Program trace optimization with constructive heuristics for combinatorial problems

This is the author accepted manuscript. The final version is available from Springer via the DOI in this record.EvoCOP: 19th European Conference on Evolutionary Computation in Combinatorial Optimisation, 24-26 April 2019, Leipzig, GermanyProgram Trace Optimisation (PTO), a highly general optimisation framework, is applied to a range of combinatorial optimisation (COP) problems. It effectively combines \smart" problem-specifi c constructive heuristics and problem-agnostic metaheuristic search, automatically and implicitly designing problem-appropriate search operators. A weakness is identifi ed in PTO's operators when applied in conjunction with smart heuristics on COP problems, and an improved method is introduced to address this. To facilitate the comparison of this new method with the original, across problems, a common format for PTO heuristics (known as generators) is demonstrated, mimicking GRASP. This also facilitates comparison of the degree of greediness (the GRASP alpha parameter) in the heuristics. Experiments across problems show that the novel operators consistently outperform the original without any loss of generality or cost in CPU time; hill-climbing is a sufficient metaheuristic; and intermediate levels of greediness are usually best

Conformational fingerprinting with Raman spectroscopy reveals protein structure as a translational biomarker of muscle pathology

\ua9 2024 The Royal Society of Chemistry.Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative ‘conformational fingerprinting’ can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Genital HSV-2 Infection Induces Short-Term NK Cell Memory

NK cells are known as innate immune cells that lack immunological memory. Recently, it has been shown that NK cells remember encounters with chemical haptens that induce contact hypersensitivity and cytomegalovirus infection. Here, we show the existence of NK cell memory following HSV-2 infection. Stimulation with HSV-2 Ags led to higher IFNγ production in NK cells that were exposed 30 days previously to HSV-2, compared to NK cells from naïve mice. More importantly, this increased production of IFNγ in NK cells was independent of B- and T- lymphocytes and specific for the HSV-2 Ags. We also showed that previously exposed NK cells in a B- and T-lymphocyte free environment mediate protection against HSV-2 infection and they are necessary for the protection of mice against HSV-2 infection. Collectively, NK cells remember prior HSV-2 encounters independent of B- and T- lymphocytes leading to protection against HSV-2 mediated morbidity and mortality upon re-exposure

Quantification of Epstein-Barr virus DNA load, interleukin-6, interleukin-10, transforming growth factor-β1 and stem cell factor in plasma of patients with nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common epithelial neoplasm among the Chinese populations in Southern China and South East Asia. Epstein-Barr virus (EBV) is known to be an important etiologic agent of NPC and the viral gene products are frequently detected in NPC tissues along with elevated antibody titres to the viral proteins (VCA and EA) in a majority of patients. Elevated plasma EBV DNA load is regarded as an important marker for the presence of the disease and for the monitoring of disease progression. However, other serum/plasma parameters such as the levels of certain interleukins and growth factors have also been implicated in NPC. The objectives of the present study are, 1) to investigate the correlations between plasma EBV DNA load and the levels of interleukin (IL)-6, IL-10, TGF-β1 and SCF (steel factor) and 2) to relate these parameters to the stages of NPC and the effect of treatment. METHODS: A total of 78 untreated NPC patients were enrolled in this study. Of these, 51 were followed-up after treatment. The remaining patients had irregular or were lost to follow-up. Plasma EBV DNA was quantified using real-time quantitative PCR. The levels of plasma interleukins and growth factors were quantified using ELISA. RESULTS: A significant decrease in EBV DNA load was detected in plasma of untreated NPC patients (1669 ± 637 copies/mL; n = 51) following treatment (57 ± 37 copies/mL, p < 0.05); n = 51). Plasma EBV DNA load was shown to be a good prognosticator for disease progression and clinical outcome in five of the follow-up patients. A significant difference in IL-6 levels was noted between the untreated patients (164 ± 37 pg/mL; n = 51) and following treatment (58 ± 16 pg/mL, p < 0.05; n = 51). Positive correlations between EBV DNA load and IL-10 (r(49) = 0.535, p < 0.01), between IL6 and IL-10 (r(49) = 0.474, p < 0.01) and between TGF and SCF (r(49) = 0.464, p < 0.01) were observed in patients following treatment. None of the parameters tested including IgA-VCA were associated with tumour stages. CONCLUSION: We conclude that among the parameters investigated, EBV DNA load and IL-6 levels were promising markers for the presence of NPC and for the assessment of treatment outcome

