Supervised Software Modularisation

This paper is concerned with the challenge of reorganising a software system into modules that both obey sound design principles and are sensible to domain experts. The problem has given rise to several unsupervised automated approaches that use techniques such as clustering and Formal Concept Analysis. Although results are often partially correct, they usually require refinement to enable the developer to integrate domain knowledge. This paper presents the SUMO algorithm, an approach that is complementary to existing techniques and enables the maintainer to refine their results. The algorithm is guaranteed to eventually yield a result that is satisfactory to the maintainer, and the evaluation on a diverse range of systems shows that this occurs with a reasonably low amount of effort

Effective and Efficient Use of Expert Knowledge in Automated Software Remodularisation

Abstract: Remodularising the components of a software system is challenging: sound design principles (e.g., coupling and cohesion) need to be balanced against developer intuition of which entities conceptually belong together. Despite this, automated approaches to remodularisation tend to ignore domain knowledge, leading to results that can be nonsensical to developers. Nevertheless, suppling such knowledge is a potentially burdensome task to perform manually. A lot information may need to be specified, particularly for large systems. Addressing these concerns, we propose the SUMO (SUpervised reMOdularisation) approach. SUMO is a technique that aims to leverage a small subset of domain knowledge about a system to produce a remodularisation that will be acceptable to a developer. With SUMO, developers refine a modularisation by iteratively supplying corrections. These corrections constrain the type of remodularisation eventually required, enabling SUMO to dramatically reduce the solution space. This in turn reduces the amount of feedback the developer needs to supply. We perform a comprehensive systematic evaluation using 100 real world subject systems. Our results show that SUMO guarantees convergence on a target remodularisation with a tractable amount of user interaction

CEP-1, the <i>Caenorhabditis elegans</i> p53 Homolog, Mediates Opposing Longevity Outcomes in Mitochondrial Electron Transport Chain Mutants

<div><p><i>Caenorhabditis elegans</i> CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that <i>cep-1</i> inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as <i>isp-1</i> and <i>nuo-6</i>, but rescued the shortened lifespan of other ETC mutants, such as <i>mev-1</i> and <i>gas-1</i>. We compared the CEP-1-regulated transcriptional profiles of the long-lived <i>isp-1</i> and the short-lived <i>mev-1</i> mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the <i>isp-1</i> and <i>mev-1</i> mutants. Interestingly, this small group of differentially regulated genes are enriched for the “aging” Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in <i>isp-1</i> and <i>mev-1</i> mutants. We further focused on one of these differentially regulated genes, <i>ftn-1</i>, which encodes ferritin in <i>C. elegans</i>, and demonstrated that it specifically contributed to the extended lifespan of <i>isp-1</i> mutant worms but did not affect the <i>mev-1</i> mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.</p></div

CEP-1-regulated transcriptomes in <i>isp-1</i> and <i>mev-1</i> mutants.

<p>(A) CEP-1-regulated genes in <i>isp-1</i> and <i>mev-1</i> mutants are largely similar. Hierarchical single linkage gene clustering was performed, and the dendrogram shows the clustered relationship of individual arrays. The numbers on the dendrogram represent the correlation coefficients between arrays. Yellow: upregulated, Blue: downregulated, Black: no change. (B) The expression of CEP-1-regulated genes that were significantly changed in <i>isp-1</i> and <i>mev-1</i> mutants, identified by SAM analysis, are represented in the Venn diagram. (C) DAVID functional annotation of similarly and differentially expressed CEP-1-regulated genes in <i>isp-1</i> and <i>mev-1</i> mutants. The numbers represent the enrichment scores for each group (score>1.3 is considered as significant). Several examples of aging and metabolic genes are listed.</p

<i>ftn-1</i> is differentially expressed in various ETC mutants and mediates their lifespan outcomes.

<p>(A, B) RNAi-mediated knockdown of <i>ftn-1</i> attenuates the long life of the <i>nuo-6</i> mutant but does not impact the lifespan of the short-lived <i>gas-1</i> mutant. (C) qRT-PCR results of <i>ftn-1</i> expression levels in various ETC mutants. The two-tailed student t-tests were performed to determine significant difference in <i>ftn-1</i> expression levels with and without CEP-1 in each ETC mutant background.</p

CEP-1-regulated ferritin induction partially mediates the extended lifespan of <i>isp-1</i> mutants.

