Scaling up algorithmic debugging with virtual execution trees

Declarative debugging is a powerful debugging technique that has been adapted to practically all programming languages. However, the technique suffers from important scalability problems in both time and memory. With realistic programs the huge size of the execution tree handled makes the debugging session impractical and too slow to be productive. In this work, we present a new architecture for declarative debuggers in which we adapt the technique to work with incomplete execution trees. This allows us to avoid the problem of loading the whole execution tree in main memory and solve the memory scalability problems. We also provide the technique with the ability to debug execution trees that are only partially generated. This allows the programmer to start the debugging session even before the execution tree is computed. This solves the time scalability problems. We have implemented the technique and show its practicality with several experiments conducted with real applications.Insa Cabrera, D.; Silva Galiana, JF. (2011). Scaling up algorithmic debugging with virtual execution trees. En Logic-Based Program Synthesis and Transformation. Springer Verlag (Germany). 6564:149-163. doi:10.1007/978-3-642-20551-4_10S1491636564Av-Ron, E.: Top-Down Diagnosis of Prolog Programs. PhD thesis, Weizmanm Institute (1984)Binks, D.: Declarative Debugging in Gödel. PhD thesis, University of Bristol (1995)Caballero, R.: A Declarative Debugger of Incorrect Answers for Constraint Functional-Logic Programs. In: Proc. of the 2005 ACM SIGPLAN Workshop on Curry and Functional Logic Programming (WCFLP 2005), pp. 8–13. ACM Press, New York (2005)Caballero, R.: Algorithmic Debugging of Java Programs. In: Proc. of the 2006 Workshop on Functional Logic Programming (WFLP 2006). Electronic Notes in Theoretical Computer Science, pp. 63–76 (2006)Caballero, R., Martí-Oliet, N., Riesco, A., Verdejo, A.: A declarative debugger for maude functional modules. Electronic Notes Theoretical Computer Science 238(3), 63–81 (2009)Davie, T., Chitil, O.: Hat-delta: One Right Does Make a Wrong. In: Seventh Symposium on Trends in Functional Programming, TFP 2006 (April 2006)Girgis, H., Jayaraman, B.: JavaDD: a Declarative Debugger for Java. Technical Report 2006-07, University at Buffalo (March 2006)Kokai, G., Nilson, J., Niss, C.: GIDTS: A Graphical Programming Environment for Prolog. In: Workshop on Program Analysis For Software Tools and Engineering (PASTE 1999), pp. 95–104. ACM Press, New York (1999)MacLarty, I.: Practical Declarative Debugging of Mercury Programs. PhD thesis, Department of Computer Science and Software Engineering, The University of Melbourne (2005)Sun Microsystems. Java Platform Debugger Architecture - JPDA (2010), http://java.sun.com/javase/technologies/core/toolsapis/jpda/Nilsson, H., Fritzson, P.: Algorithmic Debugging for Lazy Functional Languages. Journal of Functional Programming 4(3), 337–370 (1994)Shapiro, E.Y.: Algorithmic Program Debugging. MIT Press, Cambridge (1982)Silva, J.: An Empirical Evaluation of Algorithmic Debugging Strategies. Technical Report DSIC-II/10/09, UPV (2009), http://www.dsic.upv.es/~jsilva/research.htm#techsSilva, J.: Algorithmic debugging strategies. In: Proc. of International Symposium on Logic-based Program Synthesis and Transformation (LOPSTR 2006), pp. 134–140 (2006)Silva, J.: A Comparative Study of Algorithmic Debugging Strategies. In: Puebla, G. (ed.) LOPSTR 2006. LNCS, vol. 4407, pp. 143–159. Springer, Heidelberg (2007

Reduction of HbA1c levels by fucoxanthin-enriched akamoku oil possibly involves the thrifty allele of uncoupling protein 1 (UCP1): a randomised controlled trial in normal-weight and obese Japanese adults

海藻由来のカロテノイド色素であるフコキサンチンの摂取はHbA1cを改善し，その効果は肥満や糖尿病発症のリスクが高いUCP1-3826A/G多型（G/G型）保有者において著しいことを示した

Case Report Anaplastic Large-Cell Lymphoma in a Child with Type I Diabetes and Unrecognised Coeliac Disease

