Assisting Software Developers With License Compliance

Open source licensing determines how open source systems are reused, distributed, and modified from a legal perspective. While it facilitates rapid development, it can present difficulty for developers in understanding due to the legal language of these licenses. Because of misunderstandings, systems can incorporate licensed code in a way that violates the terms of the license. Such incompatibilities between licensing can result in the inability to reuse a particular library without either relicensing the system or redesigning the architecture of the system. Prior efforts have predominantly focused on license identification or understanding the underlying phenomena without reasoning about compatibility in a broad scale. The work in this dissertation first investigates the rationale of developers and identifies the areas that developers struggle with respect to free/open source software licensing. First, we investigate the diffusion of licenses and the prevalence of license changes in a large scale empirical study of 16,221 Java systems. We observed a clear lack of traceability and a lack of standardized licensing that led to difficulties and confusion for developers trying to reuse source code. We further investigated the difficulty by surveying the developers of the systems with license changes to understand why they first adopted a license and then changed licenses. Additionally, we performed an analysis on issue trackers and legal mailing lists to extract licensing bugs. From these works, we identified key areas in which developers struggled and needed support. While developers need support to identify license incompatibilities and understand both the cause and implications of the incompatibilities, we observed that state-of-the-art license identification tools did not identify license exceptions. Since these exceptions directly modify the license terms (either the permissions granted by the license or the restrictions imposed by the license), we proposed an approach to complement current license identification techniques in order to classify license exceptions. The approach relies on supervised machine learners to classify the licensing text to identify the particular license exceptions or the lack of a license exception. Subsequently, we built an infrastructure to assist developers with evaluating license compliance warnings for their system. The infrastructure evaluates compliance across the dependency tree of a system to ensure it is compliant with all of the licenses of the dependencies. When an incompatibility is present, it notes the specific library/libraries and the conflicting license(s) so that the developers can investigate these compliance warnings, which would prevent distribution of their software, in their system. We conduct a study on 121,094 open source projects spanning 6 programming languages, and we demonstrate that the infrastructure is able to identify license incompatibilities between these projects and their dependencies

Automatically Discovering, Reporting and Reproducing Android Application Crashes

Mobile developers face unique challenges when detecting and reporting crashes in apps due to their prevailing GUI event-driven nature and additional sources of inputs (e.g., sensor readings). To support developers in these tasks, we introduce a novel, automated approach called CRASHSCOPE. This tool explores a given Android app using systematic input generation, according to several strategies informed by static and dynamic analyses, with the intrinsic goal of triggering crashes. When a crash is detected, CRASHSCOPE generates an augmented crash report containing screenshots, detailed crash reproduction steps, the captured exception stack trace, and a fully replayable script that automatically reproduces the crash on a target device(s). We evaluated CRASHSCOPE's effectiveness in discovering crashes as compared to five state-of-the-art Android input generation tools on 61 applications. The results demonstrate that CRASHSCOPE performs about as well as current tools for detecting crashes and provides more detailed fault information. Additionally, in a study analyzing eight real-world Android app crashes, we found that CRASHSCOPE's reports are easily readable and allow for reliable reproduction of crashes by presenting more explicit information than human written reports.Comment: 12 pages, in Proceedings of 9th IEEE International Conference on Software Testing, Verification and Validation (ICST'16), Chicago, IL, April 10-15, 2016, pp. 33-4

Structure and substrate recognition of the Bottromycin maturation enzyme BotP

JK would like to thank the University of St Andrews, which is supported by a Wellcome Trust Capital Award (086036) and the Deutsche Forschungsgemeinschaft for an Emmy Noether fellowship (KO4116/3-1). BN would like to thank the European Research Council (339367).The bottromycins are a family of highly modified peptide natural products displaying potent antimicrobial activity against Gram-positive bacteria including methicillin-resistant Staphyloccoccus aureus. Bottromycins have recently been shown to be ribosomally synthesized and post-translationally modified peptides (RiPPs). Unique amongst RiPPs the precursor peptide BotA contains a C-terminal "follower" sequence, rather than the canonical N- terminal "leader" sequence. We report the structural and biochemical characterization of BotP, a leucyl-aminopeptidase like enzyme from the bottromycin pathway. We demonstrate that BotP is responsible for the removal of the N-terminal methionine from the precursor peptide. Determining the crystal structures of apo BotP and of BotP in complex with Mn2+ allowed us to model a BotP/substrate complex and to rationalize substrate recognition. Our data represent the first step towards targeted compound modification to unlock the full antibiotic potential of bottromycin.PostprintPeer reviewe

Molecular basis of sidekick-mediated cell-cell adhesion and specificity

Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons. Sdks mediate cell-cell adhesion with homophilic specificity that underlies their neuronal targeting function. Here we report crystal structures of Sdk1 and Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal immunoglobulin domains (Ig1–4), arranged in a horseshoe conformation. These Ig1–4 horseshoes interact in a novel back-to-back orientation in both homodimers through Ig1:Ig2, Ig1:Ig1 and Ig3:Ig4 interactions. Structure-guided mutagenesis results show that this canonical dimer is required for both Sdk-mediated cell aggregation (via trans interactions) and Sdk clustering in isolated cells (via cis interactions). Sdk1/Sdk2 recognition specificity is encoded across Ig1–4, with Ig1–2 conferring the majority of binding affinity and differential specificity. We suggest that competition between cis and trans interactions provides a novel mechanism to sharpen the specificity of cell-cell interactions

A potential new, stable state of the E-cadherin strand-swapped dimer in solution

E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other

Two Glycosylation Sites in H5N1 Influenza Virus Hemagglutinin That Affect Binding Preference by Computer-Based Analysis

Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor-binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs

Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72410/1/bjp.2008.204.pd

In Vitro and in Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide)