qc3C: reference-free quality control for Hi-C sequencing data

Hi-C is a sample preparation method that enables high-throughput sequencing to capture genome-wide spatial interactions between DNA molecules. The technique has been successfully applied to solve challenging problems such as 3D structural analysis of chromatin, scaffolding of large genome assemblies and more recently the accurate resolution of metagenome-assembled genomes (MAGs). Despite continued refinements, however, Hi-C library preparation remains a complex laboratory protocol and diligent quality management is recommended to avoid costly failure. Current wet-lab protocols for Hi-C library QC provide only a crude assay, while commonly used sequence-based QC methods demand a reference genome; the quality of which can skew results. We propose a new, reference-free approach for Hi-C library quality assessment that requires only a modest amount of sequencing data. The algorithm builds upon the observation that proximity ligation events are likely to create k -mers that would not naturally occur in the sample. Our software tool (qc3C) is to our knowledge the first to implement a reference-free Hi-C QC tool, and also provides reference-based QC, enabling Hi-C to be more easily applied to non-model organisms and environmental samples. We characterise the accuracy of the new algorithm on simulated and real datasets and compare it to reference-based methods.

Positive Regulation and Success

What is regulatory success and how is it to be achieved across the core tasks of regulation? There are familiar examples of regulatory systems that seem to have failed—the financial crash of 2009 offers an instance of a hugely costly failure of regulation and government. What, though, does successful regulation look like? This chapter looks at the challenges involved in producing regulatory systems that achieve success for affected parties. It outlines the jobs that regulators have to do and the difference made by doing these well or badly. It examines why regulation can fail and describes the qualities associated with the excellent regulators. It sets down how businesses can respond to regulatory systems in an effective manner and looks at the conditions under which ‘win-win’ outcomes are possible for firms and regulators.

Who Wants to Lead? Anticipated Gender Discrimination Reduces Women’s Leadership Ambitions

We examine whether anticipated gender discrimination—specifically, gendered sanctions for leadership failure—decreases women’s leadership ambitions. We find that laypeople expect that women leaders will be punished more harshly for failure than otherwise similar men. We also compare the leadership ambitions of women and men under conditions of benign and costly failure and find that leadership roles with costly failure—which implicitly have the potential for gendered sanctions for failure—disproportionally depress women’s leadership ambitions relative to men’s. Anticipated sanctions for failure mediate this effect, providing evidence that anticipated gender discrimination reduces women’s leadership ambitions. These results illuminate microlevel foundations of the stalled revolution by demonstrating how gendered beliefs about leadership are recreated, legitimized, and contribute to the dearth of women leaders. These findings also suggest that organizational responses to failure may produce gender differences in leadership ambitions and risk-taking behavior.

Courage and Desperation Rarely Equaled

In an attempt to relieve the mounting pressure on Vicksburg, the Confederate high command launched an assault on the Federal defences at Helena, Arkansas, a port city on the Mississippi River. Poor intelligence and reconnaissance work and a lack of coordination among the assaulting columns turned the effort into a costly failure and brought an end to the ill-starred command of Lt. Gen. Theophilus H. Holmes in the trans-Mississippi.

Determining Relative Importance and Effective Settings for Genetic Algorithm Control Parameters

Setting the control parameters of a genetic algorithm to obtain good results is a long-standing problem. We define an experiment design and analysis method to determine relative importance and effective settings for control parameters of any evolutionary algorithm, and we apply this method to a classic binary-encoded genetic algorithm (GA). Subsequently, as reported elsewhere, we applied the GA, with the control parameter settings determined here, to steer a population of cloud-computing simulators toward behaviors that reveal degraded performance and system collapse. GA-steered simulators could serve as a design tool, empowering system engineers to identify and mitigate low-probability, costly failure scenarios. In the existing GA literature, we uncovered conflicting opinions and evidence regarding key GA control parameters and effective settings to adopt. Consequently, we designed and executed an experiment to determine relative importance and effective settings for seven GA control parameters, when applied across a set of numerical optimization problems drawn from the literature. This paper describes our experiment design, analysis, and results. We found that crossover most significantly influenced GA success, followed by mutation rate and population size and then by rerandomization point and elite selection. Selection method and the precision used within the chromosome to represent numerical values had least influence. Our findings are robust over 60 numerical optimization problems.

Dynamic Fracture Toughness: Critical Review of Materials and Developments

For design to be more safe, dynamic fracture toughness (DFT) of material needs to be determined. Compared to static loading, dynamic loading procedures are not well established. Calculation of DFT is complicated and costly. Failure process of structures is greatly influenced by dynamic loading. In the past only steel and cast iron were employed for structure design purposes but now many new materials such as (a) composite, (b) alloys (titanium, magnesium), (c) ceramic, (d) concrete, and (e) brittle materials are being used. DFT calculations of materials under dynamic loading have resulted in new theories and experimental techniques. In this paper a critical review of the developments for the calculation of DFT for the materials is presented.

Using humanitarian aid to ‘win hearts and minds’: a costly failure?

This article contends that the integration of humanitarian assistance in efforts to ‘win hearts and minds’ in counter-insurgencies has not been successful, and that the costs, both operational and legal, clearly outweigh any benefits. It demonstrates how such manipulation of humanitarian assistance runs counter to fundamental principles of international humanitarian law. In addition, a growing body of research suggests that the use of short-term aid and relief programmes as part of counter-insurgency has been ineffectual, and that, in places such as Afghanistan, it may even have undermined the overall military goal of defeating insurgents. With the United States and NATO military operations winding down in Afghanistan, it is time for the military and policy-makers reviewing ‘winning hearts and minds’ as a counter-insurgency strategy to draw the lessons and recognize the importance of a neutral and independent space for humanitarian aid.

A Macroprudential Approach to Financial Regulation

Many observers have argued that the regulatory framework in place prior to the global financial crisis was deficient because it was largely “microprudential” in nature. A microprudential approach is one in which regulation is partial equilibrium in its conception and aimed at preventing the costly failure of individual financial institutions. By contrast, a “macroprudential” approach recognizes the importance of general equilibrium effects, and seeks to safeguard the financial system as a whole. In the aftermath of the crisis, there seems to be agreement among both academics and policymakers that financial regulation needs to move in a macroprudential direction. In this paper, we offer a detailed vision for how a macroprudential regime might be designed. Our prescriptions follow from a specific theory of how modern financial crises unfold and why both an unregulated financial system, as well as one based on capital rules that only apply to traditional banks, is likely to be fragile. We begin by identifying the key market failures at work: why individual financial firms, acting in their own interests, deviate from what a social planner would have them do. Next, we discuss a number of concrete steps to remedy these market failures. We conclude the paper by comparing our proposals to recent regulatory reforms in the United States and to proposed global banking reforms.