How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

Network link prediction by global silencing of indirect correlations

Predicting physical and functional links between cellular components is a fundamental challenge of biology and network science. Yet, correlations, a ubiquitous input for biological link prediction, are affected by both direct and indirect effects, confounding our ability to identify true pairwise interactions. Here we exploit the fundamental properties of dynamical correlations in networks to develop a method to silence indirect effects. The method receives as input the observed correlations between node pairs and uses a matrix transformation to turn the correlation matrix into a highly discriminative silenced matrix, which enhances only the terms associated with direct causal links. Achieving perfect accuracy in model systems, we test the method against empirical data collected for the Escherichia coli regulatory interaction network, showing that it improves on the best preforming link prediction methods. Overall the silencing methodology helps translate the abundant correlation data into valuable local information, with applications ranging from link prediction to inferring the dynamical mechanisms governing biological networks

Network Neutrality and the False Promise of Zero-Price Regulation

This Article examines zero-price regulation, the major distinguishing feature of many modern "network neutrality" proposals. A zero-price rule prohibits a broadband Internet access provider from charging an application or content provider (collectively, "content provider") to send information to consumers. The Article differentiates two access provider strategies thought to justify a zero-price rule. Exclusion is anticompetitive behavior that harms a content provider to favor its rival. Extraction is a toll imposed upon content providers to raise revenue. Neither strategy raises policy concerns that justify implementation of a broad zero-price rule. First, there is no economic exclusion argument that justifies the zero-price rule as a general matter, given existing legal protections against exclusion. A stronger but narrow argument for regulation exists in certain cases in which the output of social producers, such as Wikipedia, competes with ordinary market-produced content. Second, prohibiting direct extraction is undesirable and counterproductive, in part because it induces costly and unregulated indirect extraction. I conclude, therefore, that recent calls for broad-based zero-price regulation are mistaken.

Beyond market access : the new normal of preferential trade agreements

This paper takes stock of the growing success of preferential trade agreements. It revisits what are the defining characteristics of modern preferential trade agreements, which are typically pursued for a diverse array of motives. In particular, the market access justification traditionally used to analyze the desirability and impact of preferential trade agreements misses increasingly important dimensions. The"Beyond Market Access"agenda of preferential trade agreements presents a new and broad set of deep regulatory and policy issues that differs in substance from the removal of tariff and quantitative barriers to trade. Issues related to preferences and discrimination, as well as the nature and implementation of commitments acquire a different meaning in deep preferential trade agreements. This change of paradigm presents significant opportunities and challenges for reform-minded developing countries to use preferential trade agreements to their own advantage.Trade Law,Free Trade,Environmental Economics&Policies,Emerging Markets,Trade and Regional Integration

Mobile Network Competition, Customer Ignorance and Fixed-to-Mobile Call Prices.

This paper examines the influence of mobile network competition on the prices of fixed-to-mobile calls. Because fixed line customers cannot, in general, distinguish the identity of a specific mobile network, these networks have market power when setting termination charges for calls from fixed lines. We show that: (1) unregulated mobile termination charges will result in higher than monopoly call prices; (2) the regulation of termination charges and prices downward will affect mobile subscription rates and may lower these rates; and (3) regulation of any mobile carrier's termination charges can reduce fixed to mobile prices but will result in an increase in unregulated carriers' termination charges. When fixed line consumers can distinguish between the different mobile networks they are calling, fixed to mobile call prices will fall relative to their level under customer ignorance. Direct mobile charging for termination also exerts downward pressure on the total fixed to mobile call price. A low cost method of lowering fixed to mobile charges would be to facilitate the identification of carriers by consumers and to restructure billing so that mobile networks are able to directly charge fixed line consumers for termination services.TELECOMMUNICATIONS ; PRICES ; REGULATION

The case for absolute ligand discrimination : modeling information processing and decision by immune T cells