Mortality in Peripheral Arterial Disease: A Comparison of Patients Managed by Vascular Specialists and General Practitioners

BACKGROUND: Peripheral arterial disease (PAD) is undertreated by general practitioners (GPs). However, the impact of the suboptimal clinical management is unknown. OBJECTIVE: To assess the mortality rate of PAD patients in relation to the type of physician who provides their care (GP or vascular specialist). DESIGN: Prospective study. SETTING: Primary care practice and academic vascular laboratory. PARTICIPANTS: GP patients (n = 60) were those of the Peripheral Arteriopathy and Cardiovascular Events study (PACE). Patients managed by specialists (n = 82) were consecutive subjects with established PAD who were referred to our vascular laboratory during the enrolment period of the PACE study. MEASUREMENTS: All-cause and cardiovascular mortality. RESULTS: After 32 months of follow-up, specialist management was associated with a lower rate of all-cause mortality (RR = 0.04; 95% CI 0.01–0.34; p = .003) and cardiovascular mortality (RR = 0.07; 95% CI 0.01–0.65; p = .020), after adjustment for patients’ characteristics. Specialists were more likely to use antiplatelet agents (93% vs 73%, p < .001), statins (62% vs 25%, p < .001) and beta blockers (28% vs 3%, p < .001). Survival differences between specialists and GPs disappeared once the use of pharmacotherapies was added to the proportional hazard model. The fully adjusted model showed that the use of statins was significantly associated with a reduced risk of all-cause mortality (RR = 0.02; 95% CI 0.01–0.73, p = .034) and cardiovascular mortality (RR = 0.02; 95% CI 0.01–0.71, p = .033). CONCLUSIONS: Specialist management of patients with symptomatic PAD resulted in better survival than generalist management. This effect appears to be mainly caused by the more frequent use of effective medicines by specialists

Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

The Global Diversity of Parasitic Isopods Associated with Crustacean Hosts (Isopoda: Bopyroidea and Cryptoniscoidea)

Parasitic isopods of Bopyroidea and Cryptoniscoidea (commonly referred to as epicarideans) are unique in using crustaceans as both intermediate and definitive hosts. In total, 795 epicarideans are known, representing ∼7.7% of described isopods. The rate of description of parasitic species has not matched that of free-living isopods and this disparity will likely continue due to the more cryptic nature of these parasites. Distribution patterns of epicarideans are influenced by a combination of their definitive (both benthic and pelagic species) and intermediate (pelagic copepod) host distributions, although host specificity is poorly known for most species. Among epicarideans, nearly all species in Bopyroidea are ectoparasitic on decapod hosts. Bopyrids are the most diverse taxon (605 species), with their highest diversity in the North West Pacific (139 species), East Asian Sea (120 species), and Central Indian Ocean (44 species). The diversity patterns of Cryptoniscoidea (99 species, endoparasites of a diverse assemblage of crustacean hosts) are distinct from bopyrids, with the greatest diversity of cryptoniscoids in the North East Atlantic (18 species) followed by the Antarctic, Mediterranean, and Arctic regions (13, 12, and 8 species, respectively). Dajidae (54 species, ectoparasites of shrimp, mysids, and euphausids) exhibits highest diversity in the Antarctic (7 species) with 14 species in the Arctic and North East Atlantic regions combined. Entoniscidae (37 species, endoparasites within anomuran, brachyuran and shrimp hosts) show highest diversity in the North West Pacific (10 species) and North East Atlantic (8 species). Most epicarideans are known from relatively shallow waters, although some bopyrids are known from depths below 4000 m. Lack of parasitic groups in certain geographic areas is likely a sampling artifact and we predict that the Central Indian Ocean and East Asian Sea (in particular, the Indo-Malay-Philippines Archipelago) hold a wealth of undescribed species, reflecting our knowledge of host diversity patterns