Serum tests, liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension

BACKGROUND The diagnostic performance of biochemical scores and artificial neural network models for portal hypertension and cirrhosis is not well established. AIMS To assess diagnostic accuracy of six serum scores, artificial neural networks and liver stiffness measured by transient elastography, for diagnosing cirrhosis, clinically significant portal hypertension and oesophageal varices. METHODS 202 consecutive compensated patients requiring liver biopsy and hepatic venous pressure gradient measurement were included. Several serum tests (alone and combined into scores) and liver stiffness were measured. Artificial neural networks containing or not liver stiffness as input variable were also created. RESULTS The best non-invasive method for diagnosing cirrhosis, portal hypertension and oesophageal varices was liver stiffness (C-statistics=0.93, 0.94, and 0.90, respectively). Among serum tests/scores the best for diagnosing cirrhosis and portal hypertension and oesophageal varices were, respectively, Fibrosis-4, and Lok score. Artificial neural networks including liver stiffness had high diagnostic performance for cirrhosis, portal hypertension and oesophageal varices (accuracy>80%), but were not statistically superior to liver stiffness alone. CONCLUSIONS Liver stiffness was the best non-invasive method to assess the presence of cirrhosis, portal hypertension and oesophageal varices. The use of artificial neural networks integrating different non-invasive tests did not increase the diagnostic accuracy of liver stiffness alone.

Revealing Assembly of a Pore-Forming Complex Using Single-Cell Kinetic Analysis and Modeling

Many biological processes depend on the sequential assembly of protein complexes. However, studying the kinetics of such processes by direct methods is often not feasible. As an important class of such protein complexes, pore-forming toxins start their journey as soluble monomeric proteins, and oligomerize into transmembrane complexes to eventually form pores in the target cell membrane. Here, we monitored pore formation kinetics for the well-characterized bacterial pore-forming toxin aerolysin in single cells in real time to determine the lag times leading to the formation of the first functional pores per cell. Probabilistic modeling of these lag times revealed that one slow and seven equally fast rate-limiting reactions best explain the overall pore formation kinetics. The model predicted that monomer activation is the rate-limiting step for the entire pore formation process. We hypothesized that this could be through release of a propeptide and indeed found that peptide removal abolished these steps. This study illustrates how stochasticity in the kinetics of a complex process can be exploited to identify rate-limiting mechanisms underlying multistep biomolecular assembly pathways.

A Unified Approach to Architecture Conformance Checking

Software erosion can be controlled by periodically checking for consistency between the de facto architecture and its theoretical counterpart. Studies show that this process is often not automated and that developers still rely heavily on manual reviews, despite the availability of a large number of tools. This is partially due to the high cost involved in setting up and maintaining tool-specific and incompatible test specifications that replicate otherwise documented invariants. To reduce this cost, our approach consists in unifying the functionality provided by existing tools under the umbrella of a common business-readable DSL. By using a declarative language, we are able to write tool-agnostic rules that are simple enough to be understood by non-technical stakeholders and, at the same time, can be interpreted as a rigorous specification for checking architecture conformance

Bounded seas

Abstract Imprecise manipulation of source code (semi-parsing) is useful for tasks such as robust parsing, error recovery, lexical analysis, and rapid development of parsers for data extraction. An island grammar precisely defines only a subset of a language syntax (islands), while the rest of the syntax (water) is defined imprecisely. Usually water is defined as the negation of islands. Albeit simple, such a definition of water is naive and impedes composition of islands. When developing an island grammar, sooner or later a language engineer has to create water tailored to each individual island. Such an approach is fragile, because water can change with any change of a grammar. It is time-consuming, because water is defined manually by an engineer and not automatically. Finally, an island surrounded by water cannot be reused because water has to be defined for every grammar individually. In this paper we propose a new technique of island parsing —- bounded seas. Bounded seas are composable, robust, reusable and easy to use because island-specific water is created automatically. Our work focuses on applications of island parsing to data extraction from source code. We have integrated bounded seas into a parser combinator framework as a demonstration of their composability and reusability.

Explora: A Visualisation Tool for Metric Analysis of Software Corpora

When analysing software metrics, users find that visualisation tools lack support for (1) the detection of patterns within metrics; and (2) enabling analysis of software corpora. In this paper we present Explora, a visualisation tool designed for the simultaneous analysis of multiple metrics of systems in software corpora. Explora incorporates a novel lightweight visualisation technique called PolyGrid that promotes the detection of graphical patterns. We present an example where we analyse the relation of subtype polymorphism with inheritance and invocation in corpora of Smalltalk and Java systems and find that (1) subtype polymorphism is more likely to be found in large hierarchies; (2) as class hierarchies grow horizontally, they also do so vertically; and (3) in polymorphic hierarchies the length of the name of the classes is orthogonal to the cardinality of the call sites.

Polymorphism in the Spotlight: Studying its Prevalence in Java and Smalltalk

Subtype polymorphism is a cornerstone of object-oriented programming. By hiding variability in behavior behind a uniform interface, polymorphism decouples clients from providers and thus enables genericity, modularity and extensi- bility. At the same time, however, it scatters the implementation of the behavior over multiple classes thus potentially hampering program comprehension. The extent to which polymorphism is used in real programs and the impact of polymorphism on program comprehension are not very well understood. We report on a preliminary study of the prevalence of polymorphism in several hundred open source software systems written in Smalltalk, one of the oldest object-oriented programming languages, and in Java, one of the most widespread ones. Although a large portion of the call sites in these systems are polymorphic, a majority have a small number of potential candidates. Smalltalk uses polymorphism to a much greater extent than Java. We discuss how these findings can be used as input for more detailed studies in program comprehension and for better developer support in the IDE.

Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process

Owing to their pathogenical role and unique ability to exist both as soluble proteins and transmembrane complexes, pore-forming toxins (PFTs) have been a focus of microbiologists and structural biologists for decades. PFTs are generally secreted as water-soluble monomers and subsequently bind the membrane of target cells. Then, they assemble into circular oligomers, which undergo conformational changes that allow membrane insertion leading to pore formation and potentially cell death. Aerolysin, produced by the human pathogen Aeromonas hydrophila, is the founding member of a major PFT family found throughout all kingdoms of life. We report cryo-electron microscopy structures of three conformational intermediates and of the final aerolysin pore, jointly providing insight into the conformational changes that allow pore formation. Moreover, the structures reveal a protein fold consisting of two concentric β-barrels, tightly kept together by hydrophobic interactions. This fold suggests a basis for the prion-like ultrastability of aerolysin pore and its stoichiometry.

Explora: Infrastructure for Scaling Up Software Visualisation to Corpora

Visualisation provides good support for software analysis. It copes with the intangible nature of software by providing concrete representations of it. By reducing the complexity of software, visualisations are especially useful when dealing with large amounts of code. One domain that usually deals with large amounts of source code data is empirical analysis. Although there are many tools for analysis and visualisation, they do not cope well software corpora. In this paper we present Explora, an infrastructure that is specifically targeted at visualising corpora. We report on early results when conducting a sample analysis on Smalltalk and Java corpora.