<p>(A) <i>Pftn-1::gfp</i> expression in wt, <i>cep-1, isp-1, cep-1;isp-1, mev-1</i>, and <i>cep-1;mev-1</i> mutant worms. Scale bar = 100 µm. (B, C) The lifespans of wt, <i>cep-1, isp-1, cep-1;isp-1, mev-1</i> and <i>cep-1;mev-1</i> mutant worms treated with <i>ftn-1</i> and <i>ftn</i>-2 double RNAi. L4440 is a treatment control.</p

CEP-1 mediates the longevity and development of several mitochondrial mutants in <i>C. elegans</i>.

<p>(A) <i>cep-1</i> mutation fully suppresses the long lifespan of the <i>nuo-6</i> mutant. (B) <i>cep-1</i> mutation does not suppress <i>clk-1</i> mutant longevity as the lifespans of two <i>cep-1;clk-1</i> double mutant isolates (L4, L6) are similar to that of the <i>clk-1</i> single mutant. (C) <i>cep-1</i> mutation partially restores <i>gas-1</i> mutant lifespan as two isolates of <i>cep-1;gas-1</i> (L22, L34) live longer than the <i>gas-1</i> single mutant. (D) The percentage of worms at each developmental stage was quantified as described in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004097#pgen-1004097-g001" target="_blank">Fig. 1C</a>. <i>cep-1</i> deletion has little impact on <i>nuo-6</i> and <i>gas-1</i> mutant development.</p

CEP-1 mediates reduced physiological germline apoptosis in the <i>isp-1</i> mutant.

<p>Physiological levels of apoptosis were quantified by counting the number of apoptotic corpses per gonad arm in various <i>C. elegans</i> strains. The corpses were counted using DIC microscopy at 63× magnification 48 hr post L4. The data represent the average of at least 3 independent experimental replicates (n≥15 gonad arms for each) ± standard error. Statistical analysis was done using the Mann-Whitney U-test. ***<i>p</i><0.001.</p

CEP-1 mediates the longevity and development of two mitochondrial mutants in <i>C. elegans</i>.

<p>(A) <i>cep-1</i> mutation partially suppresses <i>isp-1</i> mutant longevity as the <i>cep-1;isp-1</i> double mutant lifespan is shorter than that of the <i>isp-1</i> single mutant. (B) <i>cep-1</i> mutation restores the <i>mev-1</i> mutant lifespan as the lifespans of two <i>cep-1;mev-1</i> isolates (L1, L32) are similar to that of wt. (C) The percentage of worms at each developmental stage was quantified for wt, <i>cep-1, isp-1, cep-1;isp-1, mev-1</i>, and <i>cep-1;mev-1</i> mutant worms after 60 hr of growth from the embryonic stage at 20°C. (D) The average number of progeny production for each line was calculated from 5 to 10 worms. The <i>isp-1</i> and <i>mev-1</i> mutants produce significantly less progeny than wt. The <i>cep-1;isp-1</i> and <i>cep-1;mev-1</i> double mutants display significantly lower brood sizes than their respective single mutant controls (*<i>p</i><0.05, **<i>p</i><0.0005). The error bars represent standard errors. Statistical analysis was performed using a two-tailed t-test.</p

Expression of similarly regulated CEP-1 targets in other ETC mutants.

<p>(A–K) These genes are similarly regulated by CEP-1 between <i>isp-1</i> and <i>mev-1</i> mutants. The relative expression of each gene was normalized to <i>act-1</i> and wt. The average log2 ratio between ETC mutants with and without <i>cep-1</i> from three independent experiments are plotted. The error bars represent standard errors. Two-tailed t-tests were performed to determine significant differences of the expression of CEP-1 target genes between the long-lived <i>isp-1(qm150)</i> and <i>nuo-6(qm200)</i> mutants and the short-lived <i>mev-1(kn1)</i> and <i>gas-1(fc21)</i> mutants. * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001.</p