end‐of‐season bets with a favourable expected return according to the model appears capable of generating a positive return. Copyright © 2004 John Wiley & Sons, Ltd.     

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.