Some cells have to take decision based on the quality of surroundings ligands, almost irrespective of their quantity, a problem we name "absolute discrimination". An example of absolute discrimination is recognition of not-self by immune T Cells. We show how the problem of absolute discrimination can be solved by a process called "adaptive sorting". We review several implementations of adaptive sorting, as well as its generic properties such as antagonism. We show how kinetic proofreading with negative feedback implements an approximate version of adaptive sorting in the immune context. Finally, we revisit the decision problem at the cell population level, showing how phenotypic variability and feedbacks between population and single cells are crucial for proper decision

Regulatory Governance Costs in Network Industries: Implicatins for postal Regulation

The various actors in regulated industries relate to each other within a broader institutional framework, i.e. by way of formal and informal rules. An important role in the implementation of liberalization processes is given to the regulation and thus to regulatory institutions. Regulation should have positive effect on social welfare. But state intervention also causes costs which we call costs of regulatory governance. These costs result from negative consequences caused by unnecessary regulatory requirements or from the implementation of inappropriate regulatory instruments. According to new institutional economics, these costs will depend upon the formal and informal rules among the involved actors, upon the allocation of property rights among these actors, as well as upon the various principal-agent or more generally contractual relationships among these actors. In this article we define an analytical framework of costs of regulatory governance. We distinguish between direct and indirect costs of regulation: Direct costs occur in relation with the institutional design of the regulatory framework and the behavior of actors. Whereas the indirect costs arise because of false incentives and finally turn out in an inefficient supply of goods and services. Using the example of the Swiss postal market we give an outline of a possible application of the framework.Regulation; Postal Sector; Regulatory Governance Costs; New Institutional Economics

The Price of Prejudice: Labour Market Discrimination on the Grounds of Gender and Ethnicity

Despite some progress, there is still evidence of discrimination on the grounds of gender and ethnic or racial origins in OECD labour markets. Field experiments show pervasive ethnic discrimination in many countries. We show indirect cross-country/time-series evidence that, using product market regulation as an instrument, suggests that on average at least 8% of the gender employment gap and a larger proportion of the gender wage gap can be attributed to discrimination. Virtually all OECD countries have enacted anti-discrimination laws in recent decades, and evaluations as well as cross-country analysis suggest that, if well-designed, these laws can be effective in reducing disparities in labour market outcomes. However, enforcement of anti-discrimination legislation is essentially based on victims' willingness to claim their rights. Thus, public awareness of legal rules and their expected consequences (notably, victims' costs and benefits of lodging complaints) is a crucial element of an effective policy strategy to establish a culture of equal treatment. However, legal rules are likely to have more impact if the enforcement is not exclusively dependent on individuals. In this respect, specific agencies may play a key role.field experiments; employment gaps; gender gaps; anti-discrimination laws

Network deconvolution as a general method to distinguish direct dependencies in networks

Recognizing direct relationships between variables connected in a network is a pervasive problem in biological, social and information sciences as correlation-based networks contain numerous indirect relationships. Here we present a general method for inferring direct effects from an observed correlation matrix containing both direct and indirect effects. We formulate the problem as the inverse of network convolution, and introduce an algorithm that removes the combined effect of all indirect paths of arbitrary length in a closed-form solution by exploiting eigen-decomposition and infinite-series sums. We demonstrate the effectiveness of our approach in several network applications: distinguishing direct targets in gene expression regulatory networks; recognizing directly interacting amino-acid residues for protein structure prediction from sequence alignments; and distinguishing strong collaborations in co-authorship social networks using connectivity information alone. In addition to its theoretical impact as a foundational graph theoretic tool, our results suggest network deconvolution is widely applicable for computing direct dependencies in network science across diverse disciplines.National Institutes of Health (U.S.) (grant R01 HG004037)National Institutes of Health (U.S.) (grant HG005639)Swiss National Science Foundation (Fellowship)National Science Foundation (U.S.) (NSF CAREER Award 0644282