Screening for coeliac disease is recommended for children from certain risk groups, with implications for diagnostic procedures and dietetic management. The risk of a malignant complication in untreated coeliac disease is not considered high in children. We present the case of a girl with type I diabetes who developed weight loss, fatigue, and inguinal lymphadenopathy. Four years before, when she was asymptomatic, a screening coeliac tTG test was positive, but gluten was not eliminated from her diet. Based on clinical examination, a duodenal biopsy, and an inguinal lymph node biopsy were performed, which confirmed both coeliac disease and an anaplastic large-cell lymphoma. HLA-typing demonstrated that she was homozygous for HLA-DQ8, which is associated with higher risk for celiac disease, more severe gluten sensitivity, and diabetes susceptibility. She responded well to chemotherapy and has been in remission for over 4 years. She remains on a gluten-free diet. This is the first case reporting the association of coeliac disease, type I diabetes, and anaplastic large-cell lymphoma in childhood. The case highlights the malignancy risk in a genetically predisposed individual, and the possible role of a perpetuated immunologic response by prolonged gluten exposure

Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b

Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureus peptidoglycan and underpins the potent bacteriolytic activity of this enzyme

A Novel Small Acid Soluble Protein Variant Is Important for Spore Resistance of Most Clostridium perfringens Food Poisoning Isolates

Clostridium perfringens is a major cause of food poisoning (FP) in developed countries. C. perfringens isolates usually induce the gastrointestinal symptoms of this FP by producing an enterotoxin that is encoded by a chromosomal (cpe) gene. Those typical FP strains also produce spores that are extremely resistant to food preservation approaches such as heating and chemical preservatives. This resistance favors their survival and subsequent germination in improperly cooked, prepared, or stored foods. The current study identified a novel α/β-type small acid soluble protein, now named Ssp4, and showed that sporulating cultures of FP isolates producing resistant spores consistently express a variant Ssp4 with an Asp substitution at residue 36. In contrast, Gly was detected at Ssp4 residue 36 in C. perfringens strains producing sensitive spores. Studies with isogenic mutants and complementing strains demonstrated the importance of the Asp 36 Ssp4 variant for the exceptional heat and sodium nitrite resistance of spores made by most FP strains carrying a chromosomal cpe gene. Electrophoretic mobility shift assays and DNA binding studies showed that Ssp4 variants with an Asp at residue 36 bind more efficiently and tightly to DNA than do Ssp4 variants with Gly at residue 36. Besides suggesting one possible mechanistic explanation for the highly resistant spore phenotype of most FP strains carrying a chromosomal cpe gene, these findings may facilitate eventual development of targeted strategies to increase killing of the resistant spores in foods. They also provide the first indication that SASP variants can be important contributors to intra-species (and perhaps inter-species) variations in bacterial spore resistance phenotypes. Finally, Ssp4 may contribute to spore resistance properties throughout the genus Clostridium since ssp4 genes also exist in the genomes of other clostridial species

Apolipoprotein E4 Frequencies in a Japanese Population with Alzheimer's Disease and Dementia with Lewy Bodies

BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been reported to be a risk factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Previous neuropathological studies have demonstrated similar frequencies of the APOE ε4 allele in AD and DLB. However, the few ante-mortem studies on APOE allele frequencies in DLB have shown lower frequencies than post-mortem studies. One reason for this may be inaccuracy of diagnosis. We examined APOE genotypes in subjects with AD, DLB, and a control group using the latest diagnostic criteria and MRI, SPECT, and MIBG myocardial scintigraphy. METHODS: The subjects of this study consisted of 145 patients with probable AD, 50 subjects with probable DLB, and a control group. AD subjects were divided into two groups based on age of onset: early onset AD (EOAD) and late onset AD (LOAD). All subjects had characteristic features on MRI, SPECT, and/or myocardial scintigraphy. RESULTS: The rate of APOE4 carrier status was 18.3% and the frequency of the ε4 allele was 9.7% in controls. The rate of APOE4 carrier status and the frequency of the ε4 allele were 47% and 27% for LOAD, 50% and 31% for EOAD, and 42% and 31% for DLB, respectively. CONCLUSION: The APOE4 genotypes in this study are consistent with previous neuropathological studies suggesting accurate diagnosis of AD and DLB. APOE4 genotypes were similar in AD and DLB, giving further evidence that the ε4 allele is a risk factor for both disorders

Cognitive and Psychological Reactions of the General Population Three Months After the 2011 Tohoku Earthquake and Tsunami

BACKGROUND: The largest earthquake on record in Japan (magnitude 9.0) occurred on March 11, 2011, and the subsequent tsunami devastated the Pacific coast of Northern Japan. These further triggered the Fukushima I nuclear power plant accidents. Such a hugely complex disaster inevitably has negative psychological effects on general populations as well as on the direct victims. While previous disaster studies enrolled descriptive approaches focusing on direct victims, the structure of the psychological adjustment process of people from the general population has remained uncertain. The current study attempted to establish a path model that sufficiently reflects the early psychological adaptation process of the general population to large-scale natural disasters. METHODS AND FINDINGS: Participants from the primary disaster area (n = 1083) and other areas (n = 2372) voluntarily participated in an online questionnaire study. By constructing path models using a structural equation model procedure (SEM), we examined the structural relationship among psychological constructs known related to disasters. As post-traumatic stress symptoms (PTS) were significantly more present in people in the primarily affected area than in those in secondary- or non-affected areas, the path models were constructed for the primary victims. The parsimoniously depicted model with the best fit was achieved for the psychological-adjustment centered model with quality of life (QoL) as a final outcome. CONCLUSION: The paths to QoL via negative routes (from negative cognitive appraisal, PTS, and general stress) were dominant, suggesting the importance of clinical intervention for reducing negative cognitive appraisal, and for caring for general stress and PTS to maintain QoL at an early stage of psychological adaptation to a disaster. The model also depicted the presence of a positive route where positive cognitive appraisal facilitates post-traumatic growth (PTG) to achieve a higher QoL, suggesting the potential importance of positive psychological preventive care for unexpected natural disasters

Phosphorylated tyrosine-containing proteins in primary lung cancer correlates with proliferation and prognosis

To determine the usefulness of tyrosine phosphorylation in evaluating biological characteristics, we attempted to evaluate the relationship between the amount of phosphorylated tyrosine-containing proteins and clinicopathological factors, cell proliferation and outcome in non-small cell lung cancer. To evaluate phosphorylated tyrosine-containing proteins we used 96 surgically resected materials of non-small cell lung cancer and normal peripheral lung, while immunohistochemical evaluation was performed. Cell proliferating ability was evaluated using the labelling index of proliferating cell nuclear antigen-positive nuclear staining cells. There were statistically significant differences between the expression levels of phosphorylated tyrosine-containing proteins of normal and cancerous tissues (P<0.0001). Evaluations based on clinicopathological factors apart from histopathological differentiation, showed no statistically significant differences of phosphorylated tyrosine-containing proteins expression. However, phosphorylated tyrosine-containing proteins correlated with cell proliferation activity evaluated (P(Low, High)<0.0001; P(Low, Int) <0.0001; P(Int, High)<0.0001). Furthermore, non-small cell lung cancer cases with high expression and intermediate expression of phosphorylated tyrosine-containing proteins had a significantly shorter disease-free postoperative survival than those with low expression of phosphorylated tyrosine-containing proteins using log-rank analysis (P(Low, Int) <0.0028; P(Low, High)=0.0002). Furthermore, phosphorylated tyrosine-containing proteins expression level statistically contributed to disease-free survival in Cox's proportional hazard model. Therefore, phosphorylated tyrosine-containing proteins in non-small cell lung cancer tissues seem to reflect its biological malignancy, and this evaluation may be valuable for constructing the most appropriate therapeutic strategy

Protein-based identification of quantitative trait loci associated with malignant transformation in two HER2+ cellular models of breast cancer

Background A contemporary view of the cancer genome reveals extensive rearrangement compared to normal cells. Yet how these genetic alterations translate into specific proteomic changes that underpin acquiring the hallmarks of cancer remains unresolved. The objectives of this study were to quantify alterations in protein expression in two HER2+ cellular models of breast cancer and to infer differentially regulated signaling pathways in these models associated with the hallmarks of cancer. Results A proteomic workflow was used to identify proteins in two HER2 positive tumorigenic cell lines (BT474 and SKBR3) that were differentially expressed relative to a normal human mammary epithelial cell line (184A1). A total of 64 (BT474-184A1) and 69 (SKBR3-184A1) proteins were uniquely identified that were differentially expressed by at least 1.5-fold. Pathway inference tools were used to interpret these proteins in terms of functionally enriched pathways in the tumor cell lines. We observed protein ubiquitination and apoptosis signaling pathways were both enriched in the two breast cancer models while IGF signaling and cell motility pathways were enriched in BT474 and amino acid metabolism were enriched in the SKBR3 cell line. Conclusion While protein ubiquitination and apoptosis signaling pathways were common to both the cell lines, the observed patterns of protein expression suggest that the evasion of apoptosis in each tumorigenic cell line occurs via different mechanisms. Evidently, apoptosis is regulated in BT474 via down regulation of Bid and in SKBR3 via up regulation of Calpain-11 as compared to 